Perineural Steroids for Saphenous Peripheral Nerve Blocks: An Equivalency Dosing Study.
Phase: PHASE4
Conditions: Osteoarthritis, Knee
Sponsor: Wake Forest University Health Sciences

 
 
 
 
 
 
 
 
 
Perineural steroids for saphenous peripheral 
nerve blocks: An equivalency dosing study 
 
NCT02462148 
 
August 7, 2015 
 

 Short Title: 
Perineural steroids for peripheral nerve blocks  
 
Study Full Title: 
Perineural steroids for saphenous peripheral nerve blocks: An equivalency dosing study. 
 
Principal Investigators, Co-investigators: 
Principal Investigators: Sean Dobson, MD and Daryl Henshaw, MD 
Co-investigator: James Turner, MD 
 
Sponsor or funding source: 
Departmental Funding 
 
Summary/Purpose/Rationale 
Regional anesthesia techniques are common modalities used to provide analgesia following both 
upper and lower extremity surgeries. Many different combinations of adjuvants added to local 
anesthetics for peripheral nerve blocks (PNB's) have been attempted to prolong the duration of 
analgesia following surgery. These adjuvants include clonidine, buprenorphine, tramadol, 
midazolam, and neostigmine [1].]. In some preliminary studies, dexamethasone appears to 
prolong the duration of analgesia in both the perineural route and intravenous route [2, 3]. 
However, many of these studies were based on subjective primary end points, such as quality of 
recovery surveys or time to first opioid analgesic request [3,4].  Interestingly, a study out of 
Toronto has more completely shown what was already seen in preliminary studies, that both 
systemic and perineural steroids are also effective in prolonging the duration of peripheral nerve 
blocks [5, 6].   
 
Dexamethasone, a glucocorticoid with minimal mineralocorticoid effect, has been shown to 
improve the overall quality of surgery in certain surgical populations as well as decrease the 
amount of opioid consumed when given intravenously [7]. Though there has been some concern 
regarding the potential neurotoxicity of dexamethasone, there have been multiple studies that 
purport to show no neurotoxic findings with single injection dexamethasone alone or in 
combination with local anesthetics as single injection doses [8, 9]. However, there have been 
limited human studies giving safety data [2].  Given this concern, it is paramount to determine if 
an effective lengthening of the peripheral nerve block can be accomplished with a lesser dose 
[10].  Many studies have used 4 mg and 8mg of dexamethasone perineurally, but none to our 
knowledge have compared a lower dose to see if it is equally effective while limiting potential 
neurotoxicity concerns [2].  The saphenous nerve would be an ideal nerve to study given that it is 
a sensory nerve with no motor function. 
 
Objectives 
The purpose of this randomized, double-blinded, placebo-controlled trial is to examine if 
dexamethasone given perineurally as an adjuvant to the nerve block will prolong the time to 
recovery from sensory nerve block. We hypothesize that dexamethasone will provide analgesic 
times greater than that seen in the control arm without dexamethasone, and that similar results 
will be obtained by the 1 mg arm when compared to the 4 mg arm. The primary outcome will be 

time to resolution of the nerve block as assessed by pinprick over the saphenous nerve 
distribution. Secondary outcomes will include pain scores, amount of post-operative opioids, and 
the incidence of nausea and vomiting will be recorded over the course of 24-48hrs. This will be 
done by asking the patient about nausea and emesis following recovery.  The answers will be 
recorded on the data sheet as yes or no.  Subjects will also be followed to evaluate for potential 
neurologic complications such as persistent paresthesias in the distribution of the saphenous 
nerve. 
 
Methods/Measurements: 
Design:  
This study will be a randomized, double-blind, placebo-controlled trial that will take 
place after Institutional Review Board approval. Written informed consent will be 
obtained from all the study participants.  We have already obtained an Investigational 
New Drug (IND) exemption from the Food and Drug Administration (IND 125810) for 
this study given the following protocol 
 
Selection Criteria: 
Inclusion: Adults, between 18 and 90 years of age, undergoing elective robotic medial 
and/or patellofemoral MAKO partial knee arthroplasty and who have agreed to a regional 
anesthesia technique will be recruited to participate. 
 
Exclusion: Subjects with contraindications to regional anesthesia, such as a history of 
allergy to amide local anesthetics, presence of a progressive neurological deficit, a pre-
existing coagulopathy, infection, or the following conditions: insulin and non-insulin 
dependent diabetes mellitus, systemic use of corticosteroids within 30 days of surgery, 
chronic use of an opioid analgesic (>3 months or a combined total of more than 40 mg 
Oxycodone equivalents a day), or whom are pregnant will be excluded.  Also, any patient 
with a prior history of an adverse event (for example: psychosis) or an allergy to 
dexamethasone will be excluded. 
 
Setting: 
All patients in the study will be undergoing non-urgent surgery at Wake Forest 
University Baptist Medical Center.  The interventions will be performed in the regional 
anesthesia area of the surgery center.   
 
Interventions and Interactions: 
Adults, between 18 and 90 years of age, undergoing elective robotic medial and/or 
patellofemoral MAKO partial knee arthroplasty will be recruited to participate. Eligible patients 
will be identified the day before surgery based on surgical postings.  Upon arrival to the regional 
anesthesia area of surgical services at Wake Forest University Baptist Medical Center they will 
be formally consented if they are interested in participating in the study.  Patients will be asked 
to provide baseline verbal pain scores both at rest and with movement on a scale of 0-10 (0 being 
no pain and 10 being the worst pain).  Preoperative opioid use including drug, dosage and 
frequency will be recorded.  Additionally, baseline patient characteristics will be recorded 
including height, weight, BMI, sex, age, surgeon and operative side.   
 

Before PNB placement each patient will be randomized blindly to one of the three 
aforementioned arms. Blinding will occur by a secondary provider in the regional and acute pain 
management area by a second provider not associated with the study.  This will obviously occur 
following randomization.  All volumes will be identical.  Once randomization and blinding 
occur, standard ASA monitors and oxygen will be applied. All saphenous nerve blocks will be 
performed by a resident or a fellow trainee supervised by an attending anesthesiologist.  
Sedation for the PNB will be provided in the usual manner at the discretion of the 
anesthesiologist providing the nerve block.  Unless there is a contraindication, each patient will 
receive 1000 mg of PO acetaminophen, 150 mg of PO pregabalin, and 400 mg of celecoxib.   
 
All subjects will receive an ultrasound-guided adductor canal nerve block and will be computer 
randomized to receive 20 ml of one of the following solutions: either 0.25% bupivacaine with 
epinephrine 1:400,000, 0.25% bupivacaine with epinephrine 1:400,000 with 4 mg of preservative 
free dexamethasone added to the solution, or 0.25% bupivacaine with epinephrine 1:400,000 
with 1 mg of preservative free dexamethasone added to the solution. Both the subject and the 
investigator will be blinded to the arm of the study. 
 
The products to be used are the following, and have been granted an FDA IND exemption (IND 
125810) 
1) Bupivacaine Hydrochloride. 30 ml single dose vial. 11 Digit NDC code: 00409-1159-02. 
Hospira, Inc. Lake Forest, IL. 
2) Dexamethasone Sodium Phosphate Injection 10mg/ml. APP Pharmaceuticals LLC, 
Schaumburg, Ill. NDC Code: 63323-506-01, 63323-516-10 
3) McKesson ID 2070274 Adrenalin Chl. Inj. 1mg/ml 1ML25 epinephrine NDC 2023015925.   
 
For each nerve block, the epinephrine will be added to the bupivacaine and dexamethasone in a 
sterile fashion and used within 24 hours of the epinephrine being added. Otherwise, the solution 
will be discarded.  All procedures will be performed under a sterile technique including the use 
of a chlorohexidine prep of the skin, sterile gloves, a sterile ultrasound probe cover with sterile 
ultrasound gel, and a cap and a mask. A 21-gauge 90 mm Arrow StimuQuick, stimulating needle 
(Teleflex, USA) will be directed under real-time ultrasound guidance into the adductor canal. 
The local anesthetic solutions will be injected incrementally in 5 mL aliquot to a total volume of 
20 mL to surround the saphenous nerve.  
 
Study subjects will receive either a spinal anesthetic with propofol sedation (25–100 μg/ kg/min) 
or a general anesthetic for their surgical procedure. Patients will undergo their surgery and be 
brought to the post-anesthesia recovery unit (PACU).  The patient will remain in the PACU until 
resolution of the spinal from the non-operative side.  
 
These participants will be observed overnight and will be evaluated every two hours with pin-
prick (performed with a 25 gauge Whitacre needle in the cutaneous distribution of the saphenous 
nerve on the medial aspect of the blocked leg) to monitor for the duration of the sensory block 
until sensation is fully returned. This testing will be performed by research assistants.  If the 
duration of their sensory block should last past admission, the patients will be educated during 
their hospitalization assessments on how to assess their own block every two hours at home 
using a safety pin.  Research assistants will continue to call patient’s every two to three hours 

during this time until block resolution occurs to instruct the participants and answer any 
questions. During their stay, their pain management will be managed by the Acute Pain Service. 
They will also be asked about their pain using the visual analog scale, post operative nausea and 
vomiting rates, and opioid consumption will be followed. Comparisons will then be made 
between the three groups and the data will be analyzed. 
 
Outcomes Measures: 
Subjects will be evaluated for the efficacy of a sensory blockade on the operative limb. Complete 
sensory analgesia will be defined as analgesia to pinprick in the distribution of the saphenous 
nerve. The primary outcome will be time to resolution of the nerve block as assessed by pinprick 
over the saphenous nerve distribution, secondary outcomes will include but not limited to pain 
scores, use of post-operative opioids, and the incidence of nausea and vomiting will be recorded 
over the course of 24-48hrs. Subjects will also be followed to evaluate for potential neurologic 
complications such as persistent paresthesias in the distribution of the saphenous nerve.   
 
Analytical Plan: 
Power / Sample Size:  
The primary sample size consideration is the comparison between the 1 mg and 4 mg of 
dexamethasone arms, where the goal is to demonstrate that the duration of PNB is clinically 
equivalent between the two arms. Note that this hypothesis, statistically, is reversed  
from what is usually tested in a superiority trial. We have assumed that clinically equivalent 
means that the average duration of PNB for 1 mg of dexamethasone is ± 4 hours from the 
average duration for 4 mg. In other words, the difference in mean duration for the two 
dexamethasone arms (D) falls on the interval (-4 hrs to 4 hrs). Statistically, a successful trial 
would then reject the null hypothesis H0: D< -4 hrs or D> 4hrs. The previously mentioned 
Toronto study [5] reported a mean duration of analgesia of 25 hours (95% CI: 19.5-27.4) for 25 
patients randomized to 8 mg of perineural dexamethasone. While the test of clinical equivalence 
will be based on the boundary of ± 4 hours, in order to permit power calculations one has to 
make an assumption about the true difference in mean duration. The most liberal assumption is 
that there is absolutely no difference in mean duration between the arms (i.e. D=0). To be more 
conservative, we have assumed that the true mean duration for 4 mg of dexamethasone is ± 1.5 
hours from the true mean duration for 8 mg. This assumption implies that a study of 50 
participants per group (allowing for 10% drop-out) will have >80% power to declare the two 
doses as clinically equivalent. Note that this calculation assumes a type 1 error rate of 0.05/3 = 
0.1667, as the study has three planned comparisons (two dexamethasone doses versus each other, 
and then both versus the placebo control). We plan to recruit a reduced sample size for the 
placebo control arm, as the difference in duration of PNB when compared to both 
dexamethasone arms is expected to be large. Provided the average duration of PNB is at least 5 
hours longer for either dexamethasone arm, we will have >90% power recruiting only 15 
subjects (allowing for 10% drop-out) to the placebo control arm. Note that the Toronto study [5] 
reported an average improvement of 11.8 hours when comparing 8 mg of perineural 
dexamethasone to their control arm.  
 
 
Human Subjects Protection: 
 

Subject Recruitment Methods: 
Potential study participants will be identified based on the posting of their surgical procedure as 
undergoing elective robotic medial and/or patellofemoral MAKO partial knee arthroplasty.  On 
the day of surgery all patients undergoing this surgical procedure normally come through the 
regional anesthesia area of surgical services to receive further anesthetic evaluation, education, 
and potential regional anesthesia procedures.  Once they have been consented by the regional 
anesthesia team for a peripheral nerve block, all patients, regardless of gender, race or age, who 
qualify for the study based on inclusion and exclusion criteria will be formally asked to 
participate in the study at this time.  All patient information will be kept confidential both during 
recruitment and throughout the duration of the study.  
 
Informed Consent: 
Written informed consent will be obtained from each subject. It can be obtained by any physician 
listed as part of the study staff.  If possible, patients scheduled for elective robotic medial and/or 
patellofemoral MAKO partial knee arthroplasty will be seen in the preoperative assessment 
clinic at North Carolina Baptist Hospital.  Otherwise, as is typical for regional anesthesia 
techniques, the study team will meet the patient in the Regional Anesthesia and Acute Pain 
Management area.  They will be informed of the purpose of the study along with the risks, 
benefits, and alternatives. Questions will be answered and consent obtained.  A copy of the 
signed informed consent will be placed in the patient’s medical record.  All subjects may decline 
participation in the study at any time.  Informed consent and all necessary study data will be 
obtained prior to the administration of any sedative medication.   
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that could 
directly identify subjects, and maintaining all study information in a secure manner.  To help 
ensure subject privacy and confidentiality, only a unique study identifier will appear on the data 
collection form.  Any collected patient identifying information corresponding to the unique study 
identifier will be maintained on a linkage file, stored separately from the data.  The linkage file 
will be kept secure, with access limited to designated study personnel.  Following data collection 
subject identifying information will be destroyed at the earliest opportunity, consistent with data 
validation and study design, producing an anonymous analytical data set.  Data access will be 
limited to study staff.  Data and records will be kept locked and secured, with any computer data 
password protected.  No reference to any individual participant will appear in reports, 
presentations, or publications that may arise from the study. 
 
Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study 
staff. 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol 
changes will be promptly reported by the principal investigator or designated member of the 
research team to the IRB and sponsor or appropriate government agency if appropriate. 

 
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dexamethasone for peripheral nerve blocks. Anaesthesia 2015(1); 70: 71-83.  
 
3. Rahangdale R, et al. The effects of perineural versus intravenous dexamethasone on sciatic 
nerve blockade outcomes: a randomized, double-blind, placebo-controlled study. Anesthesia and 
Analgesia 2014(5); 118, 1113-1119.  
 
4. Desmet M, Braems H, Reynovoet M, et al. IV and perineural dexamethasone are equivalent in 
increasing the analgesic duration of a single-shot interscalene block with ropivacaine for 
shoulder surgery: a prospective, randomized, placebo-controlled study. British Journal of 
Anaesthesia 2013; 111(3): 445-452. 
 
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Medicine 2015; 40(2): 125-132.  
 
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Appendix: 
1. Data Collection Form 
2. Consent Form 
3. FDA IND Acknowledge/Exemption 125810