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The aim of this study was to assess the incidence, natural history, and risk factors of hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) with the new polytetrafluoroethylene (PTFE)-covered stent grafts in cirrhotic patients.Seventy-eight cirrhotic patients treated by TIPS with PTFE-covered stent grafts and followed by the same medical team—according to a prospective protocol for diagnostic workup and surveillance strategy—were reviewed. The follow-up was 19.9 ± 20.6 months.At least one episode of HE occurred in 35 of 78 (44.8%) patients. The probability of remaining free of HE was 53.8% (95% confidence interval [CI] 41.4–66.2] at 1 yr and 50.9% at 2 yr (95% CI 38.2–63.8%). The total number of HE episodes was 89. Fifty-five percent of the episodes were grades III–IV. The occurrence of HE tended to be constant during the follow-up, probably because of the very low incidence of shunt dysfunction (13.6% at 2 yr). Moreover, in six patients, a refractory HE required the reduction of the shunt diameter. One patient died due to variceal bleeding after this procedure. At a multivariate analysis, an older age, high creatinine levels, and low serum sodium and low albumin values were shown to be independent factors for the occurrence of HE. Serum creatinine level was the only variable related to the development of refractory HE at the logistic multivariate analysis.HE after TIPS with PTFE-covered stent grafts is frequent; its incidence is not confined to the first post-TIPS period, but it has the tendency to be frequent over time. Refractory HE occurred in 8% of patients and may be successfully managed by reducing the stent diameter. The selection of patients undergoing TIPS placement should be very accurate, especially for those subjects with abnormal creatinine level.