Effect of Epidural Saline on Duration and Spread of Subsequent Spinal Analgesia/Anesthesia Using a CSE Technique
Phase: PHASE2
Conditions: Labor Pain
Sponsor: Wake Forest University Health Sciences

 
 
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Wake Forest University School of Medicine 
 
Effect of epidural saline on duration and spread of subsequent spinal 
analgesia/anesthesia using a CSE technique 
Principal Investigators:  Peter Pan, M.D.:  John Thomas, MD 
Funding: Funding is provided by the Department of Obstetrical Anesthesiology 
Background: 
Combined spinal epidural labor analgesia (CSE) is a common technique to provide rapid relief of labor 
pain.  In parturients requesting labor analgesia who are appropriate for a combined spinal epidural 
technique (CSE), the spinal drugs are typically 1.75 to 3.0 mg of bupivacaine and 10-20 micrograms of 
fentanyl administered intrathecally.   Combining bupivacaine and fentanyl provides synergistic effect 
leading to longer duration of analgesic effect.  However, the pruritus that frequently occurs after the 
administration of intrathecal fentanyl can be particularly bothersome to some patients.  We are interested in 
minimizing the bothersome side effects of intrathecal narcotics as well as potentially increasing the level of 
sensory block and the analgesia duration of the spinal block by injecting a predetermined amount of normal 
saline into the epidural space via the epidural needle prior to performance of the spinal block without 
narcotic while using a CSE labor analgesic technique.  Injecting normal saline into the epidural space after 
but not before an intrathecal injection has been termed epidural volume extension (EVE) and has been 
shown to increase the cephalad spread of the block.  The mechanism of extension of spinal anesthesia was 
suggested to be mainly the result of a volume effect in which the dural sac is compressed by the injectate 
which results in a cephalad shift of CSF containing local anesthetic.1,2  The effect of epidural injectate 
volume on an existing spinal block has been studied but with inconsistent clinical findings in which the 
studies were limited by either a small sample size, a small volume of epidural injectate or variable time 
interval from spinal block administered and being already “fixed”.  However, none of the studies have 
evaluated the clinical effect of a pre-existing epidural volume injection on a subsequently performed spinal 
block as we propose to study.  The study results will be clinically relevant not only for combined spinal 
epidural labor analgesia but also for those patients requiring an alternative neuraxial block after a failed 
epidural block with a large volume of epidural drugs administered. Higuchi estimated a 2.0 +/- 1.0 ml to 

 
 
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7.2 +/-ml reduction in mean lumbosacral CSF volume lasting for 30+ minutes and alterations in CSF 
velocity waveform, both associated with a 5 to 15 ml epidural volume injection with an intact dura.3   Our 
study is designed to better understand the clinical effects and mechanism of pre-existing epidural injectate 
volume effect on subsequently performed spinal block. 
Objective: 
To compare in a controlled, randomized prospective fashion the clinical effect and mechanism of pre-
existing epidural saline volume effect on subsequently performed spinal block.  Our hypothesis is that 15 
ml of a pre-existing epidural injectate volume will significantly increase the level of sensory block and 
increase the analgesic duration of action in a subsequently performed spinal block. 
 
Methods and Measures 
 
Design and Outcome Measures:  This study is a prospective randomized double-blind study whereby the 
patients will be randomized to one of two groups with either 0 ml or 15 ml of epidural saline injections 
followed by injection of 3 mg of isobaric bupivacaine intrathecally.  Primary outcome measures are highest 
sensory blockade level to pinprick and to cold.  We divided anesthesia dermatome levels to a total of 20 
levels from sacral (1 level) then L5 to T1 (as 17 levels) and then C7 (1 level) and C6 or higher as another 
level.   Modified Bromage Motor Scale will be used to assess the amount of motor blockade in the lower 
extremities. 
Secondary outcome measures are the following: 
1.) Time to Onset of analgesia (VAS <=3) 
2.) Duration of analgesia (time to request additional analgesia) 
3.) Time to highest sensory blockade level 
4.) Time for 2 dermatome level regression of sensory block 
5.) Time for regression of motor blockade 
6.) Occurrence of common spinal/epidural side effects:  hypotension, fetal bradycardia, 
vasopressor use (ephedrine), excessively high blocks (higher than T4) and postdural puncture 
headache 
Setting: The study will take place on the labor and delivery suite at Forsyth Medical Center. 

 
 
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Protocol and Procedures: 
A. 90 healthy women with uncomplicated pregnancies in early labor (>=2cm but =<6cm cervical 
dilation) requesting neuraxial analgesia will be consented to participate to obtain 60 evaluable subjects 
enrolled in this randomized controlled trial.  Patients will be greater than 12 years of age, have an 
assigned ASA physical status 1 or 2 with a singleton pregnancy.  Patients with contraindications to 
neuraxial anesthesia, inappropriate for study, or with allergies to drugs used in the study will be 
excluded.   Patients inappropriate for study would include those with an assigned ASA status 3 or 4, 
advanced labor (> 6cm cervical dilation) or less than 12 years of age.  Patients with the potential for 
distorted epidural anatomy, such as Harrington rods or prior back surgery, will also be excluded. 
B.     Patients will be randomized into 1 of 2 groups: 
Group 1.  45 subjects 
Epidural space will be identified with loss of resistance to minimal air or saline 
(<0.2-0.3 ml) with a 17 gauge epidural needle.  Then, after 20-30 seconds, the spinal needle will be inserted 
via the epidural needle in the usual manner and 3 mg isobaric bupivacaine (1.2 ml of 0.25% isobaric 
bupivacaine) will be given intrathecally. 
Group 2.  45 subjects 
Epidural space will be identified with loss of resistance to minimal air or saline 
(<0.2-0.3 ml) with a 17 gauge epidural needle.    Normal saline 15 ml will then be administered through the 
epidural needle over approximately 20 seconds and held for another 10 seconds.  The spinal needle will 
then be inserted via the epidural needle in the usual manner and 3 mg isobaric bupivacaine (1.2 ml of 
0.25% isobaric bupivacaine) will be given intrathecally. 
In both groups after administration of intrathecal study drug, the spinal needle will be removed followed by 
insertion of the epidural catheter as in the usual manner.  After placement of the epidural catheter, patients 
will be returned to the supine position with slight left tilt.  Patients will be placed with their head up at an 
angle of approximately fifteen degrees after the spinal injection.  The epidural catheter will not be tested or 
dosed until the patient requests further analgesia.  When additional analgesia is requested, the epidural 
catheter will be tested and dosed in the customary fashion.  The catheter will then be connected to a patient 
controlled epidural analgesic pump with the settings as per our normal standard of care. 
 

 
 
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C. All patients will be required to sign an informed consent document prior to participating in the study. 
We anticipate that it will take 24 months to enroll and study 60 evaluable patients.  The specifics of the 
research will be explained to patients and any questions will be answered.  Patient confidentiality will be 
maintained. 
D.  All patients will have a functioning intravenous catheter and receive appropriate intravenous fluid of 
balanced salt solution prior to insertion of their epidural catheter.  The epidural space will be located by the 
usual technique with the patient in the sitting position using a 17G epidural Tuohy sited at L3-4 +/- 1 
intervertebral space.  All patients will then have an 18G epidural catheter inserted the customary length (5 
cm) into the epidural space.  The epidural needle will be removed and the catheter secured.   
E.   Background information on age, height, weight, gestation age, gravid status, cervical dilation, pitocin 
usage, and stadol usage will be obtained from patient report or the medical record. Study participants will 
indicate their level of discomfort at peak contraction on a standard 0-10 verbal analog scale (VAS).  We 
will monitor and record the dermatome, pain score, vital signs, ephedrine usage, maternal vital signs, and 
fetal heart rate every 5 minutes for 20 minutes after initial spinal drug administration or every 5 minutes for 
15 minutes after each subsequent physician epidural drug administration.  Patient will also be assessed 
every 15 minutes until the patient requests additional analgesia.  Changes in sensory levels to temperature 
and pin prick perception will also be assessed using alcohol pads and dull pins, respectively, at these same 
time intervals.  Patients will be monitored in the usual clinical manner.  Side effects such as hypotension, 
fetal bradycardia and post dural puncture headache will be recorded and treated as in our usual clinical 
practice.  Participants will have their need for additional medication be evaluated in the routine fashion, and 
the amount and type of drug administered will be recorded.  
 
Statistical and Analytical Plan:  
 
SigmaStat for Windows by SPSS Inc is being used for statistical analysis.  Based on previous observations 
and our obstetric anesthesia unit quality assurance data, we estimated one standard deviation of our primary 
outcome measure (highest sensory dermatome level of block) to be 3 dermatome levels.  We considered a 
clinically significant difference in highest sensory block dermatome level between groups to be 3 
dermatome levels.  With these assumptions and to detect at least a 3 dermatome level difference in highest 
sensory block between groups with a power of 0.8 to 0.9 and an alpha of 0.05, the minimum sample size 

 
 
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needed is 30 patients per group.  For the secondary outcome measure (analgesic duration of action), we 
consider a  difference of 15 minutes between groups to be clinically significant with an estimated 60 
minutes for mean duration of action and a standard deviation of 15 minutes. Similarly, the minimal sample 
size required to detect a difference of 15 minutes or more in analgesic duration between groups is 23 per 
group with a power of 0.8 to 0.9 and alpha of 0.05.  Furthermore, based on our clinical quality assurance 
report, labor CSE and epidural analgesia may have up to 30% needing additional supplemental dosing 
and/or technical technique adjustments to achieve complete labor analgesia.  Therefore, we will plan to 
enroll 45 patients per group to obtain at least 30 evaluable patients per group.  The primary outcome in 
dermatome level difference will be analyzed by ANOVA on ranks using Kruskel Wallis test followed by 
posthoc Tukey test as appropriate.   
Risks: 
All the usual risks of epidural catheter placement exist including dural puncture by the epidural needle, 
threading the epidural catheter into a blood vessel (7-16% risk) or spinal space, the epidural not functioning 
properly (20-32%), as well as other very rare risks of nerve injury, hematoma, infection and seizures.  More 
common usual risks of headache (approximately 1%) are not increased by the study procedure over the 
usual combined spinal epidural or epidural technique.  Patients will be questioned the day following 
delivery for the presence of headache as per usual routine postoperative follow up visit.  Diagnosis and 
treatment of a spinal headache will be managed as per our standard of practice.  This management includes 
conservative therapy of pain medication, hydration and caffeine, followed by an epidural blood patch if 
necessary.   A literature search yielded no significant reports of serious adverse events associated with 
epidural injection of saline.    Patients may occasionally experience a sensation of pressure during the saline 
injection that may be perceived as uncomfortable transiently.  Performance of a spinal block after 
administration of a large amount of epidural injectate can clinically translate to a higher sensory and motor 
level of spinal block and increase in duration of action, both of which are what this study aims to 
demonstrate. Researchers have hypothesized that compression of the dural sac by residual anesthetic in the 
epidural space may result in rostral displacement of the CSF, and with it, the injected spinal drug.1,4  Others 
have estimated that the incidence of high spinal anesthesia when performed after epidural anesthesia is as 
high as 11% with a mean bupivacaine dose of 12 mg5.   In this study clinically significant high spinal 

 
 
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blockade is considered to be unlikely and no more than usual epidural or combined spinal epidural 
analgesia, as we will be using very small doses of bupivacaine and the epidural predistension will be 
performed using normal saline rather than local anesthetic.  A higher number of blocked dermatomes may 
potentially lead to a greater drop in mean arterial blood pressure compared to the usual epidural.   However, 
this decrease is unlikely to be clinically significant based on a prior study showing only a 6 mmHg 
difference between 2 mL and 10 mL groups.6   Blood pressures will be monitored every minute for 15 
minutes after epidural placement and treated as appropriate with intravenous medications and fluid. 
Benefits: 
A 15 ml pre-existing volume injectate may significantly increase the level of sensory block and increase the 
analgesic duration of action of a subsequently performed spinal block.  Spinal bupivacaine alone for 
combined spinal epidural analgesia with prior epidural volume injection may also provide the following 
advantages over traditional CSE with bupivacaine and fentanyl: 
Less pruritus or most likely no pruritis (without spinal narcotic) 
Potentially provides a form a spinal analgesia with longer duration of action without the need of 
higher dose of drugs. 
Minimizes the time of retrieving and record keeping of narcotic use 
Potentially better overall patient satisfaction (with less irritating side effects) 
 
Human Subjects Protection 
Informed Consent: 
Written informed consent will be obtained from each subject.  Study team members or the research nurse 
will obtain informed consent after patient is admitted for labor and is determined to meet the eligibility 
criteria for participation. The study and informed consent will be reviewed with the patients, and if 
applicable their legally authorized representative, in their labor and delivery room.  Once signed, a copy of 
the informed consent form will be placed in the patient’s medical record and a copy will be given to the 
patient for their records. 
 
 

 
 
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Confidentiality and Privacy: 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  The master study enrollment log 
containing the names, group allocation, and date of study will be kept secure in the department of OB 
Anesthesia, with access limited to designated study personnel.  Following data collection subject 
identifying information will be destroyed at the earliest opportunity, consistent with data validation and 
study design, producing an anonymous analytical data set.  Data access will be limited to study staff.  Data 
and records will be kept locked and secured, with any computer data password protected.  No reference to 
any individual participant will appear in reports, presentations, or publications that may arise from the 
study. 
Data and Safety Monitoring: 
The principal investigator will be responsible for the overall monitoring of the data and safety of study 
participants.  The principal investigator will be assisted by other members of the study staff.  A data safety 
monitoring committee made up of 1 obstetrician and 1 obstetric anesthesiologist will be utilized and 
unblinded to group allocation.  They will review the interim results bi-annually, including review of fetal 
heart rate and uterine contractions, vital signs, analgesic effects and the occurrence of any adverse 
events/side effects.    
Reporting of Unanticipated Problems, Adverse Events or Deviations: 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes will be 
promptly reported by the principal investigator or designated member of the research team to the Institute 
Review Board (IRB). 

 
 
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References: 
 
1   Blumgart CH, Ryall D, Dennison B, Thompson-Hill LM.  Mechanism of extension of spinal anesthesia 
by extradural injection of local anesthetic.  Br J Anaesth 1992; 69: 457-490 
2 Stienstra R, Dilrosun-Alhadi BZR, Dahan A, van Kleef JW, Veering B, Burm AGL. The epidural “top-       
up” in combined spinal-epidural anesthesia: the effect of volume versus dose.  Anesth Analg 1999; 88: 810-
814 
3 Higuchi Hirata J, Adachi Y, Kazama T.  Effects of epidural saline injection on cerebrospinal fluid volume 
and velocity waveform.  A magnetic resonance imaging study.  Anesthesiology 2002: 102: 285-92. 
4 Beck GN, Griffiths AG: Failed extradural anaesthesia for caesarean section. Complications of subsequent 
spinal block.  Anaesthesia 1992; 47:690-2. 
5 Furst SR, Reisner LS.  Risk of High Spinal Anesthesia Following Failed Epidural Block for Cesarean 
Section.  Journal of Clinical Anesthesia 1995: 7-71-74. 
6 Iwama H. Injection volume of saline with loss of resistance method may affect the spread of epidural 
anesthesia.  Anesthesiology 1997; 86(2): 507-8.