The Prevention of Hypotension After Epidural Analgesia After Major Surgery by Adding Epinephrine to Infusions to Counteract Sympathectomy: a Double- Blind, Controlled, Randomized, Prospective Dose-finding Study
Phase: PHASE1
Conditions: Hypotension, Pain
Sponsor: University of Florida



 
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Protocol 
1. Project Title 
The prevention of hypotension after epidural analgesia after major surgery by adding 
epinephrine to infusions to counteract sympathectomy: a double- blind, controlled, 
randomized, prospective dose-finding study 
 
Date:  02/15/2016 
 
 
03/29/2016 
 
2. Investigator(s):  
 
Olga C. Nin, MD (Principle Investigator) 
 
Andre P. Boezaart, MD, PhD (Co-Investigator) 
 
Christopher Giordano, MD (Co-Investigator) 
 
Steven J. Hughes, MD (Co-Investigator) 
 
      Hari K Parvataneni, MD (Co-Investigator) 
 
Paul L Crispen (Co-Investigator) 
 
Keith Thompson, MD (Co-Investigator) 
 
Terrie Vasilopoulos, PhD (Co-Investigator) 
 
Anna Woods, RN (Study Coordinator) 
 
 
3. Abstract: 
 
Epidural analgesia via continuous epidurally infused local anesthetic agent (LA) is 
widely and very successfully used routinely for perioperative pain control in patients 
undergoing major orthopaedic and abdominal surgery since 19281 and also at the 
University of Florida (UF).  The routine practice of the UF Acute Pain Service (APS) is to 
use either ropivacaine 0.2% without any additives at a continuous infusion rate of 8 mL 
per hour and a patient-controlled bolus injection of 4 mL, which is locked out at 60 
minutes intervals, or the above with 5 mcg per mL of epinephrine added to the 
ropivacaine.  The choice currently depends on the preference of the APS physician in 
charge of the case.   A frequent unwanted side effect of epidural block is hypotension due 
to the epidurally injected LA blocking the sympathetic nerves and thus the patient’s 

 
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response to hypotension, which is usually due to hypovolemia and/or an unopposed 
parasympathetic (via the vagus nerve) nervous system. A sympathetic block, inhibits the 
cardiovascular system and the adrenal cortexes from responding appropriately by 
releasing catecholamines which normally mitigate hypotension from any cause. This 
sympathelytic blockade is exacerbated by an unopposed parasympathetic tone that 
decreases cardiac output by decreasing contractility and heart rate as well as leading to 
more vasodilatation.  
 
 
Epinephrine is a mixed alpha- and beta-adrenergic receptor agonist.  It has alpha 1 
and 2 as well as beta 1 and 2 agonistic properties.  It thus increases the total peripheral 
vascular resistance by arteriolar and venous vasoconstriction, which increases venous 
return to heart and thereby cardiac preload.  It also increases the inotropic, chronotropic 
and lusitropic qualities of the heart through its beta-1 effects, which lead to a greater 
cardiac output. And these same beta-1 agonist effects simultaneously increase spinal 
cord and cerebral blood flow.  
 
 
The addition of epinephrine to epidural solutions, which has been in use for many 
years, has been widely studied and found to be safe. For example, Niemi et al studied 
epidural solutions that either contained ropivacaine, fentanyl, with 2mcg/mL epinephrine 
or the same solution without the epinephrine. Niemi demonstrated that the solution with 
epinephrine added improved analgesia, reduced side effects, and facilitated earlier 
mobilization without adding any risk.2 
 
 
The aim of this study will be to study the hemodynamic effect(s) of adding epinephrine 
to the local anesthetic solution and to find its optimal concentration to counteract the 
sympathectomy. 
 
4.  Background: 
 
The beneficial role of epidural anesthesia in surgical practice has been well 
documented.  Apart from the humanitarian aspects of effectively treating pain and 
suffering, other advantages have been widely studied.  For example, in a large 

 
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retrospective meta-analysis in 2003, the benefits of epidural analgesia included reduced 
perioperative cardiac morbidity (~50%), pulmonary infections (~40%), pulmonary 
embolism (~50%), ileus (~2 days), acute renal failure (~30%), and blood loss (~30%).3 The 
Multicenter Australian Study of Epidural Anesthesia (MASTER) study was another 
landmark paper in which the authors showed a substantial benefit regarding improved 
analgesia, reduced respiratory failure, and with minimal risk adverse consequences.4 
Epidural analgesia has also been shown to increase gastric motility by blocking 
thoracolumbar sympathetic flow, reducing postoperative use of opiates and increasing 
gastrointestinal blood flow.5,6.  
 
A limiting factor in the use of epidural analgesia, however, is the high incidence of 
associated hypotension. Hypotension is defined as systolic blood pressure (SBP) > 20% 
below the baseline preoperative measurements and acquired before the epidural or any 
sedation has been administered.  Effective segmental epidural block would thus 
invariably cause sympathectomy due to its location in the thoracic or lumbar areas by 
blocking the cardiac sympathetic nerves, the pre-ganglionic nerves to the adrenal glands 
or the sympathetic nerves to the blood vessels individually or in combination. 
 
 
It has been proven beyond doubt that epinephrine, when added to ropivacaine 0.2% 
and used for epidural analgesia by infusion, is safe and may even improve spinal cord 
blood flow and the analgesic effects of ropivacaine.7 It is also known that the cause of 
hypotension associated with epidural analgesia is the blockade of the sympathetic outflow 
to the cardiovascular and adrenal systems, and that the ideal mechanism to counter this 
would be by beta1-stimulation, which is ideally achieved with low-dose epinephrine.   
 
 
Finally, it is known that epidural infused epinephrine increases its serum 
concentration.8 What is not known is whether added epinephrine will counteract this 
sympathetic blockade and prevent hypotension, and what the optimal concentration of 
epinephrine infusion would be during epidural analgesia with 0.2% ropivacaine to achieve 
optimal analgesia and optimal hemodynamic status.   
 
 

 
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5. Specific Aims: 
 
We aim to examine whether adding epinephrine will counteract the sympathetic 
blockade and prevent hypotension, and what the optimal concentration of epinephrine 
infusion would be during epidural analgesia with 0.2% ropivacaine that can achieve both 
optimal analgesia and optimal hemodynamics. Specifically we plan to answer the 
following questions: 
1. Does the addition of epinephrine to the epidural infusion of 0.2% ropivacaine: 
a. Prevent hypotension? 
b. Lead to a wider spread of local anesthetic effect? 
c. Lead to a difference in the average pain scores? 
d. Lead to a difference in when ambulation occurs? 
e. Decrease potential of other opioid-related side effects 
such as pruritus, nausea/vomiting, respiratory depression 
and opioid consumption? 
2. What is the optimal concentration of epinephrine (2mcg/mL or 5mcg/mL) to 
achieving the above-mentioned outcomes? 
 
 
 

 
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6. Research Plan: 
Activity 
Screen 
Pre-op (baseline) 
Pre-op after epidural, 
before bolus 
Pre-op after epidural, 
after bolus/before 
anesthesia 
Intra-op 
Post-op  Recovery 
(PACU) 
1 hour post-op 
Transfer to floor 
POD 1 
POD 2  
POD 3 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion Criteria 
X 
  
  
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
IV Placement 
  
X 
  
  
  
  
  
  
  
  
  
Primary 
measurements(SBP,DBP,MAP, 
HR,SaO2,RR,Pain score?) every 
3-5 min 
  
X 
X 
X 
X 
  
  
  
  
  
  
Epidural Placement 
  
X 
  
  
  
  
  
  
  
  
  
Administration of Pre-op sedation 
  
  
X 
  
  
  
  
  
  
  
  
Prep and supply of test drug 
  
  
X 
  
  
  
  
  
  
  
  
Infusion of Study drug if 
randomized for test group 
  
  
  
X 
  
  
  
  
  
  
  
Infusion of Ropivacaine 
  
  
  
X 
  
  
  
  
  
  
  
Primary measurements every 15 
min 
  
  
  
  
  
X 
X 
  
  
  
  
(Secondary measurements) 
Sensory block assessment (1 
hour post-op and every 6 hours 
for the subsequent 72 hours 
  
  
  
  
  
X 
X 
  
X 
X 
X 
Intra-op surgical records 
  
  
  
  
X 
  
  
  
  
  
  
Anesthesia Pain Service records 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pain Scores DVPRS Score 
  
  
  
  
  
  
X 
  
X 
X 
X 
Record 24 hour I/Os 
  
  
  
  
  
X 
  
  
X 
X 
X 
Pain management and "Rescue 
Drug" administration as needed 
  
  
  
  
  
  
X 
X 
X 
X 
X 
Record opioid usage 
  
  
  
  
  
X 
X 
X 
X 
X 
X 
All SOC points and monitors: 
EKG, non-invasive BP; ETCO2; 
pulse ox; arterial line with Flow 
Track (if indicated); peripheral or 
central venous line; induction and 
mode of anesthesia. 
  
X 
  
  
  
  
  
  
  
  
  
Physical therapy rehabilitation 
records (Time and distance of 
ambulation) 
  
  
  
  
  
  
  
  
X 
X 
X 
 

 
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Patients will be approached about their willingness to participate in this study 
either in a pre-operative surgical or anesthetic clinic visit or in the pre-operative area on 
the day of surgery. Consent will be obtained by a member of the research team. The 
patient will be given time to read the consent, have all study related questions 
answered, and discuss the study with their family, if desired. A copy of the signed 
consent will be placed in the patient’s physical chart, and a research progress note 
documenting study enrollment will be made in the patient’s electronic medical record.  
 
Inclusion criteria:  
Up to 250 patients between the ages of 18 and 80 years undergoing epidural 
analgesia to treat perioperative pain associated with major surgery will be approached 
for their willingness to participate in the study.  Patients undergoing major thoracic, 
abdominal, urological or orthopaedic surgery for whom thoracic or lumbar epidural block 
would be indicated and planned for intraoperative and postoperative analgesia as per 
the UF Acute Pain Service (APS) usual and routine practice will be included in this 
study. Our epidural failure rate is lower than 20% and our institution performs around 
100 epidurals a month.  If only a 1/3 of our patients agree to be part of our study we 
would have 24 study patients a month.  This would then mean that our study would take 
10 months to complete data collection.  
 
Exclusion criteria: 
Sepsis (febrile, above normal and upward trending white blood count, and/or 
positive cultures for systemic infection), patients with acute trauma, coagulopathy [INR 
>1.4, platelets < 100,000, and/or anticoagulation medication given out of UF APS 
adaptation of the American Society of Regional Anesthesiologists (ASRA) guidelines9 , 
preoperative hemodynamic instability, symptomatic coronary artery disease (angina 
etc.), patients from the ICU whose tracheas were intubated for any cause, patient 
refusal, pregnancy, allergies to medications in the protocol, and primary or secondary 
block failure.  
 
 
 

 
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Standard of Care - Preoperative Period:  
All patients will receive a standardized continuous epidural block at the 
appropriate level for the planned surgery by the APS physician staffing the block room 
that day. For the standardized continuous epidural block, placement will be confirmed 
with loss of resistance technique (LORA), wave form analysis or nerve stimulation.  .  
 
Patients will receive a bolus of 500 mL of 5% Albumin intravenous infusion as per 
the usual routine practice of the APS before the main bolus dose is injected. A 
preoperative level of block will be established that is appropriate for the surgery by 
injecting an appropriate volume of ropivacaine 0.5% or lidocaine 2% w/ epinephrine 
1:200,000 (5–10 mL) into the epidural space as per the usual practice of the APS. This 
will be done after the routine test dosing with 3 mL of 2% lidocaine and 1:200,000 
epinephrine, confirmed that intrathecal and intravascular markers are negative. If an 
insensate-to-cold area in the appropriate dermatomes cannot be established within 10 
minutes following a 5 to 10 mL (maximum 10 mL) injection of ropivacaine 0.5%, the 
epidural catheter will be removed and replaced. If this process is repeated and there 
was still no level, it will be annotated and the patient will be removed from the study, 
labeled as a primary block failure, and treated appropriately by the attending 
anesthesiologist by either repeating the epidural block placement a third time or using 
other appropriate perioperative analgesia.  
 
Research-Related Procedures - Preoperative Period:  
Once consent is obtained, patients will be randomly allocated by computer-
generated randomization to one of four groups.  This will be a quintuple blinded 
prospective study. The anesthesiologist managing the intraoperative anesthesia, the 
anesthesiologists (APS) placing the blocks and following the patients on the floors, the 
research nurse taking the measurement, the surgeons, nor the patients will be aware of 
what combination of drugs are used for the epidural block infusion.  
The three groups will consist of:  
1. Group A (Ropivacaine 0.2% infusion; Control group)  
2. Group B (Ropivacaine 0.2% + 2 mcg/mL epinephrine)  

 
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3. Group C (Ropivacaine 0.2% + 5 mcg/mL epinephrine)  
 
The pharmacists will make up and supply test drugs for groups A, B and C and 
provide them labeled to the block area drug dispenser as “A, B, or C test solutions” 
without specifically identifying the content. 
 
Immediately following the establishment of an appropriate level for the planned 
surgery, an infusion of the test drug will be initiated at 4 to 8 mL per hour with a 4- to 8-
mL patient-initiated bolus at a lockout interval of 1 hour – typically 8 mL per hour for 
major abdominal or thoracic surgery and thoracic epidural placement and 4 mL per hour 
for hip arthroplasty and lumbar epidural. Once established as effective for the clinical 
situation, this infusion will be left unchanged throughout the surgery and postoperative 
period. If clinically indicated, and the infusion rate is changed above these limits, the 
patient will be removed from the study. If the infusion is changed to below the limits of 4 
– 8 mL per hour, this indicates the end of the need for the epidural infusion or otherwise 
untreatable hypotension.  
 
Standard of Care - Intraoperative and Postoperative Periods:  
Intraoperative and postoperative fluid management will be at the discretion of the 
anesthesia and primary teams.  
 
Preoperative sedation will be a maximum of 5 mg of midazolam by intravenous 
injection (IV) and alfentanil 2000 mcg IV. Monitors include: EKG, non-invasive blood 
pressure, ETCO2, pulse oximeter, arterial line with Flow-Track (if indicated and 
appropriate per intra- or postoperative operative anesthesiologist), peripheral 
intravenous or central venous line as deemed appropriate by the attending intra- or 
postoperative operative anesthesiologist. Induction of anesthesia and mode of 
anesthesia (maintenance, fluid management, intraoperative analgesia, muscle 
relaxation, etc., are at the discretion of the attending intraoperative anesthesiologists.  
 

 
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If hypotension (see definition below) is encountered intraoperatively, the 
attending anesthesiologist will start a vasoactive or positive inotropic medication as 
indicated by the patient’s medical requirements.  
 
Research-Related Procedures – Intraoperative:   
 Anesthesiologists will be encouraged to use alpha agonists if the other causes of 
hypotension are excluded and lumbar epidural is judged to be a contributory 
cause of the hypotension; and epinephrine, dobutamine, or dopamine (or indirect 
inotropic agents such as ephedrine) if thoracic epidural is judged to be the cause 
of the hypotension and the other causes of hypotension such as hypovolemia 
have been ruled out.  
 The epidural infusion will be continued intraoperatively at a rate 4 to 8 mL per 
hour. Emergence medications will be administered and recorded as judged 
appropriate by the intraoperative anesthesiologist. A bolus of 5 mL of ropivacaine 
0.5% without additives may be administered through the epidural catheter at the 
conclusion of the intraoperative phase by the intraoperative anesthesiologist or 
APS anesthesiologist in the recovery room, if required.  
 “Rescue” drugs as outlined below will be administered and recorded if deemed 
necessary. If, after sensation level testing, the epidural block was not 
appropriately covering the area of surgery, a further bolus of 5 mL of 0.5% 
ropivacaine will be injected by the APS physician and if this was still not 
managing the pain, this will be noted and the patient will be removed from the 
study. If judged appropriate by the APS physician, the epidural will either be 
replaced in the recovery area or the “rescue” medication described below will be 
initiated.  
 Hypotension is defined as SBP > 20% below the baseline in the block room area 
before the epidural or sedation for the epidural was administered or an MAP less 
than 55 mmHg. Epidurals will be turned down or turned off if the treating 
Intensive Care Primary Physician declared it an emergency, if the patient had 
hemodynamic instability stemming from other causes that was complicated by 
the sympathetic block of the epidural, or significant hypotension, or mean MAP < 

 
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30%, from baseline and other causes such as hypovolemia had been corrected. 
If this is the case, the patient will be removed from the study. 
 
Research-Related Procedures - Postoperative Periods:   
If additional pain management or “rescue” analgesics are needed, for example, from 
outside the area covered by the epidural; subjects may receive any of the following: 
 Acetaminophen (Tylenol) 1000 mg scheduled intravenously every 8 hours for the 
first 48 hours and, after oral intake is restarted, it will be changed to 1 gram every 
6 hours by mouth (patients with liver disease will be excluded if appropriate and 
after discussion with the hepatic surgeon) 
 Ketorolac Tromethamine (Toradol) 30 to 60 mg every 6 hours intravenously 
 Celecoxib (Celebrex) 100 mg per mouth every 12 hours 
 Oxycodone 5 to 10 mg per mouth every 4 hours as needed 
 Intravenous hydromorphone (Dilaudid) patient-controlled analgesia (PCA) as per 
APS routine protocol appropriate for age and body habitus of the patient. 
 
Primary measurements:  
Include the average invasively or non-invasively measured SBP, diastolic blood 
pressure (DBP), MAP, arterial blood oxygen saturation (SaO2), heart rate, respiratory 
rate, and pain by the visual analog pain score (VAS) on the “Defense and Veterans Pain 
Rating Scale” (DVPRS) measured over the following set periods:  
Preoperative period 
Primary measurements every 3 to 5 minutes and at indicated time points: 
I. 
Before the bolus epidural is injected. 
II. 
After the epidural bolus is injected but before anesthesia is induced.  
Intraoperative period 
Primary measurements every 3 to 5 minutes 
Postoperative period 
I. 
Primary measurements in the recovery room (if appropriate) every 15 
minutes 

 
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II. 
Primary measurements following transfer to the floor every 4-6 hours if 
within normal limits, but every hour if needed for closer observation in 
case of possible abnormality for as long as the epidural analgesic blocks 
are continued, but at least every 8 hours after discharge from the PACU. 
 
Secondary measurements:  
III. 
Spread of block per spinal root segment as tested by sensitivity to cold 
recorded every hour postoperatively and every 8 hours for the subsequent 
72 hours after discharge from the PACU. 
IV. 
Ambulation on the first day after surgery (POD 1), POD 2 and 3, will be 
recorded per physical therapy protocol and distance ambulated per 24-
hour period will also be recorded.  Physical Therapy information will be 
gathered to test motor effect on lumbar epidurals. 
V. 
Opioid usage data will be recorded and converted to morphine equivalents 
and averaged for POD 0, 1, 2, and 3 per group.  
VI. 
Side effects such as pruritus, nausea/vomiting, and respiratory depression 
(defined as respiratory rate less than 10 breaths per minute of oxygen 
saturation more than 7 points lower that the patients preoperative value on 
room air) will be recorded and managed as deemed appropriate by the 
attending physician. 
VII. 
24 hour I/O for the first 72 hours to assess fluid balance, length of stay, 
and amount of days before return to PO status. 
Data analysis plan 
 
All data will be entered securely using the online database or Red Cap.  To 
assess potential dose-response effects on changes in continuously measured primary 
outcomes, repeated measures mixed modeling analyses will be used. This type of 
analysis can assess the main effects of time (i.e., change) and group (i.e., epinephrine 
dose; coded as an ordinal variable) on the outcomes. Mixed models are the preferred 
approach to analyze data with repeated measures; these models can account for 

 
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correlation among repeated measurements, flexible time effects, and can handle 
missing data. Additionally, this model can estimate time × group interactions. If this 
interaction is statistically significant, that provides evidence that the changes in 
outcomes are different depending on the dose of epinephrine that a patient received.  
Logistic regression models will be used to assess the relationship between epinephrine 
dose and incidence of hypotension (SBP < 20% or MAP < 55 mmHg) and other 
categorical outcome variables. A P value of <0.05 was considered statistically 
significant for all statistical tests.  All analyses were conducted in JMP Pro 11.0 (SAS 
Institute, Cary, NC).   
 
    Sample size determination 
At 80% power (alpha = 0.05), a sample of n=200 (50 per group) will be able to 
detect 26% differences in incidence of categorical outcomes, and an effect size of 
Cohen’s f = 0.24 for group mean differences and effect size of Cohen’s f = 0.09 for 
group differences mean change over time. Figure 1 depicts how these effect sizes will 
translate to the outcomes, with assumed standard deviations in outcomes ranging from 
5 to 25. For example, assuming MAP has an SD = 10, the present study will be able to 
detect mean differences of 5 mmHg across groups and group differences of 3 mmHg for 
mean change over time. 
 

 
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ADMINISTRATIVE RESPONSIBILITIES:  
 
Study Resources:  The principal investigator will oversee the data collection, data 
analysis and will maintain the records in confidence. Should any evidence suggest that 
the study protocol require modification, the PI will notify the IRB in a timely manner for 
review and approval. Each subject will be identified by number, not by name, on all data 
forms. To protect confidentiality, all data will be numerically coded and information linking 
the numeric codes to individual participant’s names will be kept in a locked file in the PI’s 
office. 
 
7. Possible Discomforts and Risks:  
 
Regional anesthesia - The risks of regional anesthesia include, but are not limited to 
low blood pressure, allergic reaction to drugs, obstruction or cessation of breathing, 
headache, paralysis, nerve injury, bleeding, blood clots, infection or meningitis, falls after 
surgery, drug reactions (including rash, shock, and cardiac/respiratory arrest), stroke or 
brain injury, heart failure or heart attack, and death. 
0
2
4
6
8
10
12
14
5
10
15
20
25
Group differences in outcomes 
SD
Group mean differences (Cohen’s f = 0.24)
Group differences mean change (Cohen’s f = 0.09)

 
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The epidural would be immediately turned off if the patient were to have unwanted 
side effects such as uncontrolled increase in heart rate or blood pressure, arrhythmias, 
anxiety, or unwanted clinical symptoms that could be attributed to the epinephrine dose in 
the epidural.  The pharmacy would immediately be contacted to determine the 
epinephrine dose in the patient’s epidural so that clinical treatment be tailored 
appropriately. 
 
 
The PI will oversee the data collection, data analysis, and will maintain the records in 
confidence. The data collected will be stored in a secure, password protected database 
with strong encryption, on a computer server, accessible only by the study team. Any 
additional digital data files from the study will be de-identified and stored on a password 
protected laptop computer. Hence, encryption will be required. All paper records will be 
stored in locked file cabinet in the PI’s locked office.  The patient consent forms will be the 
only documentation with PHI.  The results collected and calculated by the laptop software 
will be non-PHI data including the patient demographics, administration amounts of 
drugs, the time of those administrations, and the post-operative times to emergence and 
the occurrence of respiratory depression. 
 
8. Possible Benefits: 
 
It has been proven beyond doubt that epinephrine, when added to ropivacaine 0.2% 
and used for epidural analgesia by infusion, is safe and may even improve spinal cord 
blood flow and the analgesic effects of ropivacaine.7   Because of this, the possible 
benefit to the participant is to improve the effects of the epidural anesthesia and to reduce 
the possible sympathetic side effects. 
 
9. Conflict of Interest: 
None of the investigators have a conflict of interest. 
 
 

 
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References  
1) Oschner A, Gage, IM, Cutting RA.  Treatment of Ileus by Splanchnic Anesthesia.  
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produced by a small-dose infusion of ropivacaine, fentanyl, and epinephrine after major 
thoracic or abdominal surgery: a randomized, double-blinded crossover study with and 
without epinephrine. Anesth Analg 2002;94:1598-1605. 
3) Moraca RJ, Sheldon DG, Thirlby RC. The role of epidural anesthesia and analgesia 
in surgical practice. Ann Surg 2003;238:663-673.  
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12) Ezhevskaya AA. Effects of continuous epidural anesthesia and postoperative 
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