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Background Endoscopic therapy of walled-off pancreatic necrosis (WOPN) via direct intracavitary debridement is described. Objective To compare direct endoscopic necrosectomy with conventional transmural endoscopic drainage for the treatment of WOPN. Design Retrospective, comparative study. Setting Academic tertiary-care center. Patients Patients referred to Mayo Clinic, Rochester, Minnesota, since April 1998 for endoscopic drainage of WOPN. Interventions Each patient underwent standard endoscopic drainage that consisted of transmural cavity puncture, dilation of the fistula tract, and placement of a large-bore stent(s). Patients were classified into the direct endoscopic necrosectomy group if, during any of their procedures, adjunctive direct endoscopic necrosectomy was performed; all others were in the standard drainage group. Main Outcome Measurements Success was defined as resolution of the necrotic cavity without the need for operative or percutaneous intervention. Results Forty-five patients were identified who met study criteria: 25 underwent direct endoscopic necrosectomy, and 20 underwent standard endoscopic drainage. There were no differences in baseline patient or cavity characteristics. Successful resolution was accomplished in 88% who underwent direct endoscopic necrosectomy versus 45% who received standard drainage ( P < .01), without a change in the total number of procedures. The maximum size of tract dilation was larger in the direct endoscopic necrosectomy group (17 mm vs 14 mm, P < .02). Complications were limited to mild periprocedural bleeding with equivalent rates between groups. Limitations Retrospective, referral bias, single center. Conclusions Direct endoscopic necrosectomy achieves higher rates of resolution, without a concomitant change in the number of endoscopic procedures, complication rate, or time to resolution compared with standard endoscopic drainage for WOPN. The need for fewer postprocedural inpatient hospital days and a decrease in the rate of cavity recurrence are also likely benefits of this technique.