The Effect of Pneumatic Tourniquet Use on Upper Extremity Edema Following Axillary Lymph Node Dissection
Phase: NA
Conditions: Healthy Subject
Sponsor: Stanford University

The Effect of Pneumatic Tourniquet Use on Upper Extremity Edema Following Axillary Lymph Node Dissection  
 
TITLE:  The Effect of Pneumatic Tourniquet Use on Upper Extremity Edema Following 
Axillary Lymph Node Dissection 
 
 
Coordinating Center 
Stanford Department of Orthopedic Surgery 
450 Broadway, Pavilion C 
Redwood City, CA 94063 
 
Principal Investigator 
Dr. Jeffrey Yao 
450 Broadway, MC 6342 
Redwood City, CA 94063 
xxx-xxx-xxxx 
xxx-xxx-xxxx 
jyao@stanford.edu 
 
Co-Investigators 
Dr. Edward Wu, MD 
Cara Lai 
 
Biostatistician 
Nicole Segovia 
Jamie Koltsov, PhD 
 
Study Coordinator 
Katie Meyer 
450 Broadway 
Redwood City, CA 94063 
 
 
Version Date: September 15, 2020 
 
NCT03584100 
 
 
 
 
 
 

The Effect of Pneumatic Tourniquet Use on Upper Extremity Edema Following Axillary Lymph Node Dissection  
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TABLE OF CONTENTS 
 
1.0  SPECIFIC STUDY AIMS .................................................................................................. 3 
2.0  BACKGROUND AND RATIONALE .............................................................................. 3 
3.0  STUDY ENROLLMENT AND PARTICIPANT ELIGIBLITY ................................. 3-4 
3.1 STUDY ENROLLMENT .......................................................................................................... 3 
3.2 PARTICIPANT CRITERIA....................................................................................................... 4 
3.3   ENROLLMENT .................................................................................................................... 4 
4.0  MATERIAL AND METHODS ......................................................................................... 4 
5.0 STATISTICAL CONSIDERATIONS ............................................................................... 5 
5.1 OUTCOME MEASUREMENTS ................................................................................................ 5 
5.2 ANALYSIS PLAN .................................................................................................................. 5 
5.3 SAMPLE SIZE ....................................................................................................................... 5 
6.0  DATA MANAGEMENT CONSIDERATIONS............................................................... 5 
6.1 DATA MANAGEMENT .......................................................................................................... 5 
6.2 CONFIDENTIALITY .............................................................................................................. 5 
6.3 PROTOCOL REVIEW AND AMENDMENTS ............................................................................. 5 
REFERENCES .............................................................................................................................. 6 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST............................................ 7-8 
 
 

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1.0  
SPECIFIC STUDY AIMS  
The purpose of this study is to evaluate the safety of tourniquet use and subsequent 
resolution of swelling in patients with prior axillary lymph node dissection. We 
hypothesize that a tourniquet placed for a short period of time at low pressure will cause 
edema without complication in both arms ipsilateral and contralateral to the side of 
axillary lymph node dissection in patients status post prior axillary lymph node dissection 
for cancer.  
 
2.0  
BACKGROUND AND RATIONALE  
The safety of elective hand surgery in breast cancer patients following ipsilateral axillary 
lymph node dissection (ALND) is controversial due to concerns of developing upper 
extremity lymphedema. Prior authors have discussed concern for invasive and non-
invasive manipulation of the extremity, including blood pressure measurements, 
injections, and intravenous access1-2, although the evidence for these factors in the onset 
or progression of lymphedema is limited. However, this is controversial in the oncology 
literature despite being widely accepted in the hand surgery literature3-5. Patients are 
commonly dissuaded from routine elective hand surgery for coexistent pathology6. Prior 
studies have demonstrated no to minimal risk of developing lymphedema acutely or late 
following hand surgery after prior ALND6-9. Furthermore, no evidence is available to 
demonstrate a relationship between tourniquet use and lymphedema6-9, and existing 
literature supports the use of an upper arm tourniquet in patients with prior breast cancer 
treatment of ALND. The acute effect of swelling in the setting of a tourniquet and the 
time required for swelling reduction for this population, however, remains unknown. 
 
A pilot study has been completed to evaluate tourniquet use in healthy volunteers and the 
chosen pressure of 40 mmHg was identified as leading to repeatable swelling without 
acute or chronic abnormalities. Higher pressures (250, 120, 100 and 80 mmHg) lead to a 
similar 30-40 mL increase in volume in a healthy volunteer, although transient nerve 
palsy, pain and petechiae were identified at the higher pressure. No complications were 
identified in 8 healthy volunteers at 40 mmHg over 25 minutes. The increase in hand 
volume was less than 30 mL at 30 mmHg or less. Therefore, 40 mmHg most reliably 
recreates temporary edema formation, while limiting unnecessary or prolonged tourniquet 
use. Pilot study results further found that both the on head and brace limb postures 
markedly and significantly decreased swelling greater than the sling posture (p < .001). 
 
The purpose of the proposed study is to evaluate the acute impact of swelling caused by 
low-pressure tourniquet use in the setting of ipsilateral ALND and the change in swelling 
reduction following tourniquet use in two limb postures, comparing the arms ipsilateral 
and contralateral to the side of ALND. We hypothesized that tourniquets may be safely 
applied to patients with prior ALND in either their ipsilateral or contralateral arm. We 
further hypothesized that patients who have had prior ipsilateral ALND would have an 
equivalent proportion of upper extremity edema and see improved resolution with 
increased elevation. Understanding the effect of tourniquet use and its safe practice will 
aid in the surgical management of patients with prior axillary lymph node dissection. 
 

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3.0  
STUDY ENROLLMENT AND PARTICIPANT ELIGIBLITY 
All patients over the age of 18 who have previously undergone axillary lymph node 
dissection will be invited to participate in the study. Participants will be identified via 
chart review of patients with prior ALND.  
 
3.1 
Study Enrollment 
Recruitment will occur via telephone or in-person encounters based on retrospective 
review for patients meeting the above inclusion criteria. Advertising for this study is not 
planned. Participants will be screened based on the above criteria and the exclusion 
criteria in part 3.2 below. Participants who fail inclusion on screening will be excluded.  
 
The study coordinator or the above study members will consent the patient prior to 
involvement. In a closed and quiet room, the potential research subject will be able to ask 
any questions regarding the study and its procedures. No recruitment materials will be 
provided at the time of consent. Participants may withdraw consent at any time. 
 
3.2 
Participant Criteria  
All patients over the age of 18 who have previously undergone axillary lymph node 
dissection will be invited to participate in the study. Patients will serve as their own 
internal control, using both arms which are ipsilateral and contralateral to the side of 
ALND. Patients will be excluded who have new-onset lymphedema of the involved limb, 
infection including cellulitis, or trauma or planned axillary surgery within 6 months of 
participation.  
 
3.3   
Enrollment 
Given the variability in our pilot study, we determined by power analysis that we would 
need to recruit 45 participants (for a total of 90 arms) for the current study for evaluation 
of relative edema and its reduction following tourniquet use. We expect the study to 
begin upon approval, 4/2017 and conclude after recruitment in approximately 6-12 
months. 
 
4.0  
MATERIAL AND METHODS  
Study participants will be seated and patients’ arms ipsilateral to prior axillary lymph 
node dissection will be elevated with the hand above the level of the ipsilateral shoulder 
for 15 minutes. This is to ensure an accurate baseline in all participants. Hand volume 
will be measured by aqueous volumeter to the level of the proximal wrist crease for a 
baseline. A tourniquet will then be placed on each study participant’s upper arm, again 
ipsilateral to prior axillary lymph node dissection. This will be inflated to 40 mmHg for 
25 minutes, after which hand volume will be again measured as described above. The 
limb will then be placed in an elevated position at shoulder height or in a sling at the 
waist, and hand edema will again be measured. The process will be repeated for each 
limb position after a 15-minute break time. The two limb positions are “sling,” with the 
hand at the level of the waist, and “elevated” with the hand at the level of the shoulder. 
This will be repeated for the contralateral, healthy arm which will serve as an internal 
control. 
 

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5.0 
STATISTICAL CONSIDERATIONS 
 
We will evaluate the data per recommendations of our statistician by categorical and 
continuous statistical testing, as applicable. For the primary outcomes of percentage 
change in hand volume from baseline after tourniquet application, and secondary 
outcome of residual volume as a percentage of baseline following limb positioning, we 
will compare the healthy contralateral arm versus the arm status post ALND. Paired t-
tests will be used to compare measures averaged to produce a single pre-tourniquet hand 
volume and a single post-tourniquet hand volume. The differences will again be 
compared between patients’ arms ipsilateral and contralateral to the side of ALND. 
Linear mixed effects model will also be fitted to account for the correlations between 
measurements on the same subject and history of ALND, arm position after tourniquet 
use, and patient-specific risk factors. This specific issue power analysis is further 
discussed below (5.3). 
 
5.1 
Outcome Measurements 
Study participants will be evaluated prior to and following the above process.  
Data collection:  
A. Demographic will be recorded: Age, sex, height, weight, BMI, comorbidities, number 
of lymph nodes excised in ALND, and presence of lymphedema  
B. Procedural measures: hand volume and percent change 
Primary outcome: percentage change in hand volume from baseline after 
tourniquet application 
Secondary outcome: residual volume as a percentage of baseline following limb 
positioning after tourniquet use 
C. Tourniquet complications: unresolved edema (i.e. persistent swelling lasting greater 
than the 30 minute evaluation period), petechiae (i.e. pinpoint skin redness or purple 
color caused by a minor bleed from broken capillary blood vessels), pain, paresthesias 
(tingling sensation), palsy (neurologic change related to peripheral nerve compression), 
by direct visualation and neurologic evaluation by a medical provider at the time of 
tourniquet use 
 
Acute or delayed symptoms related to tourniquet use will be assessed and managed with 
routine care. Participants may contact the study staff at any time regarding delayed 
complication. 
 
5.2 
Analysis plan 
Data will be analyzed as above. To reiterate the methods (Section 4.0), a baseline volume 
will be measured in all participants prior to tourniquet use. The absolute change in hand 
volume, percentage change from baseline, and residual volume as a percentage of 
baseline immediately following tourniquet use will then be measured in all patients. The 
mean will be compared between the arms ipsilateral and contralateral to the side of 
ALND by paired t-tests. The parameters listed above are the primary outcomes. Each 
participant will then be monitored in two limb positions (elevated and sling as described 
above), with measurements taken on both arms ipsilateral and contralateral to the side of 

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ALND. Volume is measured after each position. The change in limb edema as a factor of 
time will be analyzed by a linear mixed effects model. This is the secondary outcome. 
 
5.3 
Sample size 
We analyzed preliminary data on percent change in hand volume in normal controls as a 
response to the application of a tourniquet. Similar data is not available in the literature 
for patients following ALND. In the pilot, the median change was 9.1%, with a standard 
deviation of 1.6% assuming each subject contributed one baseline hand volume and one 
volume following the application of the tourniquet. 
 
Our scientific hypothesis is that the difference in change of mean hand volume among 
women who have had lymph node dissection, between the arms ipsilateral and 
contralateral to the side of ALND is zero or negligible. We therefore seek a sample size 
that expresses non-inferiority between ipsilateral and contralateral arms. In the absence of 
clinical norms for the margin of non-inferiority, we made the sample size calculation on 
the basis of margin of non-inferiority of 1% (in units of percent change in hand volume). 
 
We plan to accrue 45 extremities in each group, with two arms per patient. We have 90% 
power that the upper 95% confidence interval of the difference will be at or below the 
stipulated margin of 1%. A confidence bound above the stipulated margin will be taken 
as evidence of some difference between ipsilateral and contralateral arms, indicating an 
effect of the prior axillary lymph node dissection over and above the effect of the 
tourniquet.  
 
The above calculation assumed a standard deviation of 1.6 percentage point, and 45 
patients with two arms each (ipsilateral and contralateral to ALND) to provide 90% 
power for a margin of equivalence of one percentage point using a two-sided significance 
level of 5%, with a primary endpoint of percentage change from baseline following 
tourniquet use. If 10% of patients are uninformative (N=40 for ipsilateral and 
contralateral arms), we expect have 87% power for the same margin of equivalence. If 
20% are uninformative (N=35 for ipsilateral and contralateral arms), we would have 82% 
power. The secondary outcome of residual limb volume following elevation in the two 
limb positions (elevated and sling) are not included in this power analysis and are not 
primary outcomes. 
 
We expect the study to begin upon approval, and conclude after recruitment in 
approximately 6-12 months. 
 
6.0  
DATA MANAGEMENT CONSIDERATIONS 
 
6.1 
Data management  
The study members will be present at all times during the procedures, and will adhere to 
the standard methods of care and safety of the participating subjects. Patient information 
will subsequently be accessed by only those investigators involved in the study who have 
been named on this protocol. Data will be recorded electronically. Research data resulting 
from the analysis of will be safeguarded in password-secured laboratory computers where 

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careful records will be maintained, and data-backup will be performed routinely. Medical 
information acquired from subjects directly will be de-identified and stored in a secure 
location in the research office. 
 
6.2 
Confidentiality  
The privacy of the participants and data collection will be maintained in strict accordance 
to HIPAA standards. Records will be deidentified following data collection and stored 
securely as described above.  
 
6. 
Protocol Review and Amendments 
The protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the Stanford IRB and Stanford Cancer Center Scientific Review Committee 
(SRC).  Any changes made to the protocol will be submitted as a modification and will 
be approved by the IRB prior to implementation.  The Protocol Director will disseminate 
the protocol amendment information to all participating investigators. 
 
REFERENCES 
 
1. Mann T, Hammert WC. Upper extremity surgery after lymph node dissection. J Hand 
Surg Am. 2011;36:1684–1686. 
2. Habbu R, Adams JE. Role of elective hand surgery and tourniquet use in patients with 
prior breast cancer treatment. J Hand Surg [Am]. 2011;36:1537–1539. 
3. Gharbaoui, I.S., Netscher, D.T., Thornby, J., and Kessler, F.B. Safety of upper extremity 
surgery after prior treatment for ipsilateral breast cancer: Results of an American Society 
for Surgery of the Hand membership survey and literature review. J Amer Soc Surg 
Hand. 2005; 5: 232–238. 
4. Fulford D., Dalal S., Winstanley J., and Hayton M.J.: Hand surgery after axillary lymph 
node clearance for breast cancer: contra-indication to surgery? Ann R Coll Surg Engl 
2010; 92: pp. 573-576 
5. Petrek JA, Pressman PI, Smith RA. Lymphedema: current issues in research and 
management. CA Cancer J Clin. 2000 Sep-Oct;50(5):292–307. 
6. Baltzer HL, et al. De Novo Upper Extremity Lymphedema After Elective Hand Surgery 
in Breast Cancer Survivors. Ann Plast Surg 2017. Epub ahead of print. 
7. Dawson WJ, Elenz DR, Winchester DP, et al. Elective hand surgery in the breast cancer 
patient with prior ipsilateral axillary dissection. Ann Surg Oncol. 1995;2:132–137. 
8. Hershko DD, Stahl S. Safety of elective hand surgery following axillary lymph node 
dissection for breast cancer. Breast J. 2007;13:287–290. 
9. Gaston RG, et al. Lymphedema Following Elective Hand and Wrist Surgery in Women 
who are Post Axillary Lymph Node Dissection: A Prospective, Cohort Study. J Hand 
Surg 2016;41:9:s2-3.

The Effect of Pneumatic Tourniquet Use on Upper Extremity Edema Following Axillary Lymph Node Dissection  
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APPENDIX A: Participant Eligibility Checklist  
 
Protocol Title: 
The Effect of Pneumatic Tourniquet Use on Upper Extremity 
Edema Following Axillary Lymph Node Dissection  
 
Protocol Number: 
BRS0075 
Principal Investigator: 
Dr. Jeffrey Yao 
 
II. Subject Information: 
 
Subject Name/ID:   
 
Gender:    
 Male     
 Female 
III. Study Information: 
SRC Approved 
 IRB Approved 
 Contract signed 
 
IV. Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
(From IRB approved protocol) 
Yes 
No 
Supporting 
Documentation* 
1. 18 years of age or earlier      
 
 
      
2. Presence of prior axillary lymph node 
dissection (group A)      
 
 
      
3. Absence of prior axillary lymph node 
dissection (group B) 
 
 
      
Exclusion Criteria 
(From IRB approved protocol) 
 
1. New-onset lymphedema of the involved 
limb 
 
 
      
2. Infection including cellulitis 
 
 
      
3. Trauma or planned axillary surgery within 6 
months of participation. 
 
 
      
*All subject files must include supporting documentation to confirm subject eligibility.  
The method of confirmation can include, but is not limited to, laboratory test results, 
radiology test results, subject self-report, and medical record review.   
 
 
 
 
 

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IV.  Statement of Eligibility 
By signing this form of this trial I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 
 
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
 
Study Coordinator Signature: 
Date: 
Printed Name: