title: A metabolic index of ischemic injury for perfusion-recovery of cadaveric rat livers.
abstract: With over 110,000 patients waiting for organ transplantation, the current crisis in organ transplantation is based on a lack of donors after brain-death (DBD). A very large alternative pool of donor organs that remain untapped are the donors after cardiac death (DCD), recovered after cardiac activity has ceased and therefore sustained some ischemic injury. Machine perfusion has been proposed as a novel modality of organ preservation and treatment to render such cadaveric organs, and in particular livers, transplantable. Two key issues that remain unaddressed are how to assess whether a DCD liver is damaged beyond repair, and whether machine perfusion has rendered an injured organ sufficiently viable for transplantation. In this work, we present a metabolic analysis of the transient responses of cadaveric rat livers during normothermic machine perfusion (NMP), and develop an index of ischemia that enables evaluation of the organ ischemic injury level. Further, we perform a discriminant analysis to construct a classification algorithm with >0.98 specificity to identify whether a given perfused liver is ischemic or fresh, in effect a precursor for an index of transplantability and a basis for the use of statistical process control measures for automated feedback control of treatment of ischemic injury in DCD livers. The analyses yield an index based on squared prediction error (SPE) as log(SPE) >1.35 indicating ischemia. The differences between metabolic functions of fresh and ischemic livers during perfusion are outlined and the metabolites that varied significantly for ischemic livers are identified as ornithine, arginine, albumin and tyrosine.
authors.affiliation: Center for Engineering in Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Sinem
authors.initials: S
authors.lastname: Perk
authors.forename: Maria-Louisa
authors.initials: ML
authors.lastname: Izamis
authors.forename: Herman
authors.initials: H
authors.lastname: Tolboom
authors.forename: Basak
authors.initials: B
authors.lastname: Uygun
authors.forename: Francois
authors.initials: F
authors.lastname: Berthiaume
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
authors.forename: Korkut
authors.initials: K
authors.lastname: Uygun
mesh_terms: D000818:Animals; D002102:Cadaver; D016002:Discriminant Analysis; D006801:Humans; D066298:In Vitro Techniques; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D016018:Least-Squares Analysis; D008099:Liver / Q000098:blood supply* / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D010477:Perfusion; D025341:Principal Component Analysis; D051381:Rats; D011917:Rats, Inbred Lew; D015203:Reproducibility of Results; D052096:Warm Ischemia