Journal of Clinical Anesthesia (2015) 27, 7–11

Original Contribution

Effects of epinephrine in the epidural space on the

incidence of blood vessel injury by epidural
catheter insertion for cesarean section: a
prospective, randomized, double-blind study☆,☆☆
Chuanbao Han MD (Staff Anesthesiologist)⁎,
Qinhai Zhou MD (Staff Anesthesiologist),
Zhengnian Ding PhD (Professor and Chairman),
Yanning Qian PhD (Associate Professor of Anesthesia)
Department of Anesthesiology, First Affiliated Hospital, Nanjing Medical University, Nanjing, China

Received 17 May 2013; revised 30 August 2014; accepted 14 September 2014

Keywords:
Abstract
Anesthesia;
Study objective: To evaluate the effects of epinephrine (1:200,000) in the epidural space on the incidence of
Cesarean section;
blood vessel injury by epidural catheter insertion for cesarean section.
Epidural;
Design: Prospective observational study.
Epinephrine;
Setting: University-affiliated teaching hospital.
Hematoma
Patients: Four hundred laboring women with singleton cephalic presentations at term who underwent
cesarean section and requested continuous epidural analgesia.
Interventions: Predistension of 5 mL of isotonic sodium chloride solution containing epinephrine (1:200,000)
or 5 mL of isotonic sodium chloride solution through an epidural needle before catheter insertion.
Measurements: Cases with bloody fluid in the epidural needle or catheter during catheter insertion, aspiration
of frank blood from the epidural catheter, and blood noted in the caudal end of the epidural catheter upon
removal were recorded.
Main results: Eight parturients were excluded from the analysis for technical reasons. There were no
significant differences between patients in the 2 groups with respect to cases with bloody fluid in the epidural
needle during catheter insertion (7.6% vs 9.8%, P = .44), the epidural catheter during catheter placement
(6.0% vs 6.7%, P = .80), aspiration of frank blood in the epidural catheter (1.0% vs 1.0 %, P = .98), and blood
noted in the caudal end of the epidural catheter upon removal (27.3% vs 30.4 %; P N .49).
Conclusion: Twenty-five micrograms of epinephrine (1:200,000) in the epidural space does not reduce the
incidence of blood vessel injury induced by insertion of an epidural catheter.
© 2014 Elsevier Inc. All rights reserved.

☆
Funding: This project is supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
☆☆
Conflict of interest: The authors have no conflicts of interest.
⁎ Corresponding author at: Department of Anesthesiology, 1st Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Rd, 210029, Nanjing,
China. Tel.: +86 13913026699; fax: + 86 25 83718836.
E-mail address: mzhcb@126.com (C. Han).

http://dx.doi.org/10.1016/j.jclinane.2014.09.004
0952-8180/© 2014 Elsevier Inc. All rights reserved.
8 C. Han et al.
1. Introduction
There are extensive vascular plexuses in the epidural space
which may be punctured during epidural puncture [1–4],
especially in parturients. Occasionally, blood vessel injuries
occur during epidural catheter insertion [5–7]. The incidence
of injuries involving the epidural venous plexus on intravas-
cular (IV) epidural catheter insertion was between 1.3% and
15.7% for obstetric patients; the incidence was higher when the
puncture is performed with the patients in the sitting position
[2]. Furthermore, inadvertent epidural venous injuries may
lead to local anesthetic-induced cardio- or neurotoxicity, a
poor anesthetic effect, and even the occurrence of epidural
hematomas [8–10]. Therefore, it is important to make an effort
to prevent blood vessel injuries during obstetric epidural
anesthesia. As a result, it has been theorized that epinephrine
(5 μg/mL) in the epidural space may vasoconstrict the
epidural veins and possibly reduce the incidence of injuring
the epidural vascular plexus before insertion of the catheter.
We hypothesized that predistension of the epidural space
with epinephrine (5 μg/mL) would decrease the incidence of
epidural vein injuries.
2. Materials and methods
2.1. Ethics statement
The protocol was reviewed according to the Declaration
of Helsinki and approved by the Human Ethics Committee of
Nanjing Medical University on January 24, 2010. All study
participants gave written informed consent.
Between February 2010 and December 2011, after
obtaining the approval from the institutional research ethics
committee and informed consent, 400 parturients, American
Society of Anesthesiologists physical status class I or II, with
singleton cephalic presentations at full term who presented
for cesarean delivery conducted during epidural anesthesia
were enrolled in the current study. All women received
routine prenatal care, and epidural catheter placements were
performed after confirming the normal platelet counts and
coagulation assays. The exclusion criteria included bleeding
history or bleeding tendency; pregnancy-induced hypertension;
heart, lung, liver, and kidney diseases; preeclampsia; obesity
(body mass index N 35 kg/m2); history of alcohol or drug abuse,
or heavy smoking; and coagulopathies.
Parturients were randomly assigned into 2 groups (groups
E and N) using a computer-generated randomization list and
a sealed envelope technique. After receiving 10 mL/kg of
Ringer’s lactate solution intravenously, all of the parturients
underwent a lumbar epidural puncture with an 18G Tuohy
needle (SuJia Medical Device Co, ZheJiang, China) at the
L2-L3 intervertebral disk space using a midline approach
with the patients in the left lateral decubitus position.
After identification of the epidural space by loss of resistance
with 1 mL of isotonic sodium chloride solution and a
negative aspiration test for blood or cerebrospinal fluid, 5 mL
of isotonic sodium chloride solution containing epinephrine
(1:200,000) or 5 mL of isotonic sodium chloride solution
was injected into the epidural space of patients in groups E
and N, respectively, through the epidural needle (injection
speed = 1 mL/s) while the syringe plunger was held closed
for 20 seconds to ensure that the solution spread sufficiently
[5]. The isotonic sodium chloride solution or the solution
containing epinephrine (1:200,000) was prepared by an
independent investigator who was not involved in the study.
One minute thereafter [4], a polyamide multiorifice epidural
catheter (20 gauge × 90 cm; SuJia Medical Device Co,
ZheJiang, China) with 3 lateral ports at 0.5, 1.0, and 1.5 cm
from a closed distal tip was treaded 3 cm into the epidural space
through the cranially directed tip of the epidural needle. All of
the parturients were placed in the left-tilted supine position
until delivery after the catheter was fixed to the skin.
As an intrathecal test dose, 3 mL of 1.5% lidocaine was
injected. Five minutes later, if no signs of subarachnoid injection
were noticed, 5 mL of 0.75% ropivacaine was injected epidurally,
and another 5 mL was injected 5 minutes later, if necessary;
additional anesthetic was given to produce adequate anesthesia,
which was confirmed by the lack of a bilateral response to
pinprick at the T8 vertebral level. The injection speed for the local
anesthetic solution was 0.5 mL/s. Patients were maintained
hemodynamically stable by intravenous fluid expansion and
vasoactive drugs. All the injectates (with or without epinephrine)
were kept at room temperature (23°C ± 1°C).
The observation of the injures to the epidural vascular plexus
was performed by an independent anesthesiologist and consisted
of bloody fluid in the epidural needle or catheter during catheter
insertion, aspiration of frank blood from the epidural catheter, or
blood noted in the caudal end of the epidural catheter upon
removal. A 2-mL syringe was aspirated with the plunger
withdrawn to 0.5 mL for 20 seconds to provide a negative
pressure test following successful epidural catheter placement
for 3 cm. Intravascular placement was considered if the frank
blood was detected by aspiration. If IV placement occurred, the
catheter was withdrawn 1 cm and another 1 cm if IV persisted. If
this maneuver did not lead to withdrawal from the vein, the
catheter was removed and general anesthesia was given.
All of the participants underwent continuous epidural
anesthesia for the first time in the present study. General
anesthesia would be performed in case of either difficulties
during the puncturing procedure or epidural failures because
of a nonfunctional epidural catheter. All procedures were
performed by the same experienced anesthesiologist who has
engaged in obstetric anesthesia for more than 10 years.
2.2. Statistical analysis
Based on previous studies [5], to detect a reduction in
the incidence of IV catheter insertion from 10% to 3%, 140
epinephrine in epidural space and blood vessel injury
parturients per group were necessary to obtain a power of
90% (β = 0.10) with a 2-sided design at an α = 0.05. We
enrolled 400 patients (200/group) to allow for dropouts.
Data are presented as the mean ± SD. The patient variables
(including age, weight, gestation, duration of surgery, dose
of ropivacaine, IV infusion volume, and urinary volume)
were analyzed using a Student t test for independent samples.
Categorical data (the incidence of epidural venous plexus
injuries) were analyzed using the χ2 test or Fisher exact test. A
P b .05 was considered statistically significant.
All statistical processing was performed with SAS
statistical software (version 9.1; SAS Institute, Inc, Cary, NC).
3. Results
Five parturients were excluded from the analysis because
of difficulties during the epidural puncture, and 3 parturients
were excluded because of a nonfunctional epidural catheter.
Three hundred ninety-two participants completed the study
(Figure). There were no significant differences in baseline
demographic data between the groups (Table 1).
There was no significant difference between patients in
either group with respect to cases with bloody fluid in the
epidural needle during catheter insertion (15 vs 19, P = .44),
the epidural catheter during catheter placement (12 vs 13,
P = .80), aspiration of frank blood in the epidural catheter (2 vs 2,
P = .98), and blood noted in the caudal end of the epidural catheter
upon removal (54 vs 59, P = .49; Table 2).
There were no symptoms of a sudden increase in heart rate
of 10 beats per minute more than the baseline [4] because of the
effect of epidural space predistension with 5 mL of epinephrine
1:200,000 in group E. There were no intrathecal catheter
placements in either group.
4. Discussion
The epidural space is filled with soft connective tissue,
lymphatic vessels, adipose tissue, and an extensive venous
plexus. The walls of the blood vessels that form the venous
plexus are thin and easily injured by the epidural catheter
[11,12]. Many reports have shown that the epidural vascular
plexus can be injured more easily by epidural catheter
placement than the epidural puncture itself [4–6].
The appearance of bloody fluid immediately after catheter
placement suggests that epidural blood vessels are injured
[13]. Bloody fluid in the epidural needle suggests that
the injured veins are close to the epidural needle; however,
bloody fluid in the epidural catheter indicated that the injured
veins are situated a little further from the epidural needle. Frank
blood that is emitted spontaneously or by negative pressure
from the epidural catheter is suggestive that the catheter is
inserted directly into a vein. Blood noted in the caudal end of
9
the epidural catheter upon removal is an important indirect sign
of injury of the epidural venous plexus.
Epinephrine has been added to local anesthetic solutions
for greater than a century and was therefore considered to be
a “chemical tourniquet.” Extensive use of epinephrine attests
to the general safety of adjuvant epinephrine. We have a
modest understanding of the intended effects of epinephrine,
which include constriction of epidural vessels, prolonged
duration of the anesthetic block, a reduction in the plasma
concentration of local anesthetics, and intensification of the
anesthesia and analgesia [14,15]. Thus, epinephrine may
theoretically reduce the incidence of injuring the epidural
vascular plexus. In the current study, to avoid the effect
of the local anesthetic on the epidural blood vessels, we
focused on the addition of epinephrine at a concentration of
1:200,000 in isotonic sodium chloride solution and clarified
the independent effect of epinephrine (5 μg/mL) on the epidural
vascular plexus.
Research has shown that the pharmacologic effect of
epinephrine is dose related and linked to the affinity for
adrenergic receptors [16]. Low-dose epinephrine (1-2 μg/min)
stimulation of beta-2-adrenergic receptors results in arterial
vasodilation, moderate doses (2-10 μg/min) stimulate beta-2
and beta-1 receptors (increased myocardial contractility), and
high-dose epinephrine (N 10 μg/min) constricts the blood
vessels via stimulation of alpha-1 and venous alpha-2
receptors. In the current study, a total dose of 25 μg of
epinephrine (5 μg/mL) was a moderate dose; furthermore, only
a portion of the dose of epinephrine was absorbed into the
epidural vessels to produce cardiovascular effects rather than
vasoconstrictor effects by acting on beta-2 and beta-1
receptors, and the remaining dose of epinephrine only
produced an external effect, just as a topical administration.
In effect, epinephrine constricts epidural blood vessels mainly
by stimulating the alpha-1 adrenergic receptors in resistance
vessels, whereas the epidural space contains an extensive
venous plexus [17,18]. A previous study has proven the
existence of alpha-2 and beta adrenergic receptors, but no
alpha-1 adrenergic receptors are present in the vascular system
of the human spine [18]. Epinephrine (5 μg/mL), alone or in
combination with local anesthetics, did not produce significant
vasoconstriction [19–22]. In experiments with pigs (in which
the spinal vasculature resembles humans), Bernards et al [16]
demonstrated that epidural epinephrine had no effect on spinal
cord blood flow, implying that epinephrine had no vasocon-
strictive effects on epidural vasculature. An animal study
has shown that the small veins of the vascular plexus of
the epidural space revealed no significant narrowing in
blood vessel diameters after administration of epinephrine
(5 μg/mL), and epinephrine in concentrations up to 50 μg/mL
reduced the epidural venous diameter by less than 5% [22].
This may represent the main reason why preinjection of
the epidural space with isotonic sodium chloride solution
containing epinephrine was not superior to isotonic
sodium chloride solution alone, as evidenced by the
present research.
10 C. Han et al.

Enrolled n=400

5 Excluded for puncture difficulty

Randomized n=395

Group N (n=196) Group E (n=199)

Predistension of the Predistension of the epidural space
epidural space with 5 mL with 5 mL of isotonic sodium chloride
of isotonic sodium chloride solution containing epinephrine 5
solution mcg/mL

Excluded (n=2) due to a Excluded (n=1) due to a

nonfunctional epidural nonfunctional epidural
catheter catheter

194 participants 198 participants

completed study and completed study and
data were analyzed data were analyzed

Figure The flow diagram that delineates recruitment, enrollment, randomization, dropouts, and subjects analyzed in each group.

According to the study of Bernards et al [16], epidural and intensity as previously theorized, but not as a consequence
epinephrine reduces dural blood flow and the clearance of epidural venous plexus vasoconstriction. The addition
of local anesthetics from nonneural structures, such as of epinephrine, which increases the intensity of the sensory
epidural fat. Epinephrine-induced prolonged exposure to block during epidural anesthesia, was partially explained by an
local anesthetic contributes to increased anesthetic duration analgesic effect via epinephrine-induced alpha-2 adrenergic
stimulation at the spinal cord from small amounts of diffused
epinephrine [23]. The main purpose of adding epinephrine to
the epidural space is the quick determination of whether or not
Table 1 Patient baseline demographic and clinical
characteristics
Table 2 Incidence of epidural blood vessel injury
Characteristic Group E Group N t P
(n = 198) (n = 194) Parameter Group E Group N χ2 P
(n = 198) (n = 194)
Age (y) 28.6 ± 3.1 29.2 ± 3.5 1.79 .07
Weight (kg) 72.8 ± 5.1 71.9 ± 4.5 2.07 .06 Bloody fluid in epidural needle 15 (7.6) 19 (9.8) 0.61 .44
Gestation (wk) 38.8 ± 1.5 39.1 ± 1.6 1.91 .56 Bloody fluid in epidural catheter 12 (6.0) 13 (6.7) 0.07 .80
Operation duration (min) 46.2 ± 6.3 45.0 ± 7.2 1.75 .08 IV epidural catheter placement 2 (1.0) 2 (1.0) 0.00 .98
Dose of ropivacaine (mg) 118.5 ± 24.0 123.0 ± 25.0 1.82 .07 Blood noted in the caudal 54 (27.3) 59 (30.4) 0.47 .49
IV infusion volume (mL) 1290 ± 312 1250 ± 284 1.33 .18 end of the epidural catheter
Urinary volume (mL) 305 ± 95 325 ± 109 1.64 .10 upon removal
Data are expressed as the mean ± SD. Data presented as n (%).
No statistically significant differences between groups E and N (P N .05); No statistically significant difference was evident between groups E and
Student t test for independent samples. N (P N .05); χ2 test or Fisher exact test.
epinephrine in epidural space and blood vessel injury
the epidural catheter is erroneously inserted into veins [4,9];
however, it presents no superiority in preventing epidural
vascular plexus injury during catheter placement.
In conclusion, 25 μg of epinephrine (1:200,000) in the
epidural space does not reduce the incidence of blood vessel
injury induced by the insertion of an epidural catheter. It is
possible that larger doses of epinephrine may result in a
significant reduction in epidural vascular plexus injuries.
Additional research designed to elucidate the detailed
protection of epinephrine are needed.
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