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Novel Antibiotic-Irrigating Wound Protector Reduces Infectious Complications in Robot-Assisted Radical Cystectomy with Extracorporeal Urinary Diversion

Open AccessPublished:October 19, 2021DOI:https://doi.org/10.1016/j.urology.2021.10.001

      Abstract

      Objective

      To determine whether use of an antibiotic-irrigating wound protector (AWP) reduces infectious complications after robotic radical cystectomy with extracorporeal urinary diversion (RCUD).

      Methods

      A prospectively maintained bladder cancer database was queried for patients undergoing robotic RCUD at a tertiary referral center one year prior to implementing an AWP and one year after (2018–2020). All diversions were performed extra-corporally. 92 patients total. 46 consecutive patients using a traditional wound protector (TWP) and 46 consecutive with an AWP. Infections were classified as symptomatic urinary tract infection, blood stream infection, and surgical site infection. The incidence of infectious complications at 30- and 90-days were compared.

      Results

      Baseline patient characteristics between the 2 groups showed no statistically significant differences. The overall complication rate was 65.2% in the TWP group and 26.1% in the AWP group at 30-days, and 67.4% vs 30.4% at 90-days. Focusing on infections, the 30-day complication rate was 30.4% in the TWP group compared to 6.5% in the AWP group (P =.003). This pattern persisted at 90-days with 37.0% in the TWP group compared to 6.5% in the AWP group (P =.004). Most complications were symptomatic UTI and blood stream infections, 14/24 (58%), requiring parenteral antibiotic treatment.

      Conclusion

      We provide preliminary data showing use of an AWP can reduce infectious complications after RCUD. While larger prospective studies are warranted, our findings are a significant step towards decreasing morbidity of an already highly morbid procedure.
      In 2020, 81,400 new cases of bladder cancer were diagnosed which accounted for 4.5% of all new cancer diagnoses.
      Surveillance, Epidemiology, and End Results Program, bladder cancer statistics.
      Radical cystectomy with urinary diversion (RCUD) and bilateral pelvic lymph node dissection is the standard of care for patients with muscle invasive or high-risk non-muscle invasive bladder cancer.
      • Flaig TW
      • Spiess PE
      • Agarwal N
      • et al.
      Bladder cancer, version 3.2020, NCCN clinical practice guidelines in oncology.
      Recently, multiple prospective trials comparing open vs. robotic RCUD have been completed. In the RAZOR trial, Parekh et al. reported a 67% –69% overall complication rate in the robotic and open groups respectively, with 60% of the complications being attributed to infections.
      • Parekh DJ
      • Reis IM
      • Castle EP
      • et al.
      Robot-assisted radical cystectomy vs open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.
      Similarly, Bochner et al. reported an approximately 62% overall complication rate with 38% being attributed to infections.
      • Bochner BH
      • Dalbagni G
      • Sjoberg DD
      • et al.
      Comparing open radical cystectomy and robot-assisted laparoscopic radical cystectomy: a randomized clinical trial.
      Regardless of approach, it is clear that patients undergoing surgical management for bladder cancer experience significant morbidity, with infections representing the primary source. The downstream effect of this high complication rate in an elderly, co-morbid population cannot be understated as hospital readmission, additional procedures, and economic burden all negatively impact patient quality of life.
      • Badia JM
      • Casey AL
      • Petrosillo N
      • et al.
      Impact of surgical site infection on healthcare costs and patient outcomes: a systematic review in 6 European countries.
      Thus, it is the goal of this study to determine whether use of an antibiotic-irrigating wound protector (AWP) can reduce infectious complications among patients undergoing robotic RCUD for bladder cancer.

      METHODS

      CleanCision (Prescient Surgical, San Carlos, CA), is a wound retraction device that combines barrier protection and continuous antibiotic irrigation to the surgical wound (Fig. 1). An antibiotic solution of choice flows from superficial to deep portions of the wound with the aid of continuous suction, which provides constant delivery throughout the duration of the urinary diversion procedure. 2 grams of cefazolin and 240mg of gentamicin in 1L normal saline was chosen as this provided efficient coverage of common skin and bowel pathogens. The CleanCision AWP can stretch to 17cm and thus can be used for an open surgical approach as well. We began using the AWP in February of 2019. Prior to this, an Alexis traditional wound protector (TWP) was used. Cost of the AWP compared to TWP was negligible. After Institutional Review Board approval, we queried a prospectively maintained bladder cancer database for patients with T1-T4, N0-N1, M0 bladder cancer undergoing RCUD at our institution from January 2018 to February 2020. Patients receiving prior pelvic radiation were excluded. 92 patients were identified. 46 consecutive patients prior to implementing an AWP and 46 patients after. All RCUD were performed robotically using the DaVinci (Intuitive Surgical, Sunnyvale, CA) robot with extended bilateral pelvic lymphadenectomy. Urinary diversions were performed by a single surgeon through a 6–8cm lower midline incision in an extracorporeal fashion. Intravenous indocyanine green was utilized to evaluate ureteral perfusion in all cases as previously described.
      • Shen JK
      • Jamnagerwalla J
      • Yuh BE
      • et al.
      Real-time indocyanine green angiography with the SPY fluorescence imaging platform decreases benign ureteroenteric strictures in urinary diversions performed during radical cystectomy.
      All patients received perioperative antibiotics, alcohol-based skin preparation, maintenance of normothermia, and tight glucose control during surgery. Of note, separate dedicated instrumentation was used for the contaminated portions of the case, and the abdomen was not routinely irrigated with saline or water after completion of the diversion. A standardized enhanced recovery pathway was implemented which included minimization of opiates, administration of perioperative μ-opioid receptor antagonist, early feeding, omission of mechanical bowel preparation, and except in rare situations, removal of ureteral stents and drains prior to discharge. A single dose of Ceftazidime 1g was administered intravenously 30 minutes prior to stent removal.
      Figure 1
      Figure 1(A). Image of AWP device. (B). Cross-sectional image of AWP inside wound. Antibiotic flows from superficial to deep portions of the wound (dotted white line). (C). AWP deployed in wound with antibiotic solution flowing though. Images courtesy of https://www.prescientsurgical.com/cleancision. (Color version available online.)

      Definitions

      Infections were classified according to the Centers for Disease Control (CDC) definitions.
      • Horan TC
      • Andrus M
      • Dudeck MA
      CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting.
      Symptomatic urinary tract infection (SUTI): Fever greater than 38°C and positive urine culture greater than 105 CFU/mL. Blood stream infection (BSI): A positive blood culture and patient with fever greater than 38°C, chills, or hypotension. Incisional surgical site infection (SSI): Infection of skin, subcutaneous tissues, deep soft tissue, fascial or muscular layers. Organ/space SSI: Infection of the organ/space manipulated during the surgery. The Clavien-Dindo classification was used to grade all complications.

      Statistical Methods

      Baseline clinical characteristics of age, race, gender, diversion type, clinical stage, receipt of neoadjuvant chemotherapy, and Charlson co-morbidity index were compared between TWP vs AWP use. 30 and 90-day complications were collected and the incidence of infectious complications were compared using the chi-square test. Fisher's exact test and the Wilcoxon rank sum tests were used to test for differences in discrete and continuous data elements between the cohorts and for comparison of incidence of infection.

      RESULTS

      A total of 92 patients were included in our study cohort. 46 consecutive cases prior to implementation of an AWP and 46 consecutive cases with an AWP. Overall, the cohort had a median age of 72.6 years, median Charlson co-morbidity index of 5, and were predominantly Caucasian and male (Table 1). Clinically, 76% – 80% of patients had pathologic T2 disease or better in the TWP and AWP groups respectively. For urinary diversion, 62% received an ileal conduit, 13% continent cutaneous (Indiana pouch), and 25% orthotopic neobladder. Baseline clinical and demographic characteristics showed no statistically significant differences between groups.
      Table 1Patient demographics and clinical characteristics
      TWP

      (n = 46)
      AWP

      (n = 46)
      P-value
      Gender
       Female8 (17.4%)10 (21.7%).6
       Male38 (82.6%)36 (78.3%)
      Median Age (IQR)73.1 (65.5 – 79.9)73.5 (66.1 – 77.2).9
      Race
       Asian1 (2.2%)3 (6.5%).04
       Black or African American0 (0.0%)4 (8.7%)
       White40 (87.0%)38 (82.6%)
       Unknown5 (10.9%)1 (2.2%)
      Ethnicity, n (%)
       Hispanic/Latino4 (8.7%)5 (10.8%).5
       Non-Hispanic or Latino37 (80.4%)39 (84.8%)
       Unknown5 (10.9%)2 (4.4%)
      Median Charlson index (IQR)5 (4 – 6)5 (4 – 6).8
      Clinical T-stage
       <T217 (37.0%)19 (41.3%).3
       T219 (41.3%)18 (39.1%)
       T36 (13.0%)8 (17.4%)
       T44 (8.7%)0 (0.0%)
      Clinical Grade
       Low1 (2.2%)0 (0.0%).4
       High44 (95.7%)46 (100.0%)
       Not Assessed1 (2.2%)0 (0.0%)
      Neoadjuvant chemotherapy
       Yes21 (45.7%)22 (47.8%).8
       No25 (54.3%)24 (52.2%)
      Diversion type, median (IQR)
       Ileal Conduit28 (60.9%)29 (63.0%).8
        Indiana Pouch7 (15.2%)5 (10.9%)
        Studer Neobladder11 (23.9%)13 (26.1%)
      The 30-day overall complication rate was 65.2% in the TWP group and 26.1% in the AWP group. The 90-day overall complication rate was 67.4% vs 30.4% in the TWP vs AWP group respectively (Fig. 2A). Overall, most complications were low grade (Clavien I or II), with 67% (43/64) being low-grade in the TWP group and 94% (16/17) being low-grade in the AWP group. Focusing on infectious complications, the 30-day infectious complication rate was 30.4% in the TWP group compared to 6.5% in the AWP group (P =.003). This pattern persisted on 90-day infectious complication rates with 37.0% in the TWP group compared to 6.5% in the AWP group (P =.0004) (Fig. 2B). The incidence of SUTI was 7 vs 1, BSI 7 vs 1, incisional SSI 3 vs 1, and organ/space SSI 4 vs 0 in the TWP and AWP groups respectively. The breakdown of infectious complications by Clavien grade is shown in (Table 2). In the TWP group, 67% (14/21) were low-grade, requiring parenteral antibiotic treatment, 19% (4/21) were Clavien III organ/space infections requiring percutaneous drainage, 2 were Clavien IV and 1 Clavien V. In the AWP group, 3 low-grade infections were noted, 1 SUTI, 1 BSI, and 1 incisional SSI for which cultures grew S. Aureus, K. Pneumoniae, and E. Faecalis respectively. No differences were seen in other categories of complications including gastrointestinal, metabolic, renal, vascular or cardiac. Furthermore, no differences were seen in complications by diversion type. As all patients were re-admitted to treat their infections, the re-admission rate mirrored the 30- and 90-day complication rates.
      Figure 2
      Figure 2(A). Overall complications at 30- and 90-days using a TWP versus an AWP. (B). Infectious complications at 30- and 90-days using a TWP versus an AWP. * indicates statistical significance at P <.05. (Color version available online.)
      Table 2Infectious complications at 30- and 90-days broken down by Clavien Grade
      TWPAWP
      AE gradeAE grade
      AE NameAE Interval1234512345
      Symptomatic UTI (SUTI)<30 ds5110
      30-90 ds1
      Blood stream infection (BSI)<30 ds1311
      30–90 ds11
      Incisional SSI<30 ds21
      30–90 ds1
      Organ space SSI<30 ds2
      30–90 ds2
      Total11342103000

      DISCUSSION

      We present a single institution study implementing an AWP to reduce infectious complications for patients undergoing robotic RCUD. Multiple studies have demonstrated that of all complications following RCUD, infections are by far the most prevalent.
      • Parekh DJ
      • Reis IM
      • Castle EP
      • et al.
      Robot-assisted radical cystectomy vs open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.
      ,
      • Bochner BH
      • Dalbagni G
      • Sjoberg DD
      • et al.
      Comparing open radical cystectomy and robot-assisted laparoscopic radical cystectomy: a randomized clinical trial.
      ,
      • Parker WP
      • Tollefson MK
      • Heins CN
      • et al.
      Characterization of perioperative infection risk among patients undergoing radical cystectomy: results from the national surgical quality improvement program.
      • Krasnow RE
      • Mossanen M
      • Koo S
      • et al.
      Prophylactic antibiotics and postoperative complications of radical cystectomy: a population based analysis in the United States.
      • Hirobe M
      • Tanaka T
      • Shindo T
      • et al.
      Complications within 90 days after radical cystectomy for bladder cancer: results of a multicenter prospective study in Japan.
      Using the National Surgical Quality Improvement Project database, Parker et al. examined 3,187 patients for the incidence, risk factors and timing of infections following radical cystectomy.
      • Parker WP
      • Tollefson MK
      • Heins CN
      • et al.
      Characterization of perioperative infection risk among patients undergoing radical cystectomy: results from the national surgical quality improvement program.
      They found 35% of patients experienced an infection within 30 days of surgery (median time of 13 days). Examining complications at 90-days, the RAZOR trial reported a 60% infectious complication rate (35% SUTI, 10% sepsis, and 15% SSI).
      • Parekh DJ
      • Reis IM
      • Castle EP
      • et al.
      Robot-assisted radical cystectomy vs open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.
      Similarly, in a 118-patient single-center prospective study comparing open vs robotic cystectomy, Bochner et al. reported a 62% overall 90-day complication rate with 38% being infectious.
      • Bochner BH
      • Dalbagni G
      • Sjoberg DD
      • et al.
      Comparing open radical cystectomy and robot-assisted laparoscopic radical cystectomy: a randomized clinical trial.
      The 30- and 90-day infectious complication rates in these studies are similar to our study prior to implementing an AWP. However, after implementing an AWP, we observed a dramatic reduction in incidence of infectious complications to 6.5%. Taking a closer look at the grade of infectious complications, with a TWP, 67% (14/21) were low-grade (Clavien I-II) and 33% (7/21) were high-grade (Table 2). These numbers are in line with the robotic arms of both aforementioned prospective trials. However, after implementing an AWP, all complications were low-grade (100%, 3/3). Thus, use of an AWP not only reduced the incidence of infectious complications, but also reduced the incidence of high-grade complications.
      With recent emphasis on value-based care in urology, significant effort has been made to reduce the occurrence of healthcare associated infections (HAIs). Amongst HAIs, SSIs have proven to be most prevalent and have an incidence of approximately 1.0% after inpatient surgery.
      • Magill SS
      • Edwards JR
      • Bamberg W
      • et al.
      Emerging infections program healthcare-associated infections and antimicrobial use prevalence survey team. multistate point-prevalence survey of health care-associated infections.
      Aside from being preventable, SSIs are a substantial cause of morbidity, prolonged hospitalization, readmission rates, and healthcare costs in the United States.
      • de Lissovoy G
      • Fraeman K
      • Hutchins V
      • et al.
      Surgical site infection: incidence and impact on hospital utilization and treatment costs.
      CDC guidelines for prevention of SSIs include administering perioperative antibiotics, maintaining normothermia, optimizing tissue oxygenation, tight glycemic control, and skin-prep with an alcohol-based agent.
      • Berríos-Torres SI
      • Umscheid CA
      • Bratzler DW
      • et al.
      Healthcare Infection Control Practices Advisory Committee
      Centers for disease control and prevention guideline for the prevention of surgical site infection, 2017.
      In addition, the Infectious Disease Society of America added use of a TWP as a category I recommendation for surgeries involving the gastrointestinal tract.
      • Yokoe DS
      • Anderson DJ
      • Berenholtz SM
      • et al.
      Introduction to "a compendium of strategies to prevent healthcare-associated infections in acute care hospitals: 2014 updates".
      This added recommendation stemmed from a meta-analysis of 6 randomized controlled trials representing 1,008 patients.
      • Edwards JP
      • Ho AL
      • Tee MC
      • et al.
      Wound protectors reduce surgical site infection: a meta-analysis of randomized controlled trials.
      Use of a TWP was associated with a significant decrease in SSIs by 45% (RR = 0.55, 95% CI 0.31– 0.98, P =.04). In our study, SSIs were reduced from seven (15.2% or 7/46) to 1 (2.1% or 1/46) when comparing a TWP to an AWP respectively. While the absolute numbers are small, this reduction is in comparison to a TWP which had already been proven to significantly reduce infections. In the case where wound protectors are not routinely used, our data suggest the reduction of incidence in SSIs would be even greater.
      Wound protection devices form a physical barrier between the wound edges and the contaminated surgical field, providing an impervious barrier for pathogens from imbedding themselves within the wound. But why would use of an AWP reduce the incidence of infectious complications overall? We hypothesize that with an AWP, not only is the wound edge being irrigated with continuous antibiotic solution, but the surgical field itself is also being continuously irrigated, thereby reducing bacterial load. Intra-abdominal irrigation with antibiotic solution has been long described in the trauma literature to mitigate abdominal infections. In a meta-analysis of 23 studies, Qadan et al. reported an absolute risk reduction in mortality of 32.5 (P <.001) with antibiotic compared to saline lavage.
      • Qadan M
      • Dajani D
      • Dickinson A
      • et al.
      Meta-analysis of the effect of peritoneal lavage on survival in experimental peritonitis.
      Conversely, in a randomized controlled trial in trauma laparotomy, Mashbari et al. reported abdominal irrigation does not reduce post-operative complications or morbidity at 30-days.
      • Mashbari H
      • Hemdi M
      • Chow KL
      • et al.
      A Randomized controlled trial on intra-abdominal irrigation during emergency trauma laparotomy; time for yet another paradigm shift.
      Due to the conflicting literature, no specific recommendations are currently available to guide decision-making in the operating room. However, we hypothesize that by removing superficial and deep incisional contamination and lowering the bioburden of bacteria with continuous antibiotic irrigation, an AWP can reduce infectious complications and expedite the healing process.
      Prolonged antibiotic prophylaxis after RCUD has been proposed as a method to reduce SUTIs and BSIs with mixed results. Werntz et al. proposed a 30-day course of continuous antibiotic prophylaxis (ABP) after discharge. A total of 84 patients were enrolled. 42 patients without ABP at discharge and 42 patients with ABP. 15 of 42 (36%) patients without ABP developed a SUTI compared to 6/42 (12%) with ABP (P <.004).
      • Werntz RP
      • Martinez-Acevedo A
      • Amadi H
      • et al.
      Prophylactic antibiotics following radical cystectomy reduces urinary tract infections and readmission for sepsis from a urinary source.
      Furthermore, 7/42 (17%) developed a BSI without ABP compared to 1/42 (2%) with ABP (P =.02). Only 1 Clostridium difficile infection occurred which was in the no ABP group. Similarly, Kirkpatrick et al. studied whether ABP while having indwelling ureteral stents in place reduced SUTIs and BSIs.
      • Kirkpatrick C
      • Haynes A
      • Sharma P
      Antibiotic prophylaxis is not associated with reduced urinary tract infection-related complications after cystectomy and ileal conduit.
      A total of 75 patients undergoing RCUD were enrolled. 30patients without ABP and 45 patients with ABP through stent removal as an outpatient (2 – 4 weeks). The mean duration of stenting was 25 days. The 90-day UTI-related complications and UTI-related readmission rates were 27/75 (36%) and 11/75 (14.7%) respectively. ABP was not associated with reduced 90-day UTI-related complications (P >.05) nor UTI-related readmissions (P >.05). However, ABP was associated with a higher rate of Clostridium difficile infections 9/36 (20%), compared to 1/29 (3.3%), P =.038. This and other studies have corroborated the increased risk of Clostridium difficile infections with prolonged antibiotic use after RCUD.
      • Krasnow RE
      • Mossanen M
      • Koo S
      • et al.
      Prophylactic antibiotics and postoperative complications of radical cystectomy: a population based analysis in the United States.
      We observed only 1 Clostridium difficile infection in our study which was in the TWP group. Given the AWP delivers antibiotic into the wound and not systemically confers a great advantage as concerns for antibiotic-related complications are largely mitigated.
      Congruent with our study, both previous prospective studies employed extracorporeal urinary diversion after robotic RCUD. In the robotic arm of the RAZOR trial, 75% of patients received ileal conduits whereas in the Bochner et al. study, 40% of patients received ileal conduits. Our study had 60% of patients receiving ileal conduits. Several studies have examined the relationship between complications and type of diversion performed. In a single institution study of 281 RCUD, 118 ileal conduit, 51 Indiana pouch, and 62 orthotopic neobladder, Nieuwenhuizen et al. found no differences in incidence of early complications (<30 days). However, patients receiving an ileal conduit had a lower risk of developing late complications, with HR = 0.36; 95% CI 0.14 – 0.91.
      • Nieuwenhuijzen JA
      • de Vries RR
      • Bex A
      • et al.
      Urinary diversions after cystectomy: the association of clinical factors, complications and functional results of four different diversions.
      Notably, this difference in late complications was driven by increased SUTIs. Similarly, in a study of 604 patients undergoing RCUD, 445 ileal conduits and 159 orthotopic neobladder, Demaegd et al. found no difference in short-term complication rates, but did find a significant difference in long term major complication rates (ileal conduit 39.7% vs orthotopic neobladder 49%, P =.046).
      • Demaegd L
      • Albersen M
      • Muilwijk T
      • et al.
      Comparison of postoperative complications of ileal conduits vs orthotopic neobladders.
      No differences were noted in overall or infectious complications by diversion type in our study despite a high rate of continent diversions performed. We believe this is particularly encouraging as the choice of diversion for a patient should not be influenced by fear of complications, but rather a careful discussion regarding the merits of each.
      Using the Nationwide Inpatient Sample (NIS) database, Davies et al. studied the effect of SUTIs and BSIs after RCUD on cost, length of stay (LOS) and mortality.
      • Davies BJ
      • Allareddy V
      • Konety BR
      Effect of postcystectomy infectious complications on cost, length of stay, and mortality.
      Of the 6,686 patients, 241 (3.6%) were diagnosed with sepsis and was a significant predictor of in-hospital mortality (P < .001). With regards to cost and LOS, sepsis had a mean cost of $161,277 and LOS of 22 days which was three times that of patients without (P < .001). Furthermore, patients with any bacterial infection had a mean cost of $107,734 and LOS of 16 days which was 1.5 times that of patients without (P <.001). De Lissovoy et al. also queried the NIS database and determined on average, SSIs extended LOS by 9.7 days and increased hospital cost by $20,842 per admission.
      • de Lissovoy G
      • Fraeman K
      • Hutchins V
      • et al.
      Surgical site infection: incidence and impact on hospital utilization and treatment costs.
      Readmissions accounted for a further 521,933 days of care at a cost of nearly $700 million. In line with this, a cost analysis performed by the CDC estimated the mean attributable cost of SSIs to range from ten to $25,000 per infection with costs exceeding $90,000 if a resistant organism was identified.
      Centers for Disease Control and Prevention
      The direct medical costs of healthcare-associated infections in U.S. hospitals and the benefits of prevention.
      In our study, all infections required readmission. Thus, use of an AWP reduced 30-day readmission rates from 30.4% – 6.5%, and 90-day readmission rates from 37.0% – 6.5%.
      This study is not without limitations. First, our institution is a highly specialized, high volume tertiary referral center. Thus, our results may not be generalizable. Second, all urinary diversions were performed in an open fashion through a 6 – 8cm incision and thus may not translate to larger incisions required for open cystectomies or conversely to intra-corporeal diversions. Finally, the relatively small sample size and retrospective nature of the study are subject to limitations of causal inference and unknown confounders. Additional prospective randomized studies including more patients, and in less specialized centers are needed to realize the true generalizability of our results. Future studies could also query whether an AWP can be used in lieu of perioperative antibiotics. Despite these limitations, the results of this study remain valuable in highlighting that infectious complications represent the majority of complications after radical cystectomy and efforts to prevent these infections can lead to significant improvements in patient morbidity and quality of life.

      CONCLUSION

      We provide preliminary data showing use of an AWP can reduce infectious complications after RCUD. While larger prospective studies are warranted, our findings are a significant step towards decreasing morbidity of an already highly morbid procedure.

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