Post-Mastectomy Surgical Pocket Irrigation With Triple Antibiotic Solution vs Chlorhexidine Gluconate: A Randomized Controlled Trial Assessing Surgical Site Infections in Immediate Tissue Expander Breast Reconstruction
Phase: NA
Conditions: Breast Cancer
Sponsor: Vanderbilt University Medical Center

Kye Higdon, MD Department of Plastic Surgery  
Protocol Version #1 
 
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Protocol Date: April 1, 2014  
 
Title: Post-Mastectomy Surgical Pocket Irrigation with Triple Antibiotic Solution vs 
Chlorhexidine Gluconate: A Randomized Controlled Trial Assessing Surgical Site 
Infections in Immediate Tissue Expander Breast Reconstruction 
 
NCT# 02395614 
 
Date: April 1, 2014 
 
 

Kye Higdon, MD Department of Plastic Surgery  
Protocol Version #1 
 
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Protocol Date: April 1, 2014  
 
 
 
 
 
Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
 
Appendices 
Appendix A Study Procedure Calendar 
 
 
 
 
 
 
 
 
 
 

Kye Higdon, MD Department of Plastic Surgery  
Protocol Version #1 
 
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Protocol Date: April 1, 2014  
1.0 
Background 
 
Breast reconstruction with tissue expander (TE) remains widely performed 
technique of breast restoration after mastectomy.1 During first stage of reconstruction 
breast TE is placed at mastectomy site. Most commonly TE is placed into surgically 
created pocket below the pectoralis major and serratus muscles in the mastectomy wound 
(Figure 1). Alternatively, TE can be placed into subpectoral muscular pocket created with 
additional placement of acellular dermal matrix (ADM) sling (Figure 2). Regardless of 
surgical method of placement, TE is expanded gradually postoperatively over a period of 
several weeks until the desired size is achieved. Both techniques demonstrate comparable 
postoperative results including similar postoperative surgical site and tissue expander 
infection rates. 2 
The incidence of postoperative wound infection including TE infection after 
breast reconstruction ranges between 5-20% 2,3,4,6  Recently, several studies demonstrated 
that intra-operative irrigation of surgical pocket with antibiotics containing solution 
before insertion of breast TE resulted in a decrease of postoperative infection rate .5,8,9 
Irrigation of surgical wound with triple antibiotic solution (1 g of cefazolin, 50,000 U of 
bacitracin, and 80 mg of gentamicin in 500 mL of NS) was found to decrease bacterial 
growth associated with periprosthetic infections in both breast augmentation and 
reconstructive patients 5,10. The Department of Plastic Surgery at Vanderbilt University 
routinely irrigates surgically created muscular pocket with triple antibiotics solution 
before placement breast TE. This decreased the postoperative infection rate within our 
department to 14%. Despite improvement in incidence of postoperative infection after 
application of triple antibiotic solution, some authors suggested that this technique has 
several drawbacks. For example, most antimicrobials agents are effective against 
microorganisms when drug exposure occurs during bacteria’s logarithmic growth phase. 
Therefore, brief irrigation of surgical pocket with antibiotics does not provide sufficient 
contact time with bacteria in order to efficiently kill pathogenic microorganisms. 
In order to further enhance antisepsis inside surgical pocket before placing breast 
TE we purpose to use 0.05% chlorhexidine (CHG) instead of triple antibiotic solution. 
Several recent studies demonstrated exceptional antiseptic properties of CHG derivatives. 
8, 9,12-14 CHG is widely used for preparation of the surgical field and preoperative hand 

Kye Higdon, MD Department of Plastic Surgery  
Protocol Version #1 
 
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Protocol Date: April 1, 2014  
scrubbing. It demonstrates broader bacterial coverage compared to povidone iodine based 
solutions. More recently several reports demonstrated that irrigation of chronically 
infected surgical wounds with 0.05% CHG decreases bacterial contamination without 
inhibiting wound healing or toxic side effects8. Exposure to a concentration of 0.05% 
CHG effectively produced a 5- to 6-log reduction in microbial recovery. Effective 
bacterial reduction was observed with both gram-positive and gram-negative surgical 
isolates. Specifically, antibacterial effect of CHG was prominent towards biofilm-
forming strains associated with infection of prosthetic devices such as TE.8 
We hypothesize that intraoperative irrigation of surgical pocket with 0.05% CHG 
solution before insertion of breast TE allows for more significant reduction of 
postoperative wound infection compared to similar irrigation with triple antibiotic 
solution in women undergoing bilateral TE-based breast reconstruction.  
We intend to perform a prospective randomized study and compare the incidence 
of surgical wound infection between mastectomy wounds irrigated with triple antibiotic 
solution (one side) and 0.05% CHG (opposite side) in patients undergoing bilateral breast 
reconstruction. 
1.0  
Rationale and Specific Aims 
 
 Specific aim: to evaluate efficacy of 0.05% CHG solution to reduce 
postoperative surgical site infections compared to triple antibiotic solution in women 
undergoing breast reconstruction with TE.  
 
2.0 
Animal Studies and Previous Human Studies 
 
Antimicrobial effects of 0.05% CHG were studied both in vitro, in vivo and on 
human subjects previously 8-14. However, efficacy of this solution in decreasing incidence 
of surgical infection after breast reconstruction with TE has never been evaluated.  
 
3.0 
Inclusion/Exclusion Criteria 
 
Inclusion criteria: 18-81 years old females undergoing bilateral mastectomy who 
are candidates for immediate breast reconstruction with TE (either total muscle coverage 
or ADM-based techniques). 

Kye Higdon, MD Department of Plastic Surgery  
Protocol Version #1 
 
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Protocol Date: April 1, 2014  
Exclusion criteria: patients undergoing unilateral breast reconstruction, 
reconstruction with autologous tissue, bilateral reconstruction with other reconstructive 
techniques (autodermal flaps, etc) performed on either breast, patients allergic to one or 
more components of the antibiotic solution, patient allergic to CHG. 
 
4.0 
Enrollment/Randomization 
 
Study population  
The study is intended to be prospective randomized clinical trial.  
Randomization   
Site of application of CHG solution (either left or right surgical wound) in each 
patient will be randomly assigned by coin flipper application at random.org website 
(http://www.random.org/coins/). Triple antibiotic solution will be used on contralateral 
side and used as a control. Randomization will occur on the day of the operation. 
 
Randomization of subjects will not be performed. Each patient will serve as self-
control (contralateral surgical wound where triple antibiotic will be applied will be 
control side). 
Blinding/Data Collection 
Side of CHG application will be recorded by operating surgeon in patients 
database secured from other medical professionals participating in the study. 
Examination of reconstructed breasts will be performed by experienced clinic 
nursing staff. The site of application of the CHG solution will not be disclosed during 
clinic visit to nursing staff. The collection of data will be provided by Marcia Spear, 
DNP, ACNP-BC without knowledge of the side of CHG application. 
 Clinical data associated with the patient will be extracted form StarPanel and 
entered in a RedCap database. Collected data will include: type of infection (major or 
minor), side of occurrence, route of antibiotic administration (iv or PO), length of 
hospitalization, any surgical treatment of infected area (incision and drainage, 
debridement, TE removal), the need for long term iv antibiotic therapy, pathogen based 
on culture results, days till recovery, type and time of repeat reconstruction.  
 
5.0 
Study Procedures 
 

Kye Higdon, MD Department of Plastic Surgery  
Protocol Version #1 
 
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Protocol Date: April 1, 2014  
Breast reconstruction in each participating patient will be performed without 
deviation from standard technique routinely performed at Department of Plastic Surgery 
at Vanderbilt University. Upon completion of mastectomy, surgical pocket will be 
created either with pectoral and serratus muscles or with pectoral muscle and ADM. 
Before insertion of breast TE, randomly selected surgical pocket (either left or right) will 
be irrigated with 500ml of 0.05% CHG solution for 1 minute. After 1 minute CHG 
solution will be aspirated and TE inserted into surgical pocket following by muscle and 
skin closure. Accordingly, contralateral site will be irrigated with triple antibiotic solution 
for 1 minute, aspirated and breast TE will be inserted and wound closed in identical 
fashion.  
 
 Drugs that will be used: 
-triple antibiotic solution: 1 g of cefazolin, 50,000 U of bacitracin, and 80 mg of 
gentamicin in 500 mL of NS. If the patient is allergic to either component – the allergen 
will not be used in the solution.  
- 0.05% chlorhexidine solution –by diluting 6.25 ml of 4% chlorhexidine in 500ml of NS 
solution (1:80).   
  
Outcome measures  
Primary outcome: 
- frequency of surgical site infection (as defined by CDC, 
http://www.cdc.gov/hai/ssi/ssi.html) 
Surgical site infection will be subdivided into “minor” infection—defined by 
clinical signs of infection successfully treated with outpatient antibiotic therapy—or 
“major” infection requiring inpatient hospitalization for intravenous antibiotic treatment 
and/or any surgical treatment.  
 
- frequency of TE infection (any infection of surgical site requiring surgical revision of 
TE) 
 
6.0 
Risks 

Kye Higdon, MD Department of Plastic Surgery  
Protocol Version #1 
 
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Protocol Date: April 1, 2014  
We anticipate low risks given the previously demonstrated safety of CHG. 
Furthermore, minimal systemic absorption of CHG is expected since it will be used 
topically as irrigation. Allergic reaction to this drug including severe skin rash, swelling, 
trouble breathing and possibly death is rare. 
 
7.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
 
The progress of the study will be discussed formerly at regularly scheduled 
research meetings. These will serve as a forum for the voicing of concerns or problems 
with the study. If participant safety is a concern, the research investigators will 
immediately notify the P.I.  Adverse events will be reported to the IRB according to IRB 
policies and procedures, as there are specific guidelines at IRB Policy and Procedure 
III.L.1 that must be followed.  
  
8.0 
Study Withdrawal/Discontinuation 
 
Patient can be taken out of the study if patient is allergic to CHG and if the study 
is closed. 
 
9.0 
Statistical Considerations 
 
Sample size  
The frequency of surgical site infection in patients undergoing breast 
reconstruction is 14 %.We anticipate a 4-fold reduction on infection rate with 0.05% 
CHG down to approximately 3.5%. Using binary superiority the estimated sample size is 
110 breasts per group (110 patients) with significance b-alpha 5% and the power of 80% 
(1- beta ). http://www.sealedenvelope.com/power/binary-superiority 
 Statistical analysis  
 Categorical variables are compared using a chi-square test, and the Student t-test 
is used to compare continuous variables between groups. Logistic regression with 
adjustment for other possible risk factors is used to estimate the odds ratios and 95% 
confidence intervals. 

Kye Higdon, MD Department of Plastic Surgery  
Protocol Version #1 
 
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Protocol Date: April 1, 2014  
10.0 Privacy/Confidentiality Issues 
Collected data will be stored in password protected database.  
 
11.0 Follow-up and Record Retention 
 
Blinding/Data Collection 
Evaluation of the wound will be performed by experienced clinic nursing staff. 
The site of application of the CHG solution will not be disclosed during clinic visit to 
nursing staff. The collection of data will be provided Marcia Spear, DNP, ACNP-BC 
without of knowledge of drug use.  
The data will be extracted form StarPanel and entered in a RedCap database. 
Collected data will include: type of infection (major or minor), side of occurrence, route 
of antibiotic administration (iv or PO), length of hospitalization, any surgical procedures 
(incision and drainage, debridement, TE removal), the need for long term iv antibiotic 
therapy, pathogen based on culture results, days till recovery, type and time of repeat 
reconstruction.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Kye Higdon, MD Department of Plastic Surgery  
Protocol Version #1 
 
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Protocol Date: April 1, 2014  
 
References: 
1. American Society of Plastic Surgeons. 2012 Plastic Surgery Statistics Report. 
American Society of Plastic Surgeons. Available at: http:// 
www.plasticsurgery.org. 
2. Reish RG, Damjanovic B, Austen WG Jr, Winograd J, Liao EC, Cetrulo CL, 
Balkin DM, Colwell AS. Infection following implant-based reconstruction in 
1952 consecutive breast reconstructions: salvage rates and predictors of success. 
Plast Reconstr Surg. 2013 Jun;131(6):1223-30. doi: 
10.1097/PRS.0b013e31828bd377. 
3. Francis, SH, Rubert, RL, Stevenson, KB, Beck, CE, Ruppert, AS, Harper, JT, 
Boehmler, JH, Miller, MJ. Independent risk factors for infection in tissue 
expander breast reconstruction. Plastic and Reconstructive Surgery.2009. 124 (6): 
1790-1796. DOI:10.1097/PRS.Ob013e3181bf80aa. 
4. Chun, YS, Verma, K., Rosen, H., Lipsitz, S., Morris, D., Kenney, P, Eriksson, E. 
Implant-based breast reconstruction using acellular dermal matrix and the risk of 
postoperative complications. Plastic and Reconstructive Surgery. 2010. 125 (2): 
429 – 436. DOI: 10.1097/PRS.0b013e318c82d90. 
5. Adams WP Jr, Rios JL, Smith SJ. Enhancing patient outcomes in aesthetic and 
reconstructive breast surgery using triple antibiotic breast irrigation: six-year 
prospective clinical study. Plast Reconstr Surg. 2006;118:46SY52S. 
6. Kim, JY, Davila, AA, Persing, S, Connor, CM, Jovanovic, B, Khan, S, Fine, N, 
Rawlani, V. A meta-analysis of human acellular and submuscular tissue expander 
breast reconstruction. Plastic and Reconstructive Surgery. 2012. 129 (1), 28 – 41. 
DOI:10.1097/PRS.ob01e3182361fd6. 
7. Brown NM, Cipriano CA, Moric M, Sporer SM, Della-Valle CJ. Dilute betadine 
lavage before closure for the prevention of acute postoperative deep periprosthetic 
joint infection. J Arthroplasty 2012;27:27-30. 
8. Best AJ, Nixon MF, Taylor GJ. Brief exposure of 0.05% chlorhexidine does not 
impact non-osteoarthritic human cartilage metabolism. J Hosp Infect 2007;67: 67-
71. 
9. Edmiston, CE, Bruden, B, Rucinski, MC, Henen, C, Graham, MB, Lewis, BL. 
Reducing the risk of surgical site infections: does chlorhexidine gluconate provide 
a risk reduction benefit? American Journal of Infection Control. 2013. 41 (5S): 
S49 – 55. Doi: 10.1016/j.ajic.2012.10.030. 

Kye Higdon, MD Department of Plastic Surgery  
Protocol Version #1 
 
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Protocol Date: April 1, 2014  
10. Adams WP Jr, Conner WC, Barton FE Jr, et al. Optimizing breast pocket 
irrigation: an in vitro study and clinical implications. Plast Reconstr 
Surg.2000;105:334Y338; discussion 339Y343 
 
11. http://www.sealedenvelope.com/power/binary-superiority/ 
12. Crowley, DJ, Kanakaris, NK, Gionnoudis, PV. Irrigation of wounds in open 
fractures. Journal of Bone and Joint Surgery. 2007. 89B (5), 580 – 585. DOI: 
10.1302/0301-620X.89B5. 
13. Han, Y, Giannitsios, D, Duke, K, Steffen, T, Burman, M. Biomedical analysis of 
chlorhexidine power irrigation to disinfect contaminated anterior cruciate 
ligament grafts. American Journal of Sports Medicine. 2012. 39: 1528 – 1533. 
14. Culligan, PJ, Kubik, K, Murphy, M, Blackwell, Snyder, J. A randomized triat that 
compared povidone iodine and chlorhexidine as antiseptics for vaginal 
hysterectomy. Obstetrics and Gynecology. 2005. 192: 422-425. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Kye Higdon, MD Department of Plastic Surgery  
Protocol Version #1 
 
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Protocol Date: April 1, 2014  
Figure 1. TE-based breast reconstruction with creation of pectoral and serratus muscles 
pocket.  
 
 
 
 
 
 
Figure 2. TE-based breast reconstruction with creation of surgical pocket with ADM 
sling 
 
 
 
ADM sling