Methaemoglobinaemia Can Complicate Normothermic Machine Perfusion of Human Livers

Tingle, Samuel J; Ibrahim, Ibrahim; Thompson, Emily; Bates, Lucy; Sivaharan, Ashwin; Bury, Yvonne; Figuereido, R

doi:10.3389/fsurg.2021.634777

Cited by 4 publications

(6 citation statements)

References 12 publications

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“…Severe methaemoglobinaemia is a progressive complication of extended NMP. This has previously been reported in shorter clinical perfusions, most notably in suboptimal donors, and is thought to be a universal complication during NMP 11 . We encountered this problem during our development of a 5-days NMP model, where initial perfusions demonstrated universal accumulation of methaemoglobin beyond 48-h perfusions, with subsequent sharp rise in levels.…”

Section: Discussionsupporting

confidence: 52%

“…In the context of extended NMP the formation of methaemoglobinaemia has already been reported 11 . Its presence is especially notable in suboptimal or marginal organs and its insidious production can lead to impaired oxygen delivery and possible failure.…”

Section: Introductionmentioning

confidence: 97%

“…Its presence is especially notable in suboptimal or marginal organs and its insidious production can lead to impaired oxygen delivery and possible failure. Methylene blue, first line treatment in a clinical situation, has been demonstrated ineffective in reducing perfusion-associated methaemoglobinaemia and currently there is no established intervention to address this problem during NMP 11 .…”

Section: Introductionmentioning

confidence: 99%

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N-acetylcysteine: a novel approach to methaemoglobinaemia in normothermic liver machine perfusion

Clarke,

Mao,

Fan

et al. 2023

Sci Rep

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Extended duration of normothermic machine perfusion (NMP) provides opportunities to resuscitate suboptimal donor livers. This intervention requires adequate oxygen delivery typically provided by a blood-based perfusion solution. Methaemoglobin (MetHb) results from the oxidation of iron within haemoglobin and represents a serious problem in perfusions lasting > 24 h. We explored the effects of anti-oxidant, N-acetylcysteine (NAC) on the accumulation of methaemoglobin. NMP was performed on nine human donor livers declined for transplantation: three were perfused without NAC (no-NAC group), and six organs perfused with an initial NAC bolus, followed by continuous infusion (NAC group), with hourly methaemoglobin perfusate measurements. In-vitro experiments examined the impact of NAC (3 mg) on red cells (30 ml) in the absence of liver tissue. The no-NAC group sustained perfusions for an average of 96 (range 87–102) h, universally developing methaemoglobinaemia (≥ 2%) observed after an average of 45 h, with subsequent steep rise. The NAC group was perfused for an average of 148 (range 90–184) h. Only 2 livers developed methaemoglobinaemia (peak MetHb of 6%), with an average onset of 116.5 h. Addition of NAC efficiently limits formation and accumulation of methaemoglobin during NMP, and allows the significant extension of perfusion duration.

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Section: Discussionsupporting

confidence: 52%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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N-acetylcysteine: a novel approach to methaemoglobinaemia in normothermic liver machine perfusion

Clarke,

Mao,

Fan

et al. 2023

Sci Rep

View full text Add to dashboard Cite

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“…Whether porcine blood is more prone to methemoglobin formation, the additional cellular stress arising from exposure to the artificial components of the ex vivo circuit likely further contributed to its development [ 35 ]. Supporting this is the observation of methemoglobinemia developing after extended perfusion of discarded human livers [ 36 ].…”

Section: Discussionmentioning

confidence: 96%

Model of Acute Liver Failure in an Isolated Perfused Porcine Liver—Challenges and Lessons Learned

et al. 2022

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Acute liver failure (ALF) is a rare but devastating disease associated with substantial morbidity and a mortality rate of almost 45%. Medical treatments, apart from supportive care, are limited and liver transplantation may be the only rescue option. Large animal models, which most closely represent human disease, can be logistically and technically cumbersome, expensive and pose ethical challenges. The development of isolated organ perfusion technologies, originally intended for preservation before transplantation, offers a new platform for experimental models of liver disease, such as ALF. In this study, female domestic swine underwent hepatectomy, followed by perfusion of the isolated liver on a normothermic machine perfusion device. Five control livers were perfused for 24 h at 37 °C, while receiving supplemental oxygen and nutrition. Six livers received toxic doses of acetaminophen given over 12 h, titrated to methemoglobin levels. Perfusate was sampled every 4 h for measurement of biochemical markers of injury (e.g., aspartate aminotransferase [AST], alanine aminotransferase [ALT]). Liver biopsies were taken at the beginning, middle, and end of perfusion for histological assessment. Acetaminophen-treated livers received a median dose of 8.93 g (8.21–9.75 g) of acetaminophen, achieving a peak acetaminophen level of 3780 µmol/L (3189–3913 µmol/L). Peak values of ALT (76 vs. 105 U/L; p = 0.429) and AST (3576 vs. 4712 U/L; p = 0.429) were not significantly different between groups. However, by the end of perfusion, histology scores were significantly worse in the acetaminophen treated group (p = 0.016). All acetaminophen treated livers developed significant methemoglobinemia, with a peak methemoglobin level of 19.3%, compared to 2.0% for control livers (p = 0.004). The development of a model of ALF in the ex vivo setting was confounded by the development of toxic methemoglobinemia. Further attempts using alternative agents or dosing strategies may be warranted to explore this setting as a model of liver disease.

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“…Evolving trends suggest different interpretation of single liver function tests. In this setting, machine perfusion is recognized as one of the most significant improvements in the field of transplantation over the past 20 years ( 15 , 22 ). This development and the need for reliable and robust endpoints for clinical trials puts further emphasis on the necessity to refine the definition for EAD.…”

Section: Discussionmentioning

confidence: 99%

Reassessment of Relevance and Predictive Value of Parameters Indicating Early Graft Dysfunction in Liver Transplantation: AST Is a Weak, but Bilirubin and INR Strong Predictors of Mortality

et al. 2021

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Introduction: Early graft dysfunction (EAD) complicates liver transplantation (LT). The aim of this analysis was to discriminate between the weight of each variable as for its predictive value toward patient and graft survival.Methods: We reviewed all LT performed at the Medical University of Innsbruck between 2007 and 2018. EAD was recorded when one of the following criteria was present: (i) aspartate aminotransferase (AST) levels >2,000 IU/L within the first 7 days, (ii) bilirubin levels ≥10mg/dL or (iii) international normalized ratio (INR) ≥1.6 on postoperative day 7.Results: Of 616 LT, 30.7% developed EAD. Patient survival did not differ significantly (P = 0.092; log rank-test = 2.87), graft survival was significantly higher in non-EAD patients (P = 0.008; log rank-test = 7.13). Bilirubin and INR on postoperative day 7 were identified as strong mortality predictors (Bilirubin HR = 1.71 [1.34, 2.16]; INR HR = 2.69 [0.51, 14.31]), in contrast to AST (HR = 0.91 [0.75, 1.10]). Similar results were achieved for graft loss estimation. A comparison with the Model for Early Allograft Function (MEAF) and the Liver Graft Assessment Following Transplantation (L-GrAFT) score identified a superior discrimination potential but lower specificity.Conclusion: Contrarily to AST, bilirubin and INR have strong predictive capacity for patient and graft survival. This fits well with the understanding, that bile duct injury and deprivation of synthetic function rather than hepatocyte injury are key factors in LT.

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Methaemoglobinaemia Can Complicate Normothermic Machine Perfusion of Human Livers

Cited by 4 publications

References 12 publications

N-acetylcysteine: a novel approach to methaemoglobinaemia in normothermic liver machine perfusion

N-acetylcysteine: a novel approach to methaemoglobinaemia in normothermic liver machine perfusion

Model of Acute Liver Failure in an Isolated Perfused Porcine Liver—Challenges and Lessons Learned

Reassessment of Relevance and Predictive Value of Parameters Indicating Early Graft Dysfunction in Liver Transplantation: AST Is a Weak, but Bilirubin and INR Strong Predictors of Mortality

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