Effect of Epidural Infusion Bolus Delivery Rate on the Duration of Labor Analgesia
Phase: NA
Conditions: Labor Pain, Obstetric Pain
Sponsor: Northwestern University

 
 
 
 
 
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Proposed Research Protocol Form 
Northwestern University Feinberg School of Medicine 
 
Title: Association between bolus rate and the adequacy of labor analgesia using 
timed-intermittent boluses for maintenance of labor analgesia 
 
Principal Investigator: Elizabeth Lange, M.D. 
 
Co-investigator (s): Paloma Toledo, MD, MPH,   
 
Affiliation: Department of Anesthesiology, Northwestern University Feinberg 
School of Medicine  
 
1.0 Research Aims: 
Aim 1: To evaluate the association between bolus rate and duration of adequate 
labor analgesia.  
 
Hypothesis: Patients whose labor analgesia is maintained using timed 
intermittent boluses with a high-rate bolus (300 mL/h) will have a longer duration 
of adequate analgesia (time to first manual redose request) than patients whose 
timed bolus is delivered with a lower-rate bolus (100 mL/h). 
 
 
2.0 Research significance: 
 
Background:  
Neuraxial labor analgesia is usually maintained by the intermittent or continuous 
injection of local anesthetic combined with opioid through a catheter sited in the 
lumbar epidural space. Pain from the first stage of labor is primarily due to lower 
uterine segment and cervical stretching. The pain signals enter the spinal cord 
through sensory nerves at the T10 through L1 dermatomes. Pain signals from the 
late first state and second stage of labor also arise from the vaginal and 
perineum. These signals travel with the pudendal nerve and enter the spinal cord 
at S2-S4. Thus, the anesthetic solution administered through the lumbar epidural 
catheter must spread cephalad in the epidural space to reach the T10 nerve 
roots and spinal cord, and must spread caudad to reach the caudal nerve roots in 
the epidural space. 
 
Administration of anesthetic solution into the epidural space is usually 
accomplished by a combination of continuous infusion, provider-administered 
boluses and patient-administered boluses (patient controlled epidural analgesia 
[PCEA]). The optimal method for maintaining labor analgesia is unknown. 
Several studies have demonstrated that timed-intermittent boluses, in 
combination with patient-controlled epidural analgesia (PCEA), provide superior 

 
 
 
 
 
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maintenance of labor analgesia (less need and longer latency for provider 
intervention, lower local anesthetic consumption, less motor block) than 
maintenance with a continuous infusion with PCEA.1-4 The mechanism for this 
difference is not known; however, one suggested mechanism is improved spread 
of the local anesthetic within the epidural space. Kaynar et al. injected methylene 
blue dye through a multi-orifice catheter using either a continuous infusion or 
intermittent bolus and the area of diffusion was measured on a piece of paper.5 
The authors found that intermittent boluses were associated with a greater 
surface area of diffusion than continuous infusion. In a subsequent cadaver 
study, dye was injected into the lumbar epidural space, and cryomicrotome 
sections were taken.6 Dye flowed in rivulets through small channels in the 
epidural space, as opposed to moving as a unified front. The authors found dye 
injected at high pressures had more uniform spread through the epidural space, 
supporting the concept of intermittent epidural injection providing superior 
analgesia.   
 
 
Epidural infusion pumps capable of delivering timed boluses of local anesthetic 
with PCEA recently became commercially available. Several infusion rates are 
available for delivering the timed bolus, and the optimal bolus rate is unknown. 
We hypothesize that patients whose labor analgesia is maintained using timed 
intermittent boluses with a high-rate bolus (300 mL/h) will have a longer duration 
of adequate analgesia (time to first manual redose request) than patients whose 
timed bolus is delivered with a lower-rate bolus (100 mL/h). 
  
 
 
.1 Significance: The findings from this study will help us better understand 
whether there is an association between bolus rate and adequacy of labor 
analgesia. This is important for guiding future clinical practice.  
 
3.0 Investigational Plan 
 
.1 Study design:  
 
Randomized controlled double-blinded study 
 
.2 Methods: 
 
Size of study groups(s):   
 
The primary outcome is the proportion of subjects in each group that have 
breakthrough pain requiring a manual bolus (redose) by the anesthesiologist. In 
previous studies that have used timed-intermittent boluses for maintenance of 

 
 
 
 
 
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labor analgesia, the percentage of patients that have required supplemental 
manual boluses of local anesthetic has ranged between 30-50%. We hypothesize 
that patients randomized to the rate of 300 mL/h will be less likely to require a 
supplemental manual bolus than those in the 100 mL/h group.1,7 Assuming that 
50% of the patients in the 100 mL/h group will require supplemental manual 
boluses and 30% of patients in the 300 mL/hr group will required supplemental 
manual boluses, using a power of 0.8, and an alpha of 0.05Due to the dynamic 
nature of the labor and delivery floor in patients’ clinical course and resultant 
decisions regarding their choices on pain control during labor there is a greater 
degree of unpredictability of enrolled patients being excluded from this study for 
both clinical and personal reasons. As a result 300 patients meeting inclusion 
criteria will be recruited to account for dropout and still maintain the ability to 
recruit the estimated 106 patients per study group. 
Secondary outcomes are the total number of requested and delivered PCEA 
boluses, and bupivacaine consumption per hour of labor analgesia. 
  
 
.2.1 
Participant entry, exclusion and dropout criteria:   
 
Inclusion criteria: 
Nulliparous parturients who presents to the labor and delivery unit for an 
induction of labor or who are in spontaneous labor, and request neuraxial labor 
analgesia at    < or = to 5cm cervical dilation are eligible to participate.   
 
Exclusion criteria: 
Patients who are not eligible to receive a combined spinal epidural (CSE) 
technique with 25 mcg of intrathecal fentanyl, non-English speaking, who 
experience failed CSE analgesia, need to have the epidural catheter replaced 
during labor, or who deliver within 90 minutes of initiation of labor analgesia will 
be excluded from the study.   
 
  
.2.2 
Protocol specific methods:   
Parturients who meet the inclusion criteria will be approached by one of the 
investigators, or one of the anesthesiology research nurses, for study 
participation. Parturients who are willing to participate in the study will provide 
written consent. Patient demographics will be collected at study enrollment.  
 
Cervical dilation will be confirmed by a member of the obstetric team prior to 
epidural catheter placement as is routinely done at our institution. A baseline pain 
visual analog scale (VAS) score will be obtained using a 100-mm unmarked line 
with the end points labeled “no pain” and “worst pain imaginable.”  
 

 
 
 
 
 
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Labor analgesia will be initiated using CSE analgesia with 25 mcg of intrathecal 
fentanyl. An epidural test dose will be performed as routine (1.5% lidocaine with 
epinephrine 1:200, 3 mL).  
 
Labor analgesia will be maintained using timed-intermittent boluses of local 
anesthetic with PCEA using the CADD-Solis pump (Smiths Medical). An 
unblinded anesthesia research nurse will program the epidural pump and initiate 
the maintenance of labor analgesia.  
 
The maintenance epidural solution for both groups will be bupivacaine 0.625 
mg/mL with fentanyl 1.95 mcg/mL. The intermittent bolus volume will be 10 mL 
administered every 60 minutes. The first bolus will be given 30 minutes after 
intrathecal injection, as has been done in previous studies at our institution.7 
The bolus rate will be 300 mL/h ( 2 minute 10 ml bolus infusion) in the high-rate 
bolus group, and 100 mL/h ( 6 minute 10 ml bolus infusion).  In addition to the 
programmed boluses patients will be able to administer patient-controlled 
epidural analgesia (PCEA) boluses of 5 mL every 10 minutes to a maximum of 
15 mL (three PCEA boluses in a one hour period).  
The patient, anesthesiologist, and research nurse recording clinical data will be 
blinded to group assignment. 
 
Fifteen minutes following the intrathecal dose, a VAS score and a sensory level 
of analgesia will be obtained. The following information will be obtained hourly 
until complete cervical dilation (10 cm): VAS pain score, sensory level, a modified 
Bromage score (0 - no motor paralysis; 1 - inability to raise extended leg, but able 
to move knee and foot; 2 - inability to raise extended leg and to move knee, but 
able to move foot; 3 - inability to raise extended leg or to move knee and foot). 
 
The time to the first request for supplemental analgesia will be recorded on the 
study data sheet. The time, type and volume of local anesthetic used, and VAS 
scores before and 15 minutes after the redose will be recorded.  
 
All other clinical management will be as per routine, and study participation will 
not interfere with anesthetic or obstetric care. Anesthesiologists will manage 
breakthrough pain in the usual manner (assessment of stage of labor and 
extend/density of neuraxial blockade, followed by the appropriate maneuver to 
reestablish adequate analgesia).  
 
Following delivery, the patient will be asked to give one final VAS score and her 
overall satisfaction with labor using a 100 mm unmarked line (the left end labeled 
“not satisfied at all” and the right end labeled “extremely satisfied”). Mode of 
delivery, as well as the duration of the 1st and 2nd stage of labor will be recorded 
by study personnel.  
 

 
 
 
 
 
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Patient Controlled Epidural Analgesia (PCEA) pump utilization data will be 
downloaded from epidural pumps after delivery.  This will include the time to first 
PCEA request, the number of PCEA demands, the number of times that PCEA 
boluses were delivered, the total amount of local anesthetic consumed. 
  
 
 
4.0 Risks/Benefits:  
Risks: 
There is no risk of physical harm in this study.  The study will not result in any 
change in management of the patient’s pain other than the infusion rate of the 
timed-bolus epidural bolus, nor in any delay in diagnosis and treatment of 
pain.  
 
 
Participants are at risk for loss of confidentiality. Strict measures will be in 
place to ensure that no loss of confidentiality occurs. All participants will be 
assigned a participant study number that will be used to identify them. One 
document will link the participant name to their participant number, and this 
will be kept in a password-protected computer in a locked office in the 
Prentice Women’s Hospital. Only study investigators will have access to the 
study data.   
 
 
Benefits: 
  
Participants will derive no specific benefit from participation in this study; 
however, participation in this study will help us better understand the optimal 
rate for delivery of bolus doses of local anesthetic during maintenance of 
labor analgesia using timed-boluses.  
 
Confidentiality: 
The subjects’ identity will be guarded by assigning a numerical code which is 
only known by the principal investigator.  Data is stored in a department 
computer which is password protected.  Each study subject will be assigned a 
study code number. The code will be used to link study data to patient 
identification (name) in a separate database.  Subject data will be stored on 
secured computers at Northwestern University.  Data access will be password 
protected and only available to study investigators. The data forms will be de-
identified after the chart review prior to analysis. 5 years after manuscript the 
data both electronic and paper will be destroyed using the current 
departmental standards.   
 
5.0  Data Analysis: 
 
.1 Data collection form: Data collection forms will include all of the 
information outlined above in study methods. 

 
 
 
 
 
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.2 Data evaluation:  The primary outcome will be the proportion of patients 
requiring supplemental manual boluses of local anesthetic. Secondary 
outcomes are the total number of requested and delivered PCEA boluses, 
and bupivacaine consumption per hour of labor analgesia. In addition, time 
to first PCEA request, time to first supplemental manual bolus, and motor 
block at 10 cm cervical dilation will be evaluated. Categorical data 
between groups will be compared using a chi-squared or Fisher’s exact 
test, and continuous data will be compared using a two-tailed t-test or 
Mann Whitney U test as appropriate. Time outcomes will be compared 
between groups using a Kaplan–Meier survival analysis technique with log 
rank test. Patients undergo a cesarean delivery or do not request 
supplemental analgesia will be censored at the time of delivery. Labor pain 
will be calculated using the area under the VAS-time curve using the 
trapezium rule.   
 
  
1.0 Labor Requirements:  All labor will be performed by study investigators and 
the anesthesiology research nurses. 
 
 
2.0 Consent:   Please see attached consent form for this study.   
 
.1 Additional information for preparation of an IRB Submission: N/A 
 
 
References: 
1. 
Wong CA, Ratliff JT, Sullivan JT, Scavone BM, Toledo P, McCarthy RJ. A randomized 
comparison of programmed intermittent epidural bolus with continuous epidural infusion 
for labor analgesia. Anesth Analg 2006;102:904-9 
2. 
Lim Y, Sia AT, Ocampo C. Automated regular boluses for epidural analgesia: a 
comparison with continuous infusion. Int J Obstet Anesth 2005;14:305-9 
3. 
Chua SM, Sia AT. Automated intermittent epidural boluses improve analgesia induced by 
intrathecal fentanyl during labour. Can J Anaesth 2004;51:581-5 
4. 
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. Anesth Analg 2011 
5. 
Kaynar AM, Shankar KB. Epidural infusion: continuous or bolus? Anesth Analg 
1999;89:534 
6. 
Hogan Q. Distribution of solution in the epidural space: examination by cryomicrotome 
section. Reg Anesth Pain Med 2002;27:150-6 
7. 
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. Anesth Analg 2011;112:904-11 
 
 
 

 
 
 
 
 
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