TachoSil Sealed Tubeless Percutaneous Nephrolithotomy to Reduce Urine Leakage and Bleeding: Outcome of a Randomized Controlled Study

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1 TachoSil Sealed Tubeless Percutaneous Nephrolithotomy to Reduce Urine Leakage and Bleeding: Outcome of a Randomized Controlled Study Luigi Cormio,* Antonia Perrone, Giuseppe Di Fino, Nicola Ruocco, Mario De Siati, Jean de la Rosette and Giuseppe Carrieri From the Department of Urology and Renal Transplantation, University of Foggia, Foggia, Italy, and the Department of Urology, Academic Medical Center, Amsterdam, The Netherlands (JdlR) Purpose: We determined the efficacy and safety of TachoSil in sealing the tract after percutaneous nephrolithotomy compared to nephrostomy tube placement. Materials and Methods: A total of 100 consecutive patients scheduled for percutaneous nephrolithotomy were randomized 1:1 to receive a 16Fr nephrostomy tube (group 1) or TachoSil in the tract (group 2). All patients received a mono-j ureteral catheter. The primary study end points were bleeding and urinary leakage rates. The secondary end points were pain as assessed by the 0 to 10-point visual analog scale, analgesic requirement and hospital stay. Results: The groups were comparable for preoperative and operative variables. In group 1, 3 patients were excluded intraoperatively because of relevant bleeding, and in group 2, 1 patient was excluded intraoperatively because of hydrothorax. Tract complications were significantly more frequent in group 1 than in group 2 (25.5% vs 2%, p 0.001). However, the difference in urinary leakage reached statistical significance (19.1% vs 2%, p 0.007), whereas that in perirenal hematoma formation did not (6.4% vs 0%, p 0.113). There was no difference between the groups in mean SD number of analgesic doses ( vs , p 0.791) and visual analogue scale scores ( vs , p 0.270). Postoperative hospital stay was significantly shorter in group 2 than in group 1 ( vs days, p ). Conclusions: Although failing to reduce pain and analgesic requirement, Tacho- Sil provided better tract control and a shorter hospital stay than nephrostomy tube placement, thus allowing the extension of indications for tubeless percutaneous nephrolithotomy to most procedures. Abbreviations and Acronyms Hb hemoglobin NT nephrostomy tube PCNL percutaneous nephrolithotomy Perc/Urs percutaneous/ ureteroscopic RCT randomized controlled trial VAS visual analogue scale Submitted for publication September 10, Study received local ethical committee approval. * Correspondence: Via Fontanelle 16/7, Bari-Palese, Italy (telephone: ; FAX: ; luigicormio@libero.it). Key Words: drainage; lithotripsy; nephrolithiasis; nephrostomy, percutaneous CONTINUOUS technical refinements have allowed percutaneous nephrolithotomy to stand the test of time and become the preferred treatment option for large or otherwise complex renal or proximal ureteral stones. 1 One area of continuing innovation and debate is the management of the percutaneous tract at the end of the procedure due to its relevant impact on postoperative clinical outcome. The practice of routine placement of a large bore (20 to 26Fr) nephrostomy tube, traditionally recommended to achieve hemostasis, urinary drainage and access for a second look procedure, has been challenged since the early 1980s. 2 However, the concept of tubeless PCNL remained neglected until 1997, when Bellman et al demonstrated that placement of a Double-J /12/ /0 Vol. 188, , July 2012 THE JOURNAL OF UROLOGY Printed in U.S.A by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. DOI: /j.juro

2 146 SEALED TUBELESS PERCUTANEOUS NEPHROLITHOTOMY stent instead of a NT was associated with less postoperative pain, decreased analgesia requirement, shorter hospital stay and faster return to normal activities. 3 Several RCTs and meta-analyses have subsequently confirmed a reduction in postoperative pain and hospital stay with the tubeless approach, 4,5 and demonstrated that substituting double-j stents with external ureteral catheters or no drainage at all (totally tubeless) further improved patient compliance by eliminating stent related symptoms and the need for cystoscopic removal. 6,7 Nevertheless, the wisdom of tubeless PCNL continues to be challenged by recent well designed RCTs demonstrating the advantages of early NT removal 8 or placement of small bore NTs 9 over the tubeless approach. In this scenario hemostatic agents appear to be an attractive means of sealing the tract without using a tube. Sealed tubeless PCNL has been suggested to reduce patient discomfort and urinary leakage compared to unsealed tubeless PCNL 10,11 or NT placement, 12,13 but if 14 and which 15 agent should be used remain controversial. TachoSil is a sterile, ready to use absorbable patch consisting of an equine collagen matrix coated with fibrin glue components, human fibrinogen and human thrombin, thus combining the assets of a pliable patch material with the hemostatic and adhesive properties of the coagulation factors. 16 Its efficacy and safety have been demonstrated in liver resection, 17 pulmonary lobectomy 18 and kidney tumor resection trials, 16 leading to product approval in Europe as a supportive hemostatic treatment for intraoperative topical application. However, to our knowledge it has never been tested as a tract sealant after PCNL. Therefore, in this study we determined the efficacy and safety of TachoSil in sealing the PCNL tract compared to NT placement. MATERIALS AND METHODS Based on a computer generated 1:1 randomization chart, consecutive patients scheduled for PCNL between January 2008 and December 2010 received, a 16Fr Malecot NT (group 1) or TachoSil sealing of the tract (group 2) at the end of the procedure (fig. 1). Exclusion criteria were impaired intellectual ability only. The study was approved by the local ethical committee and patients signed an informed consent to be enrolled. Antiplatelet therapy was stopped 5 days before surgery and anticoagulants were stopped 5 days before surgery but replaced with low molecular weight heparin. Prophylactic wide spectrum antibiotics were administered to patients with sterile urine, starting the evening before the procedure, whereas those with bacteriuria were treated according to culture and sensitivity results. Stone size was determined by measuring the longest diameter on preoperative radiological investigations. In cases of multiple nonstaghorn calculi, stone size was defined as the sum of the longest diameter of each stone. 19 All procedures were performed with the patient under general anesthesia. Patients were placed in the supine anterolateral position 20 or in the Galdakao modified supine position 21 when combined Perc/Urs manipulation was deemed necessary. According to patient position the collecting system was visualized by injecting contrast medium through a 7Fr mono-j ureteral catheter introduced Enrollment Allocation Analysis Allocated to receive Nephrostomy Tube (Group 1: 50 pts) Analyzed (n=47) Excluded from analysis (n=3) *relevant bleeding Assessed for eligibility Randomized (n=101) Excluded (n=1) *not meeting inclusion criteria (n=1) Allocated to receive TachoSil (Group 2: 50 pts) Analyzed (n=49) Excluded from analysis (n=1) *hydrothorax Figure 1. CONSORT flow diagram of study participants

3 SEALED TUBELESS PERCUTANEOUS NEPHROLITHOTOMY 147 by flexible cystoscopy or through a rigid ureteroscope. The target calix was punctured under biplanar fluoroscopic guidance and the tract dilated with balloons, when the calix was not occupied by stones, or with sequential plastic dilators up to placement of a 30Fr Amplatz sheath. Complete stone clearance was attempted with rigid and flexible nephroscopy as well as flexible ureteroscopy as needed. Finally, the renal parenchymal portion of the tract was checked with a 26Fr bipolar resectoscope while pulling out the Amplatz sheath. Small arterial bleeders were coagulated, whereas no attempt was made to coagulate large veins. Based on randomization we inserted a 16Fr Malecot NT or a TachoSil sheath dipped in contrast medium and rolled like a cigarette over its yellow surface (fig. 2). In group 2 the skin was closed with a deep 1-zero silk stitch. Postoperatively all patients received low molecular weight heparin and antibiotics until discharge home, as well as 30 mg ketorolac intravenously or orally as needed. A complete blood count was performed at the beginning and end of PCNL, and then every 24 hours until discharge home, whereas renal ultrasound was performed every 12 hours after surgery to check for perirenal bleeding or urinary leakage. In cases of normal postoperative course, the mono-j catheter was removed on postoperative day 1 in group 2 and on postoperative day 3 in group 1, after having closed the NT on day 1 and removed it on day 2. Such protocol allowed every patient to undergo 24-hour renal pelvis drainage by a mono-j catheter to promote tract closure after NT removal or TachoSil placement. Within the frame of this study patients were closely observed in the hospital for possible urine leakage or bleeding. Stone clearance was assessed by renal ultrasound and abdominal radiography/stratigraphy on the morning after mono-j removal, just before discharge home. Patients with residual fragments (4 mm or less) or stones (larger than 4 mm) were given 0.4 mg tamsulosin daily for 6 weeks to promote spontaneous passage. Renal ultrasound and abdominal radiography/stratigraphy were then repeated to decide if and which treatment was needed. When in doubt, abdominal computerized tomography was performed. Complications occurring up to 6 weeks after the procedures were also recorded. The primary study end point was tract control in terms of bleeding and urinary leakage. The secondary end point was patient compliance in terms of pain and hospital stay. The sample size was calculated to test the hypothesis of TachoSil sealing providing a fivefold reduction of our 20% rate of urinary leakage leading to prolonged hospitalization. To detect such a difference with 80% study power and Figure 2. TachoSil sheath is dipped in contrast medium and rolled like cigarette over yellow (active) surface (A). TachoSil sheath is inserted in Amplatz sheath using rigid nephroscope (B) and placed into renal parenchymal tract under direct vision (C). Fluoroscopy shows correct position of TachoSil sheath with absence of contrast medium extravasation (D).

4 148 SEALED TUBELESS PERCUTANEOUS NEPHROLITHOTOMY a 2-sided 5% significance level, 100 patients, 50 per arm, were required. Continuous data were reported as mean SD. Those data showing a normal distribution according to the Kolmogorov-Smirnov test were analyzed by the 1-way ANOVA whereas those not showing a normal distribution were analyzed by the Mann-Whitney test. Ordinal data were analyzed by the Kruskal-Wallis test. Differences in rates were assessed using Fisher s exact test. Statistical analysis was performed using commercially available software (MedCalc version ). Significance was set at p RESULTS The 2 groups were comparable in terms of preoperative patient characteristics (table 1). There were 18 patients, 9 in group 1 and 9 in group 2, placed in the Galdakao modified supine position because combined Perc/Urs manipulation was deemed necessary from the beginning of the procedure. There were 14 patients, 10 in group 1 and 4 in group 2, who received combined Perc/Urs manipulation in the supine anterolateral position with flexible ureteroscopy as this was deemed necessary during the procedure (table 2). All patients had a single percutaneous access, through the lower calix in 57, the middle in 39 and the upper in 4, with no difference in access site and tract dilation technique between the groups. Four patients were excluded from study because of intraoperative complications, including 3 in group 1 because of relevant tract bleeding requiring a large Table 1. Preoperative patient characteristics Nephrostomy Tube TachoSil p Value No. gender (M/F) 25/25 25/ * Mean SD pt age Mean SD kg/m 2 body mass index Mean SD American * Society of Anesthesiologists score No. antiplatelet/coagulant therapy No. renal anomalies No. previous open renal surgery No. single kidney No. stone side (lt/rt) 30/20 31/ * No. stone feature (%): Staghorn 10 (20) 9 (18) Multiple 21 (42) 25 (50) Single 19 (38) 16 (32) Mean SD mm stone size * Kruskal-Wallis test. Independent samples t test. Fisher s exact test. Calculated only for single and multiple stones, and reported as the longest or the sum of the longest diameters, respectively. Table 2. Details of the surgical procedure Nephrostomy Tube TachoSil p Value No. combined Perc/Urs 19 (38) 13 (26) 0.284* manipulation (%): Galdakao modified position 9 (18) 9 (18) 1.000* Supine anterolateral 10 (20) 4 (8) 0.148* position No. percutaneous access (%): Lower calix 25 (50) 32 (64) Middle calix 24 (48) 15 (30) Upper calix 1 (2) 3 (6) No. tract dilation (%): Plastic dilator 30 (60) 27 (54) 0.686* Balloon dilator 20 (40) 23 (46) Mean SD operative mins Mean SD gm/dl operative Hb decrease * Fisher s exact test. Independent samples t test. bore (22Fr) NT clamped for 6 hours, and 1 in group 2 because of hydrothorax requiring pleural drainage (fig. 1). Mean operative time and Hb decrease were similar in the 2 groups which, thus, were also comparable for operative characteristics (table 2). There was no difference in postoperative Hb decrease and postoperative bleeding requiring transfusion or treatment. Perirenal hematomas were seen in 3 (6.4%) of the 47 patients in group 1, always after NT removal, as opposed to none in group 2 (p 0.113). The volume ranged from 50 to 100 cc, thus requiring no treatment but prolonged hospitalization in 2 of the 3 cases. In addition, urinary leakage was more frequent in group 1 than in group 2 (19.1% vs 2%, p 0.007) in terms of prolonged leakage (greater than 48 hours) requiring double-j stenting (6.4% vs 2%, p 0.357) and self-limiting leakage (between 12 and 48 hours, 12.7% vs 0%, p 0.012) that required no treatment but prolonged hospitalization (table 3). The NT did not affect patient compliance as there was no difference between the 2 groups in terms of analgesic requirement or VAS scores. Conversely hospital stay was significantly shorter in group 2 than in group 1 (table 3). There was no difference between the groups in terms of stone-free rate. DISCUSSION According to the PCNL Global Study 91.2% of the 5,803 patients treated worldwide between November 2007 and December 2009 received a NT at the end of the procedure with ureteral drainage in 36% of cases and without in 55%. 22 These figures clearly demonstrate that there is no agreement on the ideal exit strategy after PCNL and that tubeless PCNL has not gained wide acceptance among endourologists despite the increasing number of studies

5 SEALED TUBELESS PERCUTANEOUS NEPHROLITHOTOMY 149 Table 3. Outcome measures of PCNL exit strategies Nephrostomy Tube TachoSil p Value No. pts Analgesic requirement (No * doses) during first 24 postop hrs Mean SD VAS score on postop day Mean SD gm/dl postop Hb decrease No. perirenal hematoma (%) 3 (6.4) No. urinary leakage (%): 9 (19.1) 1 (2) Minor 6 (12.8) Major 3 (6.4) 1 (2) Mean SD days postop * hospital stay No. stone-free (%): Immediate 32 (68.1) 34 (69.4) Wks postop 41 (87.2) 43 (87.8) * Mann-Whitney test for independent samples. ANOVA. Fisher s exact test. demonstrating its potential advantages. 4,5,14 In addition, current European Association of Urology guidelines recommend with grade A such an approach as a safe alternative to NT placement in uncomplicated cases. 1 The main reason endourologists continue to favor NT placement is probably the fear of bleeding or urinary leakage from a tract left open. 3 Therefore, sealing the tract with a hemostatic agent seems to be an attractive means of avoiding a NT. Instillation of fibrin glue (TISSEEL ) in the nephrostomy tract was first reported by Mikhail et al. 23 In a review of 43 patients treated with tubeless PCNL, the authors failed to demonstrate a reduced risk of bleeding or urinary leakage in the 20 who received this agent compared to the 23 who did not. A subsequent RCT confirmed TISSEEL to be effective in reducing postoperative pain and analgesic requirement but not bleeding or urinary leakage. 10 The gel matrix hemostatic sealant (FLOSEAL ), consisting of bovine collagen granules coated with human derived thrombin, reduced postoperative pain and analgesic requirement, but it failed to reduce the risk of bleeding or urinary leakage compared to NT placement in retrospective and randomized controlled trials. 9,24,25 SURGICEL,a hemoglobin avid oxidized cellulose that forms artificial clots, failed to reduce bleeding or urinary leakage in a prospective study in which 20 patients who underwent tubeless PCNL were randomized to receive or not receive this agent. 26 Finally, in a RCT including 20 patients and 30 controls who underwent tubeless PCNL, 11 SPONGOSTAN, a dry absorbable porcine gelatin sponge of fibrin prepared by clotting fibrinogen with thrombin, reduced postoperative pain and the analgesic requirement but not bleeding. The authors suggested this agent reduced urinary leakage, but given the absence of urinary fistulas and the mean duration of urinary leak (6 hours vs 1) between the groups, such a conclusion seems to be excessively enthusiastic. The present study showed that, compared to NT placement, TachoSil sealed tubeless PCNL provided a statistically significant reduction in urinary leakage rate. It was also associated with no cases of perirenal hematoma formation, but such difference (0% vs 6.4%) did not reach statistical significance. These findings suggest that, providing 24 hours urinary drainage by a mono-j ureteral catheter, Tacho- Sil is effective in sealing the tract to blood and urine, even when complete stone clearance has not been obtained, a situation that occurred in as much as 30% of our patients. Such excellent tract control turned into a significant reduction in postoperative hospital stay, with obvious benefits in terms of patient compliance and costs. Surprisingly there was no difference between the groups in terms of analgesic requirement during the first 24 postoperative hours or VAS scores at postoperative day 1. Whether tubeless PCNL is beneficial in terms of pain reduction remains controversial as some studies have shown tubeless PCNL to reduce pain compared to the placement of standard or small bore NTs, 5,27 whereas others focusing on pain and nonsteroidal anti-inflammatory analgesic requirement at postoperative day 1, like the present study, showed no difference between tubeless PCNL and small bore NTs. 9,28 Taken together these findings would suggest that pain during the first 24 postoperative hours is influenced by the procedure itself rather than the presence (or lack) of percutaneous drainage. A strong point of the present study is the inclusion of consecutive cases and not only of uncomplicated cases as with almost all studies on tubeless PCNL. However, there are several potential limitations. Other end points such as patient quality of life or return to normal activities were not tested. However, this was considered to be beyond the scope of a study on the first time efficacy and safety of TachoSil in the context of PCNL. In addition, there was no group of patients having undergone a tubeless PCNL not sealed with TachoSil. However, the present study was designed to challenge the practice of routine NT placement. Further well designed studies are needed to evaluate the role of TachoSil in the setting of tubeless and totally tubeless PCNL. Finally, like all tubeless procedures, TachoSil sealed tubeless PCNL lacks the possibility of a second look nephroscopy.

6 150 SEALED TUBELESS PERCUTANEOUS NEPHROLITHOTOMY CONCLUSIONS The present study shows that in real-life clinical practice 96% of patients undergoing PCNL would be eligible for a tubeless procedure in which the percutaneous tract is sealed with TachoSil and urine is drained overnight by a mono-j ureteral catheter. TachoSil sealed tubeless PCNL does not reduce pain and analgesic requirements, but it significantly reduces urinary leakage and postoperative hospital stay, fully covering this agent that costs 300 more than a NT. Further studies are needed to determine whether TachoSil could facilitate tubeless PCNL to become the new standard of care. REFERENCES 1. Türk C, Knoll T, Petrik A et al: Guidelines on Urolithiasis. Arnhem, The Netherlands: European Association of Urology Wickham JE, Miller RA, Kellett MJ et al: Percutaneous nephrolithotomy: one stage or two? Br J Urol 1984; 56: Bellman GC, Davidoff R, Candela J et al: Tubeless percutaneous renal surgery. 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