Machine perfusion and the prevention of ischemic type biliary lesions following liver transplant: What is the evidence?

Table 1 Clinical studies assessing the impact of abdominal normothermic regional perfusion on ischemic type biliary lesions after liver transplantation

Ref.	Study design	Groups (n)	Control group	NRP protocol and viability criteria	Definition of ITBL	Follow up	ITBL in intervention (DCD NRP)	ITBL in control (DCD)	ITBL in control (DBD)
Schurink et al[42], 2022	Cohort	NRP1 (20) vs DCD (49) vs DBD (81)	DCD/DBD	Dutch protocol2	Symptomatic radiologically NAS without the presence of a HAT	Median-NRP 23 mo, DCD25 mo and DBD 26 mo	1/15 (7%); 1/5 (20%)3	8/30 (26%)	6/78 (7%)
Mohkam et al[45], 2022	Cohort	NRP (157) vs NMP (34)	DCD	France protocol4	NAS that were unrelated to any hepatic artery complications	Median-NRP 22 mo; NMP 24 mo	2/68 (2.9%)5	3/34 (8.8%)5	NA
Gaurav et al[44], 2022	Cohort	NRP (69) vs NMP (67) vs SCS (97)	DCD	United Kingdom protocol6	Presence of any biliary stricture, dilatation, or irregularity of the intra- or extrahepatic bile ducts and/or cast on MRCP away from the biliary anastomosis in the presence of patent arterial vasculature	Median-54 mo (SCS), 28 mo (NRP) and 24 mo (NMP)	0/69 (0%)7	7/67 (11%)7 NMP and 12/97 (14%)7 SCS	NA
Hessheimer et al[34], 2022	Cohort	NRP (545) vs SRR (258)	DCD	Spain protocol8	Patient with patent hepatic artery, signs or symptoms of cholestasis, and direct or indirect cholangiographic imaging reflecting strictures of the intra- and/or extrahepatic biliary tree proximal to the transplant anastomosis	Median–31 mo	6/545 (1%)	24/258 (9%)	NA
Ruiz et al[40], 2021	Cohort	NRP (100) vs DBD (200)	DBD	Spain protocol8	Non-anastomotic biliary stricture in the presence of a patent hepatic artery and confirmed based on cholangiographic evidence (T-tube cholangiogram or magnetic resonance)	Mean-36 mo	0/100 (0%)	NA	0/200 (0%)
Muñoz et al[36], 2020	Cohort	NRP (23) vs SRR (22)	DCD	Spain protocol8	NR	Mean-33.9 mo (SRR) and 14.2 mo (NRP)	0/23 (0%)	3/22 (13.6%)	NA
Savier et al[31], 2020	Cohort	NRP (50) vs DBD (100)	DBD	France protocol4	Presence of any disseminated biliary stricture on magnetic resonance and endoscopic retrograde cholangiopancreatography, regardless of the presence or absence of arterial thrombosis or stenosis	Mean-34.8 mo (cDCD NRP) and 51.7 mo (DBD)	1/50 (2%)	NA	1/100 (1%)
Miñambres et al[35], 2020	Cohort	NRP (16) vs DBD (29)	DBD	Spain protocol8	NR	Median-6 mo (cDCD) and 16 mo (DBD)	0/16 (0%)	NA	0/29 (0%)
De carlis et al[43], 2021	Cohort	DCD NRP + D-HOPE (37) vs DCD SRR SCS (37)	DCD	Italy protocol9	Cholangiographic evidence of diffuse intrahepatic, hilar, or extrahepatic biliary strictures in the presence of a patent hepatic artery. Isolated anastomotic strictures were excluded from IC	Median-17 mo (NRP + D-HOPE) and all transplants were followed at least 1 yr	1/37 (3%)	3/37 (8%)	NA
Muller et al[37], 2020	Cohort	NRP (132) vs HOPE (93)	DCD	France protocol4	NAS was defined as either multifocal, unifocal intrahepatic, or hilar strictures with or without the presence of concomitant HAT or arterial complications. NAS was detected clinically and confirmed by magnetic resonance cholangiography	Median-20 mo (NRP) and 28 mo (HOPE)	2/32 (6.3%)5	4/32 (12.5%)5	NA
Hessheimer et al[41], 2019	Cohort	NRP (95) vs SRR (117)	DCD	Spain protocol8	Cholestasis and confirmed based on cholangiographic evidence (typically coming from magnetic resonance cholangiopancreatography) of diffuse non-anastomotic biliary strictures, with or without prestenotic dilatations, in the presence of a patent hepatic artery	Median-20 mo	2/95 (2%)	15/117 (13%)	NA
Rodríguez-Sanjuán et al[39], 2019	Cohort	NRP (11) vs DBD (51)	DBD	Spain protocol8	Diffuse stenosis of the intrahepatic biliary tree–suspected by jaundice, cholangitis, abnormal biochemical liver test, or abnormal findings on ultrasound or T-tube cholangiography- provided there is no hepatic artery thrombosis	Ranges between 7-27 mo. Minimum follow-up of 3 mo	2/11 (13.3%)	NA	13/51 (27.7%)
Watson et al[33], 2019	Cohort	NRP (43) vs SRR (187)	DCD	United Kingdom protocol6	Presence of any non-anastomotic biliary stricture on ERCP or MRCP in the absence of arterial thrombosis or stenosis	Up to 5 yr of follow-up	0/42 (0%)	47/171 (27%)	NA
De Carlis et al[38], 2018	Cohort	NRP (20) vs DBD ECMO SCS (17) vs DBD non-ECMO SCS (52)	DBD-ECMO DBD-non-ECMO	Italy protocol9	Strictures, irregularities, or dilatations of the intrahepatic bile duct. Isolated anastomotic biliary strictures were not included in the definition of IC. The diagnosis of IC was confirmed with at least 1 adequate imaging study of the biliary tree, and concomitant hepatic artery thrombosis was excluded by Doppler ultrasound or computed tomography	Median-14 mo (cDCD), 20 mo (DBD-ECMO) and 17 mo (DBD-non-ECMO)	2/20 (10%)	NA	DBD-ECMO 0/17 0%; DBD-non-ECMO 2/52 (4%)

¹For logistic reasons, 5 patients received additional consecutive dual hypothermic machine perfusion (DHOPE) anticipating a longer cold ischemia time (CIT) due to difficulties in recipient hepatectomy.

²Viability criteria used: Assessment 60 min of perfusion, with stable alanine transaminase (ALT) levels < 200 U/L, a plasma glucose peak > 10 mmol/L, and decreasing lactate level, around < 5 mmol/L. Adequate bile quality was defined as a pH > 7.45 and glucose < 3.0 mmol/L. Macroscopy of the liver did not influence. Postmortem cannulation. 5 No touch period. No antemortem interventions are allowed in Netherlands.

³Normothermic Regional Perfusion (NRP) + DHOPE patients.

⁴Viability criteria used: (1) serum ALT < 1000 IU/L at the end of NRP; (2) macroscopic appearance; (3) decrease in lactate levels; and (4) presence of macrosteatosis < 30% or fibrosis Ishak score < 2; Ante mortem cannulation not allowed but identification of femoral vessels to facilitate cannulation is permitted; No touch period: 5 min; Ante mortem substances administration allowed.

⁵After propensity score matching.

⁶Viability criteria used: (1) ALT levels stabilized between the first and second hour; and (2) macroscopic appearance. Ante mortem cannulation not allowed; No touch period: 5 min; Ante mortem substances administration not allowed.

⁷Clinically significant nonanastamotic biliary strictures defined as strictures requiring endoscopic or/and surgical intervention.

⁸Viability criteria used: (1) Baseline aspartate aminotransferase (AST) and ALT < 3-4 times normal value and/or AST and ALT < 4-5 times normal value at the end of NRP; and (2) macroscopic appearance; Ante mortem cannulation allowed; No touch period: 5 min; Ante mortem substances administration allowed.

⁹Viability criteria used: (1) AST and ALT > 200 IU/L; (2) macrosteatosis < 20%; and (3) More than 60 min of NRP; Ante mortem cannulation not allowed but identification of femoral vessels to facilitate cannulation is permitted; No touch period: 20 min; Ante mortem substances administration allowed.

BS: Biliary strictures; DBD: Donor after Brain Death; DCD: Donated after circulatory death; ERCP: Endoscopic retrograde cholangiopancreatography; HA: Hepatic artery; HAT: Hepatic artery thrombosis; ITBL: Ischemic type biliary lesions; MRCP: Magnetic resonance cholangiopancreatography; NAS: Nonanastamotic biliary strictures; NR: Not reported; NRP: Normothermic Regional Perfusion; SRR: Super rapid retrieval technique.