Clinical trial NCT04558281
Conditions: Rib Fractures Trauma Anesthesia Anesthesia, Local
Sponsor: University of California, San Diego
Start date: 2021-05-23; Completion date: 2023-03-24
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Rib fractures are one of the most common injuries in trauma patients. These fractures are associated with significant pain as well as decreased ability to inspire deeply or cough to clear secretions, which together lead to complications of the lungs and breathing which leads to risks of further injury and even death.

One recent study found that the ability to move air into and out of the lungs practically doubled with the administration of a single-injection Erector Spainae Plane Block (ESPB) while pain levels nearly halved. However, a single-injection nerve block lasts less than 24 hours while a perineural local anesthetic infusion (also termed a "continuous peripheral nerve block") may be administered for multiple days. This entails inserting a tiny tube through the skin and into the area around the nerves, after which more local anesthetic may be administered prolonging the numbing effects.

The possibility of extending the duration of a ESPB with local anesthetic administration via a perineural catheter has not be investigated. We therefore are conducting a randomized, triple-masked, placebo-controlled, parallel-arm study to investigate the addition of a continuous ESPB to a single-injection ESPB following traumatic rib fractures.

The primary outcome of this study will be the maximum inspired volume measured by incentive spirometry on the afternoon following the nerve block procedure. We hypothesize that the maximum inspired volume will be significantly increased in the afternoon following the procedure with the addition of a continuous ESPB to a single-injection ESPB.

Detailed description:
Rib fractures are one of the most common injuries in trauma patients. These fractures are associated with significant pain as well as decreased ability to inspire deeply or cough to clear secretions, which together lead to complications of the lungs and breathing which leads to risks of further injury and even death.

The erector spinae plane block (ESPB) is a nerve block that covers multiple rib fractures with a single injection. This block entails injecting local anesthetic in the back superficial to the vertebral bodies. One study found that the ability to move air into and out of the lungs practically doubled with the administration of a single-injection ESPB while pain levels nearly halved.

A single-injection nerve block lasts less than 24 hours while a perineural local anesthetic infusion (also termed a "continuous peripheral nerve block") may be administered for multiple days. This entails inserting a tiny tube through the skin and into the area around the nerves, after which more local anesthetic may be administered prolonging the numbing effects. The possibility of extending the duration of a ESPB with local anesthetic administration via a perineural catheter has not be investigated.

We therefore are conducting a randomized, tripe-masked, placebo-controlled, parallel-arm study to investigate the addition of a continuous ESPB to a single-injection ESPB following traumatic rib fracture. Subjects will be individuals who present with rib fracture(s) and significant pain. Those who consent to participate in this study will have an ESP catheter inserted using ultrasound-guidance on the ipsilateral side at the level of the inferior-most fracture. For bilateral fractures, a second catheter will also be inserted on the remaining side. The single-injection ESPB will be administered to each catheter with 20 mL of ropivacaine 0.5% (with epinephrine).

Subjects with an accurately-inserted catheter based on visualization of local anesthetic spread will be allocated to one of two possible perineural treatments stratified by unilateral vs. bilateral fractures (1:1 ratio in blocks of 2):

1. active (ropivacaine 0.3%)
2. placebo (normal saline)

Computer-generated randomization lists will be created by the UCSD Investigational Drug Service which will keep the randomization lists and not release them to the investigators until the study is completed, at which time they will provide lists of subjects who received "Treatment A" and "Treatment B" so that the statistician can analyze the data. Only after the analysis is complete will "Treatment A" and "Treatment B" be defined for the investigators for manuscript preparation \[producing a triple-masked study\]. Of note, for bilateral catheters the treatments on both sides will always be identical: each subject will be randomized to a single treatment and not each side of bilateral cases.

Subjects will receive a basal infusion of study fluid (ropivacaine vs. placebo) 1 mL/h to keep the catheter lumen patent as soon as the infusion pump is initiated with a 500 mL reservoir. In addition, intermittent boluses (13 mL programmed automatic bolus every 2 hours) will begin 5 hours after pump initiation. For bilateral catheters, a 6-hour delay for one of the pumps will ensure that the pair of pumps alternate sides for the bolus doses each hour. This protocol will provide nearly 71-72 hours of study fluid administration.

Following local anesthetic reservoir exhaustion, subjects or their caretakers will remove the catheters with instructions provided by phone. This is standard at UC San Diego for all ambulatory continuous peripheral nerve blocks and will not be unique to study participation. The catheter is disposable in the trash and the infusion pump will be returned using a pre-addressed and postage-paid envelope provided to subjects prior to leaving the hospital.

Subjects will be contacted by telephone to collect study data on post procedure days 1, 2, 7, and at months 0.5, 1, 1.5, 2, 3, 6, and 12.

The ultimate objective of the proposed line of research is to determine if the addition of a continuous ESPB to a single-injection ESPB prolongs analgesia following traumatic rib fractures; and, if this analgesic intervention improves pulmonary mechanics measured with incentive spirometry.

Specific Aim 1: To determine if the addition of a continuous ESPB to a single-injection ESPB improves maximum inspiratory volume following traumatic rib fracture(s).

Hypothesis 1a: The maximum inspired volume will be significantly increased in the afternoon following the procedure \[primary endpoint\] as well as at other time points following the procedure \[secondary end points\] with the addition of a continuous ESPB to a single-injection ESPB \[measured with an incentive spirometer\].

Hypothesis 1b: The maximum inspired volume as a percentage of the baseline will be significantly increased in the afternoon following the procedure \[secondary endpoint of greatest interest\], as well as at other time points following the procedure \[secondary end points\] with the addition of a continuous ESPB to a single-injection ESPB \[measured with an incentive spirometer\].

Specific Aim 2: To determine if the addition of a continuous ESPB to a single-injection ESPB decreases the pain associated with rib fracture(s).

Hypothesis 2a: The severity of rib fracture pain at rest will be significantly decreased within the 12 months following the procedure with the addition of a continuous ESPB to a single-injection ESPB \[measured using the Numeric Rating Scale for pain\].

Hypothesis 2b: The severity of rib fracture pain when using the spirometer or coughing will be significantly decreased within the 12 months following the procedure with the addition of a continuous ESPB to a single-injection ESPB \[measured using the Numeric Rating Scale for pain\].

Hypothesis 2c: The incidence of chronic rib fracture pain will be significantly decreased 6 and 12 months following a rib fracture with the addition of a continuous ESPB to a single-injection ESPB \[measured using the Numeric Rating Scale for pain\].

Hypothesis 2d: The severity of chronic rib fracture pain will be significantly decreased 6 and 12 months following a rib fracture with the addition of a continuous ESPB to a single-injection ESPB \[measured using the Numeric Rating Scale for pain\].

Arms: arm 1: This group will receive a single injection nerve block of ropivacaine 0.5% (20 mL) followed by an infusion/boluses of ropivacaine 0.3% (continuous block) arm 2: This group will receive a single injection nerve block of ropivacaine 0.5% (20 mL) followed by an infusion/boluses of normal saline
Interventions: intervention 1: Active ropivacaine 0.3% erector spinae plane perineural administration intervention 2: Placebo erector spinae plane perineural administration
Intervention descriptions: intervention 1: Ropivacaine 0.3% administration via an erector spinae plane perineural catheter intervention 2: Normal saline administration via an erector spinae plane perineural catheter

Protocol documents:
Prot_SAP_000.pdf: 
Title:  Continuous Erector Spinae Plane Blocks for Analgesia and 
Improving Incentive Spirometry Following Traumatic Rib Fractures 
 
 
 
NCT Number:  04558281 
 
 
 
Document date:  December 12, 2021 
 
 
 
 
 
 


 
 
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: 9/30/2013 
1. 
PROJECT TITLE 
Patient-Titrated Automated Intermittent Boluses of Local Anesthetic vs. a Continuous 
Infusion via a Perineural Catheter for Postoperative Analgesia 
 
2. 
PRINCIPAL INVESTIGATOR  
Brian M. Ilfeld, MD, MS 
 
3. 
FACILITIES 
UCSD Hillcrest Hospital, Koman Outpatient Pavilion, and Jacobs Medical Center 
 
4. 
ESTIMATED DURATION OF THE STUDY 
Three years 
 
5. 
LAY LANGUAGE SUMMARY OR SYNOPSIS (no more than one paragraph) 
Continuous peripheral nerve blocks (cPNB) provide prolonged pain relief after surgical procedures, allowing 
for decreased opioid consumption and improved quality of life.1-3  There are three general methods—frequently 
combined—for dosing of local anesthetic in cPNB: continuous infusion, patient administered boluses, and 
automated intermittent boluses. To date, nearly all trials involving ultrasound-guided catheter insertion have 
failed to detect analgesic superiority of one administration modality over the other with equivalent hourly local 
anesthetic volume and dose.4-15  However, we recently completed an IRB-approved randomized, controlled trial 
at UCSD suggesting that automated intermittent boluses may provide a longer duration of treatment—thus 
prolonging analgesia—for ambulatory patients having painful foot and ankle orthopedic procedures (200247).  
While the pump would allow patients to administer additional, non-automated boluses to supplement the 
programmed automated intermittent boluses if they experienced pain, it did not permit patients to decrease the 
amount of local anesthetic they were receiving.  And it appeared that many patients were receiving more local 
anesthetic than they required.   
 
The FDA-cleared portable infusion pump used in that study (Infutronix, Natick, Massachusetts) now has a new 
and novel feature which will potentially improve the patient experience:  it is now possible for patients to easily 
self-titrate the volume of local anesthetic administered with each automatic bolus.  Using this feature, patients 
can increase or decrease the amount of local anesthetic they receive and titrate within a physician-specified 
range to their level of pain. 
 
In the United States, the vast majority of forearm fractures as well as foot and ankle surgery is now performed 
on an outpatient basis.  For ambulatory patients who are discharged home with a set local anesthetic 
reservoir volume, decreasing the rate of anesthetic consumption will allow prolonging the continuous 
peripheral nerve block and therefore analgesia.  In other words, even if automated repeated boluses provide 
equivalent analgesia compared with a continuous peripheral infusion, the automated bolus dose method will be 
superior if it consumes less local anesthetic thereby permitting a longer analgesic treatment.  In the outpatient 
arena, titratable automated intermittent boluses offer two different opportunities to improve postoperative pain 
control: (1) improved analgesia in the initial days following surgery; and, (2) improving analgesia by allowing 
prolonged administration past the time at which a continuous infusion would have exhausted the anesthetic 
reservoir. 
 
6. 
SPECIFIC AIMS 
Specific Aim:  To determine the relationship between method of local anesthetic administration (continuous with 


 
 
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PCA vs. titratable intermittent dosing with PCA) for continuous peripheral nerve block and the resulting pain 
control. 
 
Hypothesis:  We hypothesize that, compared with a traditional fixed, continuous basal infusion 
initiated prior to discharge, perineural local anesthetic administered with titratable automated 
boluses at a lower dose and a 5-hour delay following discharge will (1) provide at least noninferior 
analgesia during the period that both techniques are functioning; and, (2) will result in a longer 
overall duration of administration [dual primary end points]. 
 
7. 
BACKGROUND AND SIGNIFICANCE 
Continuous peripheral nerve blocks:  In the postoperative setting, pain is a primary concern of patients and 
healthcare providers. Over 40% of ambulatory patients undergoing orthopedic procedures experience moderate-
to-severe postoperative pain at home.  A single-injection peripheral nerve block provides up to 15 and 24 hours 
of analgesia following upper and lower extremity procedures, respectively.  However, following this initial 
period, patients must rely on other, less potent, analgesics such as oral and intravenous opioids.1 A continuous 
peripheral nerve block (CPNB)—also called perineural local anesthetic infusion—offers an alternative 
analgesic option.  This technique involves the percutaneous insertion of a catheter directly adjacent to the 
peripheral nerve(s) that innervate the surgical site at the same time the initial regional block is placed.  During 
the past decade, ultrasound-guided catheter placement has also become the common method for placing 
perineural catheters.1 Using this technique, the peripheral nerve(s) is visualized in real-time using ultrasound, 
and then the catheter is placed directly adjacent to the nerve(s), also under real-time ultrasound guidance. 
Local anesthetic infusion methods:  There are three general methods—frequently combined—for dosing of 
local anesthetic in CPNB: continuous infusion, patient administered boluses (PCA), and automated intermittent 
boluses. Automated intermittent boluses with PCA has been shown to be superior to continuous infusion with 
PCA for patients undergoing painful foot surgeries when the perineural catheter is placed using nerve 
stimulation for needle placement followed by blind insertion of a non-stimulating perineural catheter.2 
However, in the past decade ultrasound guidance has overwhelmingly become the dominant modality for 
administering peripheral nerve blocks and inserting perineural catheters.  To date, nearly all trials involving 
ultrasound-guided catheter insertion have failed to detect analgesic superiority of one administration modality 
over the other with equivalent hourly local anesthetic volume and dose.1-12  However, we recently completed an 
IRB-approved randomized, controlled trial at UCSD suggesting that automated intermittent boluses may 
provide a longer duration of treatment—thus prolonging analgesia—for ambulatory patients having painful foot 
and ankle orthopedic procedures (200247).  While the pump would allow patients to administer additional, non-
automated boluses to supplement the programmed automated intermittent boluses if they experienced pain, it 
did not permit patients to decrease the amount of local anesthetic they were receiving.  And it appeared that 
many patients were receiving more local anesthetic than they required.   
 
The FDA-cleared portable infusion pump used in that study (Infutronix, Natick, Massachusetts) now has a new 
and novel feature which will potentially improve the patient experience:  it is now possible for patients to easily 
self-titrate the volume of local anesthetic administered with each automatic bolus.  Using this feature, patients 
can increase or decrease the amount of local anesthetic they receive and titrate within a physician-specified 
range to their level of pain.  The Nimbus pump manufactured by Infutronix has 510(k) clearance for the 
following indications:  “To deliver medications and/or fluids to a patient under the direction or supervision of 
physician or other certified healthcare professional in clinical or nonclinical environments, such as homes. The 
device is intended for subcutaneous, percutaneous, perineural, epidural and intravenous infusion, including but 
not limited to patient controlled analgesia (PCA) delivery.”  The following precautions are provided by the 
manufacturer: 
 


 
 
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• Only use pump as directed by physician or other certified health care professional. 
• The pump is not to be used for delivery of blood or cellular  blood products. 
• The pump is not intended for delivery of life-sustaining medication. 
• Do not use the pump or cassette/administration set to administer any infusion to the epidural space 
unless the medication and/or fluid infused is indicated for epidural administration. 
• If the pump is used to deliver critical medication, a backup pump should be available. 
• Do not use the pump in or near an MRI (Magnetic Resonance Imaging) device. 
 
 
In the United States, the vast majority of forearm fracture as well as foot and ankle surgery is now performed 
on an outpatient basis.  For ambulatory patients who are discharged home with a set local anesthetic reservoir 
volume, decreasing their hourly consumption of anesthetic will allow prolonging their continuous peripheral 
nerve block and therefore their analgesia.  In other words, even if automated repeated bolus doses provide 
equivalent analgesia as a continuous peripheral infusion, the automated bolus dose method will be superior if it 
consumes less local anesthetic, thereby permitting a longer analgesic treatment.  In the outpatient arena, 
titratable automated intermittent boluses offer two different opportunities to improve postoperative pain 
control: (1) improved analgesia in the initial days following surgery; and, (2) improving analgesia by allowing 
prolonged administration past the time at which a continuous infusion would have exhausted the anesthetic 
reservoir. 
 
8. 
PROGRESS REPORT 
Not applicable.  
 
9. 
RESEARCH DESIGN AND METHODS 
This will be a randomized, controlled investigation.  
 
Table of Events 
Postoperative Day 
Experimental? 
Event 
0 
Yes 
Written, informed consent 
0 
No 
Anthropometric information collected 
0 
No 
Ultrasound-guided popliteal-sciatic perineural catheter insertion 
0 
No 
Single-injection peripheral nerve block with ropivacaine 0.5% 
0 
Yes 
Randomization 
0 
No 
Ropivacaine 0.2% perineural local anesthetic administration begins 
0 
Yes 
Local anesthetic administered as basal or programmed bolus doses 
1-9 
Yes 
Patients contacted by phone to collect data 
5-8 
Yes 
Perineural catheters removed with reservoir exhaustion or Day 8 
 
 
Enrollment:  Consenting adults undergoing ulnar and/or radius fracture open reduction internal fixation or 
painful foot and/or ankle surgery with a planned infraclavicular or popliteal-sciatic perineural catheter insertion, 
respectively, will be offered enrollment.  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 #10 below. 
 
Preoperative Procedures: 


 
 
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SOC (mandated for study purposes):  Following written, informed consent, subjects will have baseline 
anthropometric information (e.g., age, sex, height, weight) collected and a sciatic perineural catheter inserted by 
a regional anesthesia fellow or resident under the direct supervision and guidance of a regional anesthesia 
attending (or by the attending him/herself). 
Per standard of care, all subjects will have an ultrasound-guided infraclavicular or popliteal-sciatic perineural 
catheter inserted as previously described.   
 
SOC (mandated for study purposes):  After catheter insertion, ropivacaine 0.5% (20 mL, with epinephrine) will 
be administered via the catheter under ultrasound visualization. Sensation in the brachial plexus or 
tibial/peroneal nerve distributions will be checked for anesthetic effect.  A “successful” regional block will be 
defined as sensory- and motor-block onset within the 30 minutes following the local anesthetic injection. 
 
A saphenous nerve block with ropivacaine 0.5% (and epinephrine) may or may not be provided, depending on 
the surgical procedure, per standard of care. 
 
Intraoperative: 
The initial local anesthetic bolus may provide complete surgical anesthesia for the procedure.  Patients who 
desire a general anesthetic or experience a partial block that is not adequate for surgical anesthesia will receive 
a general anesthetic, per standard of care. 
 
Randomization: 
Experimental:  Subjects will be randomized to one of two treatment groups: (1) titratable automated 
intermittent bolus or (2) continuous infusion in a computer generated 1:1 ratio using opaque envelopes opened 
only after successful catheter insertion is documented within 30 minutes of the local anesthetic injection. 
 
Postoperative Procedures: 
SOC (mandated for study purposes):  Following completion of the procedure in the operating room, an infusion 
pump (Infutronix, Natick, Massachusetts) with a 500 mL ropivacaine 0.2% reservoir will be attached to the 
perineural catheter.  For patients in the continuous infusion group, the pump will provide an 8 (infraclavicular) 
or 6 (sciatic) mL/h basal infusion and a 4 mL patient-controlled bolus with a 30-minute lockout (standard at 
UCSD). 
 
Experimental:  For patients in the titratable automated intermittent bolus group, the pump will provide an 
automatic 11 (infraclavicular) or 8 (sciatic) mL bolus once every 2 hours and have a 4 mL patient-controlled 
bolus with a 30 minute lockout. In addition, for those in the titratable automated intermittent bolus group, 
the infusion pump will be set in a “pause” mode that delays initiation of the automated bolus doses by 5 hours 
(this can be over-ridden by patients if they would like to initiate their perineural infusion earlier than 5 hours).  
Lastly, subjects in the titratable automated intermittent bolus group will be able to titrate the volume of their 
automated bolus up or down within the range of 1-16 mL. 
 
Per standard of care, the pump will not administer more than 20 mL during each hour (below the current 
UCSD maximum).  Prior to discharge, the functioning of the infusion pump will be explained, so that they 
understand that they should push the bolus button if they have pain.  This is accurate regardless of which 
treatment group the patient is randomized to, ensuring that all subjects will receive adequate analgesia. 
 
Experimental:  Subjects will be contacted via phone for the 9 days following surgery to collect information 
regarding surgical pain (Numeric Rating Scale of 0 to 10, with “0” being no pain and “10” being the worst pain 
ever experienced), analgesic use, sleep disturbances, infusion side effects, and satisfaction with pain control. 
When 500 mL has been infused or on Day 8—whichever comes first—subjects will remove the catheter and 


 
 
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place the pump in a pre-addressed and -stamped package for return [note that it is standard of care for patients 
to remove the catheters at home; but, listed as experimental here due to the timing of catheter removal which 
will be later than is standard of care due to the experimental local anesthetic administration protocol]. 
 
Data Acquisition [all experimental]: 
Data will be gathered from the patients’ electronic medical record, by telephone follow-up, and from the 
memory of each infusion pump.  Subjects will be contacted by phone for the 9 days following surgery.  Data 
will be recorded on paper Case Report Forms, including: patient name, medical record number, age, sex, 
height, weight, surgical procedure, data of procedure, anesthesiology attending overseeing/placing catheter, 
randomization number, whether a femoral/saphenous block was placed, if the catheter was placed per protocol, 
if the block set up successfully, intraoperative fentanyl, morphine and dilaudid, and the time of infusion 
initiation. 
Outcomes (End Points):  For the first 9 postoperative days, subjects will be asked to answer the questions with 
regard to the previous 24 hours:  opioid consumption, worst pain, average pain, least pain, current pain 
(Numeric Rating Scale for all pain scores), any numbness on extremity (scale 0=absent to 10=insensate), fluid 
leakage (yes/no), number of sleep disturbances due to pain (awakenings), satisfaction with analgesia (0=very 
dissatisfied, 10=very satisfied), the bolus volume for subjects in the titration group, and the seven questions of 
the Brief Pain Inventory’s Interference Scale.  The date and time of infusion completion will be recorded as will 
the reason for catheter removal (reservoir exhaustion vs. another reason). 
Statistics:  The infraclavicular and popliteal-sciatic groups will be analyzed separately as two distinct analyses.  
This study will be powered for two primary end points:  (1) the average NRS queried on postoperative day 1; 
and (2) the duration of treatment from when the infusion pump was initially turned on until the local anesthetic 
reservoir was exhausted [recorded by the infusion pump memory].  The dual hypotheses will be tested with a 
serial testing strategy, such that Hypothesis 2 will not be formally tested unless the conclusion of Hypothesis 1 
is at least “noninferiority”.  Following the approach described in Althunian et al, noninferiority will be assessed 
by comparing the lower limit of the 95% confidence interval for the difference (CB minus AB) on the NRS 
(range: 0 to 10) to a pre-specified noninferiority margin of 1.7 NRS units (see Figure 1). This will provide 
evidence that the analgesia provided by the novel automated boluses is no worse than 1.7 NRS units compared 
to CB. 
 
Noninferiority margin and framework for concluding noninferiority or not. Adapted from Althunian et al. 
Baseline characteristics of the randomized groups will be summarized with means, standard deviations, and 
quartiles. Balance between groups will be assessed following the approach described by Schober, et al. 


 
 
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Specifically, standardized differences will be calculated using Cohen’s d whereby the difference in means or 
proportions is divided by the pooled standard deviation estimates. Any key variables (age, sex, height, weight, 
and BMI) with an absolute standardized difference >0.47 (based on Austin, 2009 with 1.96×√(2/n)=0.47) will 
be noted and included in a linear regression model to obtain an estimate of the treatment group differences 
adjusted for the imbalanced covariate(s). If residuals from the linear regression indicate violations of key 
assumptions (i.e. homoscedasticity or Guassian distribution), data transformations and/or alternative 
generalized linear models will be applied as appropriate. 
Secondary outcomes will also be analyzed by Wilcoxon-Mann-Whitney test, or linear models (or generalized 
linear models) as appropriate with covariates for any imbalanced covariates. No multiplicity adjustments will 
be applied for these analyses.  End points will be analyzed for each day (e.g., opioid consumption on Day 2) as 
well as all days combined (e.g., cumulative opioid consumption Days 1-9). 
Sample size estimate:  Power is simulated based on the distribution of pain measured with the Numeric Rating 
Scale (NRS) observed in the “Above bifurcation” group in Monahan, et al. (Anesth Analg 2016;122:1689-95) 
for the sciatic catheter group.  For the infraclavicular group, we simulated NRS scores from the basal/bolus 
treatment from Ilfeld et al. (Anesthesiology 2004;100:395-402).  Specifically, we simulate NRS scores from a 
discrete distribution as depicted in Figure 1, panel A (infraclavicular) and Figure 2 (sciatic).  This results in an 
expected interquartile range of approximately 1 to 4, and a median of approximately 3 NRS units. We 
simulated 1000 trials in which the two groups, n=35 per group, were assumed to follow the same discrete 
distribution, submitted each trial to a Wilcoxon-Mann-Whitney test, and derived 95% confidence intervals 
(Bauer 1972; Hothorn, et al. 2008). Out of the 1000 trials, 792 (79.2%) correctly resulted in a conclusion of 
non-inferiority; suggesting that the probability that the trial correctly concludes non-inferiority is about 80% 
when the groups follow exactly equivalent distributions.   


 
 
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Discrete distribution used for simulations based on the distribution observed in the Above Bifurcation group in 
Monahan, et al. 
If the test for Hypothesis 1 concludes noninferiority (scenario A, B, or C in Figure 1), we will test for a 
difference in overall duration of administration again using the Wilcoxon-Mann-Whitney test. 
Power is approximated by a two-sample t-test calculation. Assuming a standard deviation of SD=37 hours 
(corresponding to an interquartile range of 50 to 100 hours), we expect that a sample size of n=35 provides 
80% power to detect a mean group difference of 25 hours with a two-sided alpha of 5%. 
Total enrollment:  70 subjects plus 30 for misplaced catheters or subjects otherwise unable to be randomized; 
and subjects who withdraw for both infraclavicular and popliteal-sciatic groups.  This allows for a possible total 
of 200 subjects total. 
Total  
10. 
HUMAN SUBJECTS 
Inclusion criteria: (1) patients undergoing ulnar and/or radial fracture open reduction internal fixation or 
painful foot and/or ankle surgery with a planned infraclavicular or popliteal sciatic perineural catheter, 
respectively, for postoperative analgesia; and (2) age 18 years or older. 
 
Exclusion criteria:  (1) Daily opioid use within the previous 4 weeks; (2) clinical neuro-muscular deficit of 
either the brachial plexus (infraclavicular) or sciatic nerve (sciatic catheters) and its branches and/or innervating 
muscles; (3) morbid obesity [body mass index > 35 kg/m2]; surgery outside of the ipsilateral sciatic and 
saphenous nerve distributions for sciatic catheters [e.g., iliac crest bone graft]; (5) pregnancy [as determined by 


 
 
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a urine pregnancy test prior to any study interventions]; and (6) incarceration.   
 
11. 
RECRUITMENT AND PROCEDURES PREPARATORY TO RESEARCH 
Patients will be identified by the investigators as part of their routine preoperative care:  we—as 
anesthesiologists—meet with patients the morning (or early afternoon) of the surgery to review the history, 
perform a physical exam, and discuss the anesthetic/analgesic plan with the patients.  Therefore, possible 
candidates will be identified by the investigators as part of their routine medical care.  Patients will be 
“approached” regarding the study as part of this routine preoperative meeting.  Non-investigators 
(anesthesiologists, surgeons, and others) will not be involved in recruiting, and no recruiting materials will be 
displayed/dispersed (e.g, email blast, posters), other than the IRB-approved informed consent form.  The 
investigators are all regional anesthesiologists (save the program manager Baharin Abdullah) who will identify 
potential participants when they come in for their scheduled surgery.  One important inclusion criterion is that 
patients are having a perineural catheter and postoperative local anesthetic administration; and, this won’t be 
known until the investigators meet with the patients to review their history (standard of care) and subsequently 
discuss the possibility of the perineural catheter and infusion for patients who qualify for this treatment. 
 
12. 
INFORMED CONSENT 
The investigators are NOT going to review medical records for study purposes prior to signed consent—the 
investigators are regional anesthesiologists who will be providing normal, routine care and will review the 
records for purposes of standard patient care will ask patients if they are interested in study participation. 
If the patient is interested, then either the anesthesiologist will provide informed consent (written consent with 
an IRB-approved ICF if patient desires enrollment) or will gain permission from patients for a research 
coordinator (i.e., Program Manager Baharin Abdullah) to provide informed consent.  In this way, HIPAA 
regulations will be adhered to.  Importantly, subjects will have enough time to consider whether or not they 
want to participate even though consenting is done right before the procedure:  patients usually have an extra 
hour prior to surgery since they are brought in early enough that even if the surgeon is working far ahead of 
schedule, the case will not be delayed.  The result is a good deal of time for nearly all patients waiting prior to 
surgery.  If any patient does not have adequate time, they will not be enrolled in the study.  If a patient desires 
study participation, written, informed consent will be obtained.  An investigator or research coordinator 
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 
The alternative is not to participate. No patients will be coerced to participate in any way. Patients who decline 
enrollment will receive normal standard of care treatment.  
 
14. 
POTENTIAL RISKS 
Associated with standard-of-care: 
1.  Pain or discomfort during catheter insertion 
2.  Bleeding during catheter insertion 
3.  Local anesthetic toxicity from the initial nerve block or postoperative administration 
4.  Infection at the catheter insertion site 
5.  Nerve injury from either the initial nerve block or subsequent local anesthetic administration 
 
Associated specifically with study participation: 
6.  Disappointment one was not randomized to a desired treatment group 
7.  One treatment group might do better than the other 


 
 
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8.  Loss of confidentiality 
 
15. RISK MANAGEMENT PROCEDURES AND ADEQUACY OF RESOURCES 
1.  Pain or discomfort during catheter insertion.  Participants will be given intravenous midazolam and fentanyl, 
titrated to effect to minimize discomfort yet keep the participant responsive to verbal cues throughout the 
procedure. 
2.  Bleeding during catheter insertion.  Ultrasound guidance is used to identify and avoid any blood vessels. 
3.  Local anesthetic toxicity from the initial nerve block or postoperative administration.  Ultrasound guidance 
will be used to identify the target nerve and observe local anesthetic bolus administration; aspiration is always 
performed every 2-5 mL of local anesthetic injected as a bolus by anesthesiologists (to check for heme which 
would indicated a possible intravascular catheter).  Epinephrine is included in all local anesthetic used for 
single-injection peripheral nerve blocks which acts as an early indicated of an intravascular injection with 
hypertension, tachycardia, or bradycardia (due to hypertension).  Lipid emulsion is the standard treatment for 
local anesthetic toxicity and is kept on every regional anesthesia cart.  For the postoperative local anesthetic 
administration, the total volume of ropivacaine 0.2% will be less than 20 mL/hour. 
4.  Infection at the catheter insertion site.  Sterile technique will be used during catheter insertion, including the 
use of chlorhexidine skin preparation, a sterile drape, a sterile sleeve on the ultrasound transducer, and sterile 
gloves used by the anesthesiologists (along with a surgical mask and hat).  Signs and symptoms of infection 
will be inquired upon by the investigator daily. 
5.  Nerve injury from either the initial nerve block or subsequent local anesthetic administration.  An ultrasound 
is used to guide the block needle adjacent to the target nerve while avoiding nerve penetration; and, 
postoperatively, the total volume of ropivacaine 0.2% will be less than 20 mL/hour.  Patients will be instructed 
on removing the catheter by telephone. 
6.  Disappointment one was not randomized to a desired treatment group.  There is nothing we can do to avoid 
this risk. 
7.  One treatment group might do better than the other.  Surgical patients are always provided with a 
prescription for opioids to take as needed. 
 
16. PRIVACY AND CONFIDENTIALITY CONSIDERATIONS INCLUDING DATA ACCESS AND MANAGEMENT 
The following study procedures will be done to maintain confidentiality of this study.  Potential patients will be 
identified during the preoperative interview by investigators.  Enrollment forms (the first page of the uploaded 
case report forms) will include the patients’ names and randomization numbers; and, data collected 
subsequently (second page of the uploaded case report forms) will include only the randomization number and 
subject initials.  Hard copies of consent forms will be kept in a locked UCSD medical office on UCSD property 
and the patients’ own medical charts.  The data collection forms will also be kept in a locked medical office. 
Any digitized records will be stored in encrypted files on password-protected UCSD-networked and owned 
computers.  Drs. Finneran, Ilfeld, and Abdullah will have access to the code key, and Dr. Ilfeld will determine 
who gets access to it as well as the coded study data. 
 
17. POTENTIAL BENEFITS 
There is the potential for participants who are randomized to the programmed intermittent bolus group to 
receive improved analgesia and/or analgesia for a longer duration.  However, future patients may benefit if we 
determine that one method of local anesthetic infusion provides superior analgesia compared with the other.  In 
addition, current subjects may benefit if they require future surgery with a continuous popliteal sciatic nerve 
block. 
 
18. RISK/BENEFIT RATIO 
The medical risks to participants and the risk of confidentiality loss have been minimized.  The benefits to 


 
 
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society and future patients are potentially significant since there currently may be thousands of patients 
receiving less-than-optimal analgesia after painful orthopedic surgery and therefor requiring more opioid 
analgesics. 
 
19. EXPENSE TO PARTICIPANT 
All study procedures that are the same as standard care will be billed to the subject or their insurance.  The study 
will be covering the costs of creating the case report forms and the telephone calls.  The infusion pumps are being 
donated by the manufacturer and the participants are not responsible for potential damage or loss of the disposable 
infusion pumps. 
 
20. COMPENSATION FOR PARTICIPATION 
None. 
 
21. PRIVILEGES/CERTIFICATIONS/LICENSES AND RESEARCH TEAM RESPONSIBILITIES 
The Principal Investigator, Brian M. Ilfeld, MD, MS, is a board-certified anesthesiologist with fellowship training 
in and 20 post-training years of experience with regional anesthesia and perineural local anesthetic infusion.  Dr. 
Ilfeld holds a license to practice medicine in California.  Dr. Ilfeld also has medical privileges at the UC Medical 
Centers.   
 
Drs. Finneran, Gabriel, Said, Curran, Chandrabose and Swisher are board-certified anesthesiologists with 
fellowship training in and multiple post-training years of experience with regional anesthesia and perineural local 
anesthetic infusion. All of these individuals hold active licenses to practice medicine in California and medical 
privileges to practice at UCSD Medical Centers.  Baharin Abdullah, MD, is the Program Manager for this project 
and extensive training and experience as a research coordinator and regulatory specialist at the UC San Diego 
CTRI.  She should be given access to the documents on the IRB website so that he can help manage the IRB 
submission and regulatory documents. 
 
One of the investigators or another UCSD regional anesthesia faculty member with similar training/experience in 
perineural techniques, will either place or supervise a resident/fellow placing all perineural catheters. 
 
22. BIBLIOGRAPHY 
1. Ilfeld BM: Continuous peripheral nerve blocks: An update of the published evidence and comparison with 
novel, alternative analgesic modalities. Anesth Analg 2017; 124: 308-335 
2. Taboada M, Rodríguez J, Bermudez M, Amor M, Ulloa B, Aneiros F, Sebate S, Cortés J, Alvarez J, 
Atanassoff PG. Anesthesiology 2009; 110: 150-4.  
3. Monahan AM, Madison SJ, Loland VJ, Sztain JF, Bishop ML, Sandhu NS, Bellars RH, Khatibi B, 
Schwartz AK, Ahmed SS, Donohue MC, Nomura ST, Wen CH, Ilfeld BM: Continuous Popliteal Sciatic 
Nerve Blocks: Does Varying Perineural Catheter Location Relative to the Sciatic Bifurcation Influence 
Block Effects? A Dual-Center, Randomized, Subject-masked, Controlled Clinical Trial. Anesth Analg 2016; 
122 (5): 1689-95 
4. Hamdani M, Chassot O, Fournier R: Ultrasound-guided continuous interscalene block: the influence of 
local anesthetic background delivery method on postoperative analgesia after shoulder surgery: a 
randomized trial. Reg Anesth Pain Med 2014; 39: 387-93 
5. Oxlund J, Clausen AH, Veno S, Nielsen MD, Pall M, Strom T, Toft P: A randomized trial of automated 
intermittent ropivacaine administration vs. continuous infusion in an interscalene catheter. Acta 
Anaesthesiol Scand 2018; 62: 85-93 
6. Khatibi B, Said ET, Sztain JF, Monahan AM, Gabriel RA, Furnish TJ, Tran JT, Donohue MC, Ilfeld BM: 
Continuous Transversus Abdominis Plane Nerve Blocks: Does Varying Local Anesthetic Delivery Method-


 
 
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Automatic Repeated Bolus Versus Continuous Basal Infusion-Influence the Extent of Sensation to Cold?: A 
Randomized, Triple-Masked, Crossover Study in Volunteers. Anesth Analg 2017; 124: 1298-1303 
7. Rao Kadam V, Van Wijk RM, Moran JL, Ganesh S, Kumar A, Sethi R, Williams P: Continuous transversus 
abdominis plane block vs intermittent bolus for analgesia after abdominal surgery: a randomized trial. J Pain 
Res 2017; 10: 1705-1712 
8. Holmes R, Smith SR, Carroll R, Holz P, Mehrotra R, Pockney P: Randomized clinical trial to assess the 
ideal mode of delivery for local anaesthetic abdominal wall blocks. ANZ J Surg 2018; 88: 786-791 
9. Charous MT, Madison SJ, Suresh PJ, Sandhu NS, Loland VJ, Mariano ER, Donohue MC, Dutton PH, 
Ferguson EJ, Ilfeld BM: Continuous femoral nerve blocks: Varying local anesthetic delivery method (bolus 
versus basal) to minimize quadriceps motor block while maintaining sensory block. Anesthesiology 2011; 
115: 774-81 
10. Jaeger P, Baggesgaard J, Sorensen JK, Ilfeld BM, Gottschau B, Graungaard B, Dahl JB, Odgaard A, 
Grevstad U: Adductor Canal Block With Continuous Infusion Versus Intermittent Boluses and Morphine 
Consumption: A Randomized, Blinded, Controlled Clinical Trial. Anesth Analg 2018; 126: 2069-2077 
11. Monahan AM, Sztain JF, Khatibi B, Furnish TJ, Jaeger P, Sessler DI, Mascha EJ, You J, Wen CH, 
Nakanote KA, Ilfeld BM: Continuous adductor canal blocks: Does varying local anesthetic delivery method 
(automatic repeated bolus doses versus continuous basal infusion) influence cutaneous analgesia and 
quadriceps femoris strength? A randomized, double-masked, controlled, split-body volunteer study. Anesth 
Analg 2016; 122: 1681-8 
12. Hillegass MG, Field LC, Stewart SR, Borckardt JJ, Dong L, Kotlowski PE, Demos HA, Del Schutte H, 
Reeves ST: The efficacy of automated intermittent boluses for continuous femoral nerve block: a 
prospective, randomized comparison to continuous infusions. J Clin Anesth 2013; 25: 281-8 
13. Chong MA, Wang Y, Dhir S, Lin C: Programmed intermittent peripheral nerve local anesthetic bolus 
compared with continuous infusions for postoperative analgesia: A systematic review and meta-analysis. J 
Clin Anesth 2017; 42: 69-76 
14. Jagannathan R, Niesen AD, D'Souza RS, Johnson RL: Intermittent bolus versus continuous infusion 
techniques for local anesthetic delivery in peripheral and truncal nerve analgesia: the current state of 
evidence. Reg Anesth Pain Med 2019; 44: 447-451 
15. Ilfeld BM, Gabriel RA: Basal infusion versus intermittent boluses for perineural catheters: should we take 
the 'continuous' out of 'continuous peripheral nerve blocks'? Reg Anesth Pain Med 2019 
 
 
Statistical references: 
• Althunian TA, de Boer A, Groenwold RHH, Klungel OH. (2017). Defining the noninferiority margin and 
analysing noninferiority: An overview. British Journal of Clinical Pharmacology. 83, 1636–1642. 
• Monahan AM, et al. (2016). Continuous Popliteal Sciatic Blocks: Does Varying Perineural Catheter Location 
Relative to the Sciatic Bifurcation Influence Block Effects? A Dual-Center, Randomized, Subject-Masked, 
Controlled Clinical Trial. Anesth Analg. 122, 1689-96. PMID: 26962712. 
• Bauer, D. F. (1972). Constructing confidence sets using rank statistics. Journal of the American Statistical 
Association 67(339), 687–690. doi: 10.1080/01621459.1972.10481279 
• Hothorn T, Hornik K, van de Wiel MA, Zeileis A (2008). Implementing a class of permutation tests: The coin 
package. Journal of Statistical Software, 28(8), 1-23. doi: 10.18637/jss.v028.i08 (URL: 
https://doi.org/10.18637/jss.v028.i08). 
• Austin, P C (2009). Balance Diagnostics for Comparing the Distribution of Baseline Covariates between 
Treatment Groups in Propensity-Score Matched Samples. Statistics in Medicine, 28(25), 3083-3107. 
 
 
23. FUNDING SUPPORT FOR THIS STUDY 
This is an unfunded clinical trial.  The manufacturer of the infusion pumps, Infutronix, is donating the 


 
 
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disposable infusion pumps. 
 
24. BIOLOGICAL MATERIALS TRANSFER AGREEMENT 
Not applicable. 
 
25. INVESTIGATIONAL DRUG FACT SHEET AND IND/IDE HOLDER 
Not applicable.  
 
26. IMPACT ON STAFF 
There will be minimal impact on staff as the patients will be receiving standard of care procedures. Drs. Ilfeld 
and Finneran are provided time by the UCSD Department of Anesthesiology for clinical investigations.  
 
27. CONFLICT OF INTEREST 
Over the last three years, Drs. Finneran, Swisher, Gabriel, Said, Chandrabose, Curran and Ilfeld:  The 
University of California has received funding and product for other research projects from cryoneurolysis 
device manufacturer Epimed International (Farmers Branch, TX); infusion pump manufacturer Infutronics 
(Natick, MA); and a manufacturer of a peripheral nerve stimulation device, SPR Therapeutics (Cleveland, OH). 
 
28. SUPPLEMENTAL INSTRUCTIONS FOR CANCER-RELATED STUDIES 
Not applicable.  
 
29. OTHER APPROVALS/REGULATED MATERIALS 
Not applicable.  
 
30. PROCEDURES FOR SURROGATE CONSENT AND/OR DECISIONAL CAPACITY ASSESSMENT 
Not applicable.