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Background: The use of a transjugular intrahepatic portosystemic shunt (TIPS) has been established as an effective treatment for portal hypertension. Despite the rapid development of this use, serious peri-procedural complications have been reported in over 10% of cases. This has largely been attributed to the access to the portal vein, also referred to as a “blind puncture”, which often requires multiple attempts. The aim of this study was to demonstrate the safety, reproducibility and accuracy of the use of real-time 3D fusion image-guided (3DFIG) single puncture TIPS to minimize the complications that are related to the “blind puncture” of TIPS procedures. Methods: A 3DFIG TIPS approach was utilized on 22 pigs by combining pre-procedural cross-sectional imaging (CT, MR or CBCT) with intra-procedural cone beam CT or angiogram imaging, which allowed for the improved 3D visual spatial orientation of the portal vein and real-time tracking of the needle in 3D. Results: Thirty-five portosystemic shunts were successfully deployed in all 22 subjects without any peri-procedural complications. Overall, 91% (32/35) of the procedures were carried out using a single puncture. In addition, the mean fluoroscopy time in our study was more than 12 times lower than the proposed reference level that has previously been proposed for TIPS procedures. Conclusion: Multi-modality real-time 3DFIG TIPS can be performed safely using a single puncture, without complications, and can potentially be used in both emergency and non-emergency clinical situations. Full article