Impact of Portable Normothermic Blood-Based Machine Perfusion on Outcomes of Liver Transplant: The OCS Liver PROTECT Randomized Clinical Trial

Abstract

Importance: Ischemic cold storage (ICS) of livers for transplant is associated with serious posttransplant complications and underuse of liver allografts.

Objective: To determine whether portable normothermic machine perfusion preservation of livers obtained from deceased donors using the Organ Care System (OCS) Liver ameliorates early allograft dysfunction (EAD) and ischemic biliary complications (IBCs).

Design, setting, and participants: This multicenter randomized clinical trial (International Randomized Trial to Evaluate the Effectiveness of the Portable Organ Care System Liver for Preserving and Assessing Donor Livers for Transplantation) was conducted between November 2016 and October 2019 at 20 US liver transplant programs. The trial compared outcomes for 300 recipients of livers preserved using either OCS (n = 153) or ICS (n = 147). Participants were actively listed for liver transplant on the United Network of Organ Sharing national waiting list.

Interventions: Transplants were performed for recipients randomly assigned to receive donor livers preserved by either conventional ICS or the OCS Liver initiated at the donor hospital.

Main outcomes and measures: The primary effectiveness end point was incidence of EAD. Secondary end points included OCS Liver ex vivo assessment capability of donor allografts, extent of reperfusion syndrome, incidence of IBC at 6 and 12 months, and overall recipient survival after transplant. The primary safety end point was the number of liver graft-related severe adverse events within 30 days after transplant.

Results: Of 293 patients in the per-protocol population, the primary analysis population for effectiveness, 151 were in the OCS Liver group (mean [SD] age, 57.1 [10.3] years; 102 [67%] men), and 142 were in the ICS group (mean SD age, 58.6 [10.0] years; 100 [68%] men). The primary effectiveness end point was met by a significant decrease in EAD (27 of 150 [18%] vs 44 of 141 [31%]; P = .01). The OCS Liver preserved livers had significant reduction in histopathologic evidence of ischemia-reperfusion injury after reperfusion (eg, less moderate to severe lobular inflammation: 9 of 150 [6%] for OCS Liver vs 18 of 141 [13%] for ICS; P = .004). The OCS Liver resulted in significantly higher use of livers from donors after cardiac death (28 of 55 [51%] for the OCS Liver vs 13 of 51 [26%] for ICS; P = .007). The OCS Liver was also associated with significant reduction in incidence of IBC 6 months (1.3% vs 8.5%; P = .02) and 12 months (2.6% vs 9.9%; P = .02) after transplant.

Conclusions and relevance: This multicenter randomized clinical trial provides the first indication, to our knowledge, that normothermic machine perfusion preservation of deceased donor livers reduces both posttransplant EAD and IBC. Use of the OCS Liver also resulted in increased use of livers from donors after cardiac death. Together these findings indicate that OCS Liver preservation is associated with superior posttransplant outcomes and increased donor liver use.

Trial registration: ClinicalTrials.gov Identifier: NCT02522871.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Bhati reported receiving personal fees from Intuitive Surgical outside the submitted work. Dr Pelletier reported receiving funding from Organ Recovery Systems outside the submitted work. Dr Lu reported receiving nonfinancial support from Tampa General Hospital during the conduct of the study. Dr Saharia reported receiving nonfinancial support from Houston Methodist Hospital during the conduct of the study. Dr Cigarroa reported receiving financial compensation from the Ford Foundation, Capital Group, Kleberg Foundation, and Clayton Foundation for Biomedical Research outside the submitted work. Dr MacConmara reported becoming employed by TransMedics after completion of the OCS Liver PROTECT randomized clinical trial and submission of the final manuscript. No other disclosures were reported.

Figures

Figure 1.. Organ Care System (OCS) Liver Components

A, The OCS Liver is primed with buffered electrolyte solution, albumin, 4 to 5 units of packed red blood cells, and broad-spectrum antibiotics. Perfusion gradually increased to 2.0 to 2.5 L total flow, and temperature was set at 34 °C. The perfusate was supplemented with continuous infusion of a nutrient solution of 4% amino acids and 10% dextrose, supplemented with insulin and multivitamins. Liver perfusion hemodynamic parameters were monitored continuously and recorded throughout preservation. Serial blood gases and lactate levels were measured throughout preservation, and changes in lactate level were used to measure adequacy of perfusion. B, Donor livers that were transplanted vs clinically turned down based on OCS Liver assessment of lactate levels. Error bars represent SD.

Figure 2.. PROTECT Trial Consolidated Standards of Reporting Trials Diagram

ICS indicates ischemic cold storage; OCS, Organ Care System; Tx, transplant. aSome patients had more than 1 randomization event when the prior donor liver was unsuitable for clinical use after assessment in the body and the subsequent donor liver offer met study criteria. Rerandomization was performed as detailed in eFigure 1 in Supplement 2. This rerandomization process resulted in 476 randomizations in 392 patients. bOf 130 livers (57 in the OCS Liver group and 73 in the ICS group) rejected for transplant in donor body after randomization, 42 (18 in the OCS Liver group and 24 in the ICS group) were rejected because the donor (after cardiac death) did not expire within 30 minutes; 31 (9 in the OCS Liver group and 22 in the ICS group) owing to clinical judgment at retrieval; 27 (13 in the OCS Liver group and 14 in the ICS group) owing to steatosis; 9 (3 in the OCS Liver group and 6 in the ICS group) showed cirrhosis or fibrosis; 4 (2 in the OCS Liver group and 2 in the ICS group) showed vasculature abnormalities or disease; 3 (3 in the OCS Liver group and 0 in the ICS group) owing to donor-recipient organ size mismatch; 2 (2 in the OCS Liver group and 0 in the ICS group) revealed liver or kidney malignant neoplasm during retrieval; and 12 (7 in the OCS Liver group and 5 in the ICS group) owing to reallocation, donor did not progress, or logistical reasons. cOf 43 recipients (28 in the OCS Liver group and 15 in the ICS group) treated off study after randomization using cold storage, 39 (24 in the OCS Liver group and 15 in the ICS group) were because the donor liver did not meet eligibility owing to accessory vessels, liver hematoma or required surgical vascular repair; and 4 (4 in the OCS Liver group and 0 in the ICS group) were because of logistic reasons, including donor family did not consent to research (Organ Procurement Organization requirement), preretrieval liver biopsy could not be obtained; Organ Procurement Organization delayed operating room time, resulting in trained trial retrieval team being off call; and recipient deterioration with renal insufficiency on day of transplant. dOf 3 livers from donors after cardiac death that were rejected for use after OCS Liver assessment, 2 were rejected because of increasing lactate levels despite maximizing OCS Liver perfusion parameters; and 1 because donor liver preretrieval biopsy revealed extensive bridging fibrosis.

Figure 3.. PROTECT Trial Primary Effectiveness End Point (Incidence of Early Allograft Dysfunction [EAD]), Posttransplant Pathology Assessment (Incidence of Liver Lobular Inflammation), Posttransplant Histology Representative Specimens of Moderate to Severe Lobular Inflammation, and PROTECT Trial Incidence of Ischemic Biliary Complications Within 12 Months After Transplant

A, Clopper-Pearson exact CI for a binomial percentage, with 95% 1-sided upper confidence bound based on the Farrington-Manning score statistic. The noninferiority P values are based on the 1-sided Farrington-Manning score statistic, testing the null hypothesis that the true Organ Care System (OCS) Liver proportion is greater than or equal to the true ischemic cold storage (ICS) proportion δ = 0.075 vs the alternative hypothesis that it is less than the true ICS proportion plus 0.075. The superiority P values are from a 2-sided Fisher exact test, testing the null hypothesis that the true difference in proportions equals 0 vs the alternative hypothesis that it does not equal 0. This analysis was conducted only if the null hypothesis of inferiority was rejected. Error bars represent 95% CIs. B, The P value was determined using the χ2 test. C, Histologic specimens showing examples of severe lobular inflammation in a control ICS (left) liver after reperfusion, with inset showing minimal portal inflammation, and an OCS Liver–treated liver (right) showing absence of lobular inflammation and minimal portal inflammation (inset). The asterisk indicates the location of the portal tract (PT). D, Ischemic biliary complications, defined as nonanastomotic ischemic strictures or bile leaks, confirmed with an endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography radiologic examination.

Figure 4.. Effect of Early Allograft Dysfunction (EAD) in the Per-Protocol Population on Graft Survival Probability and on Posttransplant Intensive Care Unit (ICU) Stay and Overall Hospital Stay

Error bars represent 95% CI.