Tissue Concentrations of Vancomycin Achieved With Bier Block Administration Versus Intravenous Prophylaxis in Upper Extremity Surgery: A Randomized Controlled Trial
Phase: PHASE1
Conditions: Infection, Hand Injury Wrist, Hand Injuries, Hand Injuries and Disorders, Hand Arthritis
Sponsor: Mayo Clinic

Minimal Risk Protocol Template [IRB 10429.010] 
 
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IRB Minimal Risk Protocol Template  
 
General Study Information 
 
Principal Investigator: Kevin Renfree, MD        
 
 
 
 
 
 
 
 
Study Title: Tissue Concentrations of Vancomycin Achieved With Bier Block Administration versus 
Intravenous Prophylaxis in Upper Extremity Surgery: A Randomized Controlled Trial    
 
Protocol version number and date: Protocol v.1.0 - 8/23/20     
 
Research Question and Aims 
 
Hypothesis: Vancomycin administered intravenously via a Bier Block achieves superior soft tissue and 
cancellous bone concentrations compared with systemic IV administration for prophylaxis in upper extremity 
reconstruction without a higher rate of complications. 
 
Aims, purpose, or objectives: To quantify and compare vancomycin concentration in bone and soft tissue: (1) 
after Bier Block administration, (2) after systemic intravenous vancomycin administration, (3) determine if 
there is any difference in complication rate between Bier Block and systemic intravenous administration of 
vancomycin and (4) determine what complications are associated with Bier Block administration of 
vancomycin. 
 
Background (Include relevant experience, gaps in current knowledge, preliminary data, etc.):  Infections in the 
hand and upper extremity are commonly encountered in clinical practice. Depending on region of practice 
current literature estimates 25-50 to 123 patient admissions annually due to infections of the hand requiring 
surgery and IV antibiotics. This challenge has motivated interest in alternative interventions for hand and upper 
Note: If this study establishes a human specimen repository (biobank) for research 
purposes, do not use this template. Use the Mayo Clinic Human Specimen Repository 
Protocol Template found on the IRB home page under Forms and Procedures at 
http://intranet.mayo.edu/charlie/irb/ 
 
First-time Use: Use this template to describe your study for a new IRB submission. 
1. Complete the questions that apply to your study. 
2. Save an electronic copy of this protocol for future revisions.    
3. When completing your IRBe application, you will be asked to upload this document to the protocol 
section. 
Modification:  To modify this document after your study has been approved: 
1. Open your study in IRBe. Click on the study ‘Documents’ tab and select the most recent version of the 
protocol. Save it to your files. 
2. Open the saved document and activate “Track Changes”.  
3. Revise the protocol template to reflect the modification points , save the template to your files 
4. Create an IRBe Modification for the study and upload the revised protocol template. 

Minimal Risk Protocol Template [IRB 10429.010] 
 
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extremity infections, in particular nonsurgical treatment with high local concentrations of antibiotics. The 
relatively high vascular supply to the hand and upper extremity may allow for treatment of infection with 
localized therapy, allowing patients to undergo surgical interventions with potentially lengthy recovery.  
 
Previous studies in primary and revision total knee arthroplasty have shown significantly higher tissue and bone 
concentrations of a comparatively lower dose of Vancomycin administered by intraosseous regional 
administration (IORA) when compared to systemic IV administration. These differences remained significant 
through the following day, despite a period of tourniquet deflation, and have also been shown to be significantly 
higher in patients with high BMI regardless of dose adjustment. Regional administration of teicoplanin in the 
lower extremity has also been reported for TKA prophylaxis, resulting in a 10 times higher tissue concentration 
than systemic IV administration. Importantly, there have not been an increased rates of complications reported 
with local administration of these antibiotics. Specifically “red man syndrome” or nephrotoxicity,  is no more 
common with IORA of vancomycin than with systemic IV therapy.  
 
Certain types of hardware or implants may limit the feasibility of IORA in the upper extremity, where smaller 
volumes of cancellous bone are available for injection. However, the cost and availability of supplies for Bier 
Block administration are favorable compared to IORA making this an appealing option for administration of 
high doses of vancomycin within a localized tissue area. In addition, the Bier Block method is commonly 
performed by providers outside of the operating room, is broadly taught, and may have a greater utility for 
clinical use than IORA. There are several complications of Bier Block reported in the literature, although rare, 
they include potential for nerve damage, compartment syndrome, skin discoloration or petechiae, and 
thrombophlebitis. Tissue concentration of antibiotics after administration via Bier Block is currently unknown. 
To assess tissue concentrations our study will analyze patients undergoing reconstructive procedures of the 
hand/wrist. These procedures require removal of bone and soft tissue and will have no detrimental effect on the 
patient. 
 
Bier block administration of regional vancomycin has multiple theoretical advantages. As vancomycin carries a 
high risk of systemic toxicity, local administration will limit the site of action and minimize systemic 
complications of the medication. This method should and allow for a lower dose of medication to achieve an 
equal or greater effect based on previous studies examining IORT. Although the exact pharmacokinetics of 
vancomycin are not completely described, higher concentrations of vancomycin have been associated with a 
greater clinical effect. This may provide greater coverage against resistant organisms as well as lower the 
amount of medication that must be administered to prevent infection. Traditionally vancomycin is administered 
over one hour with high systemic concentrations and can cause a histamine release known as “red man 
syndrome” mirroring symptoms of anaphylaxis. Theoretically, administration to a local area will not activate a 
similar histamine release and will not require the prolonged administration of the medication pre-operatively. 
 
 
Study Design and Methods 
 
Methods:  Describe in lay terms, completely detailing the research activities that will be conducted by Mayo 
Clinic staff under this protocol. 
 

Minimal Risk Protocol Template [IRB 10429.010] 
 
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Patients undergoing upper extremity reconstruction by a single surgeon will be included. Patients will be 
randomized to two arms, with target accrual of 10 cases in the Bier block and systemic intravenous IV groups 
respectively (20 cases total). Surgical cases will include Trapeziectomy/suspensionplasty (30-60 mins duration), 
PIPJ/MPJ arthroplasty (60-90 min duration), proximal row carpectomy (60 min), and distal ulnar resection (30-
45 mins). The estimated case collection period is approximately 8 months based on averages of case logs from 
the previous 2 years. Both groups will receive 2 g systemic cefazolin 15 minutes before tourniquet inflation 
Vancomycin dosing will be identical to previous reports on total knee arthroplasty. In the systemic IV group, 1 
g of vancomycin will be delivered over a period of one hour prior to tourniquet inflation. In the Bier Block 
group, Vancomycin 500 mg will be diluted in 50 cc normal saline, and after exsanguination of the limb and 
elevation of the tourniquet in the prepped and draped patient, will be injected into a superficial vein in the hand, 
wrist or forearm. Sample collection times will be recorded from time of skin incision to equalize for any delays 
in administration of antibiotic via Bier block administration after tourniquet inflation. Time from tourniquet 
inflation to incision will also be documented for both groups. 5 tissue samples (0.5 cm3) from each patient in 
both groups will be obtained: subcutaneous fat (1) and cancellous bone (2) 5-10 minutes after skin incision, 
subcutaneous fat (3) and cancellous bone (4) 20-25 minutes after skin incision, and subcutaneous fat (5) at skin 
closure (45-60 minutes after skin incision).  In the Bier Block group, after the dressing is applied the tourniquet 
will be briefly deflated for 30 seconds and then re-inflated. If there are no signs of “red man syndrome” within 5 
minutes (skin rash of face/neck/or torso, hypotension, tachycardia), then the tourniquet will again be deflated. 
Samples will be stored the Mayo Clinic Hospital lab at -90°C, before being transported to Christchurch, New 
Zealand for analysis using a previously validated technique. Bone samples will be crushed with pliers, finely cut 
further with a scalpel, then weighed and immersed in phosphate buffered saline pH 7.3 for 15 h at 4C. The fat 
samples will finely cut with a scalpel, and then treated in a same way as the bone samples. The immersed bone 
or fat tissue suspension will be vortexed for 30 seconds and centrifuged at 15,000 g for 10 min. The supernatant 
will be transferred to a clean tube and perchloric acid added to precipitate the proteins. After centrifugation at 
15,000 g for 5 min, 50 uL of clear supernatant will be analysed. 
 
Subject Information 
 
Target accrual is the proposed total number of subjects to be included in this study at Mayo Clinic. A “Subject” 
may include medical records, images, or specimens generated at Mayo Clinic and/or received from external 
sources.    
 
Target accrual: 20 patients 
 
Subject population (children, adults, groups):  Adults undergoing reconstructive procedures of the hand/wrist 
 
Inclusion Criteria: Patients undergoing trapeziectomy/suspensionplasty, proximal interphalangeal joint or 
metacarpophalangeal joint arthroplasty, proximal row carpectomy, or distal ulnar resection 
 
Exclusion Criteria: Inability to adequately cannulate a superficial vein in the upper extremity within 5 minutes 
of tourniquet inflation or evidence of subcutaneous extravasation in Bier Block group, history of renal 
disease, vancomycin allergy, ASA >/= 3, history of lung cancer, known HIV infection, history of organ 
transplantation, current or treatment with vancomycin in the preceding 7 days, patients under the age of 
18, pregnant females (screened with pregnancy test if female under the age of 50). 

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Biospecimens
 
Collection of blood samples. When multiple groups are involved copy and paste the appropriate section below 
for example repeat section b when drawing blood from children and adults with cancer.  
 
a. From healthy, non-pregnant, adult subjects who weigh at least 110 pounds. For a minimal risk 
application, the amount of blood drawn from these subjects may not exceed 550ml in an 8 week period 
and collection may not occur more frequently than 2 times per week. 
Volume per blood draw: _____ml   
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) ___________ 
 
b. From other adults and children considering age, weight, and health of subject. For a minimal risk 
application, the amount of blood drawn from these subjects may not exceed the lesser of 50 ml or 3 ml 
per kg in an 8 week period, and collection may not occur more frequently than 2 times per week.   
Volume per blood draw: _____ml 
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) ___________  
 
Prospective collection of biological specimens other than blood: Collection of bone and soft tissue samples - 2.5 
cm3 in total from each patient in 0.5 cm3 samples. 
 
Review of medical records, images, specimens  
 
 
Check all that apply (data includes medical records, images, specimens).  
 
  Only data that exists before the IRB submission date will be collected.   
 
Date Range for Specimens and/or Review of Medical Records:   
Examples: 01/01/1999 through 12/31/2015, or all records through mm/dd/yyyy.  
 
Note: The Date Range must include the period for collection of baseline data, as well as follow-up data, 
if applicable. 
 
  The study involves data that exist at the time of IRB submission and data that will be generated after IRB 
submission. Include this activity in the Methods section.  
Examples 
 The study plans to conduct a retrospective chart review and ask subjects to complete a questionnaire.  
 The study plans to include subjects previously diagnosed with a specific disease and add newly 
diagnosed subjects in the future.  

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  The study will use data that have been collected under another IRB protocol. Include in the Methods section 
and enter the IRB number from which the research material will be obtained. When appropriate, note when 
subjects have provided consent for future use of their data and/or specimens as described in this protocol.  
 
Enter one IRB number per line, add more lines as needed 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 Data    
 Specimens  
 Data & Specimens  ______________________________________ 
 
 
Data Analysis 
 
 
Power analyses may not be appropriate if this is a feasibility or pilot study, but end-point analysis plans are 
always appropriate even if only exploratory. Provide all information requested below, or provide justification if 
not including all of the information.  
 
Power Statement: Previous studies examining IORA of vancomycin show approximately a 4.5 fold increase in 
tissue concentration compared to systemic administration. A priori analysis shows that 10 patients per study arm 
will be required to achieve 80% statistical power with a type I error rate of 0.05.  
 
 
Data Analysis Plan: Means, standard deviations, and the 95% confidence limits will be calculated for the 
concentrations in the different samples. Different tissue samples will be pooled according to collection time. 
Coefficient of variations (CV) of concentration level will be summarized at each time interval for the 
comparison between two arms. Repeat measure analysis of variance will be used to compare the average level 
of concentration across time between groups adjusted by BMI, age, and length of surgical procedure; Shapiro-
Wilk test will be used to assess the normality of the residuals. Adverse event will be recorded by contingency 
table. 
 
 
Endpoints 
Primary: Tissue concentrations of vancomycin in the hand and wrist following Bier Block administration versus 
systemic IV administration 
Secondary: Complications rate of Bier Block administered vancomycin, modes of adverse events, safety of Bier 
Block administered vancomycin,. which rarely can cause a reaction that includes low blood pressure and skin 
redness or flushing. This is temporary and can usually be treated effectively with an antihistamine. In previous 
studies using a similar technique of intraosseous administration followed by tourniquet release, this has not been 
seen.  Antihistamine will be on hand so that it can be administered should this reaction occur. Additionally, 

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patients will be observed post-operatively for signs of phelibitis, but this is not felt to be a greater risk resulting 
from Bier block administration (intravenous) compared to standard intravenous administration used clinically.