Clinical trial NCT03549234
Conditions: Breast Surgery
Keywords: Regional anesthesia Paravertebral Erector spinae Nerve block
Sponsor: University of California, San Diego
Start date: 2018-07-12; Completion date: 2019-05-08
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Following painful surgical procedures of the breast, postoperative analgesia is often provided with a paravertebral nerve block (PVB). For intense, but shorter-duration acute pain, a single-injection of local anesthetic is used with a duration of approximately 12 hours. The PVB has several limitations: it can decrease blood pressure, and very rare-but serious-complications have occurred, including neuraxial injection, neuraxial hematoma, and pleural puncture. An alternative block has been described: the erector spinae plane block. The theoretical benefits include ease of administration since it is a plane superficial to the PVB and therefore easier to identify and target with ultrasound (therefore increasing success rate); and an increased safety margin: there are few anatomic structures in the immediate area which could be injured with the needle; and, the target plane is much further from the intrathecal/epidural space relative to the PVB. Lastly, the plane may be easier to catheterize for continuous peripheral nerve blocks relative to the relatively-small volume PVB.

There are therefore multiple theoretical reasons to prefer the erector spinae plane block. Unfortunately, it remains unknown if the analgesia provided by this new technique is comparable to that provided with the PVB. The investigators therefore propose to compare these two techniques with a randomized, subject-masked, active-controlled, parallel-arm, human subjects clinical trial.

Detailed description:
This investigation will be a randomized, subject-masked, active-controlled parallel-arm, human subjects clinical trial. Of note, the investigators will be using standard-of-care local anesthetic under an FDA-approved purpose and do not plan to research a possible change of indication or use of these medications as part of this research project. The treatments in both groups are currently used at the study institution and there is true clinical equipoise at this time. The only difference in treatment between subjects who enroll versus those not enrolled in this study will be those who enroll will have the decision between which anatomic block location determined randomly, as opposed to the physician simply choosing him/herself.

Enrollment. Consenting adults undergoing breast surgery with a planned single-injection regional analgesic will be offered enrollment. Patients undergoing breast surgery with a planned perineural catheter regional analgesic will be excluded. Study inclusion will be proposed to eligible patients prior to surgery. If a patient desires study participation, written, informed consent will be obtained using a current University of California San Diego (UCSD) Institutional Review Board (IRB)-approved Informed Consent Form (ICF). Selection for inclusion will not be based on gender, race, or socioeconomic status. The study population of interest includes men and women of all races and socioeconomic status. Inclusion and exclusion criteria are listed in another section.

Preoperative Procedures. Following written, informed consent, the investigators will collect baseline anthropomorphic information (e.g., age, sex, height, and weight). All subjects will have a peripheral intravenous (IV) catheter inserted, standard noninvasive monitors applied, supplemental oxygen administered via a nasal cannula or face mask, and placed in the sitting position. Midazolam and fentanyl (IV) will be titrated for patient comfort, while ensuring that patients remain responsive to verbal cues. Both possible block locations will be viewed with ultrasound. If one or both of the locations is unacceptable for block placement in the clinician's opinion, the subject will not be randomized and will not proceed further with the study.

Subjects will then be randomized using a computer-generated list and opaque, sealed envelopes to one of two treatment groups: (blocks of 4, stratified for unilateral vs. bilateral surgery): (1) erector spinae plane or (2) paravertebral block. All blocks will be placed by a regional anesthesia fellow or resident under the direct supervision and guidance of a regional anesthesia attending (or by the attending him/herself).

The area of needle insertion will be cleaned with chlorhexidine gluconate and isopropyl alcohol. All blocks will be placed using standard UCSD ultrasound-guided techniques.

Ropivacaine 0.5% (with epinephrine 1:200,000-400,000) will be administered via the needle into the target plane. For erector spinae plane blocks, this will be at the T3 level for surgery involving the axilla and the T4 level for surgery not involving the axilla (20 mL of local anesthetic for unilateral surgery; 16 mL of local anesthetic each side for bilateral surgery). For PVBs without axillary work, this will be at the T3 and T5 levels. For PVBs with axillary work, this will be at the T2 and T4 levels. For unilateral PVBs, 10 mL of local anesthetic will be injected per level. For bilateral PVBs, 8 mL of local anesthetic will be injected per level.

Single-injection blocks will be considered successful if, within 30 minutes, the subject experiences decreased sensation to cold temperature with an alcohol pad over the approximate level of the ipsilateral 4th thoracic dermatome. Misplaced blocks will be replaced successfully, or the patient excluded from further study participation. For subjects undergoing bilateral surgical procedures, a block using the same protocol will be administered on the contralateral side.

Intraoperatively, all subjects will receive a general anesthetic using inhaled and intravenous anesthetic and oxygen. Intravenous fentanyl will be administered for cardiovascular responsiveness to noxious stimuli at the discretion of the anesthesia provider.

Postop: Subjects will be discharged with a prescription for oxycodone 5 mg tablets for supplementary analgesia and instructed to record the time at which subjects take their first opioid tablet as well as the time at which subjects believe the block starts to wear off.

Outcome measurements (end points). Pain scores will be recorded using the Numeric Rating Scale (NRS). Within the recovery room, pain scores, opioid requirements, and antiemetic administration will be recorded by nursing staff masked to treatment group. The morning following surgery, all subjects will be contacted by phone or in person \[if hospitalized\] to record lowest, average, highest, and current pain scores; sleep disturbances, and nausea using a 0-10 Likert scale (0 = no nausea; 10 = vomiting). For outpatients, opioid requirements will be recorded while inpatients will have opioid requirements extracted from the electronic medical record. In addition, the investigators will extract antiemetic use from the electronic record. The investigators will collect the times at which subjects felt their block resolve and subjects consumed their first opioid analgesic pills following recovery room discharge.

Hypothesis 1: Following breast surgery, analgesia will be non-inferior in the recovery room with an erector spinae plane block compared with a paravertebral block as measured with the Numeric Rating Scale.

Hypothesis 2: For breast surgery, opioid consumption will be non-inferior in the operating and recovery rooms with an erector spinae plane block compared with a paravertebral block (primary: cumulative intravenous morphine equivalents).

Primary end point: In order to claim that erector spinae plane blocks are non-inferior to paravertebral blocks, both Hypotheses 1 and 2 must be at least non-inferior.

Statistical methods. Descriptive statistics will be provided by arm and in aggregate. Baseline characteristics of arms will be compared using the Wilcoxon-Mann-Whitney and Fisher's Exact tests. Key characteristics that are significantly different (p\<0.05) will be included as covariates in the analysis models.

Primary aim. The investigators will test the noninferiority of the erector spinae nerve block compared to the paravertebral nerve block. The 95% confidence interval (CI) associated with the Wilcoxon-Mann-Whitney test will be derived for the group difference (paravertebral minus erector spinae) in median pain scores within the recovery room. If the lower limit of the 95% CI is greater than -1.25, the investigators will conclude noninferiority. If there are significant differences between the groups in any key characteristics, these characteristics will be included as covariates in a linear model. The same noninferiority margin (-1.25) will be applied to the 95% CI for the covariate adjusted group difference in mean pain derived from the linear model.

The noninferiority of the erector spinae nerve block with regard to total opioid consumption within the operating and recovery rooms will be tested in the same manner as pain, i.e. comparing the limits of a 95% CI associated with the Wilcoxon-Mann-Whitney test to a predefined noninferiority margin (in this case 2 mg). Covariate adjusted linear models will again be applied in the event that key characteristics are significantly different between the groups.

Sample size justification. Power for the Wilcoxon-Mann-Whitney derived noninferiority testing is based on 10,000 simulated trials. The investigators simulated pain scores from a discrete distribution with median (interquartile range) 3 (2-5) \[Kairaluoma, 2004\]. Between the quartiles, the probability of each score was assumed constant. The distribution for each group was assumed to be the same. The sample size of n=50 per group provides 82% power to detect noninferiority in pain with a margin of 1.25. Similarly, opioid consumption was assumed to follow a truncated normal distribution with mean 2.5 mg and standard deviation 2 mg, and minimum value 0 mg. The sample size of n = 50 per group provides at least 95% power to detect noninferiority with margin 2 mg. Therefore, the investigators will enroll 50 subjects for each of two treatments with a total enrollment of 100 subjects. To allow for dropouts, the investigators will request a maximum enrollment of 120 subjects. Noninferiority in pain is tested first, and if significant, noninferiority in opioid consumption is tested. Under this hierarchical testing framework, no adjustment in alpha is necessary to control Type 1 error \[Mascha, et al 2012\].

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Erector Spinae (single injection) intervention 2: Paravertebral (single injection)
Intervention descriptions: intervention 1: Ropivacaine 0.5% (with epinephrine 1:200,000-400,000) will be administered via the needle into the target plane. intervention 2: Ropivacaine 0.5% (with epinephrine 1:200,000-400,000) will be administered via the needle into the target plane.

Protocol documents:
ICF_001.pdf: 
IRB # 180122 
 
Page 1 of 4 
 
IRB #180122 
 
University of California, San Diego 
Consent to Act as a Research Subject 
 
A Randomized, Subject-Masked, Active-Controlled, 
Parallel-Arm Clinical Trial  
Comparing Erector Spinae and Paravertebral Nerve Blocks 
 
 
Who is conducting the study, why you have been asked to participate, how you were selected, 
and what is the approximate number of participants in the study? 
Brian Ilfeld, MD, MS, and colleagues, are conducting a research study.  This study will 
determine if the insertion site of local anesthetic²or numbing medicine²affects the amount of 
pain relief that is experienced after surgery.  You have been asked to participate because you are 
scheduled to undergo breast surgery and you have indicated the desire to have a peripheral nerve 
block of the nerves that go to the breast which is being operated on.   
 
Approximately 120 people will participate in this research. 
 
 
Why is this study being done? 
Currently, there are two different places that the local anesthetic ma\ be placed:  at the ³erector 
spinae´ site and ³paravertebral´ location.  Both of these sites are in the upper back area on the 
side of your planned surgery, and differ by less than an inch in depth.  Each of these locations is 
considered ³standard´ at UCSD²they both are used on a regular basis.  Which is used for each 
specific patient is currently determined by the anesthesiologists based on personal preferences.  
There is no information currently available that suggests one of these locations is better than the 
other, which is the reason why we are currently doing this study²to determine if there are 
benefits and/or risks to each of these two different locations. 
 
 
What will happen to you in this study and which procedures are standard of care and which 
are experimental? 
 
1. When you arrive for surgery, we will confirm some baseline information about you that is 
currently in your chart (for example, your age, weight, height, contacting phone numbers). 
 
2. You will have monitors placed (such as a blood-pressure cuff) and an intravenous line placed.  
You will be given some medicines through your intravenous line to make you sleepy and more 
comfortable during the placement of the nerve block.  This is standard-of-care (will occur 
whether or not you choose to participate in this study). 
 
3. An anesthesiologist will then use an ultrasound machine to guide a needle to the nerves in your 
back that go to your breast (this is standard-of-care).  However, if you choose to participate in 
this study, the location of the peripheral nerve block²erector spinae vs. paravertebral²will be 
determined randomly, like a flip of a coin.  Your chance of being assigned to each group is 1 
Human Research 
Protections Program 
 
 
 
Approved 
Current Approval: 
06/21/2018 
Do not use after 
01/24/2019 
Pages 4 


IRB # 180122 
Page 2 of 4 
 
IRB #180122 
Human Research 
Protections Program 
 
 
 
Approved 
Current Approval: 
06/21/2018 
Do not use after 
01/24/2019 
out of 2.  This is experimental.  If you do not choose to participate in this study, you will still 
receive one of these two locations²it¶s just that \our anesthesiologist Zill choose Zhich to use 
instead of the decision being made in a random fashion. 
 
4. You will be discharged home when ready with a prescription for pain pills (standard-of-care) 
and asked to record the first time you take one of these pills as well as the time when you think 
the local anesthetic block starts to wear off.  You will be called the morning after surgery to see 
how you are doing²this is standard-of-care. 
 
5. You may contact Dr. Ilfeld through the page operator at 619-543-6222 who will be available to 
you 24 hours/day, 7 days/week, should you have any discomfort, questions or concerns. 
 
 
How much time will each study procedure take, what is your total time commitment, and how 
long will the study last? 
If you participate in the study, it will not add to your time commitment since you have chosen to 
have a peripheral nerve block for postoperative pain control regardless of study participation.  
You will be called the day after returning home, but this is done regardless of study participation.  
You will begin study participation the morning of surgery, and complete it 1 or 2 days after 
surgery with a phone call.  Therefore, your total duration of study participation will be 1 or 2 
days. 
 
What risks are associated with this study? 
Participation in this study may involve some added risks or discomforts. These include the 
following:  Because the optimal block location is not known, we cannot assure you that there may 
be a benefit to participation in this study.  That is, we cannot offer a specific benefit from using one 
location over the other.  The risks of paravertebral blocks are rare but include bleeding, infection, 
damage to nerves, inadequate pain relief, and injection into nearby structures including blood 
vessels, near or into spinal canal, and lining of the lung.  The risks of erector spinae blocks have 
not been fully established.  Taking part in this study will help us determine which block location 
is safer.  There is a potential for the loss of confidentiality from collecting your information for 
research.  We will minimize this risk by storing your information in a locked office and in your 
official medical chart.  Computers used to store your information are password-protected, 
encrypted, and only accessible by study investigators.  Since this is an investigational study, 
there may be some unknown risks that are currently unforeseeable.  You will be informed of any 
significant new findings.  If you choose not to participate in this study, you can still have the 
peripheral nerve block as you have indicated that you want; but the anesthesiologist will simply 
choose which location to use instead of a computer determining this randomly (by chance). 
 
 
What are the alternatives to participating in this study? 
The alternatives to participation in this study are not participating as a research subject.  You will 
still receive a nerve block for pain control after your surgery.  The block location you receive by 
the anesthesiologist may or may not be the same location you would receive if you enroll in the 
study. 
 


IRB # 180122 
Page 3 of 4 
 
IRB #180122 
Human Research 
Protections Program 
 
 
 
Approved 
Current Approval: 
06/21/2018 
Do not use after 
01/24/2019 
 
What benefits can be reasonably expected? 
There are no direct medical benefits to volunteers.  If we are able to determine that one block 
location is more adventageous than the other, future patients could receive improved pain control 
following breast surgery using this technique.  In addition, if you, yourself, have future breast 
surgery and we determine that one location is more advantageous than the other, then you might 
benefit from this research in the future. 
 
 
Can you choose to not participate or withdraw from the study without penalty or loss of 
benefits? 
Participation in research is entirely voluntary.  You may refuse to participate or withdraw at any 
time without penalty or loss of benefits to which you are entitled.  If you decide that you no 
longer wish to continue in this study, you are free to do so at any time during your participation 
period. 
 
 
Can you be withdrawn from the study without your consent? 
You may also be withdrawn from the study if the investigator feels it is in your best interest or 
for other study-related purposes.  You may also be withdrawn from the study if you do not 
follow the instructions given you by the study personnel. 
 
 
Will you be compensated for participating in this study? 
There is no compensation for participating in this study. 
 
 
Are there any costs associated with participating in this study? 
There are no costs to you for participating in the research study. 
 
  
What if you are injured as a direct result of being in this study? 
If you are injured as a direct result of participation in this research, the University of California 
will provide any medical care you need to treat those injuries. The University will not provide 
any other form of compensation to you if you are injured. You may call the Human Research 
Protections Program Office at (858) 246-4777 for more information about this, to inquire about 
your rights as a research subject or to report research-related problems. 
 
 
What about your confidentiality? 
Research records will be kept confidential to the extent allowed by law.  Your study record will 
be de-identified using randomized numbers.  Paper copies of study documents will be kept in 
locked medical offices.  Any digitized records containing personal health information will be 
stored as password-protected and encrypted files.  Research records may be reviewed by the 
UCSD Institutional Review Board. 
 


IRB # 180122 
Page 4 of 4 
 
IRB #180122 
Human Research 
Protections Program 
 
 
 
Approved 
Current Approval: 
06/21/2018 
Do not use after 
01/24/2019 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
This study is being funded by the Department of Surgery. 
 
 
Who can you call if you have questions? 
Dr. Brian Ilfeld, and/or his colleagues has explained this study to you and answered your 
questions. If you have other questions or research-related problems, you may reach Dr. Brian 
Ilfeld through the UCSD page operator at 619-543-6222. 
 
You may call the Human Research Protections Program Office at (858) 246-4777 to inquire 
about your rights as a research subject or to report research-related problems. 
 
 
Your Signature and Consent 
You haYe receiYed a cop\ of this consent document and a cop\ of the ³E[perimental Subject's 
Bill of Rights´ to keep. 
 
You agree to participate. 
 
 
 
________________________________________________ 
_______________ 
Subject's signature 
 
 
 
 
 
 
Date 
 

Prot_SAP_002.pdf: 
 
 
UCSD Human Research Protections Program 
New Biomedical Application 
RESEARCH PLAN 
Instructions for completing the Research Plan are available on the HRPP website. 
The headings on this set of instructions correspond to the headings of the Research Plan. 
General Instructions: Enter a response for all topic headings.  
Enter “Not Applicable” rather than leaving an item blank if the item does not apply to this project. 
Version date: 6/21/2018 
1. 
PROJECT TITLE 
A Randomized, Subject-Masked, Active-Controlled, Parallel-Arm Clinical Trial Comparing 
Erector Spinae and Paravertebral Nerve Blocks 
 
 
2. 
PRINCIPAL INVESTIGATOR  
Brian M. Ilfeld, MD, MS 
 
3. 
FACILITIES 
UCSD hospitals and the UCSD CTRI 
 
4. 
ESTIMATED DURATION OF THE STUDY 
Three years (1 month preparation, 24 months enrollment, 11 months publication prior to closure) 
 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
Following painful surgical procedures of the breast, postoperative analgesia is often provided with a 
paravertebral nerve block (PVB).  For intense, but shorter-duration acute pain, a single-injection of 
local anesthetic is used with a duration of approximately 12 hours.  Recently an alternative block has 
been reported:  the erector spinae plane block.2  The theoretical benefits include ease of 
administration since it is a plane superficial to the PVB and therefore easier to identify and target with 
ultrasound (therefore increasing success rate); and an increased safety margin as there are fewer 
anatomic structures in the immediate area which could be injured with the needle; and, the target 
plane is much further from the intrathecal/epidural space relative to the PVB, therefore leakage of 
cerebrospinal fluid or injury to the spinal cord are less likely with the erector spinae compared to the 
PVB.3  There are, therefore, multiple theoretical reasons to prefer the erector spinae over the PVB.  
Unfortunately, it remains unknown if the analgesia provided by this new technique is comparable to 
that provided with the PVB.4  We therefore propose to compare these two techniques with a 
randomized, subject-masked, active-controlled, parallel-arm clinical trial. 
 
6. 
SPECIFIC AIMS 
The overall objective of the proposed research is to determine the relative risks and benefits of 
erector spinae plane versus paravertebral blocks for single-injection local anesthetic administration. 
 
Hypothesis 1:  Following breast surgery, analgesia will be non-inferior in the recovery room with an 
erector spinae plane block compared with a paravertebral block as measured with the Numeric 
Rating Scale. 
 
Hypothesis 2:  For breast surgery, opioid consumption will be non-inferior in the operating and 
recovery rooms with an erector spinae plane block compared with a paravertebral block (primary:  
cumulative intravenous morphine equivalents). 
 
Primary end point:  In order to claim that erector spinae plane blocks are non-inferior to paravertebral 
blocks, both Hypotheses 1 and 2 must be at least non-inferior. 
 
 
7. 
BACKGROUND AND SIGNIFICANCE 
Following painful surgical procedures of the breast, postoperative analgesia is often provided with a 


 
 
Biomedical IRB Application Instructions 
Page 2 
paravertebral nerve block (PVB).  For intense, but shorter-duration acute pain, a single-injection of 
local anesthetic is used with a duration of approximately 12 hours.  The PVB has several limitations:  
it can decrease blood pressure, and very rare—but serious—complications have occurred, including 
neuraxial injection, neuraxial hematoma, and pleural puncture.1  An alternative block has been 
described:  the erector spinae plane block.2  The theoretical benefits include ease of administration 
since it is a plane superficial to the PVB and therefore easier to identify and target with ultrasound 
(therefore increasing success rate); and an increased safety margin:  there are few anatomic 
structures in the immediate area which could be injured with the needle; and, the target plane is 
much further from the intrathecal/epidural space relative to the PVB.  Lastly, the plane may be easier 
to catheterize for continuous peripheral nerve blocks relative to the relatively-small volume PVB.3 
 
There are therefore multiple theoretical reasons to prefer the erector spinae plane block.  
Unfortunately, it remains unknown if the analgesia provided by this new technique is comparable to 
that provided with the PVB.4  We therefore propose to compare these two techniques with a 
randomized, subject-masked, active-controlled, parallel-arm, human subjects clinical trial. 
 
8. 
PROGRESS REPORT 
There are no preliminary or pilot study data. 
 
9. 
RESEARCH DESIGN AND METHODS 
This investigation will be a randomized, subject-masked, active-controlled parallel-arm, human 
subjects clinical trial.  Of note, we will be using standard-of-care local anesthetic under an FDA-
approved purpose and do not plan to research a possible change of indication or use of these 
medications as part of this research project.  The treatments in both groups are currently used at our 
institution and there is true clinical equipoise at this time.  The only difference in treatment between 
subjects who enroll versus those not enrolled in this study will be those who enroll will have the 
decision between which anatomic block location determined randomly, as opposed to the physician 
simply choosing him/herself. 
 
Enrollment.  Consenting adults undergoing breast surgery with a planned single-injection regional 
analgesic will be offered enrollment.  Patients undergoing breast surgery with a planned perineural 
catheter regional analgesic will be excluded.  Study inclusion will be proposed to eligible patients 
prior to surgery.  If a patient desires study participation, written, informed consent will be obtained 
using a current UCSD IRB-approved ICF.  Selection for inclusion will not be based on gender, race, 
or socioeconomic status.  The study population of interest includes men and women of all races and 
socioeconomic status.  Inclusion and exclusion criteria are listed in section #9 below. 
 
Preoperative Procedures.  Following written, informed consent, we will collect baseline 
anthropomorphic information (e.g., age, sex, height, and weight).  All subjects will have a peripheral 
intravenous (IV) catheter inserted, standard noninvasive monitors applied, supplemental oxygen 
administered via a nasal cannula or face mask, and placed in the sitting position.  Midazolam and 
fentanyl (IV) will be titrated for patient comfort, while ensuring that patients remain responsive to 
verbal cues.  Both possible block locations will be viewed with ultrasound.  If one or both of the 
locations is unacceptable for block placement in the clinician’s opinion, the subject will not be 
randomized and will not proceed further with the study. 
 
Subjects will then be randomized using a computer-generated list and opaque, sealed envelopes to 


 
 
Biomedical IRB Application Instructions 
Page 3 
one of two treatment groups: (blocks of 4, stratified for unilateral vs. bilateral surgery): (1) erector 
spinae plane or (2) paravertebral block.  All blocks will be placed by a regional anesthesia fellow or 
resident under the direct supervision and guidance of a regional anesthesia attending (or by the 
attending him/herself). 
 
The area of needle insertion will be cleaned with chlorhexidine gluconate and isopropyl alcohol.  All 
blocks will be placed using standard UCSD ultrasound-guided techniques as previously described.4,5 
 
Ropivacaine 0.5% (with epinephrine 1:200,000-400,000) will be administered via the needle into the 
target plane.  For erector spinae plane blocks, this will be at the T3 level for surgery involving the 
axilla and the T4 level for surgery not involving the axilla (20 mL of local anesthetic for unilateral 
surgery; 16 mL of local anesthetic each side for bilateral surgery).  For PVBs without axillary work, 
this will be at the T3 and T5 levels.  For PVBs with axillary work, this will be at the T2 and T4 levels.  
For unilateral PVBs, 10 mL of local anesthetic will be injected per level.  For bilateral PVBs, 8 mL of 
local anesthetic will be injected per level. 
 
Single-injection blocks will be considered successful if, within 30 minutes, the subject experiences 
decreased sensation to cold temperature with an alcohol pad over the approximate level of the 
ipsilateral 4th thoracic dermatome.  Misplaced blocks will be replaced successfully, or the patient 
excluded from further study participation.  For subjects undergoing bilateral surgical procedures, a 
block using the same protocol will be administered on the contralateral side. 
 
Intraoperatively, all subjects will receive a general anesthetic using inhaled and intravenous 
anesthetic and oxygen.  Intravenous fentanyl will be administered for cardiovascular responsiveness 
to noxious stimuli at the discretion of the anesthesia provider. 
 
Postop:  Subjects will be discharged with a prescription for oxycodone 5 mg tablets for 
supplementary analgesia and instructed to record the time at which they take their first opioid tablet 
as well as the time at which they believe the block starts to wear off. 
 
Outcome measurements (end points).  Pain scores will be recorded using the NRS.  Within the 
recovery room, pain scores, opioid requirements, and antiemetic administration will be recorded by 
nursing staff masked to treatment group.  The morning following surgery, all subjects will be 
contacted by phone or in person [if hospitalized] to record lowest, average, highest, and current pain 
scores; sleep disturbances, and nausea using a 0-10 Likert scale (0 = no nausea; 10 = vomiting).  
For outpatients, opioid requirements will be recorded while inpatients will have opioid requirements 
extracted from the electronic medical record.  In addition, we will extract antiemetic use from the 
electronic record.  We will collect the times at which subjects felt their block resolve and they 
consumed their first opioid analgesic pills following recovery room discharge. 
 
Hypothesis 1:  Following breast surgery, analgesia will be non-inferior in the recovery room with an 
erector spinae plane block compared with a paravertebral block as measured with the Numeric 
Rating Scale. 
 
Hypothesis 2:  For breast surgery, opioid consumption will be non-inferior in the operating and 
recovery rooms with an erector spinae plane block compared with a paravertebral block (primary:  
cumulative intravenous morphine equivalents). 
 
Primary end point:  In order to claim that erector spinae plane blocks are non-inferior to paravertebral 


 
 
Biomedical IRB Application Instructions 
Page 4 
blocks, both Hypotheses 1 and 2 must be at least non-inferior. 
 
 
Statistical methods.  Descriptive statistics will be provided by arm and in aggregate. Baseline 
characteristics of arms will be compared using the Wilcoxon-Mann-Whitney and Fisher’s Exact tests. 
Key characteristics that are significantly different (p<0.05) will be included as covariates in the 
analysis models. 
 
Primary aim.  We will test the noninferiority of the erector spinae nerve block compared to the 
paravertebral nerve block.  The 95% confidence interval (CI) associated with the Wilcoxon-Mann-
Whitney test will be derived for the group difference (paravertebral minus erector spinae) in median 
pain scores within the recovery room. If the lower limit of the 95% CI is greater than -1.25, we will 
conclude noninferiority.  If there are significant differences between the groups in any key 
characteristics, these characteristics will be included as covariates in a linear model. The same 
noninferiority margin (-1.25) will be applied to the 95% CI for the covariate adjusted group difference 
in mean pain derived from the linear model. 
 
The noninferiority of the erector spinae nerve block with regard to total opioid consumption within the 
operating and recovery rooms will be tested in the same manner as pain, i.e. comparing the limits of 
a 95% CI associated with the Wilcoxon-Mann-Whitney test to a predefined noninferiority margin (in 
this case 2 mg). Covariate adjusted linear models will again be applied in the event that key 
characteristics are significantly different between the groups. 
 
Sample size justification.    Power for the Wilcoxon-Mann-Whitney derived noninferiority testing is 
based on 10,000 simulated trials. We simulated pain scores from a discrete distribution with median 
(interquartile range) 3 (2-5) [Kairaluoma, 2004].  Between the quartiles, the probability of each score 
was assumed constant.  The distribution for each group was assumed to be the same.  The sample 
size of n=50 per group provides 82% power to detect noninferiority in pain with a margin of 1.25.  
Similarly, opioid consumption was assumed to follow a truncated normal distribution with mean 2.5 
mg and standard deviation 2 mg, and minimum value 0 mg.  The sample size of n = 50 per group 
provides at least 95% power to detect noninferiority with margin 2 mg.  Therefore, we will enroll 50 
subjects for each of two treatments with a total enrollment of 100 subjects.  To allow for dropouts, we 
will request a maximum enrollment of 120 subjects.  Noninferiority in pain is tested first, and if 
significant, noninferiority in opioid consumption is tested.  Under this hierarchical testing framework, 
no adjustment in alpha is necessary to control Type 1 error [Mascha, et al 2012]. 
 
 
 
 
 
10. 
HUMAN SUBJECTS 
Inclusion criteria for the trial will be:  (1) undergoing unilateral or bilateral breast surgery with at 
least moderate postoperative pain anticipated; (2) analgesic plan includes a single-injection 
peripheral nerve block(s); and (3) age 18 years or older. 
 
Exclusion criteria for the trial will be:  (1) morbid obesity as defined by a body mass index > 40 
(BMI=weight in kg / [height in meters]2); (2) renal insufficiency (preoperative creatinine > 1.5 mg/dL); 
(3) chronic opioid use (daily use within the 2 weeks prior to surgery and duration of use > 4 weeks); 
(4) history of opioid abuse; (5) any comorbidity which results in moderate or severe functional 


 
 
Biomedical IRB Application Instructions 
Page 5 
limitation; (6) inability to communicate with the investigators or hospital staff; (7) pregnancy; (8) 
planned regional analgesic with perineural catheter placement; and (9) incarceration.  We will recruit 
a maximum of 120 subjects.  Selection for inclusion will not be based on race or socioeconomic 
status.  The study population of interest includes men and women of all races and socioeconomic 
status.  There will be no participants from vulnerable populations, such as pregnant women, children, 
or prisoners. 
 
11. 
RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH 
Study inclusion will be proposed to eligible patients prior to surgery by the investigators.  Since the 
investigators will be contacting patients as part of their standard preoperative anesthesia 
consultation, HIPAA regulations will be adhered to.  For women of childbearing age with the 
possibility of pregnancy, a sample of urine is always collected for a pregnancy test prior to surgery—
regardless of study participation.  Pregnant patients will be excluded from study participation. 
 
12. 
INFORMED CONSENT 
If a patient desires study participation, written, informed consent will be obtained.  An investigator or 
research assistant/coordinator (including regional anesthesia fellows) specifically trained in both 
study details and appropriate consenting procedures will attain verbal and written informed subject 
consent.  The method of documenting consent will be using written informed consent form (including 
a written HIPAA consent form and UCSD Experimental Subjects’ Bill of Rights). 
 
13. 
ALTERNATIVES TO STUDY PARTICIPATION 
If a patient declines enrollment, s/he will receive their perioperative analgesic with the choice of which 
anatomic location to use (erector spinae plane or paravertebral block) determined by the attending 
regional anesthesiologist instead of randomly per study protocol. 
 
14. 
POTENTIAL RISKS 
Patients offered participation in this study are already planning on having a regional analgesic for 
postoperative analgesia, so the risks of having this type of analgesic modality are not affected by 
study participation.  Currently, it remains unknown whether or not there are relatively higher risks with 
one anatomic location over the other.  There is, however, the risk of loss of confidentiality with study 
participation.  The risks of PVB are bleeding including neuraxial hematoma, infection, nerve injury, 
pneumothorax or pleural puncture, intravascular injection, inadvertent epidural or spinal injection, 
hypotension, Horner’s syndrome, and failed block or inadequate analgesia.  The risks of erector 
spinae plane blocks have not been fully described due to the infancy of the technique.  Given the 
proximity to the paravertebral, neuraxial, and pleural spaces, the risks of erector spinae plane blocks 
are felt to be similar.  However, due to the increased distance between the erector spinae plane and 
the pleura and neuraxis, these risks are thought to be decreased with an improved safety margin. 
 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
The procedural risks involved with PVB and erector spinae plane blocks will be managed according 
to the complication.  All blocks will be performed after placement of intravenous access with 
adequate monitoring including continuous pulse oximetry, EKG, and noninvasive blood pressure.  
Resuscitation equipment will be readily available.  Hypotension will be treated pharmacologically 
according to the degree of hypotension.  Inadvertent pleural puncture will be diagnosed with chest 
radiography and subsequent interventions (such as tube thoracostomy) will be guided by consultation 
with surgery depending on the severity of the pneumothorax.  Inadvertent intravascular injection will 
be managed according to the degree of cardiovascular compromise with intralipid readily available 


 
 
Biomedical IRB Application Instructions 
Page 6 
during all blocks.  Bleeding, neurologic, and infectious complications will be managed according to 
the degree of neurologic sequelae in consultation with surgery. Horner’s syndrome will be managed 
expectantly as it recedes with the resolution of the block. 
 
The following study procedures will be done to maintain confidentiality of this study: hard copies will 
be kept in a locked medical office and the patients’ own medical charts.  Any digitized records will be 
stored in encrypted files on password-protected computers. 
 
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT 
Following study participation, all hard copies of the ICF and single-page CRF will be kept in the PI’s 
locked office in a separate locked file cabinet.  Digitized records will be de-identified using subjects’ 
randomization numbers—only the single-page hardcopy CRF will contain identifiable personal health 
information as well as the randomization number.  As such, subject research records will only be 
identified by a study number.  The master list linking subject name and identifiable personal health 
information to subject study number will be kept in a separate locked file cabinet in the PI’s locked 
office. 
 
17. POTENTIAL BENEFITS 
There are no known immediate medical benefits to study participation for the individual.  However, 
future patients may benefit if we determine that one anatomic location provides greater relative 
benefits or fewer relative risks.  In addition, current subjects may themselves benefit if they require 
future surgery and a postoperative analgesic. 
 
18. RISK/BENEFIT RATIO 
There are no known medical risks to subjects and the risk of confidentiality loss has been minimized.  
The benefits to society and future patients are potentially significant since there currently may be 
thousands of patients receiving less-than-optimal analgesia from providers using one of the two 
anatomic locations described in this protocol. 
 
19. EXPENSE TO PARTICIPANT 
None.  
 
20. COMPENSATION FOR PARTICIPATION 
None. 
 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
Principal Investigator, Brian M. Ilfeld, MD, MS, is a board-certified anesthesiologist with fellowship 
training in and 17 post-training years experience with regional anesthesia and perineural local 
anesthetic infusion.  Dr. Ilfeld holds a license to practice medicine in California.  Dr. Ilfeld has medical 
privileges at the UC Medical Centers.  Dr. Ilfeld, or another investigator, will follow all subjects during 
their perineural infusion.  Dr. Ilfeld will be responsible for the overall management of this study, as 
well as for the well-being of study subjects. 
 
Co-investigators, Jackie Sztain, MD, Rodney Gabriel, MD, MAS, Engy Said, MD, Bahareh 
Khatibi, MD, John Finneran, MD, Matthew Swisher, MD, MS, Wendy Abramson, MD, Jessica 
Black, MD, are all board-eligible or board-certified anesthesiologists with fellowship training in 
regional anesthesia and perineural local anesthetic infusion.  In addition, Anne Wallace, MD, is a 
board-certified surgeon with decades experience involving breast surgery.  All hold a license to 


 
 
Biomedical IRB Application Instructions 
Page 7 
practice medicine in California and have medical privileges at the UC Medical Centers.  All will help 
consent subjects, perform a history and physical exam, assist in placing nerve blocks (with the 
exception of Dr. Wallace) and collect outcome measurements. 
 
22. BIBLIOGRAPHY 
1. Naja Z, Longquvist PA. Somatic paravertebral nerve blockade. Incidence of failed block and 
complications. Anaesthesia 2001; 56: 1184-8 
2. Forero M, Adhikary SD, Lopez H, Tsui C, Chin KJ. The erector spinae plane block: a novel 
analgesic technique in thoracic neuropathic pain. Reg Anesth Pain Med 2016; 14: 621-7 
3. Forero M, Rajarathinam M, Adhikary S, Chin KJ. A&A Case Reports 2017; 8: 254-6 
4. Ilfeld BM, Madison SJ, Suresh PJ, Sandhu NS, Kormylo NJ, Malhotra N, Loland VJ, Wallace 
MS, Proudfoot JA, Morgan AC, Wen CH, Wallace AM.  Treatment of post-mastectomy pain 
with ambulatory continuous paravertebral nerve blocks: A randomized, triple-masked, placebo-
controlled study.  Reg Anesth Pain Med 2014; 39: 89-96 
5. Finneran JJ, Gabriel RA, Khatibi B.  Erector spinae plane blocks provide analgesia for breast 
and axillary surgery:  A series of 3 cases.  Reg Anesth Pain Med 2018; 43: 101-2 
6. Kairaluoma PM, Bachmann MS, Korpinen AK., Rosenberg PH, Pere PJ. Single-injection 
paravertebral block before general anesthesia enhances analgesia after breast surgery with 
and without associated lymph node biopsy. Anesth Analg 2004; 99(6): 1837-43 
7. Mascha EJ, Turan A. Joint hypothesis testing and gatekeeping procedures for studies with 
multiple endpoints. Anesth Analg 2012; 114(6): 1304-17 
 
23. FUNDING SUPPORT FOR THIS STUDY 
This is a PI-initiated investigation.  Funding will be provided by the Department of Surgery. 
 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
Not applicable. 
 
 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
Not applicable. 
 
26. IMPACT ON STAFF 
The study will not impact nursing staff as subjects will be receiving a regional analgesic in one of the 
two anatomic locations regardless of study participation. 
 
27. CONFLICT OF INTEREST 
None. 
 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
Not applicable. 
 
29. OTHER APPROVALS/REGULATED MATERIALS 
None. 
 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT 
Not applicable:  surrogate consent will not be accepted. 
 
 


 
 
Biomedical IRB Application Instructions 
Page 8