Conditions: Pregnancy
Keywords: Pain control labor epidural pregnant
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 170
Healthy volunteers: yes

Brief summary:
The purpose of this study is to determine what dose of medication administered through a combined spinal epidural (CSE) provides the optimal pain relief with the minimal amount of side effects. The 3 doses studied here (1.25, 1.66 and 2.5mg) are routinely use on the labor floor (depending on the physician preference) but the idea is to quantify safety, efficacy and side effects for each of these doses.

Detailed description:
A combined spinal epidural (CSE), which is the investigators' customary method of providing pain relief during your labor, is the identification of the epidural space in your lower back with a needle, followed by passing a thinner and longer needle through the first needle. This second needle will enter the patient's "spinal" (intrathecal) space by passing through the dura (thin covering separating the epidural space from the spinal space). The spinal (intrathecal) space is identified by flow of spinal fluid. The dura is the envelope around the spinal cord and the intrathecal space which is filled with spinal fluid. Medication will be injected at once into the spinal space, the thinner needle removed and a fine tube (catheter) will be threaded through the first needle into the epidural space. This catheter is in the epidural space and medication can be given through this catheter later on (hence the term combined) if needed. This study is a comparison of three different dosages (1.25mg, 1.66mg and 2.5 mg) of the local anesthetic (Bupivacaine) that we frequently use in the spinal, mixed with 20 mcg of Fentanyl (also routinely used in standard of care practice), and of its effects on the patient's blood pressure (risk of maternal's drop of the blood pressure with possible bad effects on the blood flow to the baby), on the patient's baby's heart rate (risk of slowing down of the baby heart rate as a consequence of decreased blood flow to the baby), and the patient's pain relief (higher dose of medications are usually more effective for maternal pain relief but have side effects that can be bad for the mother and the baby). The doses of Bupivacaine the investigator routinely use on the labor and delivery floor go from 1.25 to 2.5 mg depending on clinician preferences. These doses are considered standard of care in the literature.

Arms:
arm 1: 1.25mg of bupivacaine dose with 20 mcg of fentanyl was injected in the spinal portion of the anesthetic arm 2: 1.66mg of bupivacaine dose with 20 mcg of fentanyl was injected in the spinal portion of the anesthetic arm 3: 2.5mg of bupivacaine dose with 20 mcg of fentanyl was injected in the spinal portion of the anesthetic

Interventions: intervention 1: Bupivacaine intervention 2: Fentanyl
Intervention descriptions: intervention 1: The dose of bupivacaine administered intrathecally during placement of the spinal anesthetic. intervention 2: 20 micrograms routinely administered in combination in the spinal anesthetic

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 6 
 
 
Randomized Double-blinded Study Designed to Optimize the Dose of Bupivacaine in Combined Spinal Epidurals 
to Reduce the Incidence of Fetal Bradycardia and Maternal Hypotension  
PI: Barbara Orlando, MD 
NCT02159807 
Document Date:  5-27-2014


Page 1 of 6 
 
Final Verison date May 27th 2014  
IRB PROTOCOL# 13-0210  
 
Randomized double-blinded study designed to Optimize the Dose of Bupivacaine in Combined Spinal 
Epidurals to Reduce the Incidence of Fetal Bradycardia and Maternal Hypotension 
 
Principal investigator:Jonathan Epstein MD, 
 
Co-Investigators:Migdalia Saloum MD, Barbara Orlando MD, Deborah Stein MD, 
Julio Marenco M.D., Dimitrios Kassapidis, M.D.  
Mount Sinai-Roosevelt Hospital Center 
Department of Anesthesiology 
 
Chairmen: Alan Santos,MD, MPH,Anesthesiology; Peter McGovern, M.D.,Ph.D.,Obstetrics  & 
Gynecology 
 
 
 
 
 
 
Specific Aims: 
 
The primary objective of this study is to identify whether a smaller dose of spinal bupivacaine combined  
with fentanyl reduces the incidence of maternal hypotension and fetal bradycardia  in laboring parturients 
receiving combined spinal-epidural analgesia. 
 
The secondary objective is to evaluate the adequacy of pain relief with the reduced dose of spinal 
anesthetic. 
 
Outcomes to be measured include: 
 
1.   Maternal hypotension. Defined as 20% decrease in systolic blood pressure (when 
compared  with baseline) or a systolic blood pressure less than 100 mm Hg. 
 
2. Fetal bradycardia. Defined as a fall in heart rate to less than 110 bpm, or a prolonged 
deceleration  defined as a fall in heart rate to less than 110 bpm lasting more than 2 minutes. 
 
3. The need to administer ephedrine,phenylephrine,terbutaline, or nitroglycerin to support 
blood pressure and/or improve the fetal heart rate following the spinal dose 
 
4. Adequacy and duration of pain relief following the spinal using a numeric pain rating scale 
from zero to ten. 
 
5. Mode of Delivery- Normal spontaneous vaginal delivery, vacuum assisted/forceps, or 
caesarean section 
 
 


Page 2 of 6 
 
 
Significance: 
 
Combined spinal epidural anesthesia (CSE) is a safe and simple procedure which provides adequate analgesia in 
laboring patients. Two possible complications of this technique are maternal hypotension and fetal 
bradycardia, which have been demonstrated to result from both rapid pain relief and sympathetic  
blockade.2 Untreated hypotension  leads to diminished uteroplacental blood flow  which could result in 
fetal hypoxia and acidosis. 
 
Previous studies have determined the ED95 of bupivacaine to be 1.66 mg, less than the standard 2.5 mg 
being routinely given in CSE for laboring patients.It has also been demonstrated that half the typical dose of 
bupivacaine provides adequate pain relief in the majority of parturients. Whether the complication rate 
with a smaller dose of local anesthetic is diminished has yet to be determined. 
 
We postulate that by reducing the amount of bupivacaine given in a CSE,maternal hypotension and fetal 
bradycardia will also be reduced, while still providing adequate analgesia. Prevention of these 
complications will lead to fewer rescues with sympathomimetic and uterine relaxation agents, fewer 
invasive treatments, and an increase in patient satisfaction. 
 
Experimental Design and Method: 
 
The clinical trial will take place between January 1, 2014 to January 1, 2015 in the Labor and Delivery unit at 
the Roosevelt site of Mount-Sinai-Roosevelt Hospital Center. 
 
This randomized prospective double-blinded study is designed to investigate the development of 
maternal hypotension and fetal bradycardia in patients receiving CSE for labor analgesia. T h e  t a r g e t  
p o p u l a t i o n  a r e  l a b o r i n g  p a t i e n t  a d m i t t e d  t o  t h e  L a b o r  a n d  d e l i v e r y  u n i t .  
A n y  p a t i e n t  r e q u e s t i n g  a n  e p i d u r a l  f o r  l a b o r  w i l l  b e  a  p o t e n t i a l  c a n d i d a t e  
f o r  t h i s  s t u d y .  Discussion regarding the patient's participation in the trial will occur when she 
requests labor analgesia, as this is the customary first point of contact with the anesthesiology team.  After 
informed consent and discussion of the technique for combined spinal-epidural, patients will be blindly 
randomized to one of three groups. The randomization will be done by blindly choosing one of these 
papers from the envelope, which will assign you to one of the three groups. 
These groups relate to the dose of bupivacaine that will be administered intrathecally during placement of 
the spinal ane sthetic. Syringes will be prepared in advance by pharmacy containing one of the three doses of 
bupivacaine being identified only by a syringe number. Twenty micrograms of fentanyl is routinely 
administered in combination with bupivacaine in the spinal. The total amount in the syringe will be the same in the 
group, by adding saline when needed. Pharmacy will be providing us with prepared syringes containing either one 
of the 3 dosages of Bupivacaine for the spinal part of the combined spinal epidural (CSE). The syringes will be 
labeled with a number, and only pharmacy will know what concentration of bupivacaine is in the syringe. We 
will be given this information of what was in the syringe once final data are collected for the patients included in 
the study. The syringe will be prepared with a sterile technique, and the content will be ready to use as is by the 
anesthesia team providing the CSE. 
 
Group 1: 2.5 mg plain bupivacaine + 20 mcg fentanyl 
Group 2: 1.66 mg plain bupivacaine + 20 mcg fentanyl 


Page 2 of 6 
 
Group 3: 1.25 mg plain bupivacaine + 20mcg fentanyl 
After randomization, a baseline pain score on a scale of 0- 10 will be obtained. The fetal heart rate tracing 
will be recorded for 15 minutes  with an external continuous heart rate monitor prior to placing the CSE in 
order to obtain  an adequate baseline. Patients will be seated for the placement of the CSE. A blood pressure 
cuff and pulse oximeter will be in place and an initial blood pressure will be taken. The time of the spinal 
injection will be recorded.  After placement of the CSE, the patient will placed on her side, as is customarily 
done.  Blood pressure will be taken every 2 minutes for 20 minutes and then every 15 minutes. A continuous 
fetal heart rate monitor will record the readings electronically. Blood pressure readings will be


Page 3 of 6 
 
recorded again at 60 minutes. All patients will be given our standard PCEA with a continuous infusion of 
12ml/hr of 0.0625% bupivacaine with 2mcg/ml fentanyl. 
If hypotension and/or fetal bradycardia occur the patient will be treated with ephedrine, phenylephrine, 
nitroglycerin, or terbutaline as per our standard practice. The dose and timing of this will be recorded. 
Patients will also be asked to evaluate the effectiveness of their pain relief by asking them to rate their pain 
on a scale from 0-10 at 8 minutes ( t i m e  t o  f u l l  e f f e c t  o f  t h e  s p i n a l  d o s e )  and 60 minutes 
( t i m e  w h e n  s p i n a l  d o s e  c o u l d  s t a r t  w e a r i n g  o f f ) following the spinal dose. 
In the event that the patient does not receive adequate pain relief, additional local anesthetic will be 
administered into the ·epidural catheter until the patient achieves comfort. 
The data form is attached as Appendix B. 
Data collected will consist of: 
 
Demographics: Patient age, gestation,dilation in centimeters, gravity, parity 
 
 
Presence of labor induction/augmentation with Pitocin 
 
 
Maternal blood pressure- a baseline blood pressure and every 2 minutes for 20 minutes 
following the dose of spinal bupivacaine.  A final blood pressure will also be recorded at 60 
minutes. 
 
 
Fetal heart rate- a baseline fetal heart rate,and  a continuous recording following the dose of 
spinal bupivacaine with  an external monitor 
 
 
Cumulative ephedrine, phenylephrine, nitroglycerin, or terbutaline use and timing 
 
 
Pain scores at baseline,8minutes,and 60 minutes 
 
 
Delivery outcomes: normal spontaneous  vaginal delivery, vacuum/forceps assisted 
vaginal, or caesarean section 
 
Statistical  Analysis: 
 
Power analysis: As this is an exploratory but well controlled study, we will set the power at 0.9 and alpha 
at 0.05. 9 per group are required with an incidence fetal bradycardia/maternal hypotension of 
7%; thus we will study 30 per group = 180 subjects. Accounting for dropouts and incomplete data, we seek to 
consent 200 patients. Published data estimates that the incidence of maternal hypotension after spinal 
bupivacaine is 10- 15% at the higher 2.5 mg dose and likely reduced to 3 -5% at the 
lower doses. The incidence of fetal bradycardia is less well studied but is estimated to occur in 3- 7% 
of parturients after the higher 2.5mg bupivacaine dose.The occurrence  of fetal bradycardia  at lower doses 
of bupivacaine is not well studied but our prediction is that it will be reduced. 
 
F tests- ANOVA:Repeated measures, between factors 
Analysis: 
A priori:Compute required sample 
size 
Input: 
Effect size f 
= 
1.2472191 
a err prob 
= 
0.05 
Power (1-err  prob) 
= 
0.90 
Number of groups 
= 
3 
Repetitions 
= 
4 
Corr among rep measures 
= 
0.5 
Output:  
Noncentrality parameter A. 
= 
Critical F 
= 
5.143253 
22.399999


Page 4 of 6 
 
    Numerator df  
=2.000000 
Denominator df   = 
Sample size 
= 
Actual power  
 = 
Total sample size = 180 
6.000000 
9 
0.903879 
 
 
Human subjects: 
 
Inclusion Criteria: ASA 1-2 parturients at term requesting labor analgesia between 37 and 42 weeks 
gestational age, with maternal age of 18 years or greater. Signed informed consent will be obtained from all 
patients prior to their enrollment in the study. 
 
Exclusion criteria: Parturients with pre-eclampsia, or history of pregnancy induced hypertension will be 
excluded from the study. In addition, those patients in whom a spinal anesthetic is contraindicated (e.g. 
coagulopathy, local infection) or those in whom a CSE cannot be performed, will be excluded from the study. 
Patients who show non reassuring fetal heart rate tracings prior to placement of the CSE will also be excluded 
from the study. 
 
Consent procedures 
 
Sources of Research Material Obtained from Human Subjects: 
 
Data will be collected from two sources: from the initial anesthesiology preoperative assessment and procedural 
anesthesia record (part of the medical record). 
 
Recruitment of subjects and consent procedure:  After a patient is interviewed by the anesthesia team prior to 
labor analgesia,and is found to fulfill the inclusion criteria, she will be asked if she wishes to participate in the 
study. The study and the potential risks and benefits will be explained to the patient in order to obtain written 
informed consent. A copy of the protocol will be available to each subject and each patient will receive a copy 
of the informed consent. 
 
Potentialhealth risks: 
 
Combined spinal epidurals have become standard practice techniques for labor analgesia. The health risks for 
patients in this study will be equal to the risks associated with the routine placement of combined spinal- 
epidurals. These include a postdural puncture headache,bleeding and infection at the injection 
site,hypotension,epidural hematoma/abscess, high spinal,nerve dam.age, and failure of adequate pain relief.  
Inadequate pain relief from the lower dose of spinal anesthetic is a risk that study patients may be more likely 
to incur. Patients will be monitored closely for this and will be given additional boluses of local anesthetic 
through the epidural catheter that is already in place until relief is achieved. All research documentation that 
includes identifiers such as names and birthdates will be kept in a secure area in the research office. 


Page 5 of 6 
 
Potential Health Benefits: 
 
There are significant potential health benefits to patients participating in this study.  It has been 
shown that spinal bupivacaine given at the common dose of 2.5mg can lower maternal blood 
pressure. Patients in the study who receive lower doses will most likely have a reduced rate of 
hypotension,and potentially a lower occurrence of fetal bradycardia. Lower rates of maternal 
hypotension and fetal bradycardia would lead to a lower incidence of nausea and vomiting,less 
interventions and emergency caesarian deliveries. 
 
Potential Financial Risks: 
 
Patients will not incur any additional financial expenses as a consequence of being enrolled in this study 
beyond the costs that are typically applied for regional anesthesia for labor analgesia. 
 
Potential Financial Benefits: 
 
Patients will not be compensated for participation in this study 
 
Risk to Benefit Ratio: 
 
All the potential risks of a combined spinal-epidural have been discussed. The additional risk that patients 
may incur if they receive a lower dose of spinal bupivacaine might be inadequate pain relief. The patient 
would have an epidural in place with this procedure and would receive additional local anesthetic through 
the epidural should this occur. The potential benefits are lower risks for maternal hypotension and fetal 
bradycardia.  The risks are reasonable in relation to the anticipated benefits that are expected to result. 
 
Alternative to Research Participation: 
 
The patient's involvement in this study is completely voluntary and all subjects will be informed that they 
can withdraw at any time without loss of benefits to which they are otherwise entitled. 


Page 6 of 6 
 
Literature Cited: 
 
1. 
Chan SY, Chiu JW. Intrathecal labor analgesia using levobupivacaine 2.5 mg with fentanyl 
25 micrograms- would half the dose suffice? Med Sci Manit. 2004 (10):110-4. 
 
2. 
Chestnut DH. Obstetric Anesthesia: Principles and Practice. Mosby. 2008 Fourth Edition. 
 
3.  Lim Y,Sia AT,Ocampo CE. Comparison of intrathecallevobupivacaine with and without 
fentanyl in combined spinal epidural for labor analgesia. Med Sci Manit. 2004 (10): 87-91 
 
4.   Sia AT,Chong JL,Chiu JW. Combination of intrathecal sufentanyl10 micrograms plus 
bupivacaine  2.5 mg for labor analgesia: is half the dose enough? Anesth Analg. 1999 (88): 
326-6. 
 
5.   Whitty R, Goldszmidt  E,Parkes RK, Carvalho JC. Determination of the ED 95 for intrathecal 
plain bupivacaine  combined with fentanyl in active labor. lnt J Obstet Anesth. 2007 {16): 
341-5 
 
6.   Abrao KC et al. Elevation of uterine basal tone and fetal heart rate abnormalities after 
labor analgesia. Obstet and Gynec 2009(113) no.1: 41-47 
 
 
7.   Van de Velde M,Teunkens A,Hanssens M,Vandermeersch E,Verhaeghe J. Intrathecal 
sufentanyl and fetal heart rate abnormalities: a double- blind,placebo- controlled trial 
comparing two  forms  of combined spinal epidural analgesia with epidural analgesia in 
labor. Anesth Analg 2004;98:1153-9 
 
 
 
8.   Van de Velde M. Neuraxial analgesia and fetal bradycardia. Curr Opin Anaesthesiol 2005, 
18:253-256