Clinical trial NCT02950558
Conditions: Chronic Pain Ankle Fracture Surgery Regional Anesthesia
Sponsor: University of Cincinnati
Start date: 2018-05-29; Completion date: 2020-06-19
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pilot study will test the hypothesis that prolonged regional peripheral nerve block will reduce development of chronic pain in patients undergoing surgery for ankle fracture compared to standard of care. Subjects will be followed for one year.

Detailed description:
This pilot study will test the hypothesis that prolonged regional peripheral nerve block will reduce development of chronic pain in patients undergoing surgery for ankle fracture. Regional nerve block using local anesthetics delivered by ambulatory pump is used in some types of surgeries but is not routine for ankle fracture patients in our hospitals. Patients will be randomized to standard care (single shot peripheral nerve block prior to surgery) or experimental (the same single shot nerve block, followed by continuous popliteal nerve block with ropivacaine starting just after surgery). The primary outcome will be scores on a validated ankle/foot pain questionnaire that includes questions on function. Subjects will be followed for one year. Secondary outcome will be postoperative opioid use.

Arms: arm 1: Single injection of ropivacaine immediately prior to surgery arm 2: Single injection of ropivacaine immediately prior to surgery plus 5 day ambulatory popliteal nerve block.
Interventions: intervention 1: Ropivacaine intervention 2: Nerve block
Intervention descriptions: intervention 1: Single injection of ropivacaine immediately prior to surgery. intervention 2: insertion of catheter to deliver continuous 5 day popliteal sciatic nerve block using a disposable ambulatory pain pump.

Protocol documents:
Prot_001.pdf: 
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Study Title: Pilot Study: Extended Regional Anesthesia to Prevent Chronic Pain 
After Ankle Fracture Surgery 
Protocol date: 11/30/2018 
NCT number: NCT02950558 
 
 


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Study Title: Pilot Study: Extended Regional Anesthesia to Prevent Chronic 
Pain After Ankle Fracture Surgery 
Research Team: 
Principal Investigator: Jun-Ming Zhang 
 
 
 
 
Sponsor: 
US Air Force 711th HPW (DOD)   
 
 


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1. Length of time for research 
a. data collection completion: 1 year 6 months 
b. data analysis and report writing/publication:6 months 
 
2. Research Location(s): University of Cincinnati Medical Center (UCMC), Holmes 
Hospital (UCMC), West Chester Hospital  and UC Medical Science 
Building/CARE Crawley 
 
3. Abstract/Brief Overview: 
Chronic pain affects over a third of adults in the United States.  Trauma and 
surgery are common precipitating causes of some chronic pain conditions, and 
up to 81% of combat trauma survivors have chronic pain.  For many patients 
current treatments are ineffective. Preclinical studies suggest that blocking 
peripheral nerve activity early after a precipitating injury, for 5 – 7 days, can 
prevent chronic pain development. This pilot study will test the hypothesis that 
prolonged regional peripheral nerve block will reduce development of chronic 
pain in patients undergoing surgery for ankle fracture.  Regional nerve block 
using local anesthetics delivered by ambulatory pump is used in some types of 
surgeries but is not routine for ankle fracture patients in our hospitals.  Patients 
will be randomized to standard care (single shot peripheral nerve block prior to 
surgery) or experimental (the same single shot nerve block, followed by 
continuous popliteal nerve block with ropivacaine starting just after surgery).  The 
primary outcome will be scores on a validated ankle/foot pain questionnaire that 
includes questions on function.  Subjects will be followed for one year.  
Secondary outcome will be postoperative opioid use.  
4. Purpose of Study: (including specific aims and hypothesis) 
This is a pilot study that will begin to test the hypothesis that 5 day regional nerve 
block will reduce chronic pain after ankle fracture surgery.  Specific Aims are: 
1. 
Enroll subjects undergoing ankle fracture surgery and randomize to 
receive standard-of-care single shot nerve block or the same block 
plus 5 day regional nerve block. . 
2. 
Follow-up subjects to obtain pain ratings related to the operated ankle, 
and screen for potential problems. 
 
5. Background:  
Preclinical studies:  When nerves are injured or transected, abnormal 
spontaneous activity develops at the injury site and within the cell bodies of the 
peripheral sensory nerves [1, 2 , 3].  A wealth of preclinical research studies [4, 
5] including many from our laboratory [6-9], using a variety of pain models, shows 
that blocking this spontaneous activity early after the injury, for 5 to 7 days, 
strongly reduces or completely prevents development of chronic pain behaviors 


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and other long-lasting cellular abnormalities.  This literature suggests that pre-
emptive peripheral analgesia, applied in conditions with a known initiating event 
such as surgery or trauma, should be highly effective in reducing chronic pain.  
However, clinical studies of pre-emptive analgesia have had mixed results.  We 
propose that the failures in such studies are in part due to a disconnect between 
the preclinical and clinical studies.  Specifically:  (1) Many clinical studies of pre-
emptive analgesia have used primarily centrally acting analgesics such as 
opioids, which preclinical studies suggest would not be effective in blocking the 
critical changes and spontaneous activity occurring in peripheral sensory nerves 
and cell bodies.  (2)  Many clinical studies used pre-emptive analgesics for only 1 
– 3 days, while preclinical studies suggest 5 – 7 days may be necessary to block 
development of chronic pain[6]. 
 
Clinical studies:  Regional anesthesia techniques provide an excellent method for 
blocking nerve signals where they originate, in the peripheral nerve, which 
preclinical research suggests should be ideal for blocking development of chronic 
pain, in addition to blocking acute pain in the immediate post-operative period 
and reducing postoperative opioid use with its concomitant problems.  Trauma 
care, rather than surgical care, has led the way in adopting regional anesthesia 
methods.  Military medicine has been a leader in this regard, improving regional 
anesthesia and introducing it into field hospitals and enroute care, revolutionizing 
the care of soldiers injured in combat in the Iraq and Afghanistan conflicts [10, 
11].  Military medicine studies have demonstrated the safety and efficacy of 
regional anesthesia for combat wounds, especially for managing surgical and 
acute postoperative pain [12, 13].  However, controlled research on the 
effectiveness of regional anesthesia in preventing development of chronic pain 
syndromes is difficult in the combat situation.  Many wounded soldiers have had 
regional anesthesia lasting at least 5 – 7 days, without serious anesthetic 
complications, but under field conditions the interval between injury and starting 
regional anesthesia could not be controlled or in some cases even documented, 
the duration of regional anesthesia was not controlled, and long term follow-up 
was not always conducted to investigate chronic pain development.   This pilot 
study will more systematically test the hypothesis that local nerve blockade will 
reduce the incidence of chronic pain following ankle fracture surgery.  Ankle 
fracture, which was chosen as a defined proxy for peripheral trauma, results in a 
relatively high incidence of chronic pain conditions which have important long 
term negative effects on quality of life in 20% to 50% of patients [14-16]. 
 
Significance: Chronic pain affects over a third of adults in the United States, and 
for many patients treatments are ineffective [17]. Up to 81% of survivors of 
combat trauma have chronic pain conditions [18].  Trauma and surgery can be 
precipitating causes of chronic pain syndromes.  This pilot study will test the 
hypothesis that regional anesthesia continued for a longer time than commonly 
used, may reduce the incidence of chronic pain conditions.  If successful and 
confirmed in a larger study this work will contribute to readily implemented 


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changes in medical practice that may reduce development of chronic pain 
conditions after trauma and surgery. 
6. Study design:  
 
This is an investigator-initiated, single-center, prospective, non-blinded, 
randomized pilot study.  We are requesting authorization to enroll up to 60 
patients to allow for 40 evaluable subjects.     
Adults undergoing surgery for open reduction and internal fixation for traumatic 
ankle fracture will be invited to participate in the study comparing the 2 forms of 
nerve block.  All patients are currently given the option of popliteal nerve block 
(single injection of ropivacaine given just prior to surgery), which helps provide 
pain relief in the immediate postoperative period; the surgery itself is done under 
general anesthesia.  Participants who have agreed to have the single shot 
procedure will be randomized into the control group (standard-of-care single 
injection of local anesthetic just prior to surgery) or experimental group (standard-
of-care single injection plus 5 day ambulatory popliteal nerve block).  
 
Standard-of care procedures for placement of the popliteal nerve block are as 
follows: The blocks are performed in the Same Day Surgery (Pre Op Holding 
Area), by Anesthesia Residents with direct supervision by Anesthesia Attending 
Faculty. All residents performing blocks are at training level PGY2 (second year 
resident) or above. Monitors utilized for block placement will be EKG, SpO2,  and 
Non Invasive Blood Pressure monitor. Standard ASA monitors are on the patient 
for the block. Supplemental oxygen is in every room as needed. A Code Cart is 
readily available in SDS and PACU for resuscitative measures if needed (rescue 
medications, ACLS Medication). A Lipid rescue agent (20% Intralipid solution) is 
available at all times in the OR Pharmacy (right next to Same Day Surgery). A 
difficult airway cart is available in PACU and SDS as well for any need for 
managing the airway.  If there is a minor vascular injury (inadvertent needle 
puncture of the artery) the needle is repositioned prior to the injection. The single 
injection for popliteal nerve block generally consists of 20 ml of 0.5% ropivacaine. 
As part of standard care, patients sign a separate clinical consent form 
specifically for lower limb nerve block procedures.  
 
 
In the experimental group, in addition to the standard single shot nerve block, 
subjects will receive a catheter to deliver continuous 5 day popliteal sciatic nerve 
block using a disposable ambulatory pain pump.  The catheter will be inserted 
starting just prior to surgery. This procedure is readily added on to the procedure 
for single injection, which involves ultrasound (and in some cases nerve 
stimulation) guidance for insertion of a needle near the sciatic nerve at the 
popliteal fossa.  As part of standard care for administering a peripheral nerve 
block, sedatives are administered on as needed basis. Typically the patient will 
receive midazolam 1 mg every 5 minutes as needed.  The catheter is inserted 


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just after the nerve block injection, during the same procedure and using the 
same needle placement.  If there is a major vascular injury during the catheter 
placement (placement of the peripheral nerve catheter into the artery as 
confirmed by withdrawal of blood from the catheter itself), the catheter will be 
withdrawn and the subject will not receive a pump. An ambIT portable pump (as 
currently used in the participating hospitals after some other types of surgeries) 
will be attached to the catheter at the time the block is placed, and continuous 
block with 0.2% ropivacaine will begin immediately after surgery. The drug 
delivery rate will be 6 mL/hour.  An 800 mL bag of medication will be provided to 
the subjects to allow medication for a 5 day period without requiring the subject 
to return to the clinic for refill. This drug delivery rate is on the lower end of the 
range commonly used in our hospitals for patients taking home pumps after other 
types of surgeries, which are usually started at 8 mL/hour with the option of 
patient controlled boluses.  Previous clinical studies examined infusion rates of 6 
to 14 mL/hour.  The lower, fixed rate was chosen for this study to help avoid 
toxicity, since the duration of the pump is longer than commonly used at our 
hospitals.  The goal based on preclinical studies is to block abnormal 
spontaneous activity from the sensory nerves, which requires a lower dose than 
complete sensory block.  The selected infusion rate should also avoid motor 
block.  The daily dose will be 384 mg; the FDA data sheet [19] indicates that a 
cumulative dose of up to 770 mg over 24 hours is well tolerated and studies 
indicate that the peak systemic levels during prolonged infusion occur after 
approximately 3 days[12].   
 
Subjects with more medial ankle fractures, in whom some of the affected region 
may lie outside of the popliteal distribution, will be eligible for the study.  As part 
of standard care, such patients generally receive either a second single shot 
nerve block (saphenous) or rely on opioid anesthesia, depending on the 
preference of the anesthesiologist.  Such patients will still receive only a popliteal 
continuous nerve block after the surgery.  Since preclinical and clinical studies 
indicate that chronic pain rarely develops in purely sensory nerves such as the 
saphenous, we consider it consistent with the primary hypothesis to include such 
patients.  The characterization of the fracture will be included in the clinical 
information captured by the study. 
 
The infusion pumps and 800 mL bags of ropivacaine will be provided by the UC 
Health Investigational Pharmacy at the University of Cincinnati Medical Center. 
The ropivacaine 0.2% 800 mL bags will be compounded by certified pharmacy 
technicians and registered pharmacists in a certified ISO Class 5 biologic safety 
cabinet within an ISO Class 7 buffer room at the University of Cincinnati Medical 
Center consistent with USP 797 standards and American Society of Health-
System Pharmacists (ASHP) guidelines [20]. The bags will be prepared by 
combining four, sterile, preservative-free, commercially available ropivacaine 
0.2% 200 mL bags/bottles[21] (stable at controlled room temperature up to 
manufacturer’s expiration date) into a 1,000 mL empty sterile bag (e.g., Baxter 
Viaflex bag) using a single sterile fluid transfer set. Using aseptic technique, the 


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infusion spike of the sterile fluid transfer set will be inserted into each commercial 
bag/bottle to drain completely (including any overfill) into the empty sterile bag 
via single needle manipulation of the injection port. After the fourth bag/bottle is 
drained, the needle and transfer set will be disconnected from the compounded 
bag, and the injection port will be aseptically covered with a foil seal. A total of 4 
to 8  ropivacaine 800 mL bags will be batched at a time. Compounded 
ropivacaine 0.2% 800 mL bags will be dispensed by the inpatient investigational 
pharmacy following a patient-specific order from a research provider. 
 
There are no additives in the final ropivacaine 800 mL bag that would affect 
stability beyond that of the commercial product. In order to ensure the sterility of 
the ropivacaine during the 5 days of use, the following procedure will be used: 
The final ropivacaine 800 mL bags will be considered medium-risk compounded 
sterile products (CSP). In lieu of a separate sterility test, USP 797 guidance 
indicates medium-risk CSPs should have a beyond use date (BUD) of 30 hours 
when stored at room temperature. To extend the BUD, sterility testing will be 
performed on each batch of  ropivacaine 800  mL bags. Two of the bags in each 
batch will be tested for sterility using the QT JuniorTM System (Q.I. Medical, Inc., 
Grass Valley, CA, USA), which utilizes a 0.22-micron filtration set and fluid 
thioglycollate growth media [22]. The batched bags will remain quarantined 
before use for 14 days after preparation. On day 14, the QT systems being 
incubated from the 2 tested bags will be visually inspected for turbidity per the 
manufacturer instructions. If no turbidity is seen (i.e., negative growth) at day 14, 
then the batched bags will be released for dispensing for an additional 14 days 
(i.e., 28 days total from preparation: 14 days quarantined plus 14 days post-
release) while being stored at controlled room temperature in the investigational 
pharmacy until dispensed or expired. Released bags will only be dispensed if the 
BUD does not extend beyond the planned 5-day therapy for a specific patient. 
Following the patient-specific dispense, the ropivacaine bag and pump will be 
connected directly to the nerve block catheter at the time the catheter is inserted, 
in the same day surgery area immediately after the single popliteal nerve block is 
administered.  The catheter will be infused using a commercially available 
ambulatory infusion pump consistent with standard clinical care.  Infusion will 
begin immediately after the surgery, when the patient is in the PACU. 
 
Subjects will be contacted by phone each day by the study nurse or other clinical 
study member.  The script to be used for this follow-up is provided in a separate 
document.   This allows monitoring for post-operative analgesic use, toxicity, 
infection, or other problems related to the use of the pump, and for reminders 
about when and how to remove the catheter. 
 
The treatment will be open label due to the impracticality of blinding the physician 
or patient to the presence of local anesthetic in the 5 – day pump and the ethical 
barriers to subjecting patients to implantation of a catheter and empty or saline 
pump with no benefit to them. Per standard of care, patients in both the 


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experimental and control groups will also have other oral pain medications 
prescribed for use as needed.  
 
Additional data routinely obtained for clinical purposes will also be collected 
including demographic variables, opioid use in the PACU, pain medications 
prescribed at discharge, and type of ankle fracture. Standard database templates 
will be used to record information from the medical record where appropriate. 
 
The patients randomized to the 5 day pump group will be undergoing an 
experimental procedure: ambulatory pumps for peripheral nerve block (including 
popliteal) are already successfully used in our clinics (with patients taking the 
pumps home and doing the removal of the catheter there) in the context other 
surgeries; but this is not routinely done for ankle fracture surgery nor for the 
indication of preventing development of chronic pain.  In addition, normally the 
pumps are used for a shorter period of time.   
 
The standard follow-up appointments with the orthopedic surgeons following 
ankle surgeries are at 10 - 14 days,  5 – 6 weeks, and 3 – 4 months.  These visits 
will allow for monitoring of unexpected problems in patients receiving the pumps.  
In order to have consistent monitoring, a single orthopedic doctor will review the 
charts of all the enrolled patients in the experimental group on a regularly 
scheduled basis (at least monthly).    As per our grant proposal patient charts will 
be reviewed for up to 3 months after use of the pumps. In addition, Dr. William 
Hurford will act as medical monitor for the study.  He will review subject’s 
research data and adverse events to ensure patient safety. The medical monitor 
will have the power to temporarily or permanently halt enrollment, if it is deemed 
that patient safety is compromised. 
 
Subjects will be contacted at approximately 14 days and 3, and 6, and 12 months 
following the surgery to complete a pain questionnaire, the SEFAS (Self-
Administered Foot and Ankle Questionnaire). The SEFAS is designed to 
evaluate disorders of the foot and ankle.  It does not require physician input, and 
a study of its use after surgery found it to be a valid, reliable, and responsive 
patient-oriented outcome measure [23].  It consists of 12 questions focusing 
primarily on pain and its functional impact on daily life activities [24], meeting the 
new recommendations to use functional and patient centered outcomes in clinical 
research on pain [25].  Subjects will also be asked to provide information about 
their medication use including pain medications, at each of these time points.  
The consent form is structured to allow access to the medical records to obtain 
information about relevant clinical variables such as medications prescribed, 
complications, and diagnoses of chronic pain conditions.   
 
The follow-up contacts to obtain questionnaire data will be made according to the 
subject’s preferred contact method.  Surveys will be available for subjects to 
complete on the internet, or via paper copy mailed to them or via telephone, as 
per their preference.  For survey time points that coincide with the orthopedic 


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doctor’s follow-up, Dr. Southam, the orthopedic surgeon involved with the study, 
may administer the survey.  
7. Research data collection/study procedures:  
 
 
Encounters:  Consent and randomization will occur before the ankle surgery.  For 
subjects in the experimental group, the catheter will be inserted just before 
surgery in conjunction with the standard-of-care single shot popliteal nerve block 
procedure, and local anesthetic perfusion will begin immediately after the 
surgery.  All subjects will be contacted via their preferred method of contact to 
complete the pain survey (SEFAS) at 2 weeks, 3 months, 6 months, and 1 year 
after the surgery.  Information about current pain medication use will also be 
collected at each of these time points.   
Randomization:  We will use a block-stratified randomization schedule with 
blocks of sizes 2 and 4.  The West Chester and Uptown locations will have 
separate randomization schedules as it is thought the two locations provide 
somewhat different populations, making it desirable to have approximately equal 
numbers in the control and experimental groups at each site.  Due to the 
requirement for quarantine of the ropivacaine prepared by IDS, subject 
randomization may sometimes deviate from the schedule: a subject scheduled to 
receive a pump may be placed in the control group if no ropivacaine is available 
at the time of their surgery, which will be compensated by placing a subsequent 
subject scheduled to be in the control group into the experimental group when 
drug is available.  These deviations will not be based on subject characteristics, 
so that assignments remain random, and the total number of control and 
experimental subjects at each site will remain the same. 
Data collection: We will establish an online copy of the SEFAS which subjects 
can use to enter their responses.  This will be done using the REDCap 
(Research Electronic Data Capture) system for secure web based capture of 
questionnaire data.  For patients opting to have a link to the SEFAS sent to their 
cell phones, the REDCap-Twillio integration platform will be used.  Patients 
electing not to use the online entry format will be contacted by the research nurse 
via the preferred route indicated on the consent form, and the research nurse will 
then enter the data into the Redcap project database.  Data from the 
questionnaires will be exported out of REDCap to be merged with the data from 
the Medidata Rave ® database for analysis.  All other data will be entered directly 
into the Medidata Rave ®  clinical database.  Clinical demographic data will be 
obtained from the patient at the beginning of the study and verified with the 
electronic medical record. Analgesic use in the perioperative period will be 
obtained from the electronic medial chart.  Patients typically receive 
acetaminophen and celecoxib preoperatively, then opioids postoperatively as 
needed.  However, participating in the study will not affect the subjects’ options 
for treatment for pain.  Numerical pain ratings recorded in the PACU will be 
obtained from the electronic medical chart. The Verbal Numerical Scale (VNRS, 0 
= no pain, 5 = moderate pain, 10 = worst possible pain) is used for patients in the 


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PACU and recorded in the electronic record, until the patient is discharged from 
the PACU.  Chart review of the follow-up orthopedic appointments will be used to 
identify possible development of chronic pain conditions or unforeseen 
complications of 5 day pump use. 
 
8. Specimen collection: not applicable. 
 
9. Potential Benefits:  
Possible benefits to the subject during the time the pump is in use include better 
postoperative pain control, improved sleep, and reduced need for opioids with 
their concomitant side effects and risk of abuse [26].  Preclinical data (see above) 
and some clinical data in other conditions provide some support for the 
hypothesis being tested that the nerve block will reduce the risk of chronic pain 
[27].  If this pilot study is successful and can be extended to a full study large 
enough to fully test this hypothesis, the research may contribute generalizable 
knowledge to improve practices in combat medicine and trauma medicine. 
 
 
10. Potential Risks, Discomforts, and inconveniences:  
 
Level of risk: Greater than minimal risk   
We consider the risk level of the study to be low because the experimental 
treatment (ambulatory regional nerve block with ropivacaine) is already routinely 
used in other clinical conditions including at our clinic.  A recent review stated 
that “Serious and permanent complications related to cPNB [continuous 
peripheral nerve block] are rare, whereas minor complications occur with a 
frequency similar to single-injection peripheral nerve blockade” [27](i.e., standard 
of care arm in our proposed study).  Use of 5 day ambulatory pumps in 
postsurgical patients has become standard care at the Cleveland Clinic. They 
use the same device (Ambit) and drug (0.2% ropivacaine) that we propose to 
use, at a somewhat higher dose (8 mL/hour with 12 mL bolus-on-demand per 
hour, with reprogramming allowed if pain control was inadequate;  compared to 
our proposed 6 mL/hour without bolus).  Their standard of care is to have the 
patients use the pump for 5 days, turn them off for 6 hours, and then remove the 
catheter and pump if pain scores are less than 5, otherwise to restart the 
infusion.  In their retrospective study [28] of the safety of longer duration 
perfusions, the median duration of pump use was 5 days (shorter durations 
generally only occurring in patients who had to remove the pumps) and some 
patients used the pumps longer than this.  For the 290 popliteal blocks they 
report on, the median duration was 5 days and inter-quartile range was given as 
4, 7.  Similar to clinical practice at our institution, and as proposed in our study, 
patients using pumps at home were contacted each day by the Acute Pain 
Service to check for pain control, signs of infection, and signs of nerve damage 
or systemic toxicity.  The conclusion of this study was that “prolonged use of 
ambulatory catheters for a median period of 5 days did not lead to an increased 


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incidence of complications”.  Specifically for the 290 patients receiving popliteal 
catheters, 3 complications were reported.  Two patients had superficial infections 
at the catheter site which resolved with catheter removal (one of these was 
diabetic; our study excludes diabetic patients and this is known to increase the 
likelihood of such infections).  One patient had pharmacological complications 
(ringing in the ears during the initial injection, resolved with no intervention).  No 
complications indicative of nerve damage were observed in any of the patients 
with popliteal catheters.   
 
One primary risk of the ambulatory pump is vascular puncture allowing the local 
anesthetic to enter the general circulation.  Ultrasound guidance and (if also 
needed) peripheral nerve stimulation techniques are routinely used for inserting 
the catheters in order to minimize this risk[29].  Vascular puncture would likely 
occur during the standard-of-care initial single shot nerve block, not during the 
experimental 5 day pump procedure; and would be detected in the hospital 
setting with rescue medications and procedures available. A second source of 
risk is systemic toxicity even from a properly placed nerve block, leading to CNS 
symptoms including seizures or cardiac symptoms.  Previous studies of long 
term regional nerve blocks in trauma patients have demonstrated that systemic 
ropivacaine levels start to decline after 3 days, and ropivacaine infusion even 
lasting much longer than the proposed 5 days does not lead to toxic levels of the 
drug in plasma [12].  Military medicine studies have demonstrated the safety and 
efficacy of regional anesthesia for combat wounds, especially for managing 
surgical and acute postoperative pain [12, 13].  As described in these studies, 
many wounded soldiers have had regional anesthesia lasting at least 5 – 7 days, 
without serious anesthetic complications, albeit but under field conditions in 
which the conditions and effect on chronic pain development could not be 
rigorously controlled. Some of the exclusion criteria are based on higher risk of 
toxicity per the drug manufacturer’s information [30].  Another risk is of infection 
of the catheter site which rarely may lead to systemic infection.  This risk 
increases with duration of the catheter use.  In a study in orthopedic surgery 
patients using similar mean duration to what we propose [31] the overall risk of 
local inflammatory signs was 3%. 
 
More Common Risks of peripheral nerve block and continuous peripheral nerve 
block: 
Bleeding/blood aspiration (0.4%)  [32] 
Local Infection  0 – 3% [29, 31]  
Paresthesia (short term; 0.5% - 1.5%) [31-33] 
Inability to perform injection (see section 14 below) 
Ineffective block (see section 14, below) 
 
Extremely Rare Risks: 
Nerve damage (short duration) 
Muscle atrophy 
Worsening of pain 


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Permanent or long-lasting nerve damage   4-7/10,000 blocks[27] 
Local anesthetic systemic toxicity- (0.7 per 10,000) 
Cardiac arrest (<1/100,000 with no deaths in several studies of >100,000 
peripheral nerve blocks) [29, 34]  
 
Clinical trial monitoring will be conducted to ensure that the rights and well-being of 
human subjects are protected, to verify that the reported clinical trial data are 
accurate, complete and verifiable from source documents and to verify that the 
conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with Good Clinical Practices and with the applicable 
regulatory requirements. 
 
Safety criteria for removing a subject from the study in the period before the end of 
the 5-day ambulatory pump use: 
 
Prior to and during the popliteal nerve block and catheter placement:  Subjects with 
a failed peripheral nerve block will not have a catheter placed and will not be 
included in the study (see Exclusions, below). Subjects will be discontinued and the 
catheter removed if there is inadequate view of the popliteal nerve under ultrasound 
guidance, paresthesias that do not resolve before the local anesthetic from the nerve 
injection takes effect, blood is present in the catheter during insertion indicating 
possible vascular injury,  or one or more signs of local anesthetic systemic toxicity 
(LAST) (ringing in ears, metallic taste in mouth, lightheadedness, seizure, or cardiac 
compromise).  
  
During Surgical Procedure and General Anesthetic – Subjects will be discontinued if 
there are one or more signs of LAST (listed above) or the catheter is inadvertently 
removed during the operation.  
 
During immediate postoperative period in PACU – Subject will be removed if there 
are one or more signs of LAST (listed above) or if the catheter is removed 
inadvertently 
 
After Discharge for period the pump is used:  Based on the daily phone contacts, 
subjects will stop using the pump if there are, signs of local infection(after evaluation 
by the Acute Pain Service; subject would be called  back into the hospital), or one or 
more signs of LAST (listed above).  Subjects who experience paresthesias that 
cause them discomfort, or weakness that prevents them from participating in 
physical or occupational therapy, will be asked to return to the clinic for evaluation by 
an anesthesiologist.  If these issues cannot be resolved (e.g. by lowering the dose), 
these subjects will have the catheter and pump removed.  Subjects who must 
remove the pump early for any reason will be retained in the study for purposes of 
answering the pain surveys.   
 
Defining and Reporting of Adverse Events: 
 


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Adverse event Definitions: 
 
Adverse Event  
Adverse event means any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related. 
An adverse event (also referred to as an adverse experience) can be any 
unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, and does not 
imply any judgment about causality. An adverse event can arise with any use of 
the drug (e.g., off-label use, use in combination with another drug) and with any 
route of administration, formulation, or dose, including an overdose. 
 
Suspected Adverse Reaction  
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes 
of IND safety reporting, ‘reasonable possibility’ means there is evidence to 
suggest a causal relationship between the drug and the adverse event. A 
suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
Adverse Reaction 
An adverse reaction means any adverse event caused by a drug. Adverse 
reactions are a subset of all suspected adverse reactions where there is reason 
to conclude that the drug caused the event. 
 
Unexpected  
An adverse event or suspected adverse reaction is considered “unexpected” if it 
is not listed in the investigator brochure or is not listed at the specificity or 
severity that has been observed; or, if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended.  
 
Serious  
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or sponsor, it results in any of the following 
outcomes: Death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or 
substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the 


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patient or subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition.  
 
Life-Threatening  
An adverse event or suspected adverse reaction is considered “life-threatening” 
if, in the view of either the investigator or sponsor, its occurrence places the 
patient or subject at immediate risk of death. It does not include an adverse event 
or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
 
 
 
 
Table of Causality Definitions: 
 
Causality term 
 
Assessment criteria* 
 
Certain 
• Event or laboratory test abnormality, with 
plausible time relationship to drug intake 
• Cannot be explained by disease or other drugs 
• Response to withdrawal plausible 
(pharmacologically, pathologically) 
• Event definitive pharmacologically or 
phenomenologically (i.e. an objective and specific 
medical disorder or a recognised 
pharmacological phenomenon) 
• Rechallenge satisfactory, if necessary 
 
Probable/ Likely 
• Event or laboratory test abnormality, with 
reasonable time relationship to drug intake 
• Unlikely to be attributed to disease or other drugs 
• Response to withdrawal clinically reasonable 
• Rechallenge not required 
 
Possible 
• Event or laboratory test abnormality, with 
reasonable time relationship to drug intake 
• Could also be explained by disease or other drugs 
• Information on drug withdrawal may be lacking or 
 
Unlikely 
• Event or laboratory test abnormality, with a time to 
drug intake that makes a relationship improbable 
(but not impossible) 
• Disease or other drugs provide plausible explanations 
 
Conditional/ 
Unclassified 
• Event or laboratory test abnormality 
• More data for proper assessment needed, or 
• Additional data under examination 


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Unassessable/ 
Unclassifiable 
• Report suggesting an adverse reaction 
• Cannot be judged because information is 
insufficient or contradictory 
• Data cannot be supplemented or verified 
 
 
 


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Table 9.4. Toxicity Grading Scale: 
  
Local Reaction 
to Injectable 
Product 
Mild (Grade 1) 
Moderate(Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Repeated use of non- 
narcotic pain reliever 
> 24 hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency room 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Redness*  
2.5 – 5 cm 
5.1 – 10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling**  2.5 – 5 cm and 
does not 
interfere with 
5.1 – 10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
*In addition to grading the measured local reaction at the greatest single diameter, the 
measurement should be recorded as a continuous variable. 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the 
actual measurement. 
Vital Signs * 
Mild (Grade 1) 
Moderate(Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Fever (°C) ** 
 (°F) ** 
38.0 – 38.4 
100.4 – 101.1 
38.5 – 38.9 
101.2 – 102.0 
39.0 – 40 
102.1 – 104 
> 40 
> 104 
Tachycardia - beats per 
minute 
101 – 115 
116 – 130 
> 130 
ER visit or 
hospitalization for 
arrhythmia 
Bradycardia - beats per 
minute*** 
50 – 54 
45 – 49 
< 45 
ER visit or 
hospitalization for 
arrhythmia 
Hypertension (systolic) - 
mm Hg 
141 – 150 
151 – 155 
> 155 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypertension (diastolic) 
- 
mm Hg 
91 – 95 
96 – 100 
> 100 
ER visit or 
hospitalization for 
malignant 
hypertension 
Hypotension (systolic) – 
mm Hg 
85 – 89 
80 – 84 
< 80 
ER visit or 
hospitalization for 
hypotensive shock 
Respiratory Rate – 
breaths 
17 – 20 
21 – 25 
> 25 
Intubation 


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* Subject should be at rest for all vital sign measurements. 
** Oral temperature; no recent hot or cold beverages or smoking. 
*** When resting heart rate is between 60 - 100 beats per minute. Use clinical judgment when 
characterizing bradycardia among some healthy subject populations, for example, conditioned 
athletes. 
 
 


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Systemic (General) 
Mild (Grade 1) 
Moderate(Grade 2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Nausea/vomiting 
No interference 
with activity or 1 – 
2 episodes/24 
hours 
Some interference 
with activity or > 
2 episodes/24 
hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization for 
hypotensive shock 
Diarrhea 
2 – 3 loose stools 
or 
< 400 gms/24 
hours 
4 – 5 stools or 
400 – 800 
gms/24 hours 
6 or more watery 
stools or 
> 800gms/24 hours 
or requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with 
activity 
Repeated use of 
non- 
narcotic pain 
reliever > 24 hours 
or some 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Fatigue 
No interference 
with 
activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with 
activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
 
Table 9.4 extracted from: Guidance for Industry, Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Trials, 
U.S. Department of Health and Human Services, Food and Drug Administration, 
Center for Biologics Evaluation and Research, August 2016 
 
Treatment of cardiovascular and neurologic adverse events 
 Local anesthetic systemic toxicity  
o Treatment will be initiated as recommended as the American Society of 
Regional Anesthesia and Pain Medicine, according to the society’s 
checklist  
Treatment will include: transfer to intensive care unit setting if not already in 
intensive care unit, continuous hemodynamic monitoring for at least 24 hours, 
appropriate airway management with assistance from respiratory therapy and a 
critical care consultant as needed, cardiovascular stabilization and assistance from a 
critical care consultant as needed, administration of Lipid Emulsion therapy, as per 
ASRA checklist in Appendix, Neurology consult for any observed systemic 


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neurologic toxicity (including change in vision, mental status change, persistent 
headache, seizure), Cardiology consult for any arrhythmias that persist greater than 
30 minutes, beyond initial appropriate medical treatment, or result in hypotension 
with systolic blood pressure < 80mmHg. 
 
Every adverse event, whether or not thought to be related to study drug, will be 
recorded and entered into the Medidata Rave® Case Report Form database.   
 
Any medical condition present prior to study enrollment should not be reported as an 
adverse event, unless the medical condition worsens in severity or seriousness 
during the study.  In this case it may be reported as an adverse event at the 
discretion of the Investigator. 
 
The Investigator will review each event and assess its severity and relationship to 
the study treatment.    
 
 
Criteria for stopping the study early: 
 
Because this is a small study, criteria for stopping the study will not be based on 
statistical analysis but rather on the occurrence of any of the following serious 
adverse events in any of the subjects randomized to receive the ropivacaine pumps: 
 
During immediate peri-operative period after pump has been connected: 
 
A single serious adverse event of LAST requiring rescue medication, cardiac 
resuscitation, or transfer to the ICU. 
 
During the 5 day period of ambulatory pump use: 
 
A single serious adverse event of catheter site infection requiring hospital 
admission. 
 
A single serious adverse event  of LAST requiring hospital admission. 
 
During the entire study period: 
 
A single serious adverse event  of any life-threatening adverse event deemed 
possibly related to the use of the ropivacaine pump. 
 
Two subjects receiving pumps experiencing moderate adverse events of tinnitus 
and/or metallic taste in the mouth. 
11. Data Safety monitoring plan and/or DSMB:  
 
As discussed in section 6, the medical monitor, Dr. William Hurford,  will review 
subject’s research data and adverse events to ensure patient safety.” 
 


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12. Data Analysis:  
   
The primary outcome measure is SEFAS scores at the indicated time points.  A 
secondary outcome measure is use of opioids in the immediate postoperative 
period.   
 
Each SEFAS response has 5 ordinal response choices scored 0 through 4, with 
the lowest score (0) representing the most severe disability and the highest total 
score being 48. If subjects omit a question the score will be re-normalized; 
however, the Redcap interface will be designed to try to obtain an answer for 
each question.  The Mann-Whitney test will be used to examine differences in the 
SEFAS scores at each time point.  For analysis of SEFAS scores, the pilot study 
sample size of 20 per group is sufficient for detecting a difference in scores 
between groups of 9 points with a power of 0.8 and α = 0.05 (using the standard 
deviation obtained from SEFAS use in an ankle surgery study[35]); this score 
would represent moving up one rank in 3/4 of the questions which would be a 
functionally meaningful improvement given the 0 – 4 ordinal scale employed.  .   
Patients who are withdrawn from the study due to failure of the initial nerve block 
(see above) will be considered as screening failures; no follow-up data or 
questionnaire scores will be obtained.  We consider that such a failure is unlikely 
to have any relationship to the chronic pain outcome we are studying.  The same 
approach will be taken for patients who decide to withdraw from the study, or are 
withdrawn by the attending surgeon or anesthesiologist, after randomization but 
before the single shot nerve block procedure. 
 
Patients lost to follow-up after the end of the 5 day nerve block will be analyzed 
with a per-protocol analysis. We consider that, since the follow-up begins after 
the end of the treatment and consists only of completing questionnaires, there is 
unlikely to be a bias towards the experimental or control group having increased 
numbers of drop-outs. 
 
Patients who have to (or choose to) remove the pump before the entire 5 day 
treatment period will also be analyzed both an intent-to-treat analysis and a per-
protocol analysis.  The duration of pump use will be noted.   
 
As this is a pilot study, one intent is to develop estimates of the likelihood of drop-
outs and incomplete treatments, to aid in design of a full sized study. 
 
13. Data storage and confidentiality (include sample storage if applicable)  
 
The signed consent forms will be stored in locked cabinets at the Westchester or 
UCMC locations, accessible only to the study members who are qualified to 
obtain consents.  A single subject log (copy attached) will be kept by the study 
coordinator for matching patient study number, names, medical record number, 


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and surgery date.  Study numbers will be used to identify questionnaire and 
clinical demographic data.  As noted above, SEFAS data will be entered in the 
REDCap system, which provides password-protected security and encryption.   
 
All other data will be entered into the Medidata Rave® database, and SEFAS 
data will be exported from REDCap and merged with the Medidata Rave® data 
for analysis. The Data Management Center (DMC) will provide full data 
management support to the project.  The DMC has dedicated space within the 
Division of Biostatistics and Epidemiology (DBE) within Cincinnati Children’s 
Hospital Me.  The DMC currently consists of three Managers of Data 
Management  operations and 25+ staff members (Clinical Research Data 
Specialists, Clinical Research Database Programmers and Data Coordinators), 
five of which are Certified Clinical Data Managers.  DMC staff are active 
members of the Society of Clinical Data Management, the Drug Information 
Association, and the Society of Clinical Trials and subscribe to Good Clinical 
Data Management Practices.    
 
Neither Medidata Rave® nor REDCap databases will contain subject names. The 
subject’s enrollment into the study will be noted in the Epic chart, including a 
notation about whether or not they received the 5 day pumps, so that treating 
physicians will be aware of this history.  Only authorized study personnel will 
have access to the rest of the data. In response to our query, the REDCap staff 
indicated that the REDCap system was not the best tool for conducting some of 
the types of analysis proposed (such as Mann-Whitney).  A subset of the data (at 
least 20%) will be verified for accuracy by the study monitor.  Files exported from 
Medidata Rave® that are generated for analysis of the de-identifed data will be 
stored on the research server.  This College of Medicine server is password 
protected so that only members of the Research Director’s laboratory can have 
access, and the directory containing study data will be further restricted so only 
the researchers directly involved in the study have access.  The server contents 
are automatically backed up several times per day and retained off-site for 30 
days.  
 
Once the study has been completed, the subject log will be destroyed and only 
the de-identified electronic data will be kept.  Only study personnel will have 
access to the de-identified data except as required for regulatory oversight.  
 
 
14. Study Population (Including age, number of individuals, inclusion/exclusion) 
 
Sample Size - Up to 60 patients will be enrolled in this single site pilot study.  
 
Inclusion criteria –  
 Adult patients of either sex, age 18 to 65 
 Referred for surgery for open reduction and internal fixation for ankle 
fracture  


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 Agreed to have a single shot local nerve blockade (routinely offered as 
part of the standard-of-care but declined by some patients) 
 
Exclusion criteria:   
 
 patients unable to give informed consent in English 
 unable to complete surveys in English 
 unable to understand instructions for using the pump in English 
 unavailable for follow-up 
 Scheduled to enter a rehabilitation facility after the surgery (due to 
difficulty in conducting the 5 days of safety monitoring phone calls) 
 polytrauma, i.e. undergoing other surgeries or having other fractures 
related to the precipitating cause of the ankle fracture 
 infection such as abcess or bacterial infection; mild colds or upper 
respiratory infections do not require exclusion. 
 peripheral vascular disease 
 diabetes  
 undergoing chemotherapy 
 pregnancy (ropivacaine is FDA pregnancy category B; pregnancy test is 
routine part of the surgical procedure unless the woman signs a waiver; 
patients who sign such a waiver instead of having a pregnancy test will not 
be eligible for the study, unless their medical record clearly indicates they 
have had a hysterectomy or tubal ligation.) 
 lactating 
 have heart disease or heart rhythm disorder or taking anti- antiarrhythmic 
drugs  
 severe renal impairment (Class 3 or worse kidney disease) 
 liver disease (cirrhosis or liver failure) 
 ever had an allergic reaction to any type of local anesthetic  
 taking therapeutic doses of anti-coagulants or anti-platelet therapy 
(prophylactic doses started because of the hospital admission are not an 
exclusion) 
 taking antidepressants or other psychiatric medications (due to drug 
interaction risk per the ropivacaine data sheet) 
 single shot local nerve block prior to surgery was ineffective (rare; see 
below) 
 selected for neuraxial anesthesia rather than general anesthesia for the 
open reduction surgery (rare) 
 already receiving chronic analgesic therapy for a separate chronic pain 
condition 
 
Rarely, the single shot local nerve blockade given prior to surgery as standard-of-
care is found to be ineffective, and surgery proceeds using only general 
anesthesia.  The ineffectiveness of the single shot would indicate that the 
catheter placement was also likely to be ineffective.  For such patients, the 


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catheter will be removed before the surgery and they will be removed from the 
study; attempting to re-position and re-test the catheter outside of the standard-
of-care procedures was deemed to be undue risk.  Patients with failed nerve 
block who were not randomized to receive the pump will also be removed to 
avoid bias in the analysis, and because the lack of the single nerve block might 
also have effects on the development of chronic pain.   
 
Because the treatment period lasts only 5 days, patients who may possibly 
become pregnant during that time are allowed to participate. 
 
15. Consenting process and plan  
A typical schedule for the potential subjects is for them to be admitted to the 
emergency department, diagnosed with ankle fracture, then either admitted to 
the hospital or sent home, after being scheduled for surgery for open reduction 
and internal fixation of the fracture the next day.  In order to identify potential 
subjects, the study coordinator or others listed on the IRB protocol who have 
Epic privileges will review the orthopedic surgery schedules at the participating 
hospitals to identify potential subjects.  We have applied for an IRB waiver to do 
a preliminary research screening in the medical record to avoid approaching 
potential subjects outside the age range or with polytrauma or other excluded 
conditions. A paper prescreening form will be used, listing inclusion and 
exclusion criteria, to determine as far as possible from the medical chart of 
scheduled patients whether the patient is eligible. If the patient agrees to join the 
study, this document will be kept with the consent form; if not, the document will 
be used to document the reason for the screening failure or to note that the 
patient refused to participate.  The form will then be shredded; the sex, age in 
years, and reason for not enrolling in the study will be the only data retained.  
The orthopedic surgeon and the anesthesiologist scheduled to conduct the 
surgery will be contacted to confirm that they are willing to have the patient 
enrolled in the study, before subjects are enrolled.  We will introduce the study to 
both the Anesthesiology and Orthopedic Surgery departments prior to the 
beginning of the study.  Patients who have passed the prescreening and who will 
come to the surgery after hospital admission will be contacted in their rooms to 
invite them to participate, prior to the scheduled surgery (but after patients have 
been admitted to the hospital from the emergency room if that is where they 
initially presented).  Patients who are scheduled to come to the surgery from 
home will be contacted at home by telephone, if they have passed the 
prescreening.  In both cases patients will be requested to arrive at least 30 
minutes earlier than otherwise scheduled so that consent and enrollment can be 
done in the pre-operative period.  Consent will be obtained before the 
anesthesiologist starts the standard-of-care nerve block procedure.    
Subjects can withdraw from the study at any time per their desire or may be 
withdrawn at the discretion of the orthopedic surgeon or anesthesiologist. Any 
subject who withdraws will continue to receive standard-of-care including follow-


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up appointments and access to pain medications, which are unaffected by the 
study protocol.   
 
16. Compensation:  
Subjects will receive a $25 gift card as a token of appreciation upon completing 
each follow-up questionnaire (up to a total of 4 for $100 total).  Payments will be 
made using the Greenphire system. 
 
17. Subject costs:  
There are no direct costs to the subject. In case of injury or illness related to the 
study, the University of Cincinnati Medical Center will provide emergency medical 
care at no cost to the subject.  The University of Cincinnati will review each case 
and determine on a case by case basis whether to reimburse any out of pocket 
expenses. 
 
18. Literature cited (references should be limited to relevant and current literature 
pertinent to the proposed study) 
 
1. 
Sorkin, L.S. and T.L. Yaksh, Behavioral models of pain states evoked by physical 
injury to the peripheral nerve. Neurotherapeutics, 2009. 6(4): p. 609-19. 
2. 
Devor, M., Ectopic discharge in Aβ afferents as a source of neuropathic pain. 
Exp Brain Res, 2009. 196(1): p. 115-28. 
3. 
Bedi, S.S., et al., Chronic spontaneous activity generated in the somata of 
primary nociceptors is associated with pain-related behavior after spinal cord 
injury. J Neurosci, 2010. 30(44): p. 14870-82. 
4. 
Nieto, F.R., et al., Tetrodotoxin (TTX) as a therapeutic agent for pain. Mar Drugs, 
2012. 10(2): p. 281-305. 
5. 
Berger, J.V., et al., Cellular and molecular insights into neuropathy-induced pain 
hypersensitivity for mechanism-based treatment approaches. Brain Res Rev, 
2011. 67(1-2): p. 282-310. 
6. 
Xie, W., et al., Neuropathic pain: Early spontaneous afferent activity is the trigger. 
Pain, 2005. 116(3): p. 243-56. 
7. 
Xie, W., J.A. Strong, and J.M. Zhang, Local knockdown of the NaV1.6 sodium 
channel reduces pain behaviors, sensory neuron excitability, and sympathetic 
sprouting in rat models of neuropathic pain. Neuroscience, 2015. 291: p. 317-30. 
8. 
Xie, W., et al., Knockdown of sodium channel NaV1.6 blocks mechanical pain 
and abnormal bursting activity of afferent neurons in inflamed sensory ganglia. 
Pain, 2013. 154: p. 1170-1180. 
9. 
Xie, W., et al., Upregulation of the sodium channel NaVβ4 subunit and its 
contributions to mechanical hypersensitivity and neuronal hyperexcitability in a 
rat model of radicular pain induced by local DRG inflammation. Pain, 2016. 
157(4): p. 879-891. 
10. 
Stojadinovic, A., et al., Responding to challenges in modern combat casualty 
care: innovative use of advanced regional anesthesia. Pain Med, 2006. 7(4): p. 
330-8. 


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11. 
Fleming, I. and C. Egeler, Regional anaesthesia for trauma: an update. 
Continuing Education in Anaesthesia, Critical Care & Pain, 2014. 14(3): p. 136-
141. 
12. 
Bleckner, L., et al., Serum free ropivacaine concentrations among patients 
receiving continuous peripheral nerve block catheters: is it safe for long-term 
infusions? Anesth Analg, 2014. 118(1): p. 225-9. 
13. 
Kent, M.L., J.J. Upp, and C.C. Buckenmaier, 3rd, Acute pain on and off the 
battlefield: what we do, what we know, and future directions. Int Anesthesiol Clin, 
2011. 49(3): p. 10-32. 
14. 
McPhail, S.M., et al., Life impact of ankle fractures: qualitative analysis of patient 
and clinician experiences. BMC Musculoskelet Disord, 2012. 13: p. 224. 
15. 
Beerthuizen, A., et al., Demographic and medical parameters in the development 
of complex regional pain syndrome type 1 (CRPS1): prospective study on 596 
patients with a fracture. Pain, 2012. 153(6): p. 1187-92. 
16. 
Stufkens, S.A., et al., Long-term outcome after 1822 operatively treated ankle 
fractures: a systematic review of the literature. Injury, 2011. 42(2): p. 119-27. 
17. 
Institute of Medicine (US) Committee on Advancing Pain Research, C., and 
Education., Relieving Pain in America: A Blueprint for Transforming Prevention, 
Care, Education, and Research. The National Academies Collection: Reports 
funded by National Institutes of Health. 2011, Washington DC: National 
Academies Press. 
18. 
Lew, H.L., et al., Prevalence of chronic pain, posttraumatic stress disorder, and 
persistent postconcussive symptoms in OIF/OEF veterans: polytrauma clinical 
triad. J Rehabil Res Dev, 2009. 46(6): p. 697-702. 
19. 
FDA, Ropivacaine Hydrochloride Injection, USP. 2012. 
20. 
American Society of Health-System Pharmacists Inc. (2014) ASHP Guidelines on 
Compounding Sterile Preparations. Drug Distribution and Control: Preparation 
and Handling–Guidelines.  https://www.ashp.org/-/media/assets/policy-
guidelines/docs/guidelines-compounding-sterile-preparations.ashx. (Accessed 
4/20/2017).   
21. 
Freseniu Kabi USA LLC. (2015) Package Insert. Naropin® Ropivacaine HCl 
Injection.  http://editor.fresenius-kabi.us/PIs/Naropin_PI_451112G_Jan_2015.pdf. 
(Accessed 4/25/2017). 
22. 
Product Information. QT Junior™ System – TJ3100.  
http://www.qimedical.com/products/qt-junior-system-tj3100/. (Accessed 
4/20/2017).  
23. 
Coster, M.C., et al., Validity, reliability, and responsiveness of the Self-reported 
Foot and Ankle Score (SEFAS) in forefoot, hindfoot, and ankle disorders. Acta 
Orthop, 2014. 85(2): p. 187-94. 
24. 
Hosman, A.H., et al., A New Zealand national joint registry review of 202 total 
ankle replacements followed for up to 6 years. Acta Orthop, 2007. 78(5): p. 584-
91. 
25. 
Dworkin, R.H., et al., Interpreting the clinical importance of treatment outcomes in 
chronic pain clinical trials: IMMPACT recommendations. J Pain, 2008. 9(2): p. 
105-21. 


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26. 
Clark, L., M. Robinson, and M. Varbanova, Role of regional anesthesia in 
orthopedic trauma. Anesthesiol Clin, 2014. 32(4): p. 789-808. 
27. 
Machi, A.T. and B.M. Ilfeld, Continuous peripheral nerve blocks in the ambulatory 
setting: an update of the published evidence. Curr Opin Anaesthesiol, 2015. 
28(6): p. 648-55. 
28. 
Gharabawy, R., et al., The Cleveland Clinic experience with supraclavicular and 
popliteal ambulatory nerve catheters. ScientificWorldJournal, 2014. 2014: p. 
572507. 
29. 
Neal, J.M. and J.P. Rathmell, Complications in Regional Anesthesia and Pain 
Medicine. Second ed. 2013, Philadelphia: Wolters Kluwer - Lippincott Williams & 
Wilkins. 
30. 
Drugs.com. Ropivacaine.  2016  [cited 2016 June]; Available from: 
https://www.drugs.com/ppa/ropivacaine.html. 
31. 
Capdevila, X., et al., Continuous peripheral nerve blocks in hospital wards after 
orthopedic surgery: a multicenter prospective analysis of the quality of 
postoperative analgesia and complications in 1,416 patients. Anesthesiology, 
2005. 103(5): p. 1035-45. 
32. 
Borgeat, A., et al., The feasibility and complications of the continuous popliteal 
nerve block: a 1001-case survey. Anesth Analg, 2006. 103(1): p. 229-33, table of 
contents. 
33. 
Compere, V., et al., Major complications after 400 continuous popliteal sciatic 
nerve blocks for post-operative analgesia. Acta Anaesthesiol Scand, 2009. 53(3): 
p. 339-45. 
34. 
Heinonen, J.A., et al., Incidence of severe local anaesthetic toxicity and adoption 
of lipid rescue in Finnish anaesthesia departments in 2011-2013. Acta 
Anaesthesiol Scand, 2015. 59(8): p. 1032-7. 
35. 
Coster, M., et al., Validity, reliability, and responsiveness of a self-reported foot 
and ankle score (SEFAS). Acta Orthop, 2012. 83(2): p. 197-203. 
 

SAP_000.pdf: 


 
 
 
Version date:  Dec. 14 2017 
validated ankle/foot pain questionnaire that includes questions on function (Self-Administered 
Foot and Ankle Questionnaire, SEFAS).  Subjects will be followed for one year, with SEFAS 
scores administered at 14 days, and 3, 6, and 12 months following the ankle surgery.  Secondary 
outcomes are postoperative opioid use in the Post-Anesthesia Care Unit (PACU), and pain ratings 
in the PACU.  Data will also be obtained regarding the feasibility of doing a larger study.  
Preliminary analysis of possible confounding variables will be conducted, but as this is a pilot 
study it is anticipated that there may not be enough subjects to yield significant findings about 
patient subgroups. 
 
B. 
Specific Aims and Hypotheses 
 
Aim 1:  Test the hypothesis that SEFAS scores at the one year time point are higher (better 
outcome) in subjects who received a ropivacaine pump compared to patients who received 
standard care.  This is the primary outcome measure).   
 
Aim 2:  Test the hypothesis that SEFAS scores at earlier time points (14 day, 3 month, 6 month) 
are higher in subjects who received a ropivacaine pump compared to patients who received 
standard care. 
 
Aim 3:  Test the hypothesis that pain scores and total opioid use in the PACU are lower in 
subjects receiving the ropivacaine pump. 
 
Aim 4:  Conduct a preliminary examination of possible roles of confounding clinical and 
demographic variables, focusing on: severity of ankle fracture; sex; and body mass index 
(BMI).  
 
 
 
 
C. 
Study Design 
 
This is an investigator-initiated, single-center, prospective, non-blinded, randomized pilot study.  
We are authorized to enroll up to 60 patients to allow for 40 evaluable subjects.     
 
Adults undergoing surgery for open reduction and internal fixation for traumatic ankle fracture 
will be invited to participate in the study comparing the 2 forms of nerve block.  All patients are 
currently given the option of popliteal nerve block (single injection of ropivacaine given just 
prior to surgery), which helps provide pain relief in the immediate postoperative period; the 
surgery itself is done under general anesthesia.  Participants who have agreed to have the single 
shot procedure will be randomized into the control group (standard-of-care single popliteal 
injection of local anesthetic just prior to surgery) or experimental group (standard-of-care single 
injection plus 5 day ambulatory popliteal nerve block).  
 
The treatment will be open label due to the impracticality of blinding the physician or patient to 
the presence of local anesthetic in the 5 – day pump and the ethical barriers to subjecting patients 
to implantation of a catheter and empty or saline pump with no benefit to them. Per standard of 


 
 
 
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care, patients in both the experimental and control groups will also have other oral pain 
medications prescribed for use as needed. 
 
Standard-of care procedures will be used for placement of the single shot popliteal nerve block.   
In the experimental group, in addition to the standard single shot nerve block, subjects will 
receive a catheter to deliver continuous 5 day popliteal sciatic nerve block using a disposable 
ambulatory pain pump.  The catheter will be inserted just prior to surgery. A portable pump will 
be attached to the catheter at the time the block is placed, and continuous block with 0.2% 
ropivacaine will begin immediately after surgery when the patient arrives in the PACU.  
 
Additional data routinely obtained for clinical purposes will also be collected including 
demographic variables, analgesic use in the PACU, and details of the ankle fracture and surgery.  
 
The standard follow-up appointments with the orthopedic surgeons following ankle surgeries are 
at 10 - 14 days, 5 – 6 weeks, and 3 – 4 months.  Chart review of these follow-up appointments 
will be used to extract additional clinical variables. 
 
Subjects will be contacted at approximately 14 days and 3, and 6, and 12 months following the 
surgery to complete a pain questionnaire, the SEFAS. The SEFAS is designed to evaluate 
disorders of the foot and ankle.  It does not require physician input, and a study of its use after 
surgery found it to be a valid, reliable, and responsive patient-oriented outcome measure.  It 
consists of 12 questions focusing primarily on pain and its functional impact on daily life 
activities.  Subjects will also be asked to provide information about their medication use 
including pain medications, at each of these time points.   
. 
Inclusion criteria –  
• 
Adult patients of either sex, age 18 to 65 
• 
Referred for surgery for open reduction and internal fixation for ankle fracture  
• 
Agreed to have a single shot local nerve blockade (routinely offered as part of the 
standard-of-care but declined by some patients) 
 
Exclusion criteria:   
 
• 
patients unable to give informed consent in English 
• 
unable to complete surveys in English 
• 
unable to understand instructions for using the pump in English 
• 
likely to be unavailable for follow-up 
• 
polytrauma; undergoing other surgeries or having other orthopedic injuries related to the 
precipitating cause of the ankle fracture 
• 
infection 
• 
peripheral vascular disease 
• 
diabetes  
• 
undergoing chemotherapy 
• 
pregnancy or refusal to take pregnancy test, if of childbearing potential  
• 
lactating 
• 
have heart disease or heart rhythm disorder or taking anti- antiarrhythmic drugs  


 
 
 
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• 
severe renal impairment (Class 3 or worse kidney disease) 
• 
liver disease (cirrhosis or liver failure) 
• 
ever had an allergic reaction to any type of local anesthetic  
• 
taking therapeutic doses of anti-coagulants or anti-platelet therapy (prophylactic doses 
started because of the hospital admission are not an exclusion) 
• 
taking antidepressants or other psychiatric medications (due to drug interaction risk per 
the ropivacaine data sheet) 
• 
single shot local nerve block prior to surgery was ineffective (rare) 
• 
selected for neuraxial anesthesia rather than general anesthesia for the open reduction 
surgery (rare) 
• 
already receiving chronic analgesic therapy for a separate chronic pain condition 
 
D. 
Statistical Analysis Plan 
 
For categorical variables, counts and percentages will be presented.  As a check on 
randomization, groups will be compared using the Fisher’s exact test.  For continuous 
variables, mean, median, standard deviation (SD) and inter-quartile range (IQR) will be 
presented.  Groups will be compared using the t-test, except that non-parametric methods 
will be used for variables distributed non-symmetrically. 
 
D1. Aim 1:  
Each SEFAS response has 5 ordinal response choices scored 0 through 4.  With 12 items 
and with the lowest score (0) representing the most severe disability, the total score 
ranges from 0 to 48. If a subject omits one or more questions, the total score will be re-
normalized to 48.  Group differences in the SEFAS scores at the 12 month time point will 
be analyzed using the t-test or Mann-Whitney test, as appropriate. 
 
Patients who are withdrawn from the study due to failure of the initial nerve block will be 
considered as screening failures; no follow-up data or questionnaire scores will be 
obtained.  The same approach will be taken for patients who decide to withdraw from the 
study, or are withdrawn by the attending surgeon or anesthesiologist, after randomization 
but before the single shot nerve block procedure. 
 
Patients lost to follow-up after the end of the 5 day nerve block will be analyzed with a 
per-protocol analysis. We consider that, since the follow-up begins after the end of the 
treatment and consists only of completing questionnaires, there is unlikely to be a bias 
towards the experimental or control group having drop-outs. 
 
Patients who have to (or choose to) remove the pump before the entire 5 day treatment 
period will be analyzed both an intent-to-treat analysis and a per-protocol analysis.  The 
duration of pump use will be noted.   
 
 
 
D2. Aim 2: 
 


 
 
 
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Group differences in the SEFAS scores will be analyzed using a t-test or Mann-Whitney 
test at the 14 day, 3, and 6 month time points... 
 
D2. Aim 3: 
The times the patient enters and is discharged from the PACU will be recorded.  
Discharge from the PACU is based on several criteria, one of which is adequate pain 
control.  Hence duration of PACU stay is relevant to pain experienced by the subject but 
there may be non-pain related reasons for prolonging the PACU stay. Verbal pain scores 
on a scale of 0 (least painful) to 10 (worst pain imaginable) are recorded periodically by 
the nursing staff and entered into the chart; the timing of these entries cannot be expected 
to be completely uniform and patients with higher pain may be queried more often.  Pain 
scores will therefore be summarized by an area-under-the curve analysis, using a score of 
3 as a reference value.  A simple average of all pain ratings captured in the PACU will 
also be examined.  Both sets of values will be compared between experimental and 
control groups using the t-test or Mann-Whitney test, as appropriate. 
 
Time and amount of opioid medications will be captured from the PACU record.  
Different opioid drugs will be converted into analgesic equivalents using the values 
presented at http://www.globalrph.com/narcotic.htm.  Total equivalent opioid use will be 
compared between experimental and control groups using the t-test or Mann-Whitney 
test. 
 
D4. Aim 4: 
Demographic and clinical data will be compared between the groups to determine if 
values differ significantly despite randomization (table *** below).  A preliminary 
analysis of possible confounding clinical variables that may influence the development of 
chronic pain will be conducted.   Linear regression analysis will be used to examine the 
contributions of these 3 variables and the treatment group (experimental or control) to the 
SEFAS score at 12 months. It is expected that this small pilot study will lack the power to 
fully analyze confounders, but the analysis may be used to guide future, larger studies. 
  
 
 
 


 
 
 
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E. 
Variables in the analysis data set with Definitions 
Description 
Patient unique ID 
Age at ankle surgery 
Date of ankle surgery 
Weight and height at time of surgery 
Date of enrollment 
Gender 
Race 
Ethnicity 
Randomized to control or experimental group? 
Ankle fracture: number of  malleoli affected 
Grade of injury (defined as :closed injury, or open injury with Gustilo Anderson 
classification grade 1, grade 2, grade 3a, grade 3b, grade 3cr) 
Opioid medication use in PACU:  time, agent, dose, and route for each 
administration 
Times entered and discharged from PACU 
PACU discharge status (home, rehab facility, hospital, AMA) 
Verbal pain scores in PACU (0 – 10 scale) and times at which recorded 
Surgical Hardware: number of plates implanted, length and number of screw holes 
of each. 
Estimated blood loss during surgery 
Pain medication prescription at discharge (drug, dose) 
Start time of surgery 
End time of surgery 
SEFAS score (2 week, 3, 6, 12 month post surgery) 
Subject-reported analgesic use (2 week, 3, 6, 12 month post surgery) 
Dates of post-surgical follow-ups (FU) 
Weight bearing recommendation at each FU (non, partial, full, other) 
Weight bearing current status at each FU [full, assisted (cane, walker, boot), non 
(crutch)] 
Pain status at each FU (none, mild, severe) 
Pain medication prescriptions at each FU  (drug, dose) 
Wound healing status at each FU (dehiscence, cellulitis , deep infection, healing 
well, other) 
Range of motion at each FU 
Re-operation required? 
Date of re-operation 


 
 
 
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Indication for re-operation (infection, non-union, hardware failure, hardware 
removal, other) 
Chronic pain conditions diagnosed at one year FU. 
 
 
F. 
Variables to Create / Calculate 
Description 
BMI 
Area –under- curve  (from pain scores in PACU) 
Analgesic equivalents of prescribed opioids 
Total length of all plates implanted 
Total number of screw holes of all plates implanted 
Duration of surgery 
Duration of PACU stay 
 
 
 
G.   
Data Sources  
 EPIC chart review 
 SEFAS scores exported from REDCap 
 Opioid equivalency values:  http://www.globalrph.com/narcotic.htm 
 
 
H. 
Software Used (with References) and Specialized Macros (with References) 
 
Calculation of basic statistical parameters, t-tests, Mann-Whitney tests, and Fischer’s exact test 
will be conducted using GraphPad Prism (GraphPad Software, Inc.) or SAS 9.4 (SAS Institute).   
 
 
 


 
 
 
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I. 
Mock tables to be produced 
 
Table 1: Descriptive table of demographics of experimental and control groups prior to 
intervention. 
 
 
Description 
Control (N = ***)1 
Experimental (N = ***)1 p value 
Age at ankle surgery (years) 
 
 
 
Weight at time of surgery 
 
 
 
Height at time of surgery 
 
 
 
BMI at time of surgery 
 
 
 
Race 
 
 
 
Ethnicity 
 
 
 
Ankle fracture: number of  
malleoli affected 
 
 
 
Grade of injury (defined as 
closed injury, or open injury 
with Gustilo Anderson 
classification grade 1, grade 2, 
grade 3a, grade 3b, grade 3cr)2 
 
 
 
Time in surgery 
 
 
 
Estimated blood lost in surgery  
 
 
Number of plates implanted 
 
 
 
Total length of plates 
implanted 
 
 
 
Total number of screw holes in 
implanted hardware 
 
 
 
 
1Mean, SD, median, interquartile range for continuous variables, number and % per group for 
categorical variables. 
2 Converted to ordinal scale 1 – 6 
 
Table 2 Pain outcomes 
 
Description 
Control (N = ***) 
Experimental (N = 
***) 
p value 
Opioid medication use in 
PACU:  analgesic equivalents 
 
 
 
Time in PACU 
 
 
 
PACU discharge status (home, 
rehab facility, hospital)3 
 
 
 
PACU Pain score AUC 
 
 
 


 
 
 
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Average Pain score in PACU 
 
 
 
SEFAS score (2 week) 
 
 
 
Pain medication use analgesic 
equivalents (2 week) 
 
 
 
SEFAS score (3 month) 
 
 
 
Pain medication use analgesic 
equivalents (3 month) 
 
 
 
SEFAS score (6 month) 
 
 
 
Pain medication use analgesic 
equivalents (6 month) 
 
 
 
SEFAS score (12 month) 
 
 
 
Pain medication use analgesic 
equivalents (12 month) 
 
 
 
Number (%) with any chronic 
pain diagnosis at 12 months 
 
 
 
3 Converted to ordinal scale 1 – 3 
 
 
 
 
Table 3 Other outcomes 
 
Description 
Control (N = ***) 
Experimental (N = 
***) 
p value 
Number (%) requiring re-
operation 
 
 
 
Number (%) : Indication for 
re-operation (infection, non-
union, hardware failure, 
hardware removal, other) 
 
 
 
Wound healing status at first 
FU (dehiscence, cellulitis , 
deep infection, healing well, 
other)1 
 
 
 
Wound healing status at 
second FU (dehiscence, 
cellulitis , deep infection, 
healing well, other) 1 
 
 
 
Weight bearing current status 
at first FU [full, assisted (cane, 
walker, boot), non (crutch)] 1 
 
 
 
Weight bearing current status 
at second FU [full, assisted 
 
 
 


 
 
 
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(cane, walker, boot), non 
(crutch)] 1 
1 Converted to ordinal scale