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Use of hyaluronic acid-carboxymethylcellulose adhesion barrier on the neurovascular bundle and prostatic bed to facilitate earlier recovery of erectile function after robotic prostatectomy, "Beyond the Abstract," by Jae Young Joung, MD, PhD

BERKELEY, CA (UroToday.com) - Known elements contributing to postoperative erectile dysfunction (ED) include traction, distraction, and thermal nerve injuries.[1, 2, 3] While intra-operative mechanisms of neurovascular bundle (NVB) injury are often considered, inflammation and wound healing after RP may also be critical components. Limiting the local effects of these processes on neurovascular tissue may improve functional outcomes.[4, 5] Hyaluronic acid-carboxymethylcellulose (HACM) adhesion barrier has been shown to effectively reduce post-operative adhesions in abdominopelvic surgery.[6, 7] The mechanism of action is the physical separation of traumatized and inflammatory adhesiogenic tissues and organs while normal tissue repair takes place. In terms of safety, the compound begins to break down in 7 days, well after the acute phase of normal tissue repair is finished, and is completely resorbed by the body in 28 days. More interestingly, it has been demonstrated in rabbits that HACM improves peripheral nerve regeneration.[8] We hypothesized that placing HACM gel around the anatomic location of the NVBs intraoperatively limits local inflammatory response and reduces fibrosis, thus hastening return of neural activity and potency. Here, we present our initial experience with HACM use in RARP.

Materials and Methods

Patient Selection

HACM adhesion barrier usage is FDA-approved for the prevention of adhesions during abdominopelvic surgery. IRB approval was obtained for this retrospective study. Between 2008 and 2010, 459 patients underwent standard transperitoneal RARP with bilateral nerve sparing technique. Patients were divided into three groups based on time: first 137 patients underwent RARP without HACM use, middle 162 patients with HACM use, and the last 150 patients without HACM use. All RARPs were performed by a single surgeon who had performed more than 500 total robotic prostatectomies prior to the study initiation. All patients completed the self-administered American Urological Association Symptom Score (AUASS) and International Index of Erectile Function Short Survey (IIEF-5) before and after surgery.

For analysis of the efficacy of HACM use, patients were reclassified into two groups: HACM use (Group 1; n=162) and non-HACM use (Group 2; n=287). To analyze the influence of surgeon’s learning curve, Group 2 included the latter 150 cases following 162 cases with HACM use. Subgroup stratification was done to analyze HACM use with pre-operative IIEF-5 ≥ 20 (subgroup A; n=74) and non-HACM use with IIEF-5 ≥ 20 (subgroup B; n=153).

Surgical Technique

Our intrafascial nerve-sparing surgical technique during RARP has been previously described.2 After completing the vesicourethral anastomosis, 20 mL of dissolved HACM gel was delivered (See Figure 1) using a 35 cm cannulated laparoscopic injector through the assistant trocar in the anatomic area of the left and right NVB. Each target area received 10 mL. This anatomic area was defined laterally by the levator ani muscles, medially by the bladder, cranially by the superior pubic ramus, and caudally by the urethral stump. The injected gel, which congealed on delivery to target area tissues, consisted of 2 sheets of HACM dissolved in 20 mL of 0.9% normal saline for 30 minutes prior to use. Surgical drains were not utilized. Patients were routinely discharged home at post-operative day 1 with urethral catheters that were removed on post-operative day 7.

Clinical Follow-up

The following peri-operative data were retrospectively collected and analyzed: patient age, operative time, estimated blood loss, pre-operative PSA, pre-operative AUASS, pre-operative IIEF-5, pathologic tumor stage, final Gleason sum, prostate weight, and surgical margin status. All patients underwent routine post-operative follow up with detailed physical examinations for a minimum of 12 months. An EF assessment with an IIEF-5 survey was completed by the patients at 3, 6, 9 and 12 months. EF recovery was defined as the ability to achieve penetration ≥ 50% of the time and maintain erections significant for penetration ≥ 50% of the time as per questions 2 and 3 on the IIEF-5 survey.[9, 10] All patients were recommended to take a phosphodiesterase 5 inhibitor (sildenafil 50 mg) every other night for 90 days as part of the penile rehabilitation program.

Results

The demographic and clinical characteristics of the two groups as shown in Table 1. Pre-operative IIEF-5 score was higher in Group 2 compared with those of Group 1. No significant differences were found in age, AUASS, prostate weight, PSA and pathologic features (Table 1). With regard to continence at 6 months post-surgery, 136 (85.5%) patients in Group 1 and 257 (89.5%) patients in Group 2 were pad-free. The peri-operative complication rate was 8.0% in Group 1 and 11.8% in Group 2 (p=0.261). The complete list of major and minor complications is presented in Table 2.

Analyses of EF recovery following surgery between the two groups are shown in Table 3. No difference was found in the rate of EF recovery at 3 month post-surgery. At 6 months, 45 (28.5%) patients in Group 1 showed EF recovery, which was significantly higher than the 50 (17.4%) patients in Group 2 (p=0.006). In multivariable logistic regression model, HACM use was an independent predictor for EF recovery at 6 months post-surgery (OR, 2.432; 95% CI, 1.463-4.044; p = 0.001). Age and pre-operative IIEF-5 score were also independent predictors (Table 4). At 12 months post-surgery, Group 2 was higher in EF recovery than Group 1 (Table 3), but HACM use was not an independent predictor based on the results of multivariable logistic regression model demonstrating age and pre-operative IIEF-5 were significant predictors (supplementary Table 1). After 12 months, EF recovery was not different between two groups. Given the difference in EF recovery between the two groups, subgroups with baseline IIEF-5 > 20 were selected based on their pre-operative sexual function. At both 6 months and 9 months, subgroup A (n=74) showed a higher rate of EF recovery compared with that of subgroup B (n=153) (p < 0.001 at 6 months; p=0.022 at 9 months; supplementary Table 2). Multivariate logistic regression model demonstrated that HACM use was a strong independent predictor for EF recovery at 6 months following surgery (OR, 3.560; 95% CI, 1.926-6.580; p < 0.001; supplementary Table 3). Age was also a significant predictor. At 12 months, age was only independent predictor for recovery of EF following surgery (supplementary Table 4).

To check the possible influence of the surgeon’s learning curve on results, we compared the EF recovery of Group 1 with the last 150 patients of Group 2 who underwent surgeries subsequently to the Group 1. At 6 months, the rate of EF recovery in Group 1 was higher than Group 2 (28.5% vs. 15.3%; p = 0.005, Supplementary table 5). In subgroups with baseline IIEF-5 > 20, similar findings were found at both 6 and 9 months post-surgery (Supplementary table 6). HACM use was still an independent predictor for EF recovery at 6 months post-surgery (OR, 3.210; 95% CI, 1.717-6.003; p < 0.001) with age and pre-operative IIEF-5 score, which were similarly observed in subgroups with baseline IIEF-5 ≥ 20 (Supplementary table 7).

Discussion

Prevention of inflammation and scarring must also be considered. Van Poppel et al. note that no standard prophylactic strategy is currently utilized to treat potential NVB injury during RARP, despite the development of multiple modalities (hyperbaric oxygen, nitric oxide donor therapy, ligands to block immune system induction and/or downstream targets that stimulate inflammation and scarring, and direct trophic factors to induce nerve regeneration).[11] While intriguing, most agents remain in the early stages of development; few are ready for clinical use. Also, these may trigger systemic immunomodulation, which increases surgical complication rates and may cause inadequate surgical bed and anastomotic healing.[12]

Our aim in this study was to produce local rather than systemic immunomodulation, an effort that we contend our results support. Both Group 1 (HACM use) and Group 2 (non-HACM use) demonstrated equivalent complication rates (11.8% vs. 8.0%) with a higher rate of EF recovery at 6 months post-surgery when HACM was used. Furthermore, recent studies in the general surgery, colorectal, hepatobiliary, and gynecologic literature have demonstrated the safety and efficacy of HACM adhesion barrier in the reduction of the incidence, severity, and extent of post-operative adhesions in patients having abdominopelvic surgery.[6, 7, 13, 14, 15] The role of HACM may be therapeutic as well as protective. Adanali et al.’s 2003 study concluded that HACM use with concurrent repair of sciatic nerve injuries in rabbits resulted in a statistically significant improvement in the number of viable axons 3 months after surgery and a reduction in perineural fibrosis.[8] The introduction of a locally active agent as a physical barrier around the NVBs to separate them from adjacent inflammatory tissue and reduce fibrosis is a novel concept. Unlike an individual’s surgical technique, HACM use can be standardized in its dosage, delivery, and target area to improve early potency outcomes after RARP.

Largely because of its retrospective nature, this study does have some limitations. First, with respect to demographic characteristics, there was a difference in pre-operative IIEF-5 score between two groups, which could influence the results of EF recovery following RARP. By multivariative analysis to adjust this difference, we demonstrated HACM use to an independent predictor of EF recovery by adjusting these variables. Notably, Group 1 showed lower pre-operative IIEF-5 score than Group 2. If the baseline characteristics of Group 1 are comparable with those of Group 2, more prominent results could be observed that favor a greater benefit of HAMC use in outcomes.

Second, the potential impact of the surgeon’s learning curve on the improved the rate of EF recovery post-surgery cannot be excluded completely. However, all RARPs were performed by a single fellowship-trained surgeon with > 350 RARPs performed using the same surgical technique (AIR) and more than 500 robotic prostatectomies overall prior to study commencement. It is generally agreed that the robotic learning curve plateaus by 200-300 cases.[16, 17] Furthermore, Group 2 included the latter 150 cases following 162 cases with HACM use. In subgroup analysis between Group 1 and the last 150 cases of Group 2, HACM use was found to be a significant factor. Thus, we believe that surgeon-dependent improvement in technique would have a minimal influence on the results. Third, the HACM adhesion barrier was placed after the vesicourethral anastomosis was performed, limiting the use of the lateral prostatic fascia as a precise landmark to mark the location of the NVB for gel delivery. This was purposefully done to prevent the gel from being placed within vesicourethral anastomosis because of concerns of a possible anastomotic leak secondary to reduced wound healing. We instead chose to deliver the gel in a carefully defined area (see Methods) encompassing the most likely anatomic location of each neurovascular bundle after reconstruction was completed. While Group 1 demonstrated superiority in early EF recovery, there were no anastomotic leaks in any of the 162 patients. Finally, one may question the lack of consistent and significant improvement in potency at 3, 9, and 12 months in patients in Group 1. While we assert that the use of HACM is protective and may help to facilitate faster return of function, the pathophysiologic cavernosal nerve neuropraxia that most patients experience after surgery is the most likely a rate-limiting step in EF recovery until about 3 months following surgery. This argument is supported by the paucity of studies in the urologic literature demonstrating return of potency at 3 months after RARP and their lack of reproducibility.[18, 19, 20, 21] In 9 and 12 months, the effect of HACM use in EF recovery was not found, but patient characteristics including age and preoperative potency were significant factors in EF recovery at these times.

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Figure 1. Delivery of hyaluronic acid-carboxymethylcellulose on the anatomic location of the neurovascular bundle.

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Table 1. Demographic and clinical characteristics of patients

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Table 2. Peri-operative complications including major and minor 

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Table 3. Recovery of erectile function according to the time following surgery

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Table 4. Prediction of erectile function recovery at 6 months following surgery 

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Supplementary Table 1. Prediction of erectile function recovery at 12 months following surgery

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Supplementary Table 2. Recovery of erectile function in subgroup (IIEF-5 ≥ 20) according the time following surgery

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Supplementary Table 3. Prediction of erectile function recovery in subgroup (IIEF-5 ≥ 20) at 6 months following surgery 

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Supplementary Table 4. Prediction of erectile function recovery in subgroup (IIEF ≥ 20) at 12 months following surgery

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Supplementary Table 5. Recovery of erectile function according the time following surgery

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Supplementary Table 6. Recovery of erectile function in subgroup (IIEF-5 ≥ 20) according the time following surgery 

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Supplementary Table 7. Prediction of erectile function recovery at 6 months following surgery

References:

  1. Ahlering TE, Skarecky D, Borin J. Impact of cautery versus cautery-free preservation of neurovascular bundles on early return of potency. J Endourol. 2006 Aug;20(8):586-9. PubMed PMID: 16903820. Epub 2006/08/15. eng.
  2. Potdevin L, Ercolani M, Jeong J, Kim IY. Functional and oncologic outcomes comparing interfascial and intrafascial nerve sparing in robot-assisted laparoscopic radical prostatectomies. J Endourol. 2009 Sep;23(9):1479-84. PubMed PMID: 19694530. Epub 2009/08/22. eng.
  3. Savera AT, Kaul S, Badani K, Stark AT, Shah NL, Menon M. Robotic radical prostatectomy with the "Veil of Aphrodite" technique: histologic evidence of enhanced nerve sparing. Eur Urol. 2006 Jun;49(6):1065-73; discussion 73-4. PubMed PMID: 16597485. Epub 2006/04/07. eng.
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  12. Troppmann C, Pierce JL, Gandhi MM, Gallay BJ, McVicar JP, Perez RV. Higher surgical wound complication rates with sirolimus immunosuppression after kidney transplantation: a matched-pair pilot study. Transplantation. 2003 Jul 27;76(2):426-9. PubMed PMID: 12883205. Epub 2003/07/29. eng.
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  16. Ahlering TE, Skarecky D, Lee D, Clayman RV. Successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. J Urol. 2003 Nov;170(5):1738-41. PubMed PMID: 14532766. Epub 2003/10/09. eng.
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Written by:
Jae Young Joung, MD, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Section of Urologic Oncology and Dean and Betty Gallo Prostate Cancer Center, The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey.
Center for Prostate Cancer, National Cancer Center, Goyang, Korea.

Use of a hyaluronic acid-carboxymethylcellulose adhesion barrier on the neurovascular bundle and prostatic bed to facilitate earlier recovery of erectile function after robotic prostatectomy: An initial experience - Abstract

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