Comparison of Complications Following Implant-Based Breast Reconstruction Using Triple Antibiotic Solution versus Low Concentration Chlorhexidine Gluconate Solution

Background: Prevention of infection and capsular contracture remains a primary goal of implant-based breast reconstruction (IBBR). Previous studies have demonstrated improved outcomes with the use of triple-antibiotic solution (TAS) for breast pocket irrigation, but ready-to-use products have recently gained popularity. The purpose of this study is to compare outcomes following IBBR between TAS and low-concentration chlorhexidine gluconate (CHG) solutions. Methods: This is a retrospective analysis of 690 consecutive patients undergoing IBBR from 2008-2017. The TAS (n = 346) irrigation solution was composed of 1 g cefazolin, 80 mg gentamicin and 50,000 U bacitracin diluted in 500 mL of normal saline; the CHG (n = 344) irrigation solution was the commercially-available product Irrisept (0.05% chlorhexidine gluconate in sterile water, Irrimax Corporation, Lawrenceville, GA). Comparisons were made between demographic and clinical variables. Complications were recorded and statistical analysis, including multivariate regression analysis, was performed. Results: The TAS group underwent significantly more skin-sparing mastectomies, adjuvant chemotherapy/radiation and less direct-to-implant reconstruction than the CHG group. The CHG group experienced a significantly lower incidence of total complications (22.4% vs. 31.8%, p = 0.006), minor complications (8.7% vs. 16.5%, p = 0.003), infection (6.4% vs. 12.7%, p = 0.006) and seroma (2.6% vs. 6.9%, p = 0.011). There was a significantly increased rate of delayed wound healing in the CHG group. Multivariate analysis showed that the use of CHG solution significantly decreased the odds of any complication by 1.6-fold (OR 0.637, 95% CI 0.414 - 0.977) and the odds of infection by 2.4-fold (OR 0.420, 95% CI 0.218 - 0.809). There were no statistically significant differences in rates of capsular contracture or other complications. Conclusions: The use of CHG as a pocket irrigant in post-mastectomy breast reconstruction is a reasonable alternative to other solutions, in efforts to minimize prosthetic based complications.


Introduction
Significant advances in breast cancer screening and management over the past thirty years have led to marked improvements in survivability after diagnosis and quality of life following oncologic treatment. According to the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) database, 5-year overall survival for female patients with breast cancer from 2008-2014 was 89.7% [1]. Of the 62% of patients with localized disease and 31% of patients with regional disease, there was a 98.7% and 85.3% 5-year survival rate, respectively. These favorable statistics have paralleled global trends toward breast conserving therapy for patients with localized disease and contralateral mastectomy in patients requiring oncologic mastectomy in order to achieve an optimal reconstructive outcome. As a result, there has been a marked increase in the number of patients seeking breast reconstruction, demonstrated by a 62% increase in the rate of reconstructive procedures after mastectomy from 2009-2014 in one study [2].
The vast majority of breast reconstructive procedures following mastectomy are prosthetic-based. Of the 106,295 reconstructive breast procedures performed in the United States in 2017, 81.8% utilized tissue expanders (TE) or single-stage direct-to-implant (DTI) reconstruction [3]. According to a recent report of 67,450 patients undergoing mastectomy for breast cancer from 2005-2014, the percentage of patients undergoing reconstruction has increased from 26.94% in 2005 to 43.30% in 2014, with a significant increase in the use of TE-based implantation from 15.54% to 33.30% [4]. The use of prosthetic materials for breast reconstruction, however, presents the potential for complications associated with synthetic and foreign materials implanted in vivo [5]- [10]. One of the most important modifiable factors to decrease the rate of complications is a reduction of the bacterial load within the breast pocket prior to implant placement, which has prompted the development of various additions to standard antiseptic technique [5] [11]- [16]. One important technique reported in the literature is the use of surgical site irrigation within the breast pocket [14]

Methods
After obtaining Institutional Review Board approval, we performed an analysis of a prospectively maintained database of patients undergoing immediate im-
All subjects had a prosthetic-based reconstruction with either tissue expander (TE) or direct-to-implant (DTI). Overall, TEs were used in 537 cases (77.8%), DTI in 122 cases (17.7%) and latissimus flap + TE in 31 cases (4.5%). Patients in the TAS group had a higher percentage of women undergoing TE-based reconstruction compared to the CHG group (n = 317 (91.6%) vs. n = 220 (64.0%), p < 0.0001); while DTI-based reconstruction occurred at a higher rate in the CHG group (n = 93 (27.0%) vs. n = 29 (8.4%), p < 0.0001). All patients who underwent latissimus flap + TE were in the CHG group. Use of acellular dermal matrix was similar between both groups: 194 (56.6%) in the TAS group and 174 (50.6%) in the CHG group. There were a total of 188 complications, 124 of which were considered major.
Patients in the TAS group were more likely to experience a complication than

Discussion
In 2017, more than 80,000 tissue expander or direct-to-implant reconstructive breast procedures were performed [3], representing the vast majority of breast reconstruction following mastectomy. Given the predominance of this technique and the use of synthetic materials, the prevention of complications has been a primary goal of surgeons performing prosthetic-based breast reconstruction.
More specifically, reducing infection and capsular contracture has been of particular interest, as these pose the potential for devastating sequelae such as implant loss and the need for increasingly complex secondary reconstructions.
While capsular contracture is a poorly understood phenomenon, there is a general consensus that subclinical infection and the development of peri-prosthetic biofilm contribute significantly [19] [20]. Thus, a significant body of literature has been produced in the pursuit of improved techniques that significantly diminish the potential for bacterial seeding of breast implants and tissue expanders hours of the operation unless a surgical drain is present [12]. Local bacterial eradication and the creation of a microbe-free implant pocket are essential to preventing complications in prosthetic-based breast reconstruction. Breast pocket irrigation using antimicrobial solutions remains one of the important ways by which this can be achieved. The most common irrigation solutions include Adams' triple antibiotic solution (TAS; 50,000 IU bacitracin, 1 g cefazolin, 80 mg gentamicin in 500 mL of normal saline) and povidone-iodine (P-I). While TAS has been widely used by plastic surgeons, there is little and conflicting evidence demonstrating its efficacy in preventing complications. For example, Adams and colleagues showed that TAS decreases bacterial populations responsible for peri-prosthetic infections and leads to reduced rates of capsular contracture for breast reconstruction [25] [26]; however, subsequent contrasting studies question the effect of TAS to reduce the rate of capsular contracture [27] [28]. In comparison to TAS, P-I reduces infection risk as an antiseptic solution. Review of current literature demonstrates the effectiveness of P-I to reduce subclinical infections and capsular contracture [29] [30] [31] [32]. Additional studies have advocated for the use of breast pocket irrigation containing both antibiotic solution and P-I [17].
In 2000, the Food and Drug Administration (FDA) issued a ban on the use of Betadine for breast implants given a concern for delamination of shell integrity and the potential for implant rupture [33]. Although multiple studies have suggested this to be exceedingly unlikely [29] [30] [32] [34] [35], the proper use of Betadine to irrigate the breast pocket and resultant implant complications car-T. K. Merceron et al. ries the risk of legal implications [33]. For this reason, the immediate washout of Betadine irrigation with saline has been recommended, but this practice limits the antimicrobial effectiveness of Betadine [14] [33].
Another alternative to the above includes an antiseptic irrigation solution containing chlorhexidine gluconate (CHG), which has been shown to be an effective and relatively cheap antimicrobial that has both bacteriostatic and bactericidal effects against a wide range bacteria and fungi. CHG has been shown to be more effective in preventing surgical site infections than skin preparation with traditional povidone-iodine [36] [37] [38]. need to be taken into consideration [40], however, in lower concentrations (i.e. < 0.05%), this is less of an issue [41].
With this background, the purpose of our study was to compare the incidence of postoperative complications following implant-based breast reconstruction using either TAS or CHG for breast pocket irrigation. Our results reflect the pre-clinical studies in that patients undergoing breast pocket irrigation with CHG had significantly less risk of infection (6.4% vs. 12.7%, p = 0.006), seroma (2.6% vs. 6.9%, p = 0.011), minor complications (8.7% vs. 16.5%, p = 0.003) and total complications (22.4% vs. 31.8%, p = 0.006) when compared to patients with TAS breast pocket irrigation. Furthermore, implant failure (4.7% vs. 8.1%, p = 0.086) and capsular contracture (4.7% vs. 8.1%, p = 0.086) had trends towards significantly less incidence in the CHG group. We expect that with a larger sample size, the trends towards less implant failure and less capsular contracture would become statistically significant. These data suggest that CHG promotes sufficient breast pocket antisepsis and the potential for fewer complications when compared to TAS. Given the differences in patient follow-up and anecdotal improvements in mastectomy skin flap quality for our study population, these results should rather be regarded as CHG being a non-inferior alternative to TAS.
While our data are promising, it is important to note some potential complicating and limiting factors. First of all, this was a retrospective post-hoc analysis. Although variation in technique was significantly controlled by the fact that two surgeons performed all of the operations, there may have been small changes that led to improved outcomes in the CHG group that may not be attributed to the use of CHG alone. One noticeable change in technique was the increased use of direct-to-implant practice rather than staged tissue-expander reconstruction in the CHG group (27.0% vs. 8.4%). Clearly, single-staged reconstruction has less potential for bacterial seeding of the breast implant, which could potentially T. K. Merceron et al. muddle our results. Perhaps more importantly, however, is the fact that patients in the CHG group underwent chemotherapy and radiation at significantly decreased rates when compared to the TAS group (33.4% vs. 47.4%, p < 0.0001; and 20.1% vs. 28.6, p = 0.010, respectively). The increased rates of neoadjuvant and adjuvant therapy are important potential confounders as these are known to contribute to suboptimal healing; however, when controlling for these on multivariate analysis, our results remained valid with 2.4-fold decreased odds of infection, 2.8-fold decreased odds of minor complications and 1.6-fold decreased odds of any complication in the CHG group. Interestingly, the one complication that was increased in the CHG group was delayed wound healing (2.9% vs. 0.3%, p = 0.006). Finally, it is important to note that this was a relatively small single-center study with 690 subjects analyzed in a per-breast fashion. Thus, while our results do suggest improved outcomes with CHG compared to TAS, it is important to perform larger, multi-center studies with multiple surgeons utilizing different implants and techniques to obtain more generalizable data.

Conclusion
This was a retrospective review of a prospectively maintained database comparing triple antibiotic solution to low-concentration chlorhexidine gluconate for breast pocket irrigation in implant-based breast reconstruction. We found that the CHG group experienced significantly less overall and minor complications, had fewer infections and developed fewer seromas. There was no statistically significant difference in other complications analyzed; however, there was a trend toward decreased implant failure and capsular contracture in the CHG group as well. Future work with larger datasets is needed to confirm and expand these findings.

Financial Disclosures
None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript.

Author Contribution
All of the aforementioned authors were involved in the acquisition, analysis and/or interpretation of data, drafting and/or revision of the manuscript, gave final approval for submission of the manuscript, and agree to be accountable for the data presented in the submitted manuscript.

Conflicts of Interest
The authors declare no conflicts of interest regarding the publication of this paper.