As the waiting list for organ transplant continues to increase (over 90,000 candidates as of May 30, 2007), the pressure to increase the number of donor organs is the impetus to expand the use of organs from donation after cardiac death (DCD) donors. The focus on DCD, previously referred to as non–heart-beating donor (NHBD), has led to significant increases in its utilization (Table 1),1-3 although the contribution to the donor pool remains only 7% in the United States and is disproportionately reflected in increased kidney transplants (Table 2).4 DBD, donation after brain death; DCD, donation after cardiac death; HAT, hepatic artery thrombosis; HTK, histidine-tryptophan-ketoglutarate; ITBS, ischemic-type biliary stricture; NHBD, non–heart-beating donor; PRC, People's Republic of China; rTPA, recombinant tissue plasminogen activator; SRTR, Scientific Registry of Transplant Recipients; UW, University of Wisconsin. Prior to the acceptance of brain death, donors were required to have cessation of heart function in order to procure organs for transplantation. In some areas where brain death legislation has not been widely adopted, such as Asia,5, 6 DCD represents a significant source of organs for transplantation. Although the Maastricht Conference on DCD in 19947 identified 4 categories of DCD [Category I: dead on arrival; Category II: unsuccessful resuscitation; Category III: waiting cardiac death; and Category IV: cardiac death in a brain-dead donor], it is easier to envision DCD based on two distinct populations, one following uncontrolled cardiopulmonary arrest (Categories I and II) and the other under conditions of controlled removal from life support, without the criteria for brain death being fulfilled.8 In 1995, the University of Pittsburgh provided one of the earliest comparisons between controlled and uncontrolled DCD.9 There were 24 DCD livers, 14 in the uncontrolled group (Group 1) and 10 in the group in which controlled termination of life support was performed in the operating room (Group 2).10 Of the liver grafts that were used, the immediate graft function rate was 50% (3/6) in Group 1 and 100% (6/6) in Group 2; however, the overall 2-year patient and graft survival was only 58% and 33%, respectively. In order to improve outcomes with DCD donors, the decision was made to avoid using uncontrolled DCD livers and, with further experience, to more carefully control risk factors [e.g., avoidance of old (>60 year old) DCD donors, avoidance of donors with long (>60 minutes) warm ischemic times during procurement, avoidance of confounding factors in the DCD donors, and minimization of cold ischemic times]. While patient survival and graft survival have improved in more recent eras, the impact of DCD on liver transplantation, as assessed from the Scientific Registry of Transplant Recipients (SRTR) database, shows that DCD graft survival was significantly lower than that of donation after brain death (DBD) grafts, with 1- and 3-year graft survival of 70.2% and 63.3% for DCD recipients versus 80.4% and 72.1% for recipients of livers from conventional DBD donors. Recipients of a DCD graft had a greater incidence of primary nonfunction (11.8 versus 6.4%) and retransplantation (13.9% versus 8.3%) compared with DBD recipients.11 Similar findings have also been reported at single centers12, 13 The mandated period of warm ischemia imposed during the process of certifying death in controlled DCD leads to stagnation of blood in the microcirculation. Although heparin is permitted in many (but not all) DCD procurements,14, 15 removal of formed blood elements from the microvasculature is dependent on adequate flushing. The standard preservation solution used in the United States is the colloid-based University of Wisconsin (UW) solution. The viscosity of this solution, particularly at temperatures used for organ preservation (4°C), is far higher than that of crystalloid solutions throughout the temperature spectrum. Since flow through a hollow vessel is inversely related to the viscosity, the more viscous UW solution is less likely to penetrate and adequate flush the biliary plexus, potentiating the risk of ischemic-type biliary stricture (ITBS) development.16 This is due to the unique nature of the blood supply for the bile duct, which depends solely on a hepatic artery blood supply via a vascular plexus to ensure bile duct viability.17 Crystalloid-based preservation solutions, such as histidine-tryptophan-ketoglutarate (HTK) and Celsior, have the physical advantage of being significantly less viscous than UW solution. In addition, UW solution has been shown to develop adenosine crystals at subzero temperatures, which can further exacerbate microcirculatory embarrassment after reperfusion.18 As a result, crystalloid solutions are more likely to flush stagnant blood from the microvasculature in DCD organs than colloid-based preservation solutions. Indeed, HTK has been reported to be associated with lower rates of biliary strictures than UW solution.19 The experience with DCD in the era of UW solution–based preservation solution, which constitutes the bulk of the SRTR DCD experience, demonstrates that almost 3 times as many DCD livers (up to 35%-50% of livers) will suffer from ITBS compared to DBD livers. In this issue of Liver Transplantation, authors from the Johns Hopkins University reported their experience with the use of livers from DCD.20 Mirroring the previously noted SRTR outcomes, they reported poorer patient (75%) and graft (55%) survival with a median follow-up of only 7.5 months. Causes of graft losses included hepatic artery thrombosis (HAT), primary nonfunction, and biliary strictures. Besides the contribution of biliary strictures to graft loss, this complication also contributed to significant morbidity. A total of 75% of DCD recipients developed biliary strictures, the majority of which were intrahepatic, hilar, or donor common duct. The authors did note that HTK was used in the last 40% of the cases in this case series, although no data were provided regarding the nature, magnitude, and outcomes based on preservation solution. Not all biliary strictures in DCD recipients behave the same. This is highlighted in a separate study also published in this issue of Liver Transplantation. One hundred seventy-two Korean recipient survivors, receiving liver transplants in the People's Republic of China (PRC) between 2001 and 2005, were followed at Seoul National University.21 As mentioned in the February 2007 issue of Liver Transplantation, the major source of cadaveric grafts in PRC is DCD.22 As a result, a high rate of biliary strictures among those that survived to return to Korea was not unexpected. Although the authors did not have access to perioperative factors, such as preservation solution and cold ischemia times, during this period of time, only the colloid-based UW preservation solution was available in PRC. The authors noted that patients with limited focal strictures (e.g., unilateral or at the confluence) could be treated with interventional dilatation and stenting with an overall 100% survival. On the other hand, bilateral or diffuse biliary strictures were associated with a reduced survival of 86% and 0%, respectively. If DCD livers are to be used with greater frequency, the outcomes will need to be predictably similar to those of standard DBD. How can this be achieved? Some hints can be derived from other clinical settings and in animal and human DCD studies. The development of HAT following liver transplantation is one of the most devastating complications, with a high risk of subsequent biliary tract ischemia and necrosis with a high rate of retransplantation. In 1996, in a series of 17 patients that developed HAT early after liver transplant, an approach of immediate thrombectomy with the use of thrombolytic therapy directly instilled into the hepatic artery and revascularization demonstrated that 88% of liver allografts could be successfully treated for long-term patency of the hepatic artery, and more importantly, no patient developed ITBS.23 The research group from the University of Bonn demonstrated graft alterations including erythrocyte aggregation and thrombus formation, which affected equilibration of the preservation solution within the microvasculature, preventing effective cold preservation in a rat NHBD model. The compromised microvascular perfusion and release of liver enzymes associated with the use of UW solution for the initial flushout of livers were markedly attenuated by the additional warm preflush with Ringer's lactated solution containing streptokinase.24 Other animal models have also validated the use of thrombolytic agents in NHBD.25 Investigators at the University of Newcastle upon Tyne then conducted a double-blinded, randomized, controlled trial of streptokinase preflush or placebo in human DCD kidneys. Following declaration of cardiac death, a solution containing therapeutic doses of streptokinase was given prior to initiation of infusion of the preservation solution, which in this case was Euro-Collins solution. DCD kidneys were machine-preserved and transplanted within 24 hours of procurement. These investigators noted that kidneys from the streptokinase-treated donors had a significantly better appearance at procurement, and there was a higher proportion of kidneys transplanted through the use of streptokinase (63.6% with streptokinase versus 42.6% with placebo). Given that the majority of DCD kidneys were uncontrolled, the high incidence of delayed graft function was not surprising, but all streptokinase-treated kidneys recovered function.26 However, are there any data to support this approach for livers? Some centers have relayed (Yue Zhu, Yuan Hospital, Shanghai, PRC, personal communication, April 2007) or published27 their experiences with protocols incorporating thrombolytic agent use, with encouraging rates of biliary strictures. At our own center, we have utilized a protocol of giving 50 mg of recombinant tissue plasminogen activator (rTPA) along with 30,000 units of heparin systemically, preferably in situ, before declaration of death, followed by preservation flush with HTK. In those instances where rTPA or heparin cannot be used before declaration of death, heparin is given along with HTK (at 2500 units of heparin per liter of HTK), and the liver is cold-preserved. After portal revascularization in the recipient and warming of the liver (to maximize the enzymatic activity of rTPA), 25 mg of rTPA in a volume of 10-12 cc of normal saline is instilled into the donor hepatic artery, which is clamped for 20-30 minutes. The hepatic artery is then back-bled to allow excess rTPA to be discarded in order to minimize its introduction into the recipient's circulation. In this manner, we have noted that in 12 DCD livers procured and transplanted with this technique at our institution, there were no cases of ITBS noted. These practical experiences address some of the concerns raised by others,28 such as exacerbating ischemia-reperfusion injury and enhancing operative bleeding. The appropriate timing of the administration of anticoagulants and vasodilators during the DCD process is unresolved. Flushing organs with anticoagulants/vasodilators after procurement may be as effective as preprocurement administration. Thrombolytics may be of value after the declaration of death, but there is little data to answer this question. For cold storage, the optimal preservation solution (UW, HTK, and others) has yet to be established. Since the type of preservation solution has only recently been added to the SRTR database, no information was available for the conference participants to consider. With regard to DCD liver transplantation, studies are needed to determine the impact of the preservation solution on the development of biliary strictures. In conclusion, as we expand our knowledge of biologic and physiologic alterations in these donors, integration of available, replicable, and transferable technologies into practice can improve clinical outcomes, leading to greater adoption of conventional DCD. The pathophysiologic mechanisms of graft dysfunction in DCD transplantation represent some of the most extreme manifestations of the ischemia-reperfusion pathway that we encounter in clinical transplantation, magnified by varying degrees of microcirculatory thrombosis. The impact of this vascular stasis and thrombosis depends on the organ: with kidneys, this is manifested by a high rate of acute tubular necrosis and delayed graft function; with livers, there is a higher incidence of macrovascular thrombosis and primary nonfunction leading to a higher rate of early retransplantation, and more importantly, there is an increased rate of late biliary strictures leading to increased morbidity and mortality. Recent experimental and clinical studies suggest that crystalloid-based preservation solutions combined with thrombolytic agents may lead to better outcomes by enhancing microcirculatory integrity and addressing microvascular thrombosis. However, in light of the small numbers and unique practices reported by single centers, larger, prospective, multicenter studies validating such approaches are critically needed. If these approaches are successful, DCD can be viewed as a means to help alleviate the organ shortage while minimizing the penalty of using such donors by, in particular, reducing the risk of ITBS, the true Achilles heel of using DCD donors.
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Fung et al. (2007) studied this question.
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