A Novel Approach to Optimize Programmed Intermittent Epidural Bolus (PIEB) Delivery for Labour Analgesia
Phase: NA
Conditions: Labor Pain
Sponsor: IWK Health Centre

 
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Research Protocol 
 
 
Study Title: 
A novel approach to optimize Programmed Intermittent Epidural Bolus 
(PIEB) delivery for labour analgesia 
 
Investigators:  
Allana Munro, MD FRCPC 1 
 
 
 
Ronald George, MD FRCPC1 
 
 
 
Pantelis Andreou, PhD2 
 
Research 
 
Aryn Benoit, BA MA Research Assistant1                               
Staff:  
 
Lorraine Chiasson, BSc MA Research Manager1  
                                    Jackie Ryan, BA PG Dip Research Assistant1 
 
 
 
 
Department of Women’s & Obstetric Anesthesia1  
IWK Health Centre 
 
 
 
Halifax, Nova Scotia, Canada 
 
Department of Community Health & Epidemiology2 
Dalhousie University 
Halifax, Nova Scotia, Canada 
 
 
Background 
Labor pain is highly variable, but often described as severe(1),
 
and reported to be the most intense 
pain that a woman experiences in her lifetime(2). Many factors influence labour pain such as 
parity, the duration of labour, maternal pelvic anatomy, fetal size and presentation, gestational 
age at birth, labour induction or augmentation and the presence of support(1, 3, 4). Pain and pain 
relief are often mentioned as important contributors to women’s birth experience(5-8). The ideal 
pain relief method must be safe, effective, timely, efficient, equitable, women-centered and 
should not interfere with labour or the mobility of the labouring woman(9).
 
Epidural analgesia is 
the most effective form of pain relief for women in labour(10, 11). Previously, the practice was 
maintenance of labour epidural analgesia through a pump to deliver local anesthetic in 
combination with an opioid via a continuous epidural infusion (CEI)(12).Commonly utilized 
maintenance solutions for CEI include the local anesthetics bupivacaine (0.0625-0.125%) or 
ropivacaine (0.1-0.16%) combined with sufentanil (0.5-0.75 ug/mL) or fentanyl (2-3 ug/mL)(13). 
Continuous epidural infusion was used at the IWK Health Centre as routine care for labour 

 
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analgesia until 2015. The epidural pump dosing parameters can be found in Table 1.Continuous 
epidural infusion was used with patient-controlled epidural analgesia (PCEA) for breakthrough 
pain. PCEA allows the patient to deliver small doses of the anesthetic solution to supplement the 
ongoing epidural infusion.  The PCEA bolus dose can be set between 4 and 12 mL, with the most 
common settings between 5 and 8 mL. The lockout interval can be varied, but usually based 
around the knowledge that approximately 10 minutes is required for the patient to experience 
pain relief(14).  
 
Continuous epidural infusion has been associated with an increased risk of assisted vaginal birth 
(vacuum or forceps delivery)(15) and may cause significant motor block (leg heaviness and 
weakness that limits the woman’s ability to ambulate(16). Motor block can contribute to 
prolonged labour and a prolonged second stage of labour that has been associated with increased 
maternal morbidity and operative delivery rates(17-20).
 
A woman with significant motor block will 
require more nursing assistance for toileting, hygiene care and ambulation. A study on the 
economic implications of various methods of delivery using data from the authors’ institution 
showed that the cost associated with assisted vaginal delivery was significantly more than that of 
spontaneous vaginal delivery ($1594 vs. $1340), and was even higher for cesarean delivery in 
labour ($2137)(21).Thus, the importance of reducing the risk of motor block and operative 
delivery is evident from both a patient safety as well an economic standpoint.  
 
Evidence now suggests that providing the local anesthetic and opioid solution as a bolus at 
regularly timed intervals may allow better pain management(22-24). The pressure generated by 
injecting a bolus produces a more uniform spread of solution within the epidural space compared 
to a continuous infusion. The ability to deliver regularly timed manual doses is labour intensive 
and not feasible on a busy obstetrical unit. Recent advances in epidural pump technology allows 
for programmed intermittent epidural bolus (PIEB) administration. In November 2012, Health 
Canada approved PIEB combined with PCEA (CADD®-Solis Epidural Pump, Smiths Medical, 
St. Paul, MN, USA) for clinical use. PIEB for labour analgesia allows the epidural pump to be 
programmed to deliver small amounts of the local anesthetic and opioid solution at regularly 
timed intervals; a process that mimics manual doses delivered by an anesthesia provider. The 
programmer can specify the volume of medication to be provided as a bolus and the timing 

 
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between the boluses. The patient can also use the PCEA button to administer an additional dose 
of the same medication at their discretion. A “lockout” interval is programmed for the PCEA to 
ensure there is not an overdose of medication that may lead to motor block and hypotension 
(Figure 1).  In 2015 at the IWK Health Centre, PIEB replaced CEI as routine care for the 
delivery of labour analgesia. Table 1 lists the PIEB pump setting used at the IWK Health Centre 
for PIEB. The attending anesthesiologist has the ability to alter the settings provided the settings 
are still within the predefined safety parameters. The pump settings are verified by nursing staff 
to further ensure patient safety.  
 
Early studies found clinical advantages of PIEB when compared to a continuous infusion(22, 23, 25-
30). George et al. completed a systematic review in 2013, which highlighted that PIEB delivery 
was associated with several important outcomes including: improved patient satisfaction, 
reduced local anesthetic consumption, and decreased duration of the second stage of labour(12). A  
recent study found that PIEB with PCEA had significantly fewer patients with motor block, a 
shorter second stage of labour for primiparous women and women received less ropivacaine 
compared to CEI with PCEA(31). However, there was no significant difference in mode of 
delivery or maternal satisfaction in this study(31).  
 
As health care practices evolve toward patient-centered care and patient engagement, 
consideration of patient satisfaction with their labour analgesia is paramount. Capogna et al. 
designed a study to detect a difference in instrumental delivery rates reported a significant 
reduction with PIEB compared with CEI (7% vs 20%; P = 0.03)(22). The authors attribute the 
higher rates of instrumental delivery to greater motor blockade present in the CEI group. Further 
support for the reduction in total local anesthetic consumption using PIEB for labour analgesia is 
observed when evaluating the need for rescue clinician boluses. The occurrence of breakthrough 
pain may be treated with a dose of local anesthetic, known as a rescue bolus, supplied manually 
by a member of the anesthesia team (anesthesiologist, anesthesia assistant or anesthesia resident). 
The need for a rescue bolus results in increased demand for anesthesia clinical services and may 
lead to a delay in pain relief for the patient if the clinician is not readily available. While an 
earlier systematic review did not find a significant difference in the need for clinician top-up 
bolus between PIEB and CEI, more recent studies have shown different results(12, 32, 33). Both 

 
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studies by MacKenzie et al. and Delagado et al. have demonstrated less need for epidural top-ups 
with the use of PIEB. The study examining programmed bolus of 10ml bupivacaine 0.0625% 
with fentanyl 2mcg/ml every 45 or 60 minutes or every 45 min with high flow (500 ml/hour)(33) 
found the top-up rate was lower in the 45 minute interval group compared with the 60 minute 
interval group(33). 
 
Despite its growing use as the routine care for delivery of labour analgesia, and adoption at the 
IWK Health Centre, little evidence is available to guide optimal settings for PIEB. The gaps in 
evidence include: (1) programmed timing for the first PIEB bolus (referred to as the “NEXT 
bolus”) (2) determination of PIEB bolus volume (3) the interval for subsequent doses (PIEB 
interval). Figure 1 outlines the functions of the PIEB pump. When an epidural is initiated, the 
clinician provides the first dose manually through the epidural catheter. The epidural catheter is 
then connected to the PIEB pump, and the pump is programmed according to the current 
institutional settings (Table 1). Once programmed, 15 minutes later the first pump-delivered 
dose, known as the “NEXT Bolus” is provided, followed by a programmed dose every 45 
minutes (Figure 1). This 45-minute interval between regular boluses is known as the PIEB 
interval. If patients require additional pain control, they are able to press a button to receive a 
rescue PCEA bolus (6mLs) every 10 minutes. This timing can also be adjusted, and is known as 
the “PCEA lockout”. If a patient presses the PCEA button requesting a bolus within this lockout 
time period, the pump records the request but does not administer a dose.  
 
PIEB offers an advantage, given the customizability of the various parameters, to reduce patient 
complications, increase pain control, and increase patient satisfaction. However, clinical practice 
has seen large variation in PIEB pump parameters and there has been no consensus in dose, 
volumes and intervals amongst the randomized trials(12, 31, 34). The timing for the NEXT bolus has 
been varied between 15 and 45 minutes. Similarly, previous research has suggested a PIEB 
interval between 15 to 60 minutes(31). Lastly, optimal PIEB volume has had very little research 
but available studies used volumes that range between 2.5 to 10 mL of a local anesthetic and 
opioid solution (30, 31). The PCEA bolus and lockout interval have been maintained at similar 
volume and intervals used with traditional labour epidural pumps(31, 35). 
 

 
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Choosing the parameters for the pump has implications for patient safety (risk of hypotension 
and motor block) and patient satisfaction. A fine balance is required in choosing the settings for 
PIEB delivery, as each extreme has its own disadvantages. A small bolus volume with a short 
interval may be associated with similar drawbacks mentioned for continuous epidural infusions, 
while a large volume bolus with a longer interval may be associated with breakthrough pain and 
reduced patient satisfaction(36). Longer intervals between PIEBs may mean that overall, more 
local anesthetic and opioid is consumed in the form of PCEA or clinician administered manual 
boluses for inadequate pain control. More local anesthetic could contribute to a sudden decrease 
in blood pressure or greater motor blockade(11).
 
Despite the obvious need to determine the 
optimal setting for these PIEB variables, few studies have been designed to evaluate this 
question.  
 
An early study by Wong et al. randomized patients to one of three PIEB dose regimens for 
maintenance of analgesia: 2.5 mL every 15 minutes (2.5/15), 5 mL every 30 minutes (5/30), or 
10 mL every 60 minutes (10/60). The study showed that extending the PIEB interval from 15 
min to 60 min with a larger PIEB volume (10 mL vs. 2.5 mL) resulted in decreased anesthetic 
consumption without affecting patient satisfaction(36). This finding complemented previous work 
which suggested that larger boluses with a longer lockout interval may improve spread of the 
local anesthetic and opioid solution in the epidural space leading to superior analgesia(13).  
Another study was designed to establish the optimal time interval between boluses (PIEB 
interval) using 10 mL of bupivacaine 0.0625% with fentanyl 2 μg/mL to produce effective 
analgesia in 90% of women during first stage of labour(37). This study was a double-
blind sequential allocation trial with a biased-coin up-down design with the PIEB interval set at 
60 minutes for the first patient and at varying time intervals (60, 50, 40, and 30 minutes; groups 
60, 50, 40 and 30, respectively) for the subsequent patients. The primary outcome was 
effective analgesia, defined as no requirement for PCEA or a manual bolus for 6 hours after the 
initiation of the epidural analgesia or until the patient was fully dilated. The author’s found that 
the optimal PIEB interval was approximately 40 minutes.  
 
The study by Delagado et al. examining programmed bolus of 10ml bupivacaine 0.0625% with 
fentanyl 2mcg/ml every 45 or 60 minutes or every 45 min with high flow (500 ml/hour)(33) found 

 
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the manual bolus  rate was lower in the 45 minute interval group compared with the 60 minute 
interval group(33). This information helps to further determine the optimal PIEB interval. 
However, despite their findings the authors concluded that additional parameters need further 
testing such as the interval between the intrathecal dose and the delivery of the first programmed 
bolus (NEXT bolus), the volume of the programmed bolus, the interval between programmed 
boluses, the volume of the patient-controlled bolus (PCEA bolus) and the flow at which all 
boluses are delivered(33). 
 
Current PIEB studies are only applicable to the corresponding institutes and specific for their 
standard epidural solution. Additionally, many of the aforementioned studies have evaluated one 
or two PIEB variables, but have not evaluated how the three main PIEB settings work together, 
and how they can be optimized to improve patient satisfaction and pain control and to reduce 
clinical work load. Key issues identified in existing studies that evaluate success with PIEB 
include reliance on singular assessments of pain with unidimensional tools such as Visual 
Analog or Numeric Rating Scales (NRS). Choosing a single outcome as the method of 
assessment ignores the multidimensional nature of women’s pain and may be associated with 
lower levels of reliability and a ceiling effect to measurement(38, 39). The latter is demonstrated 
clinically by reports of labour pain that exceed the upper anchors of these scales (i.e., pain 
greater than 10/10)(40). To address this, the authors propose a novel approach to determine the 
optimal PIEB settings as evaluated by three predefined outcomes: maternal satisfaction, need for 
clinician rescue bolus, and ratio of PCEA requested doses to PCEA delivered doses. A 
multivariate design will reduce time, effort, and resources compared to univariate procedures that 
are traditionally employed in this field of research.  
 
The optimal labour analgesia PIEB pump settings will be estimated using an established 
mathematical technique known as Response Surface Methodology (RSM). RSM is a collection 
of statistical and mathematical techniques used with a sequence of designed experiments to 
obtain an optimal response. Box–Behnken designs (BBD) are specific experimental designs of 
RSM that are frequently applied to the optimization of analytical methods. RSM selects the 
optimal combination of several factors to maximize or minimize the effect on a single or 
multiple outcomes. The technique has been used for analytical applications in the industrial 

 
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world and in bioprocesses. The main purpose is to discover conditions which produce the best 
possible performance. RSM will be used to analyze the influence and importance of several 
explanatory variables (the PIEB pump settings) on the three response variables (maternal 
satisfaction, need for clinician rescue bolus, and ratio of PCEA delivered doses to requested 
doses) (Figure 2)(41). The results of this study will generate an algorithm that identifies optimal 
PIEB settings that will be generalizable to institutions across Nova Scotia, nationally and in other 
countries using PIEB for the maintenance of labour analgesia.  
 
OBJECTIVE: To use Response Surface Methodology to best estimate the optimal PIEB settings 
(NEXT bolus interval, PIEB interval time, PIEB volume) by using the following clinical primary 
outcome measures: maternal satisfaction score, need for a clinician administered rescue bolus, 
and the ratio of PCEA boluses requested/delivered.  
 
HYPOTHESIS: Response Surface Methodology will reliably determine the optimal timing and 
volume of labour analgesia. The optimal system will result in higher patient satisfaction, reduced 
anesthesia interventions, and improved ratio of requested to delivered PCEA boluses.  
 
METHODS  
This study is a randomized trial of predetermined combinations of PIEB pump settings. After 
administration of an epidural, participating women will be randomly assigned by computer 
generation to a combination of PIEB settings (Table 2). The participants nurse will be recording 
safety information during the duration of the epidural. Outcome data for clinical outcomes will 
be gathered by the research coordinator after delivery. Data will be retrieved from the epidural 
pump, the anesthesia database Innovian (Draeger, Inc. Telford, USA) a web-based information 
management system that creates a complete, continuous, paperless record of patient’s anesthetic 
care) and IntelliSpace Perinatal software (Phillips Medical Systems, Koninklijke Philips N.V.) an 
electronic comprehensive patient documentation and data storage of obstetrical care. In addition, 
a patient satisfaction numeric rating scale will be completed by a research coordinator within 24 
hours of delivery. Monitoring for patient safety and side effects will be completed by birth unit 
nurses as part of the routine standard of epidural analgesia care.  
 

 
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Inclusion/Exclusion Criteria  
Inclusion Criteria: Nulliparous, English speaking, aged 18-45 years, single gestation ≥ 37 weeks, 
vertex presentation, American Society of Anesthesiologists (ASA) Physical Status II (mild and 
controlled systemic disease and/or pregnancy)(42),
 
requesting an epidural for labour analgesia, 
cervical dilation ≤ 7 cm at the time of initiation of epidural analgesia. 
 
Exclusion Criteria: Preeclampsia or HELLP syndrome, maternal cardiac disease, severe or 
uncontrolled maternal systemic disease, contraindication to neuraxial analgesia (i.e. 
coagulopathy, infection, neuropathy), abnormal spinal anatomy (i.e. severe scoliosis, spina 
bifida, spinal instrumentation), chronic analgesic use, a physical or psychiatric condition which 
may impair cooperation, known fetal anomalies/intrauterine fetal demise, height < 5’0”, Body 
Mass Index > 45 kg/m
2,  
 
Withdrawal Criteria: Failure to establish epidural analgesia, failure to insert epidural catheter, 
intrathecal or intravenous epidural catheter, delivery within 180 minutes of study 
commencement. 
 
Procedures  
Potential participants will be identified by research personnel by communicating with the 
attending anesthesiologist on the Birth Unit, the Birth Unit charge nurse, and nurses in the Early 
Labour and Assessment unit at the IWK Health Centre. Nurses will receive education regarding 
the study as an education session prior to study commencement. The patient’s nurse will ask the 
patient if they would be willing to speak with research staff. With their consent, participants will 
be approached by study personnel to discuss the study in detail. Inclusion and exclusion criteria 
will be verified and informed, written consent will be obtained. All participants will be female, 
as the study is designed for labouring patients. Recruitment on the Birth Unit is standard 
procedure for labour analgesia research.   
 
As standard care in the Birth Unit, upon request of labour analgesia, the cervix will be measured, 
a baseline pain score will be determined by Birth Unit nurses and the patients’ blood pressure 

 
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will be determined. An intravenous catheter will be in place before epidural initiation. A staff 
anesthesiologist will use an epidural technique to initiate labour analgesia. With the patient in the 
sitting position, the epidural space will be identified at the L3-4 or L2-3 interspace with a 17G, 9 
cm Tuohy epidural needle using a loss of resistance to air or saline (< 1 mL) technique. A 
multiple-orifice catheter will be inserted five centimeters into the epidural space and a pharmacy 
prepared bolus of 10 ml ropivacaine 0.2% with 10 ug/ml fentanyl solution will be administered 
via the catheter. This is the standard initial bolus that all patients with LEA receive. The catheter 
will then be attached to the CADD-Solis Ambulatory Infusion System
®. After the epidural 
catheter is secured, the patient will be placed on their left side for a blood pressure assessment. 
Data collection will take place in the patient's assigned labour room in the IWK Birth Unit. 
Patients will not be recruited on Fridays to avoid the inability of collecting the satisfaction score 
≤ 24 hours postpartum. The following physiologic assessments will be completed by the nursing 
staff as routine care for women with epidural analgesia for labour to ensure their safety 
(Appendix 1): 
 
1. Degree of pain (to determine the need for PCEA or a clinician administered rescue bolus). 
Competed at baseline and then hourly  
2. Highest thoracic dermatome sensory level to pin prick (to determine extent of the epidural 
block), completed hourly after epidural placement  
3. Presence of motor block assessed using Modified Bromage scale(43) completed hourly after 
epidural placement 
 4. Blood Pressure (measured before epidural placement, then assessed every 5 minutes for three 
measurements after epidural placement, again at the 30-minute mark and hourly thereafter as per 
Birth Unit protocol).  
 
Additional data will be collected by the research assistant using information collected from 
IntelliSpace Perinatal and the CADD Solis Pump:  
5. Total local anesthetic dose consumed 
6. Total opioid dose consumed  
7. Duration of the second stage of labour 
8. Mode of delivery including the indication for cesarean delivery 

 
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9. Time from epidural to delivery 
 
The standard PIEB settings used at the IWK are included in Table 1. The only difference from 
standard of care for the delivery of labour analgesia for study participants will be the PIEB pump 
settings. However, all possible pump settings used for the study are within the safety limits 
established at the IWK and have been used in clinical research. Each participant will be 
randomly allocated (by block randomization) to a combination of predetermined PIEB settings 
for the NEXT bolus interval, PIEB volume, and PIEB interval (Table 2). Once the patient has 
been consented, the envelope containing the data collection sheet for the nurse will be placed in 
the participants chart. The Research Assistant will adhere the randomization envelope for 
anesthesia to the patient’s epidural pump. Additionally, the flag indicating that the pump needs to 
be returned to the anesthesia work room at the end of its use will be adhered to the patient’s 
epidural pump. The patient and nurse collecting data will be blinded to the PIEB setting 
assignments. The setting assignments will be sealed in sequentially numbered envelopes. When 
the participant requests their epidural, the sealed envelope will be opened by an un-blinded 
member of the anesthesia team (anesthesiologist, anesthesia assistant, or anesthesia resident). 
The anesthesia team member performing the epidural will program the pump with the designated 
settings. Verification of the pump settings will be achieved by a second un-blinded healthcare 
member.  The pump will be covered to blind investigators, nurses, and participants. The pump 
will start 5 minutes after the initial epidural manual bolus. The PCEA doses will remain 
standardized (6 mL ropivacaine 0.1% with 2ug/mL fentanyl every 10 minutes, as required). If 
after two confirmed PCEA doses the participant’s pain is not suitably controlled, the anesthesia 
team member will be consulted to provide a manual rescue bolus (10 mL of 0.2% ropivacaine or 
10 mL clinician bolus of ropivacaine 0.1% with 2ug/mL fentanyl via the CADD®-Solis Epidural 
Pump).  
 
Following completion of the study procedures, the randomization envelope will be placed into 
the study package along with the completed data collection sheet. The study package will be 
returned to the Birth Unit desk to be collected by the Research Assistant. The Research Assistant 
will also collect the data from the participant’s epidural pump. As an incentive for the nursing 
staff who have collected the data, after every five participants there will be a draw for a $20 Tim 

 
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Horton’s gift card.  
 
The following primary outcome measures will be used with RSM to generate the mathematical 
model for optimizing PIEB settings:  
 
1. Maternal satisfaction score (44)
 
(quantified as 0-100, where 0 – not satisfied, and 100 – 
completely satisfied). Optimal response: ≥ 90(45) determined within 24 hours of delivery by the 
research coordinator. If the patient is discharged home from the Birth Unit before 24 hours 
postpartum, the research assistant will complete a telephone follow-up for the satisfaction score 
within 24 hours postpartum.  
2. Number of clinician administered rescue boluses or CADD®-Solis Epidural Pump Boluses, 
recorded in the Innovian anesthesia database, IntelliSpace Perinatal, or CADD®-Solis Epidural 
Pump. Optimal response: 0 boluses  
3. Ratio of the number of PCEA boluses requested to the number of PCEA boluses delivered 
(Recorded on the CADD®-Solis Epidural Pump during labour and downloaded by research 
coordinator after delivery). Optimal response: 1 – a larger ratio means the patient requested 
PCEA boluses but they were not delivered because the pump was in the 10-minute safety lockout 
period, implying inadequate pain control.  
 
Statistical Analysis Methodology  
Box–Behnken designs (BBD) are experimental designs for response surface methodology RSM. 
BBM are frequently applied to optimize analytical methods due to their advantages such as a 
reduction in the number of experiments that need be executed resulting in less patient burden and 
reduced cost. RSM explores the relationships between several explanatory variables and one or 
more response variables (Figure 2). It allows the development of mathematical models that 
permit assessment of statistical significance of the factor effects being studied as well as 
evaluates the interaction effects between the factors. The main concept behind RSM is to use a 
sequence of designed experiments to obtain an optimal response. The BBD is a spherical RSM 
design, with all points lying on a surface of a sphere within the set values of our variables 
(Figure 3: Coordinates A to M). All of the analysis will be managed by our collaborator and 
biostatistician, Dr. Andreou. Analysis of the model provides an estimate whether the optimum 

 
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outcome is located near the design area or further away. A graphical overlay of the contour plots 
of each individual outcome can then be used to determine the PIEB settings that produce the 
desired outcomes to deliver optimal labour analgesia.  
 
The minimum and maximum values for each variable have been chosen based on the literature(12, 
36)
 
and clinical experience: NEXT bolus interval: 15 to 45 min; PIEB interval: 40 to 60 min; 
PIEB volume: 5 to 8 mL. The optimal dose likely falls on the surface of the sphere within this 
cube (Figure 3). These thirteen coordinates on the surface of the sphere (Table 2) represent 
combinations of the variables (Figure 3). Simulations of this analysis suggests that 5 patients 
assigned to each of the twelve surface coordinates and 10 patients assigned to the center (M & 
N) coordinate (n=70) will predict the optimal dosage plane with a reasonable degree of certainty. 
An additional patient will be randomized to the twelve surface coordinates and two patients 
assigned to the center coordinate to account for any potential drop outs. There will be a total 
number of 84 patients required to complete the study.  The power assumption as based on the 
hypothesis that maternal satisfaction outcome would have a mean difference of 7.10 with a 95% 
CI of 6.19 to 7.84, anesthesia interventions occurrence would have a median of 1 with an 
interquartile range of 1-2, and the ratio of the number of PCEA boluses requested to the number 
of PCEA boluses delivered would have a median of 1.4 and an interquartile range of 1.0 to 2.2.  
 
The sample size estimation was based on a standard error of 2% and a simulation of 70 trials. 
The power calculation indicates at least 80% of the response surface will be estimated with 
standard error less than 2%.  
 
Safety and Monitoring 
The investigators will forward all concerns to the independent safety committee consisting of 
Dr.’s P. Bolleddula (Quality Assurance, Women’s & Obstetric Anesthesia, IWK Health Centre), 
G. Dobson (Quality Assurance Officer, Department of Anesthesia, Pain Management, and 
Perioperative Medicine, QE II Health Sciences Centre) and a member of the Department of 
Obstetrics and Gynecology, IWK Health Centre, to review. 
 
 

 
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Funding and Disclosures 
The P.I. has received a grant from the Office of Research, Anesthesia Research Fund at 
Dalhousie University to complete the proposed study.  
None of the study investigators have commercial conflicts to declare. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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References 
1. 
Markley JC, Rollins MD. Non-Neuraxial Labor Analgesia: Options. Clinical obstetrics and 
gynecology. 2017. 
2. 
Melzack R. The myth of painless childbirth. Pain. 1984;19(4):321-37. 
3. 
Lowe NK. The nature of labor pain. American journal of obstetrics and gynecology. 
2002;186(5 Suppl Nature):S16-24. 
4. 
Inducing Labour: Clinical Guideline. Manchester, UK: National Institute for Health and 
Care Excellence (NICE); 2008. 
5. 
Fowles ER. Labor concerns of women two months after delivery. Birth (Berkeley, Calif). 
1998;25(4):235-40. 
6. 
Lavender T, Walkinshaw SA, Walton I. A prospective study of women's views of factors 
contributing to a positive birth experience. Midwifery. 1999;15(1):40-6. 
7. 
Rijnders M, Baston H, Schonbeck Y, van der Pal K, Prins M, Green J, et al. Perinatal 
factors related to negative or positive recall of birth experience in women 3 years postpartum 
in the Netherlands. Birth (Berkeley, Calif). 2008;35(2):107-16. 
8. 
Angle P, Landy CK, Charles C, Yee J, Watson J, Kung R, et al. Phase 1 development of an 
index to measure the quality of neuraxial labour analgesia: exploring the perspectives of 
childbearing women. Canadian journal of anaesthesia = Journal canadien d'anesthesie. 
2010;57(5):468-78. 
9. 
Promoting effective perinatal care: Essential antenatal, perinatal and postpartum care 
training module Copenhagen, DK: World Health Organization: Regional Office for Europe; 2002 
[ 
10. 
Anim-Somuah M, Smyth R, Howell C. Epidural versus non-epidural or no analgesia in 
labour. The Cochrane database of systematic reviews. 2005(4):Cd000331. 
11. 
Boutros A, Blary S, Bronchard R, Bonnet F. Comparison of intermittent epidural bolus, 
continuous epidural infusion and patient controlled-epidural analgesia during labor. 
International journal of obstetric anesthesia. 1999;8(4):236-41. 
12. 
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(1):133-44. 
13. 
Halpern SH, Carvalho B. Patient-controlled epidural analgesia for labor. Anesthesia and 
analgesia. 2009;108(3):921-8. 
14. 
Marcos S, Halpern S. Epidural analgesia for labor: Current techniques. Local Reg Anesth. 
2010;3:143-53. 
15. 
Vincent RD, Jr., Chestnut DH. Epidural analgesia during labor. American family physician. 
1998;58(8):1785-92. 
16. 
Jones L, Othman M, Dowswell T, Alfirevic Z, Gates S, Newburn M, et al. Pain 
management for women in labour: an overview of systematic reviews. The Cochrane database 
of systematic reviews. 2012(3):Cd009234. 
17. 
Chen SY, Lin PL, Yang YH, Yang YM, Lee CN, Fan SZ, et al. The effects of different epidural 
analgesia formulas on labor and mode of delivery in nulliparous women. Taiwanese journal of 
obstetrics & gynecology. 2014;53(1):8-11. 

 
Page 15 of 21 
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18. 
Allen VM, Baskett TF, O'Connell CM, McKeen D, Allen AC. Maternal and perinatal 
outcomes with increasing duration of the second stage of labor. Obstetrics and gynecology. 
2009;113(6):1248-58. 
19. 
Cheng YW, Hopkins LM, Caughey AB. How long is too long: Does a prolonged second 
stage of labor in nulliparous women affect maternal and neonatal outcomes? American journal 
of obstetrics and gynecology. 2004;191(3):933-8. 
20. 
Vyas NA, Vink JS, Ghidini A, Pezzullo JC, Korker V, Landy HJ, et al. Risk factors for cervical 
insufficiency after term delivery. American journal of obstetrics and gynecology. 
2006;195(3):787-91. 
21. 
Allen VM, O'Connell CM, Farrell SA, Baskett TF. Economic implications of method of 
delivery. American journal of obstetrics and gynecology. 2005;193(1):192-7. 
22. 
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(4):826-31. 
23. 
Chua SM, Sia AT. Automated intermittent epidural boluses improve analgesia induced 
by intrathecal fentanyl during labour. Canadian journal of anaesthesia = Journal canadien 
d'anesthesie. 2004;51(6):581-5. 
24. 
Kaynar AM, Shankar KB. Epidural infusion: continuous or bolus? Anesthesia and 
analgesia. 1999;89(2):534. 
25. 
Fettes PD, Moore CS, Whiteside JB, McLeod GA, Wildsmith JA. Intermittent vs 
continuous administration of epidural ropivacaine with fentanyl for analgesia during labour. 
British journal of anaesthesia. 2006;97(3):359-64. 
26. 
Leo S, Sia AT. Maintaining labour epidural analgesia: what is the best option? Current 
opinion in anaesthesiology. 2008;21(3):263-9. 
27. 
Lim Y, Chakravarty S, Ocampo CE, Sia AT. Comparison of automated intermittent low 
volume bolus with continuous infusion for labour epidural analgesia. Anaesthesia and intensive 
care. 2010;38(5):894-9. 
28. 
Lim Y, Sia AT, Ocampo C. Automated regular boluses for epidural analgesia: a 
comparison with continuous infusion. International journal of obstetric anesthesia. 
2005;14(4):305-9. 
29. 
Sia AT, Lim Y, Ocampo C. A comparison of a basal infusion with automated mandatory 
boluses in parturient-controlled epidural analgesia during labor. Anesthesia and analgesia. 
2007;104(3):673-8. 
30. 
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. Anesthesia and analgesia. 2006;102(3):904-9. 
31. 
Bullingham A, Liang S, Edmonds A, Mathur S, Sharma S. Continuous epidural infusion vs 
programmed intermittent epidural bolus for labour analgesia: a prospective, controlled, before-
and-after cohort study of labour outcomes. British journal of anaesthesia. 2018;121(2):432-7. 
32. 
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. 2015. 

 
Page 16 of 21 
REB#: 1023951                                       Version: May 22nd 2019 
33. 
Delgado C, Ciliberto C, Bollag L, Sedensky M, Landau R. Continuous epidural infusion 
versus programmed intermittent epidural bolus for labor analgesia: Optimal configuration of 
parameters to reduce physician-administered top-up Curr Med Res Opin.34(4):649-56. 
34. 
Montgomery DC. Design and Analysis of Experiments. 6th ed. Hoboken, NJ: Wiley; 2005. 
35. 
Wong CA. Advances in labor analgesia. International journal of women's health. 
2010;1:139-54. 
36. 
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(4):904-11. 
37. 
Epsztein Kanczuk M, Barrett NM, Arzola C, Downey K, Ye XY, Carvalho JC. Programmed 
Intermittent Epidural Bolus for Labor Analgesia During First Stage of Labor: A Biased-Coin Up-
and-Down Sequential Allocation Trial to Determine the Optimum Interval Time Between 
Boluses of a Fixed Volume of 10 mL of Bupivacaine 0.0625% With Fentanyl 2 mug/mL. 
Anesthesia and analgesia. 2016. 
38. 
Huskisson EC. Measurement of pain. Lancet (London, England). 1974;2(7889):1127-31. 
39. 
Welchek CM, Mastrangelo L, Sinatra RS, Martinez R. Qualitative and Quantitative 
Assessment of Pain. In: Sinatra RS, de Leon-Cassasola OA, Viscusi ER, Ginsberg B, editors. Acute 
Pain Management:. Cambridge: Cambridge University Press; 2009. p. 147-71. 
40. 
Angle PJ, Kurtz Landy C, Djordjevic J, Barrett J, Kibbe A, Sriparamananthan S, et al. 
Performance of the Angle Labor Pain Questionnaire During Initiation of Epidural Analgesia in 
Early Active Labor. Anesthesia and analgesia. 2016;123(6):1546-53. 
41. 
Tsai FH, Kitamura Y, Kokawa M. Liquid-core alginate hydrogel beads loaded with 
functional compounds of radish by-products by reverse spherification: Optimization by 
Response surface methodology. International journal of biological macromolecules. 2016. 
42. 
ASA physical status classification system, (2014). 
43. 
Breen TW, Shapiro T, Glass B, Foster-Payne D, Oriol NE. Epidural anesthesia for labor in 
an ambulatory patient. Anesthesia and analgesia. 1993;77(5):919-24. 
44. 
Brokelman RBG, Haverkamp D, van Loon C, Hol A, van Kampen A, Veth R. The validation 
of the visual analogue scale for patient satisfaction after total hip arthroplasty. European 
Orthopaedics and Traumatology. 2012;3(2):101-5. 
45. 
Dickinson JE, Paech MJ, McDonald SJ, Evans SF. Maternal satisfaction with childbirth and 
intrapartum analgesia in nulliparous labour. The Australian & New Zealand journal of obstetrics 
& gynaecology. 2003;43(6):463-8. 
 
 
 
 
 
 

 
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Table 1. IWK Health Centre Continuous Epidural Infusion (CEI) and Programmed 
Intermittent Bolus (PIEB) anesthesia pump parameters 
 
Labour 
Analgesia 
Method 
 
Maintenance 
Solution and 
rate 
Start of 
maintenance 
solution 
PCEA volume 
 
PCEA interval 
CEI until 2015 
6 mLs/hr 
ropivacaine 
0.1% with 2 
ug/mL fentanyl 
Immediately 
after epidural 
catheter 
placement and 
pump set up 
6 mLs 
ropivacaine 
0.1% with 2 
ug/mL fentanyl 
10 minutes 
PIEB from 2015 
8 mLs every 45 
min 
ropivacaine 
0.1% with 2 
ug/mL fentanyl 
15 minutes after 
epidural 
catheter 
placement and 
pump set up 
6 mLs 
ropivacaine 
0.1% with 2 
ug/mL fentanyl 
10 minutes 
 
 
 
 
 
 
 
 

 
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REB#: 1023951                                       Version: May 22nd 2019 
Table 2. Programmed Intermittent Epidural Bolus (PIEB) Variable Combinations.  
 
 
 
 
 
 
 
 
 

 
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REB#: 1023951                                       Version: May 22nd 2019 
Figure 1. Programmed Intermittent Epidural Bolus (PIEB) Delivery with Patient 
Controlled Epidural Analgesia (PCEA)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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REB#: 1023951                                       Version: May 22nd 2019 
Figure 2. Explanatory and Response Variables for Surface Response Methodology  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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REB#: 1023951                                       Version: May 22nd 2019 
Figure 3. Box-Behnken design (BBD) to predict Optimal Response Surface Methodology 
(RSM).