LIVER TRANSPLANTATION 20:63–71, 2014
ORIGINAL ARTICLE
Increasing the Donor Pool: Consideration of Prehospital Cardiac Arrest in Controlled Donation After Circulatory Death for Liver Transplantation Ahmed H. Elaffandi, Glenn K. Bonney, Bridget Gunson, Irene Scalera, Hynek Mergental, John R. Isaac, Simon R. Bramhall, Darius F. Mirza, M. Thamara P.R. Perera, Paolo Muiesan Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
Donor warm ischemia has implications for outcomes after liver transplantation (LT) using organs from donation after circulatory death (DCD) donors. Prehospital cardiac arrest (PHCA) before donation may generate a further ischemic insult. The aim of this single-center study of 108 consecutive DCD LT procedures was to compare the outcomes of PHCA and nonPHCA cohorts. A review of a prospectively collected database of all DCD grafts transplanted between January 2007 and October 2011 was undertaken to identify donors who had sustained PHCA. The unit policy was to consider such donors when transaminase levels were 4 times the normal range and had an improving trend. Twenty-six of the 108 DCD transplants were from DCD donors with PHCA, and 82 were in the non-PHCA cohort. A comparative analysis of the PHCA and non-PHCA cohorts showed better short-term results (a low incidence of acute kidney injury) for the PHCA group but satisfactory long-term results for both groups with no significant differences in graft or patient survival between them. In conclusion, a careful donor selection policy for including PHCA DCD donors with normalized liver function tests or transaminase levels 4 times the norm resulted in successful transplantation and could boost the donor pool with no adverse outcomes. C 2013 AASLD. Liver Transpl 20:63-71, 2014. V Received July 4, 2013; accepted October 1, 2013. The United Kingdom has seen a sustained rise in the number of patients on the liver transplantation (LT) waiting list. This has been met in recent years with the increased use of donation after circulatory death (DCD) grafts.1 According to the currently accepted guidelines recommended by the Institute of Medicine2 and the British Transplantation Society,3 organ donation can proceed after at least 5 minutes of asystole following the withdrawal of treatment. The warm ischemia insult linked to DCD donors (Maastricht category III) is associated with specific early and late
posttransplant complications in comparison with donation after brain death (DBD) grafts.4 Both hemodynamic instability and hypoxemia in DCD organs contribute to the donor warm ischemia time (DWIT), which may result in an increased rate of complications after DCD LT.5 The careful selection of DCD donor and recipient combinations is crucial for maintaining an overall benefit and excellent results in comparison with DBD grafts after LT.6 Currently, a DWIT greater than 30 minutes is considered a relative contraindication to transplantation.7
Abbreviations: AKI, acute kidney injury; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CIT, cold ischemia time; DBD, donation after brain death; DCD, donation after circulatory death; DWIT, donor warm ischemia time; GGT, gamma-glutamyltransferase; ITBL, ischemic-type biliary lesion; ITU, intensive treatment unit; LFT, liver function test; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; PHCA, prehospital cardiac arrest; PNF, primary nonfunction; UKELD, UK Model for End-Stage Liver Disease. The authors have no conflict of interest to declare. Address reprint requests to Paolo Muiesan, MD, FEBS, FRCS, Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom. E-mail: [email protected] Tel: 144 (0) 121 627 2418 DOI 10.1002/lt.23772 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2013 American Association for the Study of Liver Diseases. V
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However, even before donation, a proportion of DCD grafts will have sustained an initial ischemic insult810 because of prehospital cardiac arrest (PHCA). The duration of PHCA may have profound implications for the potential quality of a DCD organ, and it generates an additional ischemic insult to the liver graft. At several centers, PHCA is considered a relative contraindication for DCD liver donation and transplantation: 46% of the PHCA DCD grafts accepted by us were rejected by other transplant units because of PHCA before they were used by our unit. To date, the issue of PHCA in DCD donors and its implications for LT outcomes have not yet been reported. The aim of this study was to describe the process of donor selection, including donors with abnormal liver function tests (LFTs), at a single, large-volume center in the United Kingdom and the outcomes for recipients of grafts from DCD donors who had experienced PHCA; this may have a positive influence on the DCD donation pool.
PATIENTS AND METHODS Study Design Using a prospectively maintained database from the Liver Unit of Queen Elizabeth Hospital (Birmingham, United Kingdom), we undertook a retrospective analysis of all sequential DCD LT procedures performed between January 1, 2007 and October 1, 2011. The study protocol received a priori approval by the institutional review committee. Additional data were obtained from National Health Service Blood and Transplant. The DCD cohort was divided into 2 groups: those who had sustained PHCA and those who had not. The analyzed donor details included the following: demographic criteria, cause of death, history related to the occurrence and length of PHCA, predonation biochemical results, body mass index (BMI), cold ischemia time (CIT), and DWIT. Downtime was defined as the time between witnessed PHCA and the reported start of cardiopulmonary resuscitation. The analyzed recipient variables included demographic criteria, indications for transplantation, and Model for EndStage Liver Disease (MELD) and UK Model for EndStage Liver Disease (UKELD) scores. Postoperative LFTs and coagulation studies were used as markers of early graft function. Primary nonfunction (PNF) was defined as primary graft failure within 7 days of transplantation requiring retransplantation or leading to patient death. Delayed graft function was defined as primary graft failure characterized by cholestasis within 6 months of transplantation in the absence of hepatic artery thrombosis or biliary complications also leading to retransplantation or patient death.8 The incidence of posttransplant acute kidney injury (AKI) and the need for dialysis in the first 5 days were also measured as surrogate markers of delayed graft function because of the recent evidence for a significant increase in AKI with DCD LT versus DBD LT,
LIVER TRANSPLANTATION, January 2014
which is related to the severity of the ischemia/reperfusion injury and peak transaminase levels.11 In accordance with the Acute Dialysis Quality Initiative Group, AKI was defined as an increase in the serum creatinine level greater than 2 times the baseline serum creatinine level.12 The analyzed outcomes included early graft function, AKI, posttransplant dialysis requirements, biliary complications, and long-term patient and graft survival.
Donor and Recipient Considerations The consideration of a DCD liver donor by the transplant surgeon was based on several factors, including age, BMI, cause of death, organ support, past medical history, and blood results. For donors who had sustained PHCA, donation was considered if the peak transaminase levels were no greater than 4 times the norm and the trend of liver function had been improving in the previous 6 to 12 hours. Following what was considered a relatively safe upper limit for a viable uncontrolled DCD graft after normothermic regional perfusion, we set this restriction on transaminase levels.13 At no point was the transplant team involved in the withdrawal process before donation. Circulatory death was determined by a sustained asystole, and an interval of at least 5 minutes was required before the certification of death by the attending physician in accordance with national guidelines. Generally, donors who did not proceed to asystole within an hour of treatment withdrawal or who sustained a DWIT greater than 30 minutes were not considered further for liver donation. The procurement was performed with a modification of the super-rapid technique previously described.14,15 DWIT was defined as the interval between hypotension with a systolic blood pressure < 50 mm Hg and/or desaturation < 80% (whichever came first) and the initiation of aortic perfusion. CIT was defined as the time between aortic perfusion at organ retrieval and the start of implantation (when the liver was taken out of the ice). In general, recipients expected to have a difficult explant (ie, a previous history of upper abdominal surgery, preoperative portal vein thrombosis, or retransplantation) were excluded from receiving a DCD liver graft in an attempt to minimize CIT, whereas those with less severe portal hypertension and hepatocellular carcinoma were more likely to receive DCD grafts.
Outcome Measures An analysis of peak liver function and coagulation studies during the first posttransplant week was performed for PHCA recipients; the data were compared with those for the non-PHCA group. Also, the incidence of AKI and posttransplant dialysis in the first 5 days was compared between the 2 groups. The incidence of biliary complications was also compared
LIVER TRANSPLANTATION, Vol. 20, No. 1, 2014
between the groups. All patients were followed up at the posttransplant clinic on a regular basis. Liver ultrasonography was used as the first imaging technique in case of cholestatic liver function. Patients with abnormal ultrasonography findings were further investigated with magnetic resonance cholangiopancreatography accordingly. Biliary complications were classified as anastomotic strictures, nonanastomotic strictures, or ischemic-type biliary lesions (ITBLs; defined as intrahepatic lesions in the absence of arterial complications). Overall patient survival and graft survival as well as causes of death and graft loss were described. Graft survival was timed from the transplant date to the date of retransplantation or death (whichever came first), and it was censored for the date of the end of the study period.
Statistical Analysis Categorical variables were examined with a chisquare test. A Shapiro-Wilk test for normality was performed for continuous variables, and subsequently, a Mann-Whitney U test and a Student t test were performed for nonparametric and parametric data, respectively. Graft survival and patient survival between the groups were compared with Kaplan-Meier plots and log-rank tests. SPSS 17.0 (SPSS, Chicago, IL) was used for the statistical analysis. A P value < 0.05 was considered significant.
RESULTS
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(184-709 minutes, standard deviation 5 106 minutes), respectively. Recipients of DCD grafts had a median age of 56.1 years (range 5 21-70 years) and mean MELD and UKELD scores at transplantation of 14 (range 5 6-27) and 53 (range 5 39-75), respectively. Twenty-six of the potential DCD donors had previously sustained PHCA with a median downtime of 20 minutes (range 5 1-50 minutes) and a median ITU stay of 2 days (range 5 1-14 days) before organ procurement. At the time of donation, the mean alanine aminotransferase (ALT) level for DCD donors was 83 U/L. In a subgroup analysis, we divided the PHCA cohort into 2 groups: those who received grafts from donors with an ALT level 100 U/L (n 5 19) and those who received grafts from donors with an ALT level < 100 U/L (n 5 7). We found that a donor ALT level 100 U/L did not significantly affect recipient survival (P 5 0.07). The recipients’ aspartate aminotransferase (AST) levels on days 0 and 1 were 1002 U/L (range 5 35-11,850 U/L) and 1528 U/L (range 5 535-11,037 U/L), respectively. The peak LFTs after transplantation were as follows: AST, 2460 U/L (range 5 694-11,850 U/L); alkaline phosphatase (ALP), 1188 U/L (range 5 303-3128 U/L); bilirubin, 77.5 lmol/L (range 5 23-757 lmol/L); and international normalized ratio, 1.8 (range 5 1.3-5.9). In this PHCA cohort, the recipients spent an average of 3 days in the ITU after transplantation (range 5 1-16 days).
Patient and Donor Demographics
Comparative Analysis of the PHCA and Non-PHCA Cohorts
Between January 1, 2007 and October 1, 2011, livers from 95 potential DCD donors who had sustained PHCA were offered to our unit. Twenty-six of these liver offers were accepted and subsequently transplanted; the details are described later. Twelve of the 26 PHCA donors (46%) were rejected by other units before being offered to our center. For the 69 remaining potential donors, the median PHCA downtime was 42 minutes (range 5 30-60 minutes) with a median intensive treatment unit (ITU) stay of 1.5 days (range 5 0-5 days) before the offer. On these grounds, 13 of the remaining 69 offers were declined solely because of PHCA. The remaining 56 offers were declined because of the association of PHCA and other risk factors, so 1 offer could have been rejected because of multiple risk factors. Such factors included logistics (n 5 8), past medical history (n 5 17), age (n 5 13), alcohol consumption (n 5 5), BMI (n 5 7), no suitable recipients (n 5 3), abnormal LFTs (n 5 14), and others [small donor size (n 5 2), virology (n 5 1), high lactate level (n 5 1), unstable donor (n 5 1), and donor sepsis (n 5 2)]. In the same study period, DCD LT was performed 108 times at Queen Elizabeth Hospital. The median age of the DCD donors was 50 years (range 5 11-72 years), and 52% of the donors were males. The mean DWIT and CIT values were 20 minutes (7-32 minutes, standard deviation 5 8.4 minutes) and 445 minutes
The grafts from the 26 donors who had sustained PHCA were compared against the 82 non-PHCA DCD grafts. The donor and recipient variables for these 2 cohorts are tabulated in Tables 1 and 2. There were no differences in age, sex, ITU stay, or blood results before donation [AST, ALP, gammaglutamyltransferase (GGT), sodium, and bilirubin] between the 2 groups (Table 1). Apart from the donor ALT serum levels, which were significantly higher among PHCA donors (P 5 0.001), the predonation blood tests were not significantly different. It was also observed that CIT (431.8 minutes for the PHCA group versus 449.8 minutes for the non-PHCA group) and DWIT (19.2 minutes for the PHCA group versus 20.2 minutes for the non-PHCA group) had a tendency to be longer for the non-PHCA group, although this did not reach statistical significance (P 5 0.5 and P 5 0.6, respectively). Unsurprisingly, in the group that had sustained PHCA before donation, the proportion of donors who had anoxic brain injury was larger than that in the non-PHCA group (23% versus 1%), with trauma and stroke being the most common causes of death in the non-PHCA group (24% and 66%, respectively; P < 0.001). Recipient variables were similarly subcategorized into the PHCA and non-PHCA groups (Table 2). There were no differences in the recipient ages or MELD/ UKELD scores between the 2 groups. The difference
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TABLE 1. Donor Variables for the PHCA and Non-PHCA Groups Variable
PHCA Group (n 5 26)
Non-PHCA Group (n 5 82)
P Value
50.5 13
50 43
0.89 0.81
1 8 6 11 25.4 1.4
20 54 1 7 25.9 1.9
P 100 U/L did not negatively affect recipient survival (P 5 0.07). The overall cutoff for transaminases that we considered was no greater than 4 times the normal level. This was in keeping with a recent report demonstrating that select grafts from donors with high serum transaminase levels could be used for transplantation with satisfactory results.18 The donor risk index proposed by Feng et al.19 shows that organs from donors who have suffered trauma have better long-term outcomes after transplantation than organs from donors who have suffered anoxic brain injury. This may be due to the fact that donors who have sustained trauma are younger or donors who have suffered anoxia are more frequently associated with hypotension and hypoxemia, which may negatively affect long-term outcomes. Although the PHCA cohort in our study included significantly more donors who had suffered anoxia, the long-term outcomes were not significantly different. This may be due to the fact that the donor risk index was not specifically designed for a DCD setting.19 Thus, the effect of a donor’s cause of death on longterm graft survival after DCD is as yet undetermined. Potentially, PHCA may add significant additional risk to the existing risks of DWIT and CIT in the setting of DCD LT. Adverse outcomes of DCD transplantation, including high rates of PNF and ITBLs, have been linked with the duration of DWIT and CIT.20-22 Following large-scale studies on the outcomes of DCD LT based on the Organ Procurement and Transplantation Network and United Network for Organ Sharing databases, the American Society of Transplant
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Surgeons23-25 issued recommendations to select DCD liver grafts with a DWIT less than 30 minutes and to aim for a CIT less than 8 hours. Efforts to minimize CIT include efficient organization, careful recipient selection, and expedited implantation. The mean DWIT and CIT values in this study were similar for the PHCA and non-PHCA groups and were within the suggested national guidelines. These findings may be associated with our particularly strict selection of donors with PHCA, which is aimed at reducing the already greater risks for the recipient of a DCD liver. We compared both the short- and long-term outcomes of PHCA and non-PHCA cohorts. AKI, the need for dialysis, and acute liver injury based on peak serum transaminase levels are often used as surrogate markers of early outcomes of DCD LT.9,26 Surprisingly, the short-term outcomes were better for the PHCA cohort because AKI was noted significantly more frequently in the non-PHCA cohort. The 1-year patient and graft survival rates of 86% and 84% were consistent with most series27 and better than others after DCD LT.8,28 Although these findings may show better short-term outcomes and satisfactory long-term outcomes for the PHCA cohort, they may in fact reflect a very conservative and selective policy for PHCA donors with limited additional risk factors. The selection criteria for controlled DCD liver donors have been more restrictive because of the greater potential risk of PNF and biliary complications. When marginal DCD grafts are used, it is logical to argue against compounding multiple risk factors (eg, long DWIT, CIT, advanced age, obesity, long ITU stay, and absence of PHCA), which may contribute to the increased susceptibility of these grafts to AKI, PNF, and biliary complications. In this study, we have shown that our overall rate of PNF (1%) is in keeping with others’ rates.8,20 It is also possible to hypothesize that a mechanism of ischemic preconditioning may have positively affected the initial graft function by maintaining the hepatic microcirculation and decreasing Kupffer cell activation for clinically relevant ischemic periods.29 The main mechanism of its protection is probably the release of nitric oxide, by which it prevents sinusoidal perfusion failure and leukocyte adherence. In addition, the short interval of ischemia during ischemic preconditioning generates mild oxidative stress, which then induces natural defense mechanisms against subsequently lethal injury.29 Recipient selection is a difficult task, with the aim being to achieve the maximum benefit from this additional organ resource. Preferably, organs from PHCA donors should be used for recipients capable of withstanding a period of initial dysfunction. However, decisions were made in a case-by-case fashion and depended on the calculated risks for each PHCA donor at the time of the transplant. Our results showed no difference between the recipients of the 2 cohorts. Biliary complications after DCD transplantation continue to be a clinical issue. It is accepted that the initial injury to the bile duct is more likely to be ische-
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mic in nature, and this makes it a further concern for patients who have sustained PHCA. The risk of biliary complications is high, and they have been reported in up to 50% of recipients of uncontrolled DCD livers20 versus 30% to 40% in a controlled DCD setting.30,31 In this study, the ITBL rate was relatively low in comparison with rates in other reports32-34 and was surprisingly recorded only in the non-PHCA cohort (3.7%), whereas the PHCA group showed no incidence of ITBLs in the long-term follow-up (median 5 18 months). It remains our unit protocol to closely monitor liver function in DCD recipients, and even mild cholestatic derangements are promptly investigated with ultrasound and magnetic resonance cholangiopancreatography. In this study, there were 10 biliary complications in the non-PHCA cohort (12.2%); several studies have shown similar or higher rates of biliary complications (13.7%-33%) after DCD LT.8,30,35 The average time to developing ITBLs is usually 90 to 120 days.35 The lack of biliary complications in the PHCA cohort is difficult to explain. We can only speculate that the superselection of PHCA donors may have produced generally better quality grafts in comparison with the grafts from non-PHCA donors. A bias due to the relatively small cohort may, however, best explain this finding. We describe here the outcomes of DCD transplantation using grafts from donors who had suffered PHCA. PHCA has historically been a relative contraindication for a consideration of DCD donation. We found no difference in overall patient or graft survival, PNF, or biliary complications in comparison with a non-PHCA cohort. Carefully selecting PHCA DCD donors, inquiring in detail about the circumstances of PHCA, assessing the trend of serum transaminases as a marker of cellular damage, and excluding donors with multiple risk factors for donation have produced outcomes comparable to those with non-PHCA DCD liver grafts. The significance of such a comparative study is limited only by the prescreening pattern used to select PHCA liver grafts suitable for transplantation. Such practices are not uncommon with DCD liver grafts because without a tight selection process, the possibilities of PNF or early graft failure would make a randomized trial unacceptably risky.36 Although this is a retrospective study with a preliminary analysis of a relatively small cohort, our findings show that PHCA DCD donors should not be excluded from liver donation and, if they are adequately selected, can provide additional liver grafts with satisfactory early and late outcomes. DBD grafts are well known for their superior quality in comparison with DCD grafts, so such a conservative and highly selective policy for PHCA DCDs may not only positively influence the DCD donation pool in the United Kingdom but also have a similar effect on DBD donation. Moreover, National Health Service Blood and Transplant has limited the potential erosion of DBD donors into the DCD pool, and this resulted in an increase in net DBD liver donation in 2012.
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REFERENCES 1. Summers DM, Counter C, Johnson RJ, Murphy PG, Neuberger JM, Bradley JA. Is the increase in DCD organ donors in the United Kingdom contributing to a decline in DBD donors? Transplantation 2010;90:1506-1510. 2. Institute of Medicine. Non-Heart-Beating Organ Transplantation: Practice and Protocols. Washington, DC: National Academy Press; 2000. 3. Guidelines Relating to Solid Organ Transplants From Non-Heart Beating Donors. London, United Kingdom: British Transplantation Society; 2004. 4. Perera MT. The super-rapid technique in Maastricht category III donors: has it developed enough for marginal liver grafts from donors after cardiac death? Curr Opin Organ Transplant 2012;17:131-136. 5. Piratvisuth T, Tredger JM, Hayllar KA, Williams R. Contribution of true cold and rewarming ischemia times to factors determining outcome after orthotopic liver transplantation. Liver Transpl Surg 1995;1:296-301. 6. Dubbeld J, Hoekstra H, Farid W, Ringers J, Porte RJ, Metselaar HJ, et al. Similar liver transplantation survival with selected cardiac death donors and brain death donors. Br J Surg 2010;97:744-753. 7. Bernat JL, D’Alessandro AM, Port FK, Bleck TP, Heard SO, Medina J, et al. Report of a national conference on donation after cardiac death. Am J Transplant 2006;6: 281-291. 8. de Vera ME, Lopez-Solis R, Dvorchik I, Campos S, Morris W, Demetris AJ, et al. Liver transplantation using donation after cardiac death donors: long-term follow-up from a single center. Am J Transplant 2009;9:773-781. 9. Merion RM, Pelletier SJ, Goodrich N, Englesbe MJ, Delmonico FL. Donation after cardiac death as a strategy to increase deceased donor liver availability. Ann Surg 2006;244:555-562. 10. Qian YB, Liu CL, Lo CM, Fan ST. Risk factors for biliary complications after liver transplantation. Arch Surg 2004;139:1101-1105. 11. Leithead JA, Tariciotti L, Gunson B, Holt A, Isaac J, Mirza DF, et al. Donation after cardiac death liver transplant recipients have an increased frequency of acute kidney injury. Am J Transplant 2012;12:965-975. 12. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; for Acute Dialysis Quality Initiative Workgroup. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204-R212. 13. Jim enez-Galanes S, Meneu-Diaz MJ, Elola-Olaso AM, P erez-Saborido B, Yiliam FS, Calvo AG, et al. Liver transplantation using uncontrolled non-heart-beating donors under normothermic extracorporeal membrane oxygenation. Liver Transpl 2009;15:1110-1118. 14. Casavilla A, Ramirez C, Shapiro R, Nghiem D, Miracle K, Bronsther O, et al. Experience with liver and kidney allografts from non-heart-beating donors. Transplantation 1995;59:197-203. 15. Muiesan P, Girlanda R, Jassem W, Melendez HV, O’Grady J, Bowles M, et al. Single-center experience with liver transplantation from controlled non-heartbeating donors: a viable source of grafts. Ann Surg 2005;242: 732-738. 16. Tector AJ, Mangus RS, Chestovich P, Vianna R, Fridell JA, Milgrom ML, et al. Use of extended criteria livers decreases wait time for liver transplantation without adversely impacting posttransplant survival. Ann Surg 2006;244:439-450.
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17. Lee KW, Simpkins CE, Montgomery RA, Locke JE, Segev DL, Maley WR. Factors affecting graft survival after liver transplantation from donation after cardiac death donors. Transplantation 2006;82:1683-1688. 18. Radunz S, Paul A, Nowak K, Treckmann JW, Saner FH, Math e Z. Liver transplantation using donor organs with markedly elevated liver enzymes: how far can we go? Liver Int 2011;31:1021-1027. 19. Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant 2006;6:783-790. 20. Su arez F, Otero A, Solla M, Arnal F, Lorenzo MJ, Marini M, et al. Biliary complications after liver transplantation from Maastricht category-2 non-heart-beating donors. Transplantation 2008;85:9-14. 21. Reddy S, Greenwood J, Maniakin N, Bhattacharjya S, Zilvetti M, Brockmann J, et al. Non-heart-beating donor porcine livers: the adverse effect of cooling. Liver Transpl 2005;11:35-38. 22. Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci U S A 1997;94:2557-2562. 23. Mateo R, Cho Y, Singh G, Stapfer M, Donovan J, Kahn J, et al. Risk factors for graft survival after liver transplantation from donation after cardiac death donors: an analysis of OPTN/UNOS data. Am J Transplant 2006;6:791796. 24. Abt PL, Desai NM, Crawford MD, Forman LM, Markmann JW, Olthoff KM, Markmann JF. Survival following liver transplantation from non-heart-beating donors. Ann Surg 2004;239:87-92. 25. Reich DJ, Mulligan DC, Abt PL, Pruett TL, Abecassis MM, D’Alessandro A, et al.; for ASTS Standards on Organ Transplantation Committee. ASTS recommended practice guidelines for controlled donation after cardiac death organ procurement and transplantation. Am J Transplant 2009;9:2004-2011. 26. Schneider L, Latanowicz S, Spiegel M, Stremmel W, B€ uchler MW, Schmidt J, Eisenbach C. Prospective validation of a simple laboratory score to predict outcome after orthotopic liver transplantation. Transplant Proc 2011;43:1747-1750. 27. Nguyen JH, Bonatti H, Dickson RC, Hewitt WR, Grewal HP, Willingham DL, et al. Long-term outcomes of donation after cardiac death liver allografts from a single center. Clin Transplant 2009;23:168-173. 28. Skaro AI, Jay CL, Baker TB, Wang E, Pasricha S, Lyuksemburg V, et al. The impact of ischemic cholangiopathy in liver transplantation using donors after cardiac death: the untold story. Surgery 2009;146:543552. 29. Vajdov a K, Heinrich S, Tian Y, Graf R, Clavien PA. Ischemic preconditioning and intermittent clamping improve murine hepatic microcirculation and Kupffer cell function after ischemic injury. Liver Transpl 2004;10:520528. 30. Abt P, Crawford M, Desai N, Markmann J, Olthoff K, Shaked A. Liver transplantation from controlled non-heart-beating donors: an increased incidence of biliary complications. Transplantation 2003;75:16591663. 31. Lee HW, Suh KS, Shin WY, Cho EH, Yi NJ, Lee JM, et al. Classification and prognosis of intrahepatic biliary stricture after liver transplantation. Liver Transpl 2007;13: 1736-1742. 32. Heidenhain C, Pratschke J, Puhl G, Neumann U, Pascher A, Veltzke-Schlieker W, Neuhaus P. Incidence of and risk factors for ischemic-type biliary lesions
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following orthotopic liver transplantation. Transpl Int 2010;23:14-22. 33. DeOliveira ML, Jassem W, Valente R, Khorsandi SE, Santori G, Prachalias A, et al. Biliary complications after liver transplantation using grafts from donors after cardiac death: results from a matched control study in a single large volume center. Ann Surg 2011;254:716-722. 34. Foley DP, Fernandez LA, Leverson G, Anderson M, Mezrich J, Sollinger HW, D’Alessandro A. Biliary complications after liver transplantation from donation after cardiac death donors: an analysis of risk factors and
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long-term outcomes from a single center. Ann Surg 2011;253:817-825. 35. Chan EY, Olson LC, Kisthard JA, Perkins JD, Bakthavatsalam R, Halldorson JB, et al. Ischemic cholangiopathy following liver transplantation from donation after cardiac death donors. Liver Transpl 2008;14:604610. 36. Wertheim JA, Petrowsky H, Saab S, Kupiec-Weglinski JW, Busuttil RW. Major challenges limiting liver transplantation in the United States. Am J Transplant 2011; 11:1773-1784.
ORIGINAL ARTICLE
Increasing the Donor Pool: Consideration of Prehospital Cardiac Arrest in Controlled Donation After Circulatory Death for Liver Transplantation Ahmed H. Elaffandi, Glenn K. Bonney, Bridget Gunson, Irene Scalera, Hynek Mergental, John R. Isaac, Simon R. Bramhall, Darius F. Mirza, M. Thamara P.R. Perera, Paolo Muiesan Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom
Donor warm ischemia has implications for outcomes after liver transplantation (LT) using organs from donation after circulatory death (DCD) donors. Prehospital cardiac arrest (PHCA) before donation may generate a further ischemic insult. The aim of this single-center study of 108 consecutive DCD LT procedures was to compare the outcomes of PHCA and nonPHCA cohorts. A review of a prospectively collected database of all DCD grafts transplanted between January 2007 and October 2011 was undertaken to identify donors who had sustained PHCA. The unit policy was to consider such donors when transaminase levels were 4 times the normal range and had an improving trend. Twenty-six of the 108 DCD transplants were from DCD donors with PHCA, and 82 were in the non-PHCA cohort. A comparative analysis of the PHCA and non-PHCA cohorts showed better short-term results (a low incidence of acute kidney injury) for the PHCA group but satisfactory long-term results for both groups with no significant differences in graft or patient survival between them. In conclusion, a careful donor selection policy for including PHCA DCD donors with normalized liver function tests or transaminase levels 4 times the norm resulted in successful transplantation and could boost the donor pool with no adverse outcomes. C 2013 AASLD. Liver Transpl 20:63-71, 2014. V Received July 4, 2013; accepted October 1, 2013. The United Kingdom has seen a sustained rise in the number of patients on the liver transplantation (LT) waiting list. This has been met in recent years with the increased use of donation after circulatory death (DCD) grafts.1 According to the currently accepted guidelines recommended by the Institute of Medicine2 and the British Transplantation Society,3 organ donation can proceed after at least 5 minutes of asystole following the withdrawal of treatment. The warm ischemia insult linked to DCD donors (Maastricht category III) is associated with specific early and late
posttransplant complications in comparison with donation after brain death (DBD) grafts.4 Both hemodynamic instability and hypoxemia in DCD organs contribute to the donor warm ischemia time (DWIT), which may result in an increased rate of complications after DCD LT.5 The careful selection of DCD donor and recipient combinations is crucial for maintaining an overall benefit and excellent results in comparison with DBD grafts after LT.6 Currently, a DWIT greater than 30 minutes is considered a relative contraindication to transplantation.7
Abbreviations: AKI, acute kidney injury; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CIT, cold ischemia time; DBD, donation after brain death; DCD, donation after circulatory death; DWIT, donor warm ischemia time; GGT, gamma-glutamyltransferase; ITBL, ischemic-type biliary lesion; ITU, intensive treatment unit; LFT, liver function test; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; PHCA, prehospital cardiac arrest; PNF, primary nonfunction; UKELD, UK Model for End-Stage Liver Disease. The authors have no conflict of interest to declare. Address reprint requests to Paolo Muiesan, MD, FEBS, FRCS, Liver Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom. E-mail: [email protected] Tel: 144 (0) 121 627 2418 DOI 10.1002/lt.23772 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2013 American Association for the Study of Liver Diseases. V
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However, even before donation, a proportion of DCD grafts will have sustained an initial ischemic insult810 because of prehospital cardiac arrest (PHCA). The duration of PHCA may have profound implications for the potential quality of a DCD organ, and it generates an additional ischemic insult to the liver graft. At several centers, PHCA is considered a relative contraindication for DCD liver donation and transplantation: 46% of the PHCA DCD grafts accepted by us were rejected by other transplant units because of PHCA before they were used by our unit. To date, the issue of PHCA in DCD donors and its implications for LT outcomes have not yet been reported. The aim of this study was to describe the process of donor selection, including donors with abnormal liver function tests (LFTs), at a single, large-volume center in the United Kingdom and the outcomes for recipients of grafts from DCD donors who had experienced PHCA; this may have a positive influence on the DCD donation pool.
PATIENTS AND METHODS Study Design Using a prospectively maintained database from the Liver Unit of Queen Elizabeth Hospital (Birmingham, United Kingdom), we undertook a retrospective analysis of all sequential DCD LT procedures performed between January 1, 2007 and October 1, 2011. The study protocol received a priori approval by the institutional review committee. Additional data were obtained from National Health Service Blood and Transplant. The DCD cohort was divided into 2 groups: those who had sustained PHCA and those who had not. The analyzed donor details included the following: demographic criteria, cause of death, history related to the occurrence and length of PHCA, predonation biochemical results, body mass index (BMI), cold ischemia time (CIT), and DWIT. Downtime was defined as the time between witnessed PHCA and the reported start of cardiopulmonary resuscitation. The analyzed recipient variables included demographic criteria, indications for transplantation, and Model for EndStage Liver Disease (MELD) and UK Model for EndStage Liver Disease (UKELD) scores. Postoperative LFTs and coagulation studies were used as markers of early graft function. Primary nonfunction (PNF) was defined as primary graft failure within 7 days of transplantation requiring retransplantation or leading to patient death. Delayed graft function was defined as primary graft failure characterized by cholestasis within 6 months of transplantation in the absence of hepatic artery thrombosis or biliary complications also leading to retransplantation or patient death.8 The incidence of posttransplant acute kidney injury (AKI) and the need for dialysis in the first 5 days were also measured as surrogate markers of delayed graft function because of the recent evidence for a significant increase in AKI with DCD LT versus DBD LT,
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which is related to the severity of the ischemia/reperfusion injury and peak transaminase levels.11 In accordance with the Acute Dialysis Quality Initiative Group, AKI was defined as an increase in the serum creatinine level greater than 2 times the baseline serum creatinine level.12 The analyzed outcomes included early graft function, AKI, posttransplant dialysis requirements, biliary complications, and long-term patient and graft survival.
Donor and Recipient Considerations The consideration of a DCD liver donor by the transplant surgeon was based on several factors, including age, BMI, cause of death, organ support, past medical history, and blood results. For donors who had sustained PHCA, donation was considered if the peak transaminase levels were no greater than 4 times the norm and the trend of liver function had been improving in the previous 6 to 12 hours. Following what was considered a relatively safe upper limit for a viable uncontrolled DCD graft after normothermic regional perfusion, we set this restriction on transaminase levels.13 At no point was the transplant team involved in the withdrawal process before donation. Circulatory death was determined by a sustained asystole, and an interval of at least 5 minutes was required before the certification of death by the attending physician in accordance with national guidelines. Generally, donors who did not proceed to asystole within an hour of treatment withdrawal or who sustained a DWIT greater than 30 minutes were not considered further for liver donation. The procurement was performed with a modification of the super-rapid technique previously described.14,15 DWIT was defined as the interval between hypotension with a systolic blood pressure < 50 mm Hg and/or desaturation < 80% (whichever came first) and the initiation of aortic perfusion. CIT was defined as the time between aortic perfusion at organ retrieval and the start of implantation (when the liver was taken out of the ice). In general, recipients expected to have a difficult explant (ie, a previous history of upper abdominal surgery, preoperative portal vein thrombosis, or retransplantation) were excluded from receiving a DCD liver graft in an attempt to minimize CIT, whereas those with less severe portal hypertension and hepatocellular carcinoma were more likely to receive DCD grafts.
Outcome Measures An analysis of peak liver function and coagulation studies during the first posttransplant week was performed for PHCA recipients; the data were compared with those for the non-PHCA group. Also, the incidence of AKI and posttransplant dialysis in the first 5 days was compared between the 2 groups. The incidence of biliary complications was also compared
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between the groups. All patients were followed up at the posttransplant clinic on a regular basis. Liver ultrasonography was used as the first imaging technique in case of cholestatic liver function. Patients with abnormal ultrasonography findings were further investigated with magnetic resonance cholangiopancreatography accordingly. Biliary complications were classified as anastomotic strictures, nonanastomotic strictures, or ischemic-type biliary lesions (ITBLs; defined as intrahepatic lesions in the absence of arterial complications). Overall patient survival and graft survival as well as causes of death and graft loss were described. Graft survival was timed from the transplant date to the date of retransplantation or death (whichever came first), and it was censored for the date of the end of the study period.
Statistical Analysis Categorical variables were examined with a chisquare test. A Shapiro-Wilk test for normality was performed for continuous variables, and subsequently, a Mann-Whitney U test and a Student t test were performed for nonparametric and parametric data, respectively. Graft survival and patient survival between the groups were compared with Kaplan-Meier plots and log-rank tests. SPSS 17.0 (SPSS, Chicago, IL) was used for the statistical analysis. A P value < 0.05 was considered significant.
RESULTS
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(184-709 minutes, standard deviation 5 106 minutes), respectively. Recipients of DCD grafts had a median age of 56.1 years (range 5 21-70 years) and mean MELD and UKELD scores at transplantation of 14 (range 5 6-27) and 53 (range 5 39-75), respectively. Twenty-six of the potential DCD donors had previously sustained PHCA with a median downtime of 20 minutes (range 5 1-50 minutes) and a median ITU stay of 2 days (range 5 1-14 days) before organ procurement. At the time of donation, the mean alanine aminotransferase (ALT) level for DCD donors was 83 U/L. In a subgroup analysis, we divided the PHCA cohort into 2 groups: those who received grafts from donors with an ALT level 100 U/L (n 5 19) and those who received grafts from donors with an ALT level < 100 U/L (n 5 7). We found that a donor ALT level 100 U/L did not significantly affect recipient survival (P 5 0.07). The recipients’ aspartate aminotransferase (AST) levels on days 0 and 1 were 1002 U/L (range 5 35-11,850 U/L) and 1528 U/L (range 5 535-11,037 U/L), respectively. The peak LFTs after transplantation were as follows: AST, 2460 U/L (range 5 694-11,850 U/L); alkaline phosphatase (ALP), 1188 U/L (range 5 303-3128 U/L); bilirubin, 77.5 lmol/L (range 5 23-757 lmol/L); and international normalized ratio, 1.8 (range 5 1.3-5.9). In this PHCA cohort, the recipients spent an average of 3 days in the ITU after transplantation (range 5 1-16 days).
Patient and Donor Demographics
Comparative Analysis of the PHCA and Non-PHCA Cohorts
Between January 1, 2007 and October 1, 2011, livers from 95 potential DCD donors who had sustained PHCA were offered to our unit. Twenty-six of these liver offers were accepted and subsequently transplanted; the details are described later. Twelve of the 26 PHCA donors (46%) were rejected by other units before being offered to our center. For the 69 remaining potential donors, the median PHCA downtime was 42 minutes (range 5 30-60 minutes) with a median intensive treatment unit (ITU) stay of 1.5 days (range 5 0-5 days) before the offer. On these grounds, 13 of the remaining 69 offers were declined solely because of PHCA. The remaining 56 offers were declined because of the association of PHCA and other risk factors, so 1 offer could have been rejected because of multiple risk factors. Such factors included logistics (n 5 8), past medical history (n 5 17), age (n 5 13), alcohol consumption (n 5 5), BMI (n 5 7), no suitable recipients (n 5 3), abnormal LFTs (n 5 14), and others [small donor size (n 5 2), virology (n 5 1), high lactate level (n 5 1), unstable donor (n 5 1), and donor sepsis (n 5 2)]. In the same study period, DCD LT was performed 108 times at Queen Elizabeth Hospital. The median age of the DCD donors was 50 years (range 5 11-72 years), and 52% of the donors were males. The mean DWIT and CIT values were 20 minutes (7-32 minutes, standard deviation 5 8.4 minutes) and 445 minutes
The grafts from the 26 donors who had sustained PHCA were compared against the 82 non-PHCA DCD grafts. The donor and recipient variables for these 2 cohorts are tabulated in Tables 1 and 2. There were no differences in age, sex, ITU stay, or blood results before donation [AST, ALP, gammaglutamyltransferase (GGT), sodium, and bilirubin] between the 2 groups (Table 1). Apart from the donor ALT serum levels, which were significantly higher among PHCA donors (P 5 0.001), the predonation blood tests were not significantly different. It was also observed that CIT (431.8 minutes for the PHCA group versus 449.8 minutes for the non-PHCA group) and DWIT (19.2 minutes for the PHCA group versus 20.2 minutes for the non-PHCA group) had a tendency to be longer for the non-PHCA group, although this did not reach statistical significance (P 5 0.5 and P 5 0.6, respectively). Unsurprisingly, in the group that had sustained PHCA before donation, the proportion of donors who had anoxic brain injury was larger than that in the non-PHCA group (23% versus 1%), with trauma and stroke being the most common causes of death in the non-PHCA group (24% and 66%, respectively; P < 0.001). Recipient variables were similarly subcategorized into the PHCA and non-PHCA groups (Table 2). There were no differences in the recipient ages or MELD/ UKELD scores between the 2 groups. The difference
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TABLE 1. Donor Variables for the PHCA and Non-PHCA Groups Variable
PHCA Group (n 5 26)
Non-PHCA Group (n 5 82)
P Value
50.5 13
50 43
0.89 0.81
1 8 6 11 25.4 1.4
20 54 1 7 25.9 1.9
P 100 U/L did not negatively affect recipient survival (P 5 0.07). The overall cutoff for transaminases that we considered was no greater than 4 times the normal level. This was in keeping with a recent report demonstrating that select grafts from donors with high serum transaminase levels could be used for transplantation with satisfactory results.18 The donor risk index proposed by Feng et al.19 shows that organs from donors who have suffered trauma have better long-term outcomes after transplantation than organs from donors who have suffered anoxic brain injury. This may be due to the fact that donors who have sustained trauma are younger or donors who have suffered anoxia are more frequently associated with hypotension and hypoxemia, which may negatively affect long-term outcomes. Although the PHCA cohort in our study included significantly more donors who had suffered anoxia, the long-term outcomes were not significantly different. This may be due to the fact that the donor risk index was not specifically designed for a DCD setting.19 Thus, the effect of a donor’s cause of death on longterm graft survival after DCD is as yet undetermined. Potentially, PHCA may add significant additional risk to the existing risks of DWIT and CIT in the setting of DCD LT. Adverse outcomes of DCD transplantation, including high rates of PNF and ITBLs, have been linked with the duration of DWIT and CIT.20-22 Following large-scale studies on the outcomes of DCD LT based on the Organ Procurement and Transplantation Network and United Network for Organ Sharing databases, the American Society of Transplant
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Surgeons23-25 issued recommendations to select DCD liver grafts with a DWIT less than 30 minutes and to aim for a CIT less than 8 hours. Efforts to minimize CIT include efficient organization, careful recipient selection, and expedited implantation. The mean DWIT and CIT values in this study were similar for the PHCA and non-PHCA groups and were within the suggested national guidelines. These findings may be associated with our particularly strict selection of donors with PHCA, which is aimed at reducing the already greater risks for the recipient of a DCD liver. We compared both the short- and long-term outcomes of PHCA and non-PHCA cohorts. AKI, the need for dialysis, and acute liver injury based on peak serum transaminase levels are often used as surrogate markers of early outcomes of DCD LT.9,26 Surprisingly, the short-term outcomes were better for the PHCA cohort because AKI was noted significantly more frequently in the non-PHCA cohort. The 1-year patient and graft survival rates of 86% and 84% were consistent with most series27 and better than others after DCD LT.8,28 Although these findings may show better short-term outcomes and satisfactory long-term outcomes for the PHCA cohort, they may in fact reflect a very conservative and selective policy for PHCA donors with limited additional risk factors. The selection criteria for controlled DCD liver donors have been more restrictive because of the greater potential risk of PNF and biliary complications. When marginal DCD grafts are used, it is logical to argue against compounding multiple risk factors (eg, long DWIT, CIT, advanced age, obesity, long ITU stay, and absence of PHCA), which may contribute to the increased susceptibility of these grafts to AKI, PNF, and biliary complications. In this study, we have shown that our overall rate of PNF (1%) is in keeping with others’ rates.8,20 It is also possible to hypothesize that a mechanism of ischemic preconditioning may have positively affected the initial graft function by maintaining the hepatic microcirculation and decreasing Kupffer cell activation for clinically relevant ischemic periods.29 The main mechanism of its protection is probably the release of nitric oxide, by which it prevents sinusoidal perfusion failure and leukocyte adherence. In addition, the short interval of ischemia during ischemic preconditioning generates mild oxidative stress, which then induces natural defense mechanisms against subsequently lethal injury.29 Recipient selection is a difficult task, with the aim being to achieve the maximum benefit from this additional organ resource. Preferably, organs from PHCA donors should be used for recipients capable of withstanding a period of initial dysfunction. However, decisions were made in a case-by-case fashion and depended on the calculated risks for each PHCA donor at the time of the transplant. Our results showed no difference between the recipients of the 2 cohorts. Biliary complications after DCD transplantation continue to be a clinical issue. It is accepted that the initial injury to the bile duct is more likely to be ische-
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mic in nature, and this makes it a further concern for patients who have sustained PHCA. The risk of biliary complications is high, and they have been reported in up to 50% of recipients of uncontrolled DCD livers20 versus 30% to 40% in a controlled DCD setting.30,31 In this study, the ITBL rate was relatively low in comparison with rates in other reports32-34 and was surprisingly recorded only in the non-PHCA cohort (3.7%), whereas the PHCA group showed no incidence of ITBLs in the long-term follow-up (median 5 18 months). It remains our unit protocol to closely monitor liver function in DCD recipients, and even mild cholestatic derangements are promptly investigated with ultrasound and magnetic resonance cholangiopancreatography. In this study, there were 10 biliary complications in the non-PHCA cohort (12.2%); several studies have shown similar or higher rates of biliary complications (13.7%-33%) after DCD LT.8,30,35 The average time to developing ITBLs is usually 90 to 120 days.35 The lack of biliary complications in the PHCA cohort is difficult to explain. We can only speculate that the superselection of PHCA donors may have produced generally better quality grafts in comparison with the grafts from non-PHCA donors. A bias due to the relatively small cohort may, however, best explain this finding. We describe here the outcomes of DCD transplantation using grafts from donors who had suffered PHCA. PHCA has historically been a relative contraindication for a consideration of DCD donation. We found no difference in overall patient or graft survival, PNF, or biliary complications in comparison with a non-PHCA cohort. Carefully selecting PHCA DCD donors, inquiring in detail about the circumstances of PHCA, assessing the trend of serum transaminases as a marker of cellular damage, and excluding donors with multiple risk factors for donation have produced outcomes comparable to those with non-PHCA DCD liver grafts. The significance of such a comparative study is limited only by the prescreening pattern used to select PHCA liver grafts suitable for transplantation. Such practices are not uncommon with DCD liver grafts because without a tight selection process, the possibilities of PNF or early graft failure would make a randomized trial unacceptably risky.36 Although this is a retrospective study with a preliminary analysis of a relatively small cohort, our findings show that PHCA DCD donors should not be excluded from liver donation and, if they are adequately selected, can provide additional liver grafts with satisfactory early and late outcomes. DBD grafts are well known for their superior quality in comparison with DCD grafts, so such a conservative and highly selective policy for PHCA DCDs may not only positively influence the DCD donation pool in the United Kingdom but also have a similar effect on DBD donation. Moreover, National Health Service Blood and Transplant has limited the potential erosion of DBD donors into the DCD pool, and this resulted in an increase in net DBD liver donation in 2012.
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following orthotopic liver transplantation. Transpl Int 2010;23:14-22. 33. DeOliveira ML, Jassem W, Valente R, Khorsandi SE, Santori G, Prachalias A, et al. Biliary complications after liver transplantation using grafts from donors after cardiac death: results from a matched control study in a single large volume center. Ann Surg 2011;254:716-722. 34. Foley DP, Fernandez LA, Leverson G, Anderson M, Mezrich J, Sollinger HW, D’Alessandro A. Biliary complications after liver transplantation from donation after cardiac death donors: an analysis of risk factors and
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long-term outcomes from a single center. Ann Surg 2011;253:817-825. 35. Chan EY, Olson LC, Kisthard JA, Perkins JD, Bakthavatsalam R, Halldorson JB, et al. Ischemic cholangiopathy following liver transplantation from donation after cardiac death donors. Liver Transpl 2008;14:604610. 36. Wertheim JA, Petrowsky H, Saab S, Kupiec-Weglinski JW, Busuttil RW. Major challenges limiting liver transplantation in the United States. Am J Transplant 2011; 11:1773-1784.
