Department of Surgery, Swiss Hepatopancreatobiliary and Transplantation Center, University Hospital Zurich, Switzerland.
Wyss Zurich - ETH Zurich/University of Zurich, Zurich, Switzerland.
Surgery. 2021 Apr;169(4):894-902. doi: 10.1016/j.surg.2020.11.042. Epub 2021 Jan 6.
Long-term ex situ liver perfusion may rescue injured grafts. Little is known about bile flow during long-term perfusion. We report the development of a bile stimulation protocol and motivate bile flow as a viability marker during long-term ex situ liver perfusion.
Porcine and human livers were perfused with blood at close to physiologic conditions. Our perfusion protocol was established during phase 1 with porcine livers (n = 23). Taurocholic acid was applied to stimulate bile flow. The addition of piperacillin-tazobactam (tazobac) and methylprednisolone was modified from daily bolus to controlled continuous application. We adapted the protocol to human livers (n = 12) during phase 2. Taurocholic acid was replaced with medical grade ursodeoxycholic acid.
Phase 2: Despite administering taurocholic acid, bile flow declined from 29.3 ± 6.5 to 9.3 ± 1.4 mL/h (P < .001). Shortly after bolus of tazobac/methylprednisolone, bile flow recovered to 39.0 ± 9.7 mL/h with a decrease of solid bile components. This implied bile salt independent bile flow stimulation by tazobac/methylprednisolone. Phase 2: Ursodeoxycholic acid was shown to stimulate bile flow ex situ in human livers. Eight livers were perfused successfully for 1 week with continuous bile flow. The other 4 livers demonstrated progressive cell death, of which only 1 exhibited bile flow.
A lack of bile flow stimulation leads to a decline in bile flow and is not necessarily a sign of deterioration in liver function. Proper administration of stimulators can induce constant bile flow during ex situ liver perfusion for up to 1 week. Medical grade ursodeoxycholic acid is a suitable replacement for nonmedical grade taurocholic acid. The presence of bile flow alone is not sufficient to assess liver viability.
长期的离体肝脏灌注可以挽救受损的移植物。对于长期灌注过程中的胆汁流量知之甚少。我们报告了一种胆汁刺激方案的发展，并将胆汁流量作为长期离体肝脏灌注过程中存活的标志物。
用接近生理条件的血液对猪和人肝脏进行灌注。我们的灌注方案是在第一阶段使用猪肝脏（n=23）建立的。应用牛磺胆酸刺激胆汁流量。哌拉西林他唑巴坦（他唑巴坦）和甲基强的松龙的添加方式从每日推注改为连续控制应用。在第二阶段，我们将方案应用于人肝脏（n=12）。用医用级熊去氧胆酸代替牛磺胆酸。
第二阶段：尽管给予牛磺胆酸，但胆汁流量从 29.3±6.5 降至 9.3±1.4 mL/h（P<0.001）。在他唑巴坦/甲基强的松龙推注后不久，胆汁流量恢复至 39.0±9.7 mL/h，固体胆汁成分减少。这意味着他唑巴坦/甲基强的松龙通过胆汁盐独立刺激胆汁流量。第二阶段：熊去氧胆酸在人肝脏中被证明可以离体刺激胆汁流量。8 个肝脏成功灌注 1 周，持续有胆汁流出。另外 4 个肝脏显示出进行性细胞死亡，其中只有 1 个有胆汁流出。
缺乏胆汁流量刺激会导致胆汁流量下降，不一定是肝功能恶化的迹象。适当给予刺激物可以在离体肝脏灌注过程中诱导持续的胆汁流量长达 1 周。医用级熊去氧胆酸是替代非医用级牛磺胆酸的合适选择。仅存在胆汁流量本身不足以评估肝脏的存活能力。
