A Prospective Triple-masked Randomized Controlled Trial Measuring Analgesia Duration of Dexamethasone, Buprenorphine, or Clonidine With Ropivacaine for Interscalene Nerve Block
Phase: PHASE4
Conditions: Anesthesia, Local
Sponsor: Melinda Seering

A Prospective Triple-Masked Randomized Controlled Trial of Analgesia Duration of  
Local Anesthetic Adjuvants in Interscalene Nerve Block 
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A PROSPECTIVE TRIPLE-MASKED RANDOMIZED 
CONTROLLED TRIAL MEASURING ANALGESIA 
DURATION OF DEXAMETHASONE, BUPRENORPHINE, OR 
CLONIDINE WITH ROPIVACAINE FOR INTERSCALENE 
NERVE BLOCK 
 
STUDY PROTOCOL 
 
1) Protocol Title:  A prospective triple-masked randomized controlled trial measuring 
duration of buprenorphine, dexamethasone, clonidine with ropivacaine for 
interscalene block 
2) Protocol Version:  2.0 
3) Protocol Initiated:  June 18th, 2012 
4) Protocol Revision Date:   
5) Protocol Completed Date:  pending 
6) Principal Investigator: Mindy Seering, MD 
7) Research Team: Michael Todd, MD; John Laur, MD, MS; Julie Weeks, MPT; 
Pamela Jacobs, RN; Emine Bayman, Ph.D.; All research team members must be IRB 
certified. 
8) Study Design:  This is a prospective randomized controlled triple-masked study 
looking at the duration of nerve block analgesia when using the listed adjuvants plus 
ropivacaine versus plain ropivacaine alone. 
9) Questions:   
a) When providing a interscalene nerve block (ISB) for painful shoulder surgery 
using the following four regimens: 
i)  0.75% plain ropivacaine. The reference comparator. 
ii) 
A mixture of 0.75% ropivacaine with 300 mcg buprenorphine 
iii) 
A mixture of 0.75% ropivacaine with 0.1 mcg/kg clonidine  
iv) 
A mixture of 0.75% ropivacaine with and 8mg dexamethasone  
b) Compared to 0.75% plain ropivacaine, will the adjuvant mixture: 
i)  Increase block analgesic duration? 
(Defined as elapsed times from block-needle withdrawal until patient-reported time that they were 
first aware of painful sensation in the operated region of the limb.) 
  
10) Hypothesis: 

A Prospective Triple-Masked Randomized Controlled Trial of Analgesia Duration of  
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a) Null Hypothesis: Compared to plain ropivacaine, the adjuvant mixture:  
i) Will not increase the nerve block analgesic duration time by 25% or more. 
b) Alternate Hypothesis: Compared to plain ropivacaine, the adjuvant mixture: 
i) Will increase the nerve block analgesic duration time by 25% or more. 
11) Primary Outcome:   
a) Our primary outcome is the time from nerve block-needle withdrawal to return of:  
 
i) 
Painful perception in the operated upon area of the limb. 
 
b) Block Quality: Achieving an inability to sense cold ice-water in the cutaneous 
distribution of the brachial plexus trunk distal to the block within 30 minutes will 
be considered a successful nerve block preoperatively.  If the patient has an 
inability to sense cold ice-water in the cutaneous distribution of the brachial 
plexus trunk distal to the block within 30 minutes will be considered a successful 
nerve block postoperatively. Anything less will be considered a failed nerve 
block. 
 
12) Secondary Outcomes:   
i) 
Return of sensory function in the blocked area of the limb. 
ii) 
Return of motor function in the blocked area of the limb. 
iii) 
Post-op Nausea and vomiting before discharge 
iv) 
Nausea and Vomiting after discharge 
v) 
Changes in Blood Pressure (BP) in the PACU defined as any blood 
pressure +/- 20% of patient’s baseline (either BP on admission if no clinic 
BP is documented, or most recent clinic BP as documented if that exists) 
vi) 
Changes in Blood Pressure in Second Stage defined as any blood pressure 
+/- 20% of patient’s baseline (either BP on admission if no clinic BP is 
documented, or most recent clinic BP as documented if that exists) 
 
 
Motor Block Scale Table 
 
Scale 
 
Muscle function level 
 
Grade 
 
Percent of normal 
No evidence of contractility 
0 
0 % 
Slight contractility, no 
movement 
1 
10 % 
Full range of motion with 
gravity eliminated 
2 
25 % 
Full range of motion against 
gravity 
3 
50 % 
Full range of motion against 
gravity, some resistance 
4 
75 % 
Full range of motion against 5 
100 % 

A Prospective Triple-Masked Randomized Controlled Trial of Analgesia Duration of  
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gravity, full resistance 
 
Definitions: 
a) Duration of Analgesic Block 
i) 
Time from nerve block-needle withdrawal until the time reported by the 
patient that they first had awareness of painful sensation returning 
anywhere in the surgically operated upon area of the limb. 
ii) 
Patient will be given a form to write time down as it occurs. 
iii) 
They are expected to write down the date and time (hour and minute) they 
first perceive pain in the arm anywhere in the surgical area. (even if they 
wake up from sleep and first notice pain there).   
iv) 
They will be telephoned within three days from the block to gather the 
data from the patient.  
v) 
If they cannot find the form or did not write the date and time down, we 
will then use the date and time the patient recalls from memory.  
 
a) Duration of Sensory Block 
i) 
Time from nerve block-needle withdrawal until the time reported by the 
patient that they first had awareness of tactile (light touch) sensation 
returning anywhere in the blocked area. Patients will be given a form to 
write time down as it occurs. They are expected to write down the date 
and time (hour and minute) they first felt sensation return to the blocked 
area (even if they wake up from sleep and first notice sensation returned).  
ii) 
They will be telephoned within three days from the block to gather the 
data from the patient.  
iii) 
If they cannot find the form or did not write the date and time down, we 
will then use the date and time the patient recalls from memory.  
 
a) Approximate Duration of Motor Block 
i) 
Time from nerve block-needle withdrawal until the time reported by the 
patient that, with the arm of the blocked extremity, they are able to flex 
their bicep.  Patient will be given a form with a diagram and instruct them 
prior to sedation and placing the block. They will write the time down 
when they are able to achieve this outcome. They are to write down the 
date and time (hour and minute) they were first able to flex their bicep on 
the blocked limb.   
ii) 
They will be telephoned within three days to gather the time from the 
form. 
iii) 
If they cannot find the form or did not write the data down, we will then 
use the time the patient recalls from memory.  
 
a) Patient Satisfaction with the block 
i) 
Patients will be asked the question: “Would you want a nerve block again 
if you needed a similar surgery in the future?”    Yes  /  No 
 

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Secondary Outcomes Table 
 
Did patient have nausea before discharge 
Yes 
No 
 
Did patient have vomiting before discharge 
Yes 
No 
 
Did patient have nausea after discharge (72 hours) 
Yes 
No 
 
Did patient have vomiting after discharge (72 hours) 
Yes 
No 
 
Did the patient have +/- 20% deviation of baseline Blood 
pressure in PACU from admission 
Yes 
No 
 
Did the patient have +/- 20% deviation of baseline Blood 
pressure in Second Stage Recovery from admission 
Yes 
No 
 
2) Study Background Information:   
Regional anesthesia in the ambulatory surgery center venue has been shown to decrease 
unwanted side effects of anesthesia and improve patient satisfaction with their operative 
care.  Clinicians often seek ways to increase the duration of peripheral nerve blocks(1, 2) 
for outpatient surgery.  This may enhance patient satisfaction and make for fewer 
unwanted post-operative side effects from anesthesia such as nausea and vomiting.  One 
way to prolong regional anesthesia for patients is to send them home with a peripheral 
nerve catheter. (3-6) However, there can be multiple interventions associated with these.  
Catheter adverse conditions include infection, local anesthetic toxicity, catheter failure or 
dislodgement, infusion leakage, difficulty for the patient to remove their own catheter, 
and inadequate access to medical resources(7-9). 
 
Adding adjuvants to local anesthetics has been a principle for some time.  
Anesthesiologists have been adding epinephrine to spinal Marcaine to extend the spinal 
duration for years.  Candido and Franco both added buprenorphine to upper extremity 
blocks and received triple the pain relief duration from their nerve blocks(10, 11).  In 
addition Candido also added buprenorphine to a sciatic nerve block and received and 
additional 6 hours of pain relief(12).  Cummings (13)of the Cleveland Clinic studied 
dexamethasone added to interscalene blocks and showed it added twice as much 
analgesic duration to the nerve block(14-16).  Kim and Movafegh also studied adding 
decadron to local anesthetics and showed prolongation of sensory and motor block (16-
17).  Casati’s research showed that adding Clonidine to Ropivacaine extended his sciatic 
femoral nerve block extended his pain relief for 3 hours(17-19).  Although neither three 
adjuvant is FDA approved for perineural applications, they have been used in many 
studies without any detriment to patients(20).  Dr. Brian Williams, of the University of 

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Pittsburg has extensiveky studied these adjuvants on a laboratory level and has not shown 
any neural toxicity with these adjuvant additions(21, 22).  Steroids have also been used in 
epidural injections for years without problems.  Dexamethasone has even been used (23).  
Clonidine has been studied for epidural and intrathecal applications(24-26).  It is FDA 
approved for used in epidural with chronic pain patients.  Currently, we are using 
clonidine at the University of Iowa Hospitals and Clinics in our Acute Pain Service.  We 
have it in our epidural solution for pediatric patients.  Buprenorphine has also been 
studied for use intrathecally without problems(27).  There is a study by an oral surgery 
department showing its safety and efficacy when added to oral nerve blocks(28).   
Study Methods:   
This study will be performed in the Ambulatory Surgery Center at the University of 
Iowa.  All included patients will be undergoing orthopedic surgery on their shoulder for a 
surgery on the shoulder girdle, excluding the scapula.  All regional blocks will be 
performed or directly observed and guided by the listed investigators.  Blocks will be 
done using the interscalene approach to the brachial plexus.  All the injections will be 
placed using simultaneous ultrasound guidance and a nerve stimulator technique with a 
previously published compressed air injection technique to limit injection pressure.(29, 
30)  
 
Per previous protocols involving anesthesia studies at University of Iowa Hospitals and 
Clinics (UIHC), those patients who are eligible will be given information on the day of 
surgery.  A nurse not involved with the study will give the patient a card briefly 
informing the patient that they are eligible for a nerve block study.  If the patient 
indicates their consent to hear more and possibly enroll in the study, a representative 
from the investigating team will then meet with the patient to explain the study and 
obtain informed consent.   
 
An offer of regional anesthesia with or without intravenous sedation or general anesthesia 
will be provided to all patients regardless of their decision to participate or not.  The 
techniques, practices, medications and use of ice-water to test blocks described in this 
protocol are currently used in common practice.  
 
3) Inclusion Criteria:   
Patients who have or are: 
a) Orthopedics service patients having shoulder surgery 
b) ASA class I, II, or III. 
c) Patients at least 18 years old but less than 71 years old. 
d) Patients giving informed consent. 
 
2) Exclusion Criteria:   
Patients who have or are: 
a) An inability to cooperate during the block placement. 
b) Any neuropathy 
c) Diabetes 
d) Documented kidney disease 
e) Documented Hepatic disease 

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f) A lack of or inability to give informed consent. 
g) Currently incarcerated. 
h) Pregnancy 
 
 

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3) Consent:   
a) The study will be explained to the patient’s satisfaction, their questions will be 
answered, and informed consent will be obtained from the patient after 
explanation of the risks, benefits, and alternatives. 
b)  Once the patient has consented to the study, they will be included in the study 
and followed throughout. 
c) Patients with failed blocks will be included in the intention to treat analysis. 
d) If the block is unable to be placed due to infection at the site, poor visualization of 
structures with the ultrasound, inability to obtain study drugs within a reasonable 
time frame, or unexpected operator difficulty in placing the block, the patient will 
not be included in the intention to treat analysis and dropped from the study. 
 
4) Randomization:   
a) A computerized random number generator will be used by a staff of the 
Anesthesia Department not involved with the study. They will create a 
randomized numbered sequence with four groups (A, B, C or D) that will be 
given to the pharmacy team. This will be used to fill study syringes in the 
sequence according to the randomization schema.  
b) The UIHC Pharmacy will compound the study drugs and will fill and label the 
coded study syringes. 
c) Coded study syringes must be created and delivered within 30 minutes of the 
physician’s request. 
d) The Pharmacy will keep a record of which patient received each coded syringe 
and the solution they contained. 
e) They will be given to the practitioner at the time of block placement.   
f) Practitioners will perform the block using the pharmacy coded study drug.  
 
5) Masking: 
a) Masking will be accomplished by using coded labels on the study mixtures. 
b) At the end of the study enrollment, information given to the statistical analyst will 
be blindly coded as groups A, B, C or D for data analysis.   
c) The Pharmacy will keep the group codes until after data analysis is complete.  
d) The anesthesiologist and nurse assistants will be masked to the study mixtures. 
e) Any assisting anesthesia Staff, Fellows, Residents, CRNAs, SRNAs, or medical 
students will be masked to the study mixtures. 
f) Patients will be masked to the study mixtures. 
g) Any person collecting and/or scribing the data will be masked to the study 
mixtures. 
h) Any person analyzing the data will be masked to the study mixtures. 
i) Once all the data has been collected and analyzed according to group code, the 
blinding on the study mixtures can be broken and the codes for the study mixtures 
made known. 
j) Safety monitors will not be masked to the mixtures.  They can communicate with 
the pharmacy to unmask the mixtures for only themselves.  They will not report 
the mixtures or pharmacy codes to anyone except for patient safety purposes. 

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k) The coded sample syringes will be kept for reanalysis in case there is any question 
of what mixture was given to any patient.  The syringe contents can be tested by 
the pharmacy and a group code for that patient or set of patients will then be given 
to the analyst.  The masking will remain intact. 
 
6)  Study Mixtures 
a) The local anesthetic study mixtures volumes will be the same (32mL) and 
contained in two thirty-milliliter syringes with 16 mL in each. They consist of: 
i) 
0.75% Ropivacaine x 30mL (225 mg max dose) + 2 mL saline for a total 
volume of 32 mL 
ii) 
0.75% Ropivacaine x 30mL (225 mg max dose) with 300 mcg 
buprenorphine (1 mL) + 1 mL sterile saline for a total volume of 32 mL 
iii) 
0.75% Ropivacaine x 30mL (225 mg max dose) with 100 mcg/kg 
clonidine (0.1 mL) + 1.9 mL sterile saline for a total volume of 32 mL 
iv) 
0.75% Ropivacaine x 30mL (225 mg max dose) with 8mg dexamethasone 
(2 mL) + 0 mL sterile saline for a total volume of 32 mL. 
v) 
Note: If drug shortages occur during the study and we are unable to use 
the same concentration of any additive drugs (e.g. dexamethasone 
10mg/mL instead of 4mg/mL), then a substitution will be allowed and the 
total volume in the syringe will be changed so that all syringes will be the 
same volume and final ropivacaine drug mass.   
 
7) Techniques:   
All the blocks will be performed: 
a) Either by, or under the direct supervision and direction of the Primary Investigator 
or regional anesthesia faculty listed on the investigation team. 
b) In the Ambulatory Surgery Center at the University of Iowa Hospitals and Clinics 
using the posterior approach to the brachial plexus at the trunk level.  
c) A timeout will be performed before the block to verify the patient, site of surgery 
and that we are blocking the correct side (already marked). 
d) Using sterile technique, cleaning the skin with tinted chlorhexidine and with the 
operators wearing caps, masks, and sterile gloves.  The ultrasound probe will have 
a sterile sheath over it. Sterile ultrasound gel will be used. 
e) With ultrasound guidance and nerve stimulator from 0.2 mA to 2.0 mA using a 
sterile Arrow 90mm insulated stimulation needle (StimuQuick). 
f) If we are unable to stimulate the brachial plexus at the trunk level with the nerve 
stimulator, we will place local anesthetic in the region where the brachial plexus 
nerves are visualized using ultrasound based on the practitioner’s experience with 
ultrasound-guided interscalene (brachial plexus trunks) nerve blocks.  
g) Block start and end times will be recorded. Start time begins at block needle 
insertion. Stop time is the time of nerve block-needle withdrawal. 
h) All patients will be monitored with blood pressure, pulse oximetry, ECG and have 
2 liters per minute of oxygen administered by nasal cannula. 
i) Emergency resuscitation equipment, intralipid, and emergency medications are 
present and immediately available for patient safety.  

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j) Anesthesiologists will be present and/or immediately available should 
resuscitation efforts be necessary in the unlikely event of drug toxicity, cardiac 
arrest, or other adverse event. 
k) Any adverse outcomes (listed in “stopping rules” #23 below) will be reported to 
the Safety Monitors on the day it happens. 
l) The use of rescue blocks in the PACU will be counted and analyzed. 
 
8) Statistics  
a) For our primary outcome, we will use ANOVA or Kruskall-Wallis test, after 
checking the normality of the data, to compare the duration of the analgesic block.  
If we find a difference among all 4 groups, we will use 2-sample t-test or Mann-
Whitney U-test to explore differences between the individual groups.  
b) For our continuously distributed secondary outcomes, given that outcomes will 
be observed on every patient, we will use ANOVA or Kruskall-Wallis test. For 
outcomes with categories (nausea and vomiting and blood pressure), we will use 
the chi-square test.  Similarly, we will explore the different group or groups using 
chi-square test or Fisher’s Exact test.  
c) We based our estimates upon Cumming’s, Candido’s and Casati’s previous 
studies and our clinical experience.  We have estimated the expected additional 
analgesic time between the three groups.  
d) Using the above parameters, a sample size is 40 per group with 4 total groups 
calculates to a sum of 160 subjects while using 90% power and 0.05 type I error 
rate.  
 
9) Safety Monitoring:  
a) An Anesthesiology Faculty member who is not involved in the study will act as 
safety monitor and will review the data and any complications when half of the 
patients (n = 80) have been completed.  
 
10) Stopping Rules:   
a) Any incidence of patient complications that occur with an incidence higher than 
published data for the following complications for peripheral nerve blocks will be 
enough cause for the Safety Monitors to stop the study(31, 32). Numbers in 
parentheses below are the highest incidence reported in the referenced article for 
peripheral nerve block complications.  The highest incidence of complications 
was reported to be from the supraclavicular block, which we will not be 
performing.  We are relying on results reported from our own regional anesthesia 
follow-up clinic.  This is a clinic developed here to see patients with troublesome 
complications of peripheral nerve blocks.  The complication rates have been 
reviewed and studied since the clinic inception over 4 years ago(33). We are 
erring on the side of caution by using higher complication rates of the 
supraclavicular adverse event reports. 
 
b)  Published Peripheral Nerve Block Complication rates: 
i) 
Seizure (26.3/10,000)  
ii) 
Cardiac arrest (Code Blue)  (15.9/10,000) 

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iii) 
Respiratory Failure  (15.9/10,000) 
iv) 
Peripheral neuropathy  (32/10,000) 
v) 
Patient death  (15.9/10,000) 
 
 

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