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Obligatory exposure to a period of warm ischemia is the defining feature of liver allografts from donation after cardiac death (DCD) donors. We explored novel methods for characterizing the dynamic aspects of donor warm ischemia that might be useful in assessing organ quality. The hemodynamic profile during donor warm ischemia was retrospectively studied for 110 Maastricht category III DCD donors. Three methods were used to summarize the hemodynamic changes after extubation: (1) the area under the systolic blood pressure curve (AUCSBP), (2) the slope of the systolic blood pressure regressed onto the time from extubation until cross-clamping, and (3) the slope of the systolic blood pressure regressed onto the time from extubation but calculated with only the values during the first 10 minutes after extubation (SBP10). Stepwise multivariate Cox models were created to study the association of these measures with graft survival. The duration of the donor warm ischemia time (23.6 ± 8.5 minutes) was not associated with graft survival (P = 0.35), although AUCSBP and SBP10 demonstrated significant associations (P = 0.02 and P = 0.05, respectively) in a univariate analysis. Multivariate regression models incorporating donor and recipient covariates indicated that among all covariates, SBP10 had the closest association with graft survival (hazard ratio = 1.08, P = 0.01). This association was even stronger when SBP10 was dichotomized into values above or below the median (−7.2 mm Hg/minute). Patients with SBP10s steeper than the median had an estimated 5-year graft survival rate of 76%, whereas patients with slopes less than the median had a 5-year survival rate of 45% (P < 0.007). In conclusion, the incorporation of novel methods for characterizing the donor warm ischemia time may help in selecting DCD liver allografts with favorable outcomes. Liver Transpl 20:165-172, 2014. © 2013 AASLD.
Donation after cardiac death (DCD) donors have been promulgated as a resource for abrogating the unresolved mortality rate among patients awaiting a liver transplant. Although the number of DCD donors and the number of kidney transplants from DCD donors in the United States have increased markedly within the last decade, the utilization of livers from DCD donors has plateaued, and this attests to continuing concerns about these organs.[1, 2] Several analyses using Organ Procurement and Transplantation Network (OPTN) data have demonstrated inferior survival among recipients of DCD liver allografts versus recipients of allografts from donors with neurological determination of death (DNDDs).[3-6] Although numerous individual center-specific analyses are congruent with national findings, some centers have reported allograft survival rates equivalent to those with transplants from DNDDs.[7-12]
Inferior liver allograft survival with DCD donors has been ascribed to the period of obligatory donor warm ischemia, which is the primary element differentiating DCD donors from DNDDs (Fig. 1). Recipients of DCD livers have increased rates of primary nonfunction, hepatic artery thrombosis, and biliary complications (particularly ischemic cholangiopathy); these factors likely underlie the graft survival statistics.[11-14] Previous publications have attempted to delineate the association between donor warm ischemia and posttransplant complications and graft failure. In an analysis of OPTN data, Lee et al. identified a donor warm ischemia time greater than 15 minutes as a risk for graft loss [hazard ratio (HR) = 1.37, P = 0.03], and the risk increased beyond 30 minutes (HR = 1.78, P = 0.01); however, in a subsequent analysis of OPTN data by Mathur et al., an association with graft loss was not observed until the donor warm ischemia time exceeded 35 minutes (HR = 1.84, P = 0.003). Single-center analyses have provided conflicting findings about the impact of the duration of the donor warm ischemia time on graft outcomes.[8, 9, 16, 17] Likewise, the data regarding the association of the donor warm ischemia time with biliary complications remain contradictory.[8, 9, 11, 12]
Figure 1. Timeline of the events during DCD organ procurement. The donor warm ischemia time is defined as the period from the planned withdrawal of care by extubation until aortic cross-clamping and flushing of the organs with a chilled preservation solution.
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The failure of the collective literature to demonstrate an unequivocal association between warm ischemia and untoward events in DCD liver transplantation may be related to a variety of factors, including nonstandardized criteria for certifying cardiopulmonary death, variability in defining the duration of the donor warm ischemia time, inadequate statistical power, and the use of static measures to characterize donor warm ischemia. It has been recognized that the hemodynamic perturbations occurring after the withdrawal of care are dynamic and that a wide range of profiles are encountered among donors that are discernible by variations in organ perfusion and not solely in duration. Without consideration of the quality of the donor warm ischemia time, an assessment of quantity measured by time alone may fail to recognize the importance of donor warm ischemia to the outcome of a DCD allograft. We hypothesized that an investigation of the dynamic nature of the donor warm ischemia time might offer an opportunity for stratifying the risk of failure among DCD allografts. This is an exploratory analysis using 3 different techniques to measure donor hemodynamic profiles for a cohort of Maastricht category III donors.
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- PATIENTS AND METHODS
The hemodynamic changes that occur during DCD donor warm ischemia may offer opportunities for assessing organ quality before transplantation. This study has explored several methods for characterizing donor warm ischemia that consider the dynamic nature of organ perfusion after extubation because the duration alone is unlikely to accurately reflect the impact of warm ischemia on donor organs.
In the present analysis, we found that the duration of warm ischemia was not associated with graft survival; however, measures providing a dynamic characterization of donor warm ischemia (AUCSBP and SBP10) were related to graft outcomes in stepwise multivariate analyses. The relationship between SBP10 and graft survival appeared to be nonlinear, and this suggested that the median value of SBP10 could designate grafts with inferior outcomes. These findings require substantiation in an additional cohort, but they can serve as a starting point for considering a refined approach to understanding donor warm ischemia as it relates to transplant outcomes and potentially organ selection from DCD donors.
Previous analyses using static measures of the warm ischemia time have demonstrated a variable association between warm ischemia and graft survival. OPTN data indicate that an increasing duration of warm ischemia is detrimental to the graft. An initial analysis by Lee et al. found that a warm ischemia time greater than 15 minutes was associated with an increased risk of graft failure; however, a subsequent analysis with a larger cohort by Mathur et al. demonstrated that the risk of graft failure did not increase until 35 minutes. Single-center reports have provided conflicting results. de Vera et al. described the experience at the University of Pittsburgh and noted inferior outcomes when the warm ischemia time exceeded 20 minutes. Ho et al. were unable to find an association between the donor warm ischemia time and an inferior outcome, but they demonstrated that the duration of a systolic blood pressure < 50 mm Hg to cold flushing predicted poor graft survival as defined by a composite endpoint of death, graft loss, and biliary strictures within 1 year of transplantation. Taner et al., on the other hand, did not find an association between the warm ischemia time and graft loss. Likewise, the data regarding the association of the donor warm ischemia time with biliary complications remain contradictory[7, 8, 11, 12, 16]
The 3 methods presented in this article reflect an attempt to characterize different aspects of the dynamic nature of the donor warm ischemia time (Fig. 1). When considering these methods, one should recognize that the length of donor warm ischemia is related not only to the intrinsic agonal phase distinguished by the demise and cessation of cardiopulmonary activity but also to the variability within the process of DCD organ recovery, which is not in and of itself a reflection of the donor physiology. One source of variability is incurred through the utilization of diverse criteria for cardiopulmonary death, which are related to physician and/or hospital-based practices. Certification of death for DCD donors is commonly established with one of several criteria, including auscultation of heart tones, a pulse pressure detected manually or via an arterial line, and cessation of cardiac electrical activity. The total warm ischemia time is a direct reflection of the criteria chosen by an independent physician and cannot be dictated by the organ procurement organization or the recovery surgeon. A second source of variability, though limited, is the mandatory stand-down time for monitoring a potential donor for the return of spontaneous cardiopulmonary activity. The 5-minute respite was proposed by the Institute of Medicine, but other organizations have supported a 2-minute interlude.[18, 22] A third contributor to the donor ischemia time that is not reflective of the donor physiology is the time needed by the recovering team to make an incision, cannulate the aorta, and cross-clamp; this variable is associated with the development of biliary complications. As for the measures studied in this article, AUCSBP captures the entire donor exposure to warm ischemia, and the SBP slope reflects the entire trajectory of the systolic blood pressure from the withdrawal of care until cross-clamping. Thus, AUCSBP and the SBP slope reflect the physiology during the agonal phase and also directly capture contributors to the warm ischemia time that are dictated by external sources. SBP10 captures the early trajectory of the systolic blood pressure immediately after the withdrawal of care. In most donors, SBP10 will reflect only the agonal phase, and it is not influenced by the method for determining death, the definition of warm ischemia time, or the technical aspects of the surgical team that may influence the time to aortic cross-clamping.
We speculate that unlike the association between the donor warm ischemia time and graft survival, the association between SBP10 and graft survival is significant because SBP10 subselects for donors with a favorable blood pressure trajectory during the agonal phase. The exposure of the donor organ to ischemic damage is influenced not only by the length of ischemia but also by the perturbations of perfusion that occur during the agonal phase. The donor warm ischemia time, even if it is relatively brief, does not provide any information about the blood pressure trajectory during the agonal phase; it just provides information about the duration. Among donors, there is heterogeneity not only in the length of the warm ischemia time but also in the patterns of perfusion during the agonal period. SBP10 may be effective in identifying organs from donors with more favorable survival characteristics through the exclusion of some of the donor heterogeneity that is incurred when the donor warm ischemia time is used to solely assess donor quality.
The current study was designed as an exploratory analysis to consider several new methods for evaluating the contribution of DCD donor warm ischemia to liver allograft outcomes. There are several limitations inherent to this analysis, including the small sample size, the nonuniform criteria for establishing donor death, and a pretransplant selection bias by the transplant surgeons to opt for organs felt to have superior survival characteristics. The study is also limited by an inability to determine the association of the SBP slope, AUCSBP, and SBP10 with the development of biliary complications or recipient causes of death.
In summary, this report provides evidence that a more complete characterization of the donor warm ischemia time may offer an opportunity for informing the selection of organs from DCD liver donors. The validation of this study's findings in a separate cohort, the inclusion of additional recipient covariates in future models, and an effort to identify an association between these findings and ischemic-type biliary strictures are a logical evolution for future inquiry.