FORUM
Donation After Circulatory Death: Current Practices, Ongoing Challenges, and Potential Improvements Paul E. Morrissey1,3 and Anthony P. Monaco2 Organ donation after circulatory death (DCD) has been endorsed by the World Health Organization and is practiced worldwide. This overview examines current DCD practices, identifies problems and challenges, and suggests clinical strategies for possible improvement. Although there is uniform agreement on DCD donor candidacy (ventilatordependent individuals with nonrecoverable or irreversible neurologic injury not meeting brain death criteria), there are variations in all aspects of DCD practice. Utilization of DCD organs is limited by hypoxia, hypotension, reduced Y then absent Y organ perfusion, and ischemia/reperfusion syndrome. Nevertheless, DCD kidneys exhibit comparable function and survival to donors with brain death kidneys, although they have higher rates of primary graft nonfunction, delayed graft function, discard, and retrieval associated injury. Concern over ischemic organ injury underscores the reluctance to recover extrarenal DCD organs since lack of medical therapy to support inadequate allograft function limits their acceptability. Nevertheless, limited results with DCD pancreas, liver, and lung allografts (but not heart) are now approaching that of donors with brain death organs. Pretransplant machine perfusion of DCD kidneys (vs. static storage) may reduce delayed graft function but has no effect on long-term organ function and survival. Normothermic regional perfusion used during DCD abdominal organ retrieval may reduce ischemic organ injury and increase the number of usable organs, although critical confirmative studies have yet to be done. Minor increases in usable DCD kidneys could accrue from increased use of pediatric DCD kidneys and from selective use of DCD/ECD kidneys, whereas a modest increase could result through utilization of donors declared dead beyond 1 hr from withdrawal of life support therapy. A significant increase in transplantable kidneys could be achieved by extension of the concept of living kidney donation in relation to imminent death of potential DCD donors. Progress in research to identify, prevent, and repair DCD-associated organ retrieval injury should improve utilization of DCD organs. Recent results using ex situ pretransplant organ perfusion of DCD organs has been encouraging in this regard. Keywords: Donation after circulatory death, Organ donation, Organ preservation, Solid organ transplantation. (Transplantation 2014;97: 258Y264)
olid organs for transplantation are recovered from deceased donors with brain death (DBD) or by donation after circulatory death (DCD). Originally called non-heartbeating-donation and later donation after cardiac death, the current terminology (donation after circulatory death) more precisely reflects identification of the cessation of peripheral blood flow by the absence of peripheral pulses and blood pressure over asystole to declare death. In the United States, most organ procurement agencies (OPOs) abandoned DCD after brain death legislation was adopted in 1968, although some centers continued to use DCD donors (1). In the 1990s,
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The authors declare no funding or conflicts of interest. 1 Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI. 2 Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, MA. 3 Address correspondence to: Paul E. Morrissey, M.D., Division of Organ Transplantation, Rhode Island Hospital, 593 Eddy St, APC 921, Providence, RI 02903. E-mail: [email protected] P.E.M. and A.P.M. contributed equally to the research and writing of this article. Received 10 June 2013. Revision requested 3 July 2013. Accepted 18 September 2013. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9703-258 DOI: 10.1097/01.TP. 0000437178.48174.db
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the Maastricht (Netherlands) group rekindled interest in DCD in Europe where it is currently practiced in 10 of 27 EU nations (2, 3) as well as the United States, Canada, Australia, Japan, China, the Far East, and a few South American nations (4, 5). In the United States, the DHHS and IOM (6) endorsed non-heart-beating donation, the OPTN mandated that all transplant programs develop protocols for DCD, and the Joint Commission on Accreditation of Healthcare Organizations required hospitals to implement written policies and procedures for organ and tissue recovery (7). The World Health Organization (WHO) (5) has encouraged all societies to develop responsible policies concerning donation after death and the adoption of DCD worldwide. This review describes recent experience with DCD donors and focuses on clinical strategies to safely expand the number of useable DCD organs. Categories of DCD The 1995 Maastricht classification (modified in 2003) defines DCD categories according to the circumstances of the donor’s death (8, 9) (Table 1). Current DCD Practices Individuals with nonrecoverable or irreversible neurologic injury with ventilator dependency not meeting criteria Transplantation
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TABLE 1.
Categories of donation after circulatory death
Category I. Dead on arrival. Tissue (corneas, heart valves, skin, bone, etc.) can be recovered from category I donors or any individuals who die in a hospital in a manner not suitable for solid organ recovery. Since there are no immediate time constraints to minimize tissue injury, there is no requirement for a precisely timed approach to tissue recovery. Category II. Unsuccessful resuscitation (CPR). These are patients who suffer a witnessed cardiac arrest outside the hospital and undergo unsuccessful cardiopulmonary resuscitation (CPR). When CPR fails in a medically suitable organ donor, uncontrolled organ donation is an option. Category III. Awaiting cardiac arrest following withdrawal of care. With the permission of the donor or donor family, organs may be recovered after death is declared from patients with irreversible brain injury or respiratory failure in whom treatment is withdrawn. Death is declared after a predetermined period, usually 5 min, of circulatory arrest. Category IV. Cardiac arrest after brain death. Rarely, a consented brain dead donor has a cardiac arrest before scheduled organ recovery. Such category IV donors should either proceed as for a normal multiorgan retrievalVif this has already startedVor should be managed as a category III donor as appropriate to the circumstances of cardiac arrest. Category V. Cardiac arrest in a hospital patient. Newly added in 2000, this category is made up of category II donors that originate in-hospital. The distinction allows for improved tracking the outcomes (9).
for brain death are considered candidates for controlled type III DCD donation. The family designates the donor candidate Do Not Resuscitate (DNR) order and gives permission for organ retrieval upon declaration of death (DOD). Protocols for DCD organ retrievals vary with local practices (10, 11). Withdrawal of life support therapy (WLST) is usually initiated in the intensive care unit or other specifically designated hospital area, and the patient is serially monitored for peripheral circulation. Death may be declared on cessation of circulation. In some countries, there is a mandatory stand-off or waiting period usually of 5 min, and in others, the verification of death can only be done 5 min after circulatory arrest. Some OPOs use the mandatory 5-min interval to transport the donor to the operating room (OR). Upon verification of death, organ retrieval begins. The entry event in uncontrolled DCD donation is cardiopulmonary arrest rather than a neurological insult. In type II DCD, once cardiopulmonary resuscitation (CPR) is deemed unsuccessful, simultaneous efforts are engaged to obtain family consent or document first-person consent by the newly deceased and to preserve the organs by cold perfusion in anticipation of expeditious organ retrieval. After declaration of death, CPR is resumed in some protocols, although not in others (10). A 5- to 10-min stand-off period is observed after cessation of CPR to ensure that death has occurred. The potential donor is transported to the OR or procedure area. Organ retrieval techniques for DCD donations are different from those for DBD in terms of cannulation, perfusion, tempo, and extent. Some centers initiate cold perfusion via direct aortic cannulation after rapid celiotomy, whereas other centers begin cold perfusion outside the OR via femoral artery cannulation instilling a preflush with thrombolytic medication followed by up to 20 L of cold kidney perfusion fluid.
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In Europe, normothermic regional perfusion (NRP) is practiced widely replacing cold perfusion. It is achieved (12) using occlusive balloon catheters placed in the thoracic aorta and in the vena cava at the level of the diaphragm/hepatic veins via the femoral vessels while separate contralateral femoral arterial and venous lines are connected to a circuit consisting of reservoir, pump, oxygenator, and heater for regional perfusion. Differences in DCD Protocols Multiple recommendations for standardization of DCD protocols have been made (10, 11, 13Y18). Nevertheless, variations in exclusion and inclusion criteria, the venue for WLST, the criteria for DCD, the definition of circulatory arrest, the length of mandatory observation waiting time, and the separation of roles of transplant physicians and clinicians responsible for WLST and declaring death persist. Standard DCD practices would achieve maximal DCD organ procurement and preserve optimal end-of-life care, public trust, and professional integrity (18, 19). The majority of DCD donors in Belgium, The Netherlands, the United Kingdom, and the United States are type III, whereas type II donors predominate in France and Spain (3). In Japan, DCD is the predominant form of organ donation, where brain death was illegal until very recently and remains culturally unpopular (20). A recent report from China describes the outcome from 50 DCD donors, 40 of whom were brain dead but recovered as elective category IV donors (21). Specific details of premortem interventions, the time interval for circulatory arrest, and which organs can be safely transplanted are based on clinical experience rather than welldesigned clinical trials. There is mixed enthusiasm for DCD at all levels within the transplant community owing to these complex medical, legal, ethical, and logistical concerns.
CLINICAL ISSUES Organ Injury Warm ischemia time (WIT) is defined as the time from arrest to cold flush or regional perfusion. DCD donors inevitably suffer hypoxia, hypotension, and inadequate organ perfusion (22) during the progression to circulatory arrest (agonal phase) and the mandatory 5-min period of warm, pulseless ischemia. No outcome differences were noted for premortem cannulation and immediate cold perfusion after DOD compared with immediate celiotomy and aortic cannulation (22). Premortem catheter placement required additional time and radiological studies and was associated with occasional technical problems that minimized any time advantage over the less cumbersome operative approach (22, 23). Many potential therapeutic donor interventions are limited by legal constraints in DCD (24). Brain death causes variations in catecholamine levels, leading to hemodynamic perturbations (hypotension, organ hypoperfusion) that may be further exacerbated by inflammatory molecules, including interleukin-1, -6, and -8 that adversely affect renal allografts (25). Injury from hypoperfusion and the proinflammatory milieu before ischemiaYreperfusion may explain the lower graft survival from DBD donors when compared with that from living donors. Whether the proinflammatory milieu is substantially different in the setting of severe, irreversible head injury without herniation (DCD)
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versus brain death (DBD) has not been established. DCD grafts may not be as immunogenic in the recipient because of this potential difference (26). Outcomes Kidney DCD kidneys show comparable function and survival to DBD kidneys after the immediate postoperative period and a survival benefit to recipients over waiting for DBD kidneys (27, 28). Using UK Registry data, Summers et al. (29) found no difference in graft survival up to 5 years in DCD (n=739) versus DBD (n=6759) recipients (hazard ratio=1.01, 95% confidence limits 0.83Y1.19, P=0.97) or in epidermal growth factor receptor (eGFR) at 1 to 5 years after transplantation (at 12 months: j0.36 mL/min, 95% confidence limits=j2.00 to 1.27, P=0.66). DCD kidneys with increased recipient/donor age mismatches, increased cold ischemia time (912 hr), and repeat transplantation exhibited worse graft survival. DCD kidneys poorly matched for the recipient HLA had inferior graft outcomes that were not significant, whereas delayed graft function (DGF) and WIT had no effect on graft outcome. Summers et al. (30) also found no difference in 3-year graft survival between DCD (n=1768) and DBD (n=4127) recipient groups. Donor age clearly had an adverse affect on GFR, with the highest risk observed for donors older than 45 years (risk ratio=4.81, P=0.001). Again, DGF was common after DCD but did not influence kidney function or graft survival. Donor age (960 vs. G40 years) was a risk for graft loss for all deceased donor kidneys (risk ratio=2.35, 95% confidence limits=1.85Y3.00, PG0.0001) but not for graft loss for DCD donors older than 60 years compared with DBD donors of the same age group (P=0.30). Prolonged cold ischemia (924 vs. G12 hr) was not associated with decreased graft survival for all deceased donors but was associated with poor graft survival of kidneys from DCD donors versus those from DBD donors (risk ratio=2.36, 1.39Y4.00, P for interaction=0.004). DCD kidneys tolerate cold storage less well, a finding important for allocation policies. While some studies demonstrate identical graft survival from older DCD donors, one important study (31) compared iothalamate GFR in 64 DCD versus 248 DBD kidney recipients. Donor age clearly had an adverse effect on GFR, with the highest risk observed for donors older than 45 years (risk ratio=4.81, PG0.001). Again, DGF was common after DCD but did not influence kidney function or graft survival. DCD kidneys accounted for 11% of all renal transplants in the United States (32) and make up 30% to 50% of all deceased donors in some European countries (3). During 2000 to 2008, European centers transplanted 5004 DCD organs (4261 kidneys, 505 livers, 157 lungs, and 81 pancreases). Outcomes in 2343 controlled versus 649 uncontrolled DCD kidney transplants demonstrated similar primary graft nonfunction (PGNF; 5% vs. 6.4%, respectively) and 1-year graft survival (85.1% vs. 86.7%, respectively) but significantly more DGF (50.2% vs. 75.7%, respectively) after uncontrolled DCD. Similar excellent results for DCD kidney transplantation have been validated at many centers (26Y28). Hoogland et al. (33) reported similar good long-term outcomes in 336 recipients of type II and type III DCD kidneys. Although the incidence of PGNF and DGF was
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substantially high in both type II (n=128) and the type III (n=208) groups (22% vs. 21% and 61% vs. 56%, respectively, P=0.43), the 10-year graft and recipient survival rates were essentially the same (50% vs. 45%, respectively, P=0.74 and 61% vs. 60%, respectively, P=0.76) as were the eGFRs after 1 year (40T16 vs. 47T19 mL/min/1.73 m2, P=0.55). Singh and Kim (34) examined whether ECD status modified outcomes of DCD kidney transplants in a cohort study of 67,816 recipients of deceased donor kidney transplants that included 562 ECD/DCD recipients. The modestly increased risk of total graft failure in DCD versus DBD transplants was not significantly modified by combined ECD/ DCD status. Similar results were identified for death censored graft and patient outcomes. The authors suggested that judicious use of ECD/DCD donor kidneys may be appropriate to expand the DCD pool, a conclusion cautiously supported by McDonald and Clayton (35) who provided an elegant analysis of the risks/benefits of this approach and underscored the need for standard protocols, uniform metrics, collaborative multinational registries, and regular data collection to define the best way to use these donors. Donor obesity may adversely affect DCD kidney function. Ortiz et al. (36) reviewed 6932 DCD donors in the United States between 1997 and 2010. Body mass index (BMI) did not affect death-censored graft survival in DBD and only adversely affected survival after DCD when BMI was greater than 45 kg/m2. DGF was more common with higher BMI in DBD and DCD. Ausania et al. (37) noted that, in a total of 13,260 kidney procurements performed in the United Kingdom during the 10-year period (2000Y2010), in which 12,372 (93.3%) DBD kidneys and 888 DCD kidneys were recovered, injuries occurred in 903 procedures (7.1%). The rate of surgical damage was significantly higher in DCD than in DBD donor kidneys (11.4% vs. 6.8%, respectively, PG00.1). Capsular, ureteric, and vascular injuries were all significantly more frequent contributing to a higher discard rate after DCD donation (P=0.002). Extrarenal Organs From DCD Donors In the United States, the number of organs transplanted per donor in 2011 for a standard criteria DBD donor was 3.71 versus 2.07 for DCD donors (38). Over the past decade, organ yield per donor is consistently greater from DCD (range=1.83Y2.28) compared with ECD (range=1.78Y1.91). The associated ischemic organ injury contributes to a reluctance to recover extrarenal DCD organs. Utilization of extrarenal DCD organs may increase as successful methods of in situ organ resuscitation are applied to clinical practice (see below). Pancreas Outcomes of DCD pancreas transplants are acceptable (39). A UK analysis of 134 DCD versus 875 DBD pancreas transplants showed similar 1-year patient and graft survival, with graft survival actually being significantly better in the DCD cohort if performed as part of a simultaneous pancreaskidney transplant. Early graft loss due to thrombosis (8% vs. 4%) was more responsible for graft loss in the DCD cohort (40). Liver DCD liver transplantation initially had inferior survival and higher complication rates (41) but has recently
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flourished in Europe where careful donor selection based on donor age, transaminase values, intensive care unit length of stay, and vasopressor use has improved outcomes that now approximate DBD liver transplantation (42), although ischemic cholangiopathy (43) and associated diminished graft survival (44) due to warm ischemia persist with DCD. Technical factors to speed organ recovery have had minimal impact, most likely because limited circulation and organ injury begins well before circulatory arrest (22). Failure of DCD donors to progress to circulatory arrest within a specified time frame, typically 25 to 30 min for liver donors, means that many planned recoveries do not yield transplantable livers. Graft failure and other complications increase the economic costs of DCD liver transplantation, which are 1.5 times higher than DBD liver transplantation (45). Although only 32 (9%) of liver transplants from 400 potential type II DCD donors could be performed because 59% (236) and 32% (130) were rejected for absolute and relative contraindications, respectively (12), the 1-year patient and graft survival was 82% and 70%. Improved preservation technology and expanded transplant criteria might significantly improve DCD utilization (see below). Type III liver recipients exhibit more acute kidney injury (AKI) versus DBD liver recipients (DCD [n=88] 53.4%, DBD [n= 86] 31.8%, P=0.004) and AKI is a risk factor for CKD (P=0.035) and mortality (P=0.017) (46). The cumulative 3-year CKD incidence was 53.7% and 42.1% for DCD and DBD patients, respectively. Peak postoperative AST, a surrogate marker for hepatic ischemia reperfusion injury, was the only predictor of renal dysfunction after DCD liver transplant (AKI, PG0.001; CKD, P=0.032). Hepatic reperfusion injury may cause renal dysfunction after DCD liver transplantation. Lung Results of lung transplantation from both controlled (47) and uncontrolled (48) DCD have been acceptable, although somewhat inferior to DBD transplants. The Australian Multicenter National DCD Lung Transplant Collaborative reported excellent outcomes with type III DCD lung transplants (49). From 2006 through 2011, there were 174 actual type III donors (with an additional 37 suitable donors who did not have an arrest in the mandatory 90-min withdrawal window) of whom 71 donated to 70 bilateral lung transplants and two single lung transplants. The incidence of grade 3 PGNF was 8.5% at 24 hr, and the incidence of grade 3 chronic rejection was 5%. One- and five-year actuarial survival was 97% and 90% versus 90% and 61% for 503 contemporaneous DBD lung transplants. The authors emphasized that type III lung transplants could provide a significant, effective, quality source of transplantable lungs. Heart As a testimony to the reluctance to use DCD donor hearts for transplantation, only five (all children) were transplanted in the United States from 1996 to 2012 (Table 2). Strategies to Modulate Organ Injury and Improve Organ Function After DCD Numerous strategies have been suggested to reduce cumulative injury sustained by organs during DCD, but
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only limited clinical trials and data are available and none are compelling (24). Static Storage Versus Machine Perfusion Two large, randomized controlled trials (50, 51) of static storage versus machine perfusion of human DCD kidneys, in which one kidney from each donor was stored without perfusion and the other machine-perfused with accepting teams blinded to flow and resistance readings, confirmed that pretransplant machine perfusion had no effect on 1-year patient and graft survival and estimated post transplant GFR. One study identified decreased incidence and duration of DGF after machine perfusion in 82 pairs of DCD kidneys (50), whereas the other study showed no beneficial effect on DGF (51). A 2012 meta-analysis of multiple studies of pulsatile perfusion in DCD showed reduced DGF rates compared to kidneys placed in cold storage (P=0.03; odds ratio=0.64, confidence interval=0.43Y0.95) but no difference in 1-year graft survival (52). Another meta-analysis comparing 175 machine-perfused DCD kidney grafts with 176 cold storage grafts showed that perfused kidneys suffered less DGF (P=0.008, odds ratio=0.56, confidence interval=0.36Y0.86) (53) but no differences in PGNF and 1-year graft or patient survival. Given the increased cost of machine perfusion and similar intermediate-term graft and patient survival, the utility of machine perfusion is unclear (54). Normothermic Regional Perfusion NRP can be established after death to perfuse the abdominal organs with circulating, warm, oxygenated blood. This technique has been proposed as a means to reduce kidney injury, restore cellular metabolism, and thereby increase organ transplantation. NRP was first used for liver transplantation in animal models and has now been used for human kidney, kidney-pancreas, and liver DCD organ procurement (12, 55, 56). In 2000, Valero et al. (56) compared three methods of kidney recovery: in situ cooling, hypothermic extracorporeal circulation of the body, and NRP. A considerable reduction in PGNF and DGF with satisfactory long-term graft survival was observed in the NRP group. Excellent results with 30 type II DCD liver transplants (12) were achieved with DCD organs retrieved with NRP. Definitive controlled, randomized clinical studies in DCD donors using normothermic regional perfusion and/or extracorporeal circulation are required. Ex Situ Perfusion of DCD Organs The recent world congress on Donation after Circulatory Death agreed to refer to perfusion of DCD organs outside the human body as ex situ perfusion (ESP) (57). Ex situ lung
TABLE 2. Pediatric recipients of DCD versus DBD organ transplants from 1995 to 2010 in the United States (73)
Heart Lung Liver Kidney
DCD
DBD
5 2 45 154
4944 851 8120 6762
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perfusion (ESLP) provides a mechanism to evaluate the lung as well as improve lung function before transplantation through the resolution of edema. Cypel et al. (58) reported on 50 lung transplants after ESLP including 22 DCD donor lungs. The incidence of primary graft dysfunction, 30-day mortality (4% in the ESLP group and 3.5% in controls), and 1-year survival (87% in the ESLP group vs. 86% in controls) were similar in both groups. op den Dries et al. (59) performed ESP on four discarded human livers. Biochemical markers in the perfusion fluid reflected minimal hepatic injury and improving function. Lactate levels decreased to normal, reflecting active liver metabolism, and bile production was observed. Histological examination after 6 hr of perfusion showed preserved liver morphology without signs of hepatocellular ischemia, biliary injury, or sinusoidal injury. They concluded that ESLP was technically feasible and could allow assessment of graft viability, possible therapeutic interventions, and potential preconditioning. Peter Friend and the Oxford group (personal communication) performed eight liver transplants after pretransplant ESP with encouraging results. Nicholson and Hosgood (60) assessed the effect of ESP on kidneys from marginal donors. Eighteen ECD kidneys underwent a period of ESLP, using a plasma-free, red blood cellYbased solution immediately pretransplant, and their outcomes were compared with those of 47 ECD kidneys given static storage. The 1-week DGF rate was 1 (5.6%) of 18 in the ESLP group versus 17 (36.2%) of 47 in the cold storage group (P=0.014), with no difference in 1-year patient and graft survival. This technique was obviously feasible and safe and offered significant promise for improved kidney preservation. In the future, various ex vivo pharmacologic or molecular reparative strategies may further improve the ability to transplant DCD lungs and other solid organs.
recovery team and OR staff for an extended period may limit the applicability of this approach.
Strategies to Increase the Number of Usable DCD Organs Several modifications of DCD protocols have been examined to increase the number of donors yielding DCD organs.
Living Kidney Donation in DCD Candidates Current DCD protocols have significant problems: organs damaged from hypotension, hypoxia, or ischemia; failure of DCD donors to adequately progress to circulatory arrest resulting in no organ recovery, family disappointment, and lack of closure; requests to extend the waiting period for determination of death; and the structured approach to end-of-life care in the OR is traumatic and insensitive to the emotional needs of families. Extending living kidney donation to patients with severe irreversible brain injury who would otherwise qualify for DCD procedures (74) might modulate some of these problemsVa concept advanced in the lay literature and supported by DCD donor families (75). Nephrectomy would be performed as a controlled operative procedure in a person whose family previously consented to DNR and DCD. This option might provide a preferential alternative for some families of potential DNR/DCD donor. After nephrectomy, the donor would be returned to the ward for elective WLST and end-of-life care delivered by a combined primary care and palliative care team. The proposal does not violate the dead donor rule, because organ donation does not cause the donor’s demise, since it is a form of living kidney donation. Recovered kidneys would be less damaged, the recipients would fair better with less DGF, and the donor’s death, occurring hours (or days) later after elective WLST, in the absence of stress and urgency
Extension of the Waiting Time to Circulatory Arrest Most DCD protocols recommend a maximal period of 60 to 90 min from WLST to observe for circulatory arrest (14). Reid et al. (62) studied extending the cutoff time for recovery to a minimum of 4 hr. Of 173 potential DCD donors, 117 (67.6%) became donors, of which 90 (76.9%) arrested within 1 hr and an additional 27 (23.1%) donors arrested after 1 hr (8 by 2 hr, 11 more between 2 and 4 hr, and 8 more after 4 hr). The agonal phase (time from WLST to DOD) of all 173 potential donors was studied for the presence or absence of acidemia, lactic acidosis, hypotension for more than 30 min, hypoxia, oliguria, and the impact of these parameters on 3- and 12-month transplant outcomes determined by multivariate analysis. Longer agonal phases had greater donor instability, but increased agonal phase instability or its duration did not influence transplant outcome. Of 190 DCD kidneys transplanted, the 3and 12-month eGFRs were influenced independently by donor age and the 3-month eGFR was influenced by the cold ischemia time. Although extending the waiting time could increase the number of DCD kidneys, maintaining a
Re-evaluation of Timing and/or Declaration of Death The timing of the death declaration has been one of the most controversial parts of DCD protocols particularly as to whether the brain is irreversibly damaged after 5 min of circulatory arrest and, as such, whether DCD adheres to the dead donor ruleVthe guiding principle that the donor must be dead before organs are recovered (63Y67). Some ethicists (65) and clinicians (67) argue that the DCD donor is not dead, but rather in the process of dying; others emphasize the difference between ‘‘irreversible’’ and ‘‘permanent’’ cessation of cardiac function (68)Va crucial factor in end-of-life care. In one pediatric cardiac transplantation case, death was declared in two donors after 75 sec of circulatory arrest (69). Truog and Miller (70) advocated abandoning the dead donor rule and adopting a policy of fully informed consent for families of potential DCD candidates that would allow them to make an ethically acceptable decision as to the endof-life care of the decedent. Increased use of Pediatric DCD Organs Transplanted to Adult and Pediatric Recipients The pediatric community has been reticent to fully adopt DCD, and children are less likely to receive a DCD organ (Table 2). Three concerns regarding pediatric DCD donors are relevant (71): uncertainty about the potential for recovery of meaningful brain function in children, making decisions about WLST difficult; concerns over consent because children are less likely to have expressed a personal preference on donation; and insufficient scientific data on the duration of asystole required before organ recovery. Nevertheless, results from pediatric DCD renal transplants are acceptable (72, 73).
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imposed by current DCD protocols, would take place in a more sensitive and appropriate environment than the OR. This option might offer a desirable alternative to families of potential DNR/DCD donors. Depending on the family motivation, attitudes, and circumstances, DNR/DCD candidates who have donated a kidney in relation to imminent death could subsequently be considered for donation of other organs by standard DCD protocols. Legal concerns, primarily the family’s right to consent to this surgical procedure, and ethical considerations such as providing a foothold to circumvent the dead donor rule have been raised as challenges to this proposal (76). Others have claimed that the concept requires review and serious discussion among the transplant community (77). Involvement of the hospital ethics committee and the local OPO would provide further oversight and scrutiny for each donor as well as assurances for the surgical team and donor family.
Progress in utilization of DCD extrarenal organs should result from current scientific research to identify therapies that minimize organ injury and facilitate useful organ recovery. REFERENCES 1. 2. 3. 4. 5. 6. 7.
CONCLUSIONS
8.
Kidney and extrarenal organs suitable for transplantation are recovered from deceased donors after circulatory arrest throughout the world in increasing numbers (Table 3). Organ injury and failure of the donor to progress in an acceptable time limit DCD utilization. The number of usable DCD kidneys may be incrementally increased through the following:
9.
& & & &
utilization of donors declared dead beyond 1 hr after WLST, increased transplant of pediatric DCD organs, expanded use of NRP or ex situ organ resuscitation, or extending living kidney donation to potential DCD candidates before end-of-life care as a possible preferable alternative to DCD for some families.
TABLE 3. DCD donors recovered for transplant in the United States (January 1, 1996 to December 31, 2012)a Year
Donors Recovered
Kidneys Transplanted
Livers Transplanted
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Total
70 78 75 87 117 167 189 268 393 564 644 791 849 920 941 1055 1089 8297
107 116 110 148 175 249 306 411 566 795 1014 1171 1308 1385 1468 1766 1662 12657
12 17 24 23 39 67 79 112 184 272 289 306 277 289 269 270 260 2789
a
OPTN data assessed on April 4, 2013.
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10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
Bellingham JM, Santhanakrishnan C, Neidlinger N, et al. Donation after cardiac death: a 29-year experience. Surgery 2011; 150: 692. Rudge C, Matesanz R, Delmonico FL, et al. International practices of organ donation. Br J Anaesth 2012; 108(Suppl 1): i48. Domı´nguez-Gil B, Haase-Kromwijk B, Van Leiden H, et al. Current situation of donation after circulatory death in European countries. Transpl Int 2011; 24: 676. Third WHO Global Consultation on Organ Donation and Transplantation: striving to achieve self-sufficiency. Transplantation 2011; 91: S39. Daemen JW, Kootstra G, Wijnen RM, et al. Nonheart-beating donors: The Maastricht experience. Clin Transpl 1994; 7: 303. IOM Report. Non-Heart-Beating Organ Transplantation: Medical and Ethical Issues in Procurement. Washington, DC: National Academy Press; 1997. Healthcare the Crossroads: Strategies for Narrowing Organ Donation Gap and Protecting Patients. Oakbrook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations; 2004. Kootstra G, Daemen JH, Oomen AP. Categories of nonheart-beating donors. Transplant Proc 1995; 27: 2893. Sa´nchez-Fructuoso AI, Prats D, Torrente J, et al. Renal transplantation from non-heart beating donors: a promising alternative to enlarge the donor pool. J Am Soc Nephrol 2000; 11: 350. Donation after Circulatory Death. British Transplant Society. Available at: http://www.bts.org.uk/Documents/Guidelines. Accessed August 1, 2013. Model Elements for Controlled DCD Recovery Protocols. UNOS Bylaws Attachment III, 2007. Available at: www.unos.org/docs/ Appendix_B_AttachIII.pdf. Accessed August 1, 2013. Fondevilla C, Hessheimer AJ, Flores E, et al. Applicability and results of Maastricht type 2 donation after cardiac death liver transplantation. Am J Transplant 2012; 12: 162. Bernat JL, Capron AM, Bleck TP, et al. The circulatory-respiratory determination of death in organ donation. Crit Care Med 2010; 38: 963. Bernat JL, D’Alessandro AM, Port FK, et al. Report of a national conference on donation after cardiac death. Am J Transplant 2006; 6: 281. Shemie SD, Baker AJ, Knoll G, et al. National recommendations for donation after cardiocirculatory death in Canada: donation after cardiocirculatory death in Canada. CMAJ 2006; 175: S1. Australian Organ and Tissue donation and Transplantation Authority. National protocol for donation after cardiac death. Available at: http:// www.donatelife.gov.au/Media/docs/DCD.pdf. Accessed August 1, 2013. Manara R, Murphy PG, O’Callaghan G. Donation after circulatory death. Br J Anaesth 2012; 108: 108. Fugate JE, Stadler M, Rabinstein AA, et al. Variability in donation after cardiac death protocols: a national survey. Transplantation 2011; 91: 386. Rady MY, Verheijde JL, McGregor AJ. Scientific, legal, and ethical challenges of end-of-life organ procurement in emergency medicine. Resuscitation 2010; 81: 1069. Tojimbara T, Fuchinoue S, Iwadoh K, et al. Improved outcomes of renal transplantation from cardiac death donors: a 30-year single center experience. Am J Transplant 2007; 7: 609. Chen GD, Ko DS-C, Wang CX, et al. Kidney transplantation from donors after cardiac death: an initial report of 71 cases from China. Am J Transplant 2013; 13: 1323. 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. Kootstra G, van Heurn E. Nonheartbeating donation of kidneys for transplantation. Nat Clin Pract Nephrol 2007; 3: 154. Dikdan GS, Mora-Esteves C, Koneru B. Review of randomized clinical trials of donor management and organ preservation in deceased donors: opportunities and issues. Transplantation 2012; 94: 425. Pratschke J, Wilhelm MJ, Laskowski I, et al. Influence of donor brain death on chronic rejection of renal transplants in rats. J Am Soc Nephrol 2001; 12: 2474. Brook NR, White SA, Waller JR, et al. Nonheart beating donor kidneys with delayed graft function have superior graft survival compared with conventional heart-beating donor kidneys that develop delayed graft function. Am J Transplant 2003; 3: 614.
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Weber M, Dindo D, Demartines N, et al. Kidney transplantation from donors without a heartbeat. N Engl J Med 2002; 347: 248. Snoeijs MG, Schaubel DE, Hene R, et al. Kidneys from donors after cardiac death provide survival benefit. J Am Soc Nephrol 2010; 21: 1015. Summers DM, Johnson RJ, Allen J, et al. Analysis of factors that affect outcome after transplantation of kidneys donated after cardiac death in the UK: a cohort study. Lancet 2010; 376: 1276. Summers DM, Johnson RJ, Hudson A, et al. Effect of donor age and cold storage time on outcome in recipients of kidneys donated after circulatory death in the UK: a cohort study. Lancet 2013; 381: 703. Wadei HM, Heckman MG, Rawal B, et al. Comparison of kidney function between donation after cardiac death donation and donation after brain death kidney transplantation. Transplantation 2013; 96: 274. Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2011 annual data report: kidney. Am J Transplant 2013; 13: 11. Hoogland ERP, Smoejs MGJ, Winkers B, et al. Kidney transplantation from donors after cardiac death: uncontrolled versus controlled donation. Am J Transplant 2011; 11: 1427. Singh SK, Kim SJ. Does expanded criteria donor status modify the outcomes of kidney transplantation from donors after cardiac death? Am J Transplant 2013; 13: 329. MacDonald S, Clayton P. DCD ECD kidneysVcan you make a silk purse out of a sow’s ear? Am J Transplant 2013; 13: 249. Ortiz J, Gregg A, Wen X, et al. Impact of donor obesity and donation after cardiac death on outcomes after kidney transplantation. Clin Transplant 2012; 26: E284. Ausania F, White SA, Pocock P, et al. Kidney damage during organ recovery in donation after circulatory death donors: data from UK National Transplant Database. Am J Transplant 2012; 12: 932. Israni AK, Zaun DA, Rosendale JD, et al. OPTN/SRTR 2011 annual data report: deceased organ donation. Am J Transplant 2013; 13: 179. Maglione M, Ploeg RJ, Friend PJ. Donor risk factors, retrieval technique, preservation and ischemia/reperfusion injury in pancreas transplantation. Curr Opin Organ Transplant 2013; 18: 83. Muthusamy ASR, Mumford L, Hudson A, et al. Pancreas transplantation from donors after circulatory death from the United Kingdom. Am J Transplant 2012; 12: 2150. Reich DJ, Hong JC. Current status of donation after cardiac death liver transplantation. Curr Opin Organ Transplant 2010; 15: 316. Dubbeld J, Hoekstra H, Farid W, et al. Similar liver transplantation survival with selected cardiac death donors and brain death donors. Br J Surg 2010; 97: 744. Jay CL, Lyuksemburg V, Ladner DP, et al. Ischemic cholangiopathy after controlled donation after cardiac death liver transplantation: a meta-analysis. Ann Surg 2011; 253: 259. Waki K. UNOS Liver Registry: ten year survivals. Clin Transpl 2006: 29. Jay CL, Lyuksemburg V, Kang R, et al. The increased costs of donation after cardiac death liver transplantation: caveat emptor. Ann Surg 2010; 251: 743. Leithead JA, Taricotti L, Gunson B, et al. Donation after cardiac death liver transplant recipients have an increased frequency of acute kidney injury. Am J Transplant 2012; 12: 965. Van De Wauwer C, Verschuuren EA, van der Bij W, et al. The use of non-heart-beating lung donors category III can increase the donor pool. Eur J Cardiothorac Surg 2011; 39: e175. Gomez-de-Antonio D, Campo-Can˜averal JL, Crowley S, et al. Clinical lung transplantation from uncontrolled non-heart-beating donors revisited. J Heart Lung Transplant 2012; 31: 349. Levvey BJ, Harkees M, Hopkins P, et al. Excellent clinical outcomes from a national donation-after-determination-of-cardiac-death lung transplant collaborative. Am J Transplant 2012; 12: 2406. Jochmans I, Moers C, Smits JM, et al. Machine perfusion versus cold storage for the preservation of kidneys donated after cardiac death: a multicenter, randomized, controlled trial. Ann Surg 2010; 252: 756. Watson CJE, Wells AC, Roberts RJ, et al. Cold machine perfusion versus static cold storage of kidneys donated after cardiac death: a UK multicenter randomized controlled trial. Am J Transplant 2010; 10: 1991.
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Bathini V, McGregor T, McAlister VC, et al. Renal perfusion pump vs. cold storage for donation after cardiac death kidneys: a systematic review. J Urol. 2012; 189: 2214. Deng R, Gu G, Wang D, et al. Machine perfusion verus cold storage of kidneys derived from donation after cardiac death: a meta-analysis. PloS One 2013; 8: e56368. Machnicki G, Lentine KL, Salvalaggio PR, et al. Kidney transplant Medicare payments and length of stay: associations with comorbidities and organ quality. Arch Med Sci 2011; 7: 278. Farney AC, Singh RP, Hines MH, et al. Experience in renal and extrarenal transplantation with donation after cardiac death donors with selective use of extracorporeal support. J Am Coll Surg 2008; 206: 1028. Valero R, Cabrer C, Oppenheimer F, et al. Normothermic recirculation reduces primary graft dysfunction of kidneys obtained from non-heartbeating donors. Transpl Int 2000; 13: 303. Sixth International Conference on Organ Donation after Circulatory Death: Practices, Expert Recommendations and Future of DCD Donation and Transplantation in Europe. Paris, 7Y9 February 2013. Cypel M, Yeung JC, Machuca T, et al. Experience with the first 50 ex vivo lung perfusions in clinical transplantation. J Thorac Cardiovasc Surg 2012; 144: 1200. op den Dries S, Karimian N, Sutton ME, et al. Ex vivo normothermic machine perfusion and viability testing of discarded human donor livers. Am J Transplant 2013; 13: 1327. Nicholson ML, Hosgood SA. Renal transplantation after ex vivo normothermic perfusion: the first clinical study. Am J Transplant 2013; 13: 1246. Harring TR, Nguyen NT, Cotton RT, et al. Liver transplantation with donation after cardiac death donors: a comprehensive update. J Surg Res 2012; 178: 502. Reid AW, Harper S, Jackson CH, et al. Expansion of the kidney donor pool by using cardiac death donors with prolonged time to cardiorespiratory arrest. Am J Transplant 2011; 11: 995. Arnold RM, Youngner SJ. The dead donor rule: should we stretch it, bend it, or abandon it? Kennedy Inst Ethics J 1993; 3: 263. Marquis D. Are DCD donors dead? Hastings Center Report 2010; 40: 24. Bernat JL. Point: are donors after circulatory death really dead, and does it matter? Yes and Yes. Chest 2010; 138: 13. Truog RD, Miller FG. Counterpoint: are donors after circulatory death really dead and does it matter? No and not really. Chest 2010; 138: 16. Joffe AR, Carcillo J, Anton N, et al. Donation after cardiocirculatory death: a call for a moratorium pending full public disclosure and fully informed consent. Philos Ethics Humanit Med 2011; 6: 17. Bernat JL. How the distinction between ‘‘irreversible’’ and ‘‘permanent’’ illuminates circulatory-respiratory death determination. J Med Philos 2010; 35: 242. Boucek MM, Mashburn C, Dunn SM, et al. Pediatric heart transplantation after declaration of cardiocirculatory death. N Engl J Med 2008; 359: 709. Truog RD, Miller FG. The dead donor rule and organ transplantation. N Engl J Med 2008; 359: 674. Harrison CH, Laussen PC. Controversy and consensus on pediatric donation after cardiac death: ethical issues and institutional process. Transplant Proc 2008; 40: 1044. Dagher NN, Lonze BE, Singer AL, et al. Outcomes and discard of kidneys from pediatric donors after cardiac death. Transplantation 2011; 91: 765. Yoo PS, Olthoff KM, Abt PL. Donation after cardiac death in pediatric organ transplantation. Curr Opin Organ Transplant 2011; 16: 483. Morrissey PE. The case for kidney donation before end-of-life care. Am J Bioeth 2012; 12: 1. Greenberg G. As good as dead: is there really such a thing as brain death? New Yorker Magazine 2001, August 13: 36. Cantor NL. Could premortem organ retrieval be lawful? Am J Bioeth 2012; 12: 12. Marquis D. In defense of Morrissey’s strategy. Am J Bioeth 2012; 12: 9.
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Donation After Circulatory Death: Current Practices, Ongoing Challenges, and Potential Improvements Paul E. Morrissey1,3 and Anthony P. Monaco2 Organ donation after circulatory death (DCD) has been endorsed by the World Health Organization and is practiced worldwide. This overview examines current DCD practices, identifies problems and challenges, and suggests clinical strategies for possible improvement. Although there is uniform agreement on DCD donor candidacy (ventilatordependent individuals with nonrecoverable or irreversible neurologic injury not meeting brain death criteria), there are variations in all aspects of DCD practice. Utilization of DCD organs is limited by hypoxia, hypotension, reduced Y then absent Y organ perfusion, and ischemia/reperfusion syndrome. Nevertheless, DCD kidneys exhibit comparable function and survival to donors with brain death kidneys, although they have higher rates of primary graft nonfunction, delayed graft function, discard, and retrieval associated injury. Concern over ischemic organ injury underscores the reluctance to recover extrarenal DCD organs since lack of medical therapy to support inadequate allograft function limits their acceptability. Nevertheless, limited results with DCD pancreas, liver, and lung allografts (but not heart) are now approaching that of donors with brain death organs. Pretransplant machine perfusion of DCD kidneys (vs. static storage) may reduce delayed graft function but has no effect on long-term organ function and survival. Normothermic regional perfusion used during DCD abdominal organ retrieval may reduce ischemic organ injury and increase the number of usable organs, although critical confirmative studies have yet to be done. Minor increases in usable DCD kidneys could accrue from increased use of pediatric DCD kidneys and from selective use of DCD/ECD kidneys, whereas a modest increase could result through utilization of donors declared dead beyond 1 hr from withdrawal of life support therapy. A significant increase in transplantable kidneys could be achieved by extension of the concept of living kidney donation in relation to imminent death of potential DCD donors. Progress in research to identify, prevent, and repair DCD-associated organ retrieval injury should improve utilization of DCD organs. Recent results using ex situ pretransplant organ perfusion of DCD organs has been encouraging in this regard. Keywords: Donation after circulatory death, Organ donation, Organ preservation, Solid organ transplantation. (Transplantation 2014;97: 258Y264)
olid organs for transplantation are recovered from deceased donors with brain death (DBD) or by donation after circulatory death (DCD). Originally called non-heartbeating-donation and later donation after cardiac death, the current terminology (donation after circulatory death) more precisely reflects identification of the cessation of peripheral blood flow by the absence of peripheral pulses and blood pressure over asystole to declare death. In the United States, most organ procurement agencies (OPOs) abandoned DCD after brain death legislation was adopted in 1968, although some centers continued to use DCD donors (1). In the 1990s,
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The authors declare no funding or conflicts of interest. 1 Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI. 2 Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, MA. 3 Address correspondence to: Paul E. Morrissey, M.D., Division of Organ Transplantation, Rhode Island Hospital, 593 Eddy St, APC 921, Providence, RI 02903. E-mail: [email protected] P.E.M. and A.P.M. contributed equally to the research and writing of this article. Received 10 June 2013. Revision requested 3 July 2013. Accepted 18 September 2013. Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9703-258 DOI: 10.1097/01.TP. 0000437178.48174.db
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the Maastricht (Netherlands) group rekindled interest in DCD in Europe where it is currently practiced in 10 of 27 EU nations (2, 3) as well as the United States, Canada, Australia, Japan, China, the Far East, and a few South American nations (4, 5). In the United States, the DHHS and IOM (6) endorsed non-heart-beating donation, the OPTN mandated that all transplant programs develop protocols for DCD, and the Joint Commission on Accreditation of Healthcare Organizations required hospitals to implement written policies and procedures for organ and tissue recovery (7). The World Health Organization (WHO) (5) has encouraged all societies to develop responsible policies concerning donation after death and the adoption of DCD worldwide. This review describes recent experience with DCD donors and focuses on clinical strategies to safely expand the number of useable DCD organs. Categories of DCD The 1995 Maastricht classification (modified in 2003) defines DCD categories according to the circumstances of the donor’s death (8, 9) (Table 1). Current DCD Practices Individuals with nonrecoverable or irreversible neurologic injury with ventilator dependency not meeting criteria Transplantation
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TABLE 1.
Categories of donation after circulatory death
Category I. Dead on arrival. Tissue (corneas, heart valves, skin, bone, etc.) can be recovered from category I donors or any individuals who die in a hospital in a manner not suitable for solid organ recovery. Since there are no immediate time constraints to minimize tissue injury, there is no requirement for a precisely timed approach to tissue recovery. Category II. Unsuccessful resuscitation (CPR). These are patients who suffer a witnessed cardiac arrest outside the hospital and undergo unsuccessful cardiopulmonary resuscitation (CPR). When CPR fails in a medically suitable organ donor, uncontrolled organ donation is an option. Category III. Awaiting cardiac arrest following withdrawal of care. With the permission of the donor or donor family, organs may be recovered after death is declared from patients with irreversible brain injury or respiratory failure in whom treatment is withdrawn. Death is declared after a predetermined period, usually 5 min, of circulatory arrest. Category IV. Cardiac arrest after brain death. Rarely, a consented brain dead donor has a cardiac arrest before scheduled organ recovery. Such category IV donors should either proceed as for a normal multiorgan retrievalVif this has already startedVor should be managed as a category III donor as appropriate to the circumstances of cardiac arrest. Category V. Cardiac arrest in a hospital patient. Newly added in 2000, this category is made up of category II donors that originate in-hospital. The distinction allows for improved tracking the outcomes (9).
for brain death are considered candidates for controlled type III DCD donation. The family designates the donor candidate Do Not Resuscitate (DNR) order and gives permission for organ retrieval upon declaration of death (DOD). Protocols for DCD organ retrievals vary with local practices (10, 11). Withdrawal of life support therapy (WLST) is usually initiated in the intensive care unit or other specifically designated hospital area, and the patient is serially monitored for peripheral circulation. Death may be declared on cessation of circulation. In some countries, there is a mandatory stand-off or waiting period usually of 5 min, and in others, the verification of death can only be done 5 min after circulatory arrest. Some OPOs use the mandatory 5-min interval to transport the donor to the operating room (OR). Upon verification of death, organ retrieval begins. The entry event in uncontrolled DCD donation is cardiopulmonary arrest rather than a neurological insult. In type II DCD, once cardiopulmonary resuscitation (CPR) is deemed unsuccessful, simultaneous efforts are engaged to obtain family consent or document first-person consent by the newly deceased and to preserve the organs by cold perfusion in anticipation of expeditious organ retrieval. After declaration of death, CPR is resumed in some protocols, although not in others (10). A 5- to 10-min stand-off period is observed after cessation of CPR to ensure that death has occurred. The potential donor is transported to the OR or procedure area. Organ retrieval techniques for DCD donations are different from those for DBD in terms of cannulation, perfusion, tempo, and extent. Some centers initiate cold perfusion via direct aortic cannulation after rapid celiotomy, whereas other centers begin cold perfusion outside the OR via femoral artery cannulation instilling a preflush with thrombolytic medication followed by up to 20 L of cold kidney perfusion fluid.
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In Europe, normothermic regional perfusion (NRP) is practiced widely replacing cold perfusion. It is achieved (12) using occlusive balloon catheters placed in the thoracic aorta and in the vena cava at the level of the diaphragm/hepatic veins via the femoral vessels while separate contralateral femoral arterial and venous lines are connected to a circuit consisting of reservoir, pump, oxygenator, and heater for regional perfusion. Differences in DCD Protocols Multiple recommendations for standardization of DCD protocols have been made (10, 11, 13Y18). Nevertheless, variations in exclusion and inclusion criteria, the venue for WLST, the criteria for DCD, the definition of circulatory arrest, the length of mandatory observation waiting time, and the separation of roles of transplant physicians and clinicians responsible for WLST and declaring death persist. Standard DCD practices would achieve maximal DCD organ procurement and preserve optimal end-of-life care, public trust, and professional integrity (18, 19). The majority of DCD donors in Belgium, The Netherlands, the United Kingdom, and the United States are type III, whereas type II donors predominate in France and Spain (3). In Japan, DCD is the predominant form of organ donation, where brain death was illegal until very recently and remains culturally unpopular (20). A recent report from China describes the outcome from 50 DCD donors, 40 of whom were brain dead but recovered as elective category IV donors (21). Specific details of premortem interventions, the time interval for circulatory arrest, and which organs can be safely transplanted are based on clinical experience rather than welldesigned clinical trials. There is mixed enthusiasm for DCD at all levels within the transplant community owing to these complex medical, legal, ethical, and logistical concerns.
CLINICAL ISSUES Organ Injury Warm ischemia time (WIT) is defined as the time from arrest to cold flush or regional perfusion. DCD donors inevitably suffer hypoxia, hypotension, and inadequate organ perfusion (22) during the progression to circulatory arrest (agonal phase) and the mandatory 5-min period of warm, pulseless ischemia. No outcome differences were noted for premortem cannulation and immediate cold perfusion after DOD compared with immediate celiotomy and aortic cannulation (22). Premortem catheter placement required additional time and radiological studies and was associated with occasional technical problems that minimized any time advantage over the less cumbersome operative approach (22, 23). Many potential therapeutic donor interventions are limited by legal constraints in DCD (24). Brain death causes variations in catecholamine levels, leading to hemodynamic perturbations (hypotension, organ hypoperfusion) that may be further exacerbated by inflammatory molecules, including interleukin-1, -6, and -8 that adversely affect renal allografts (25). Injury from hypoperfusion and the proinflammatory milieu before ischemiaYreperfusion may explain the lower graft survival from DBD donors when compared with that from living donors. Whether the proinflammatory milieu is substantially different in the setting of severe, irreversible head injury without herniation (DCD)
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versus brain death (DBD) has not been established. DCD grafts may not be as immunogenic in the recipient because of this potential difference (26). Outcomes Kidney DCD kidneys show comparable function and survival to DBD kidneys after the immediate postoperative period and a survival benefit to recipients over waiting for DBD kidneys (27, 28). Using UK Registry data, Summers et al. (29) found no difference in graft survival up to 5 years in DCD (n=739) versus DBD (n=6759) recipients (hazard ratio=1.01, 95% confidence limits 0.83Y1.19, P=0.97) or in epidermal growth factor receptor (eGFR) at 1 to 5 years after transplantation (at 12 months: j0.36 mL/min, 95% confidence limits=j2.00 to 1.27, P=0.66). DCD kidneys with increased recipient/donor age mismatches, increased cold ischemia time (912 hr), and repeat transplantation exhibited worse graft survival. DCD kidneys poorly matched for the recipient HLA had inferior graft outcomes that were not significant, whereas delayed graft function (DGF) and WIT had no effect on graft outcome. Summers et al. (30) also found no difference in 3-year graft survival between DCD (n=1768) and DBD (n=4127) recipient groups. Donor age clearly had an adverse affect on GFR, with the highest risk observed for donors older than 45 years (risk ratio=4.81, P=0.001). Again, DGF was common after DCD but did not influence kidney function or graft survival. Donor age (960 vs. G40 years) was a risk for graft loss for all deceased donor kidneys (risk ratio=2.35, 95% confidence limits=1.85Y3.00, PG0.0001) but not for graft loss for DCD donors older than 60 years compared with DBD donors of the same age group (P=0.30). Prolonged cold ischemia (924 vs. G12 hr) was not associated with decreased graft survival for all deceased donors but was associated with poor graft survival of kidneys from DCD donors versus those from DBD donors (risk ratio=2.36, 1.39Y4.00, P for interaction=0.004). DCD kidneys tolerate cold storage less well, a finding important for allocation policies. While some studies demonstrate identical graft survival from older DCD donors, one important study (31) compared iothalamate GFR in 64 DCD versus 248 DBD kidney recipients. Donor age clearly had an adverse effect on GFR, with the highest risk observed for donors older than 45 years (risk ratio=4.81, PG0.001). Again, DGF was common after DCD but did not influence kidney function or graft survival. DCD kidneys accounted for 11% of all renal transplants in the United States (32) and make up 30% to 50% of all deceased donors in some European countries (3). During 2000 to 2008, European centers transplanted 5004 DCD organs (4261 kidneys, 505 livers, 157 lungs, and 81 pancreases). Outcomes in 2343 controlled versus 649 uncontrolled DCD kidney transplants demonstrated similar primary graft nonfunction (PGNF; 5% vs. 6.4%, respectively) and 1-year graft survival (85.1% vs. 86.7%, respectively) but significantly more DGF (50.2% vs. 75.7%, respectively) after uncontrolled DCD. Similar excellent results for DCD kidney transplantation have been validated at many centers (26Y28). Hoogland et al. (33) reported similar good long-term outcomes in 336 recipients of type II and type III DCD kidneys. Although the incidence of PGNF and DGF was
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substantially high in both type II (n=128) and the type III (n=208) groups (22% vs. 21% and 61% vs. 56%, respectively, P=0.43), the 10-year graft and recipient survival rates were essentially the same (50% vs. 45%, respectively, P=0.74 and 61% vs. 60%, respectively, P=0.76) as were the eGFRs after 1 year (40T16 vs. 47T19 mL/min/1.73 m2, P=0.55). Singh and Kim (34) examined whether ECD status modified outcomes of DCD kidney transplants in a cohort study of 67,816 recipients of deceased donor kidney transplants that included 562 ECD/DCD recipients. The modestly increased risk of total graft failure in DCD versus DBD transplants was not significantly modified by combined ECD/ DCD status. Similar results were identified for death censored graft and patient outcomes. The authors suggested that judicious use of ECD/DCD donor kidneys may be appropriate to expand the DCD pool, a conclusion cautiously supported by McDonald and Clayton (35) who provided an elegant analysis of the risks/benefits of this approach and underscored the need for standard protocols, uniform metrics, collaborative multinational registries, and regular data collection to define the best way to use these donors. Donor obesity may adversely affect DCD kidney function. Ortiz et al. (36) reviewed 6932 DCD donors in the United States between 1997 and 2010. Body mass index (BMI) did not affect death-censored graft survival in DBD and only adversely affected survival after DCD when BMI was greater than 45 kg/m2. DGF was more common with higher BMI in DBD and DCD. Ausania et al. (37) noted that, in a total of 13,260 kidney procurements performed in the United Kingdom during the 10-year period (2000Y2010), in which 12,372 (93.3%) DBD kidneys and 888 DCD kidneys were recovered, injuries occurred in 903 procedures (7.1%). The rate of surgical damage was significantly higher in DCD than in DBD donor kidneys (11.4% vs. 6.8%, respectively, PG00.1). Capsular, ureteric, and vascular injuries were all significantly more frequent contributing to a higher discard rate after DCD donation (P=0.002). Extrarenal Organs From DCD Donors In the United States, the number of organs transplanted per donor in 2011 for a standard criteria DBD donor was 3.71 versus 2.07 for DCD donors (38). Over the past decade, organ yield per donor is consistently greater from DCD (range=1.83Y2.28) compared with ECD (range=1.78Y1.91). The associated ischemic organ injury contributes to a reluctance to recover extrarenal DCD organs. Utilization of extrarenal DCD organs may increase as successful methods of in situ organ resuscitation are applied to clinical practice (see below). Pancreas Outcomes of DCD pancreas transplants are acceptable (39). A UK analysis of 134 DCD versus 875 DBD pancreas transplants showed similar 1-year patient and graft survival, with graft survival actually being significantly better in the DCD cohort if performed as part of a simultaneous pancreaskidney transplant. Early graft loss due to thrombosis (8% vs. 4%) was more responsible for graft loss in the DCD cohort (40). Liver DCD liver transplantation initially had inferior survival and higher complication rates (41) but has recently
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flourished in Europe where careful donor selection based on donor age, transaminase values, intensive care unit length of stay, and vasopressor use has improved outcomes that now approximate DBD liver transplantation (42), although ischemic cholangiopathy (43) and associated diminished graft survival (44) due to warm ischemia persist with DCD. Technical factors to speed organ recovery have had minimal impact, most likely because limited circulation and organ injury begins well before circulatory arrest (22). Failure of DCD donors to progress to circulatory arrest within a specified time frame, typically 25 to 30 min for liver donors, means that many planned recoveries do not yield transplantable livers. Graft failure and other complications increase the economic costs of DCD liver transplantation, which are 1.5 times higher than DBD liver transplantation (45). Although only 32 (9%) of liver transplants from 400 potential type II DCD donors could be performed because 59% (236) and 32% (130) were rejected for absolute and relative contraindications, respectively (12), the 1-year patient and graft survival was 82% and 70%. Improved preservation technology and expanded transplant criteria might significantly improve DCD utilization (see below). Type III liver recipients exhibit more acute kidney injury (AKI) versus DBD liver recipients (DCD [n=88] 53.4%, DBD [n= 86] 31.8%, P=0.004) and AKI is a risk factor for CKD (P=0.035) and mortality (P=0.017) (46). The cumulative 3-year CKD incidence was 53.7% and 42.1% for DCD and DBD patients, respectively. Peak postoperative AST, a surrogate marker for hepatic ischemia reperfusion injury, was the only predictor of renal dysfunction after DCD liver transplant (AKI, PG0.001; CKD, P=0.032). Hepatic reperfusion injury may cause renal dysfunction after DCD liver transplantation. Lung Results of lung transplantation from both controlled (47) and uncontrolled (48) DCD have been acceptable, although somewhat inferior to DBD transplants. The Australian Multicenter National DCD Lung Transplant Collaborative reported excellent outcomes with type III DCD lung transplants (49). From 2006 through 2011, there were 174 actual type III donors (with an additional 37 suitable donors who did not have an arrest in the mandatory 90-min withdrawal window) of whom 71 donated to 70 bilateral lung transplants and two single lung transplants. The incidence of grade 3 PGNF was 8.5% at 24 hr, and the incidence of grade 3 chronic rejection was 5%. One- and five-year actuarial survival was 97% and 90% versus 90% and 61% for 503 contemporaneous DBD lung transplants. The authors emphasized that type III lung transplants could provide a significant, effective, quality source of transplantable lungs. Heart As a testimony to the reluctance to use DCD donor hearts for transplantation, only five (all children) were transplanted in the United States from 1996 to 2012 (Table 2). Strategies to Modulate Organ Injury and Improve Organ Function After DCD Numerous strategies have been suggested to reduce cumulative injury sustained by organs during DCD, but
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only limited clinical trials and data are available and none are compelling (24). Static Storage Versus Machine Perfusion Two large, randomized controlled trials (50, 51) of static storage versus machine perfusion of human DCD kidneys, in which one kidney from each donor was stored without perfusion and the other machine-perfused with accepting teams blinded to flow and resistance readings, confirmed that pretransplant machine perfusion had no effect on 1-year patient and graft survival and estimated post transplant GFR. One study identified decreased incidence and duration of DGF after machine perfusion in 82 pairs of DCD kidneys (50), whereas the other study showed no beneficial effect on DGF (51). A 2012 meta-analysis of multiple studies of pulsatile perfusion in DCD showed reduced DGF rates compared to kidneys placed in cold storage (P=0.03; odds ratio=0.64, confidence interval=0.43Y0.95) but no difference in 1-year graft survival (52). Another meta-analysis comparing 175 machine-perfused DCD kidney grafts with 176 cold storage grafts showed that perfused kidneys suffered less DGF (P=0.008, odds ratio=0.56, confidence interval=0.36Y0.86) (53) but no differences in PGNF and 1-year graft or patient survival. Given the increased cost of machine perfusion and similar intermediate-term graft and patient survival, the utility of machine perfusion is unclear (54). Normothermic Regional Perfusion NRP can be established after death to perfuse the abdominal organs with circulating, warm, oxygenated blood. This technique has been proposed as a means to reduce kidney injury, restore cellular metabolism, and thereby increase organ transplantation. NRP was first used for liver transplantation in animal models and has now been used for human kidney, kidney-pancreas, and liver DCD organ procurement (12, 55, 56). In 2000, Valero et al. (56) compared three methods of kidney recovery: in situ cooling, hypothermic extracorporeal circulation of the body, and NRP. A considerable reduction in PGNF and DGF with satisfactory long-term graft survival was observed in the NRP group. Excellent results with 30 type II DCD liver transplants (12) were achieved with DCD organs retrieved with NRP. Definitive controlled, randomized clinical studies in DCD donors using normothermic regional perfusion and/or extracorporeal circulation are required. Ex Situ Perfusion of DCD Organs The recent world congress on Donation after Circulatory Death agreed to refer to perfusion of DCD organs outside the human body as ex situ perfusion (ESP) (57). Ex situ lung
TABLE 2. Pediatric recipients of DCD versus DBD organ transplants from 1995 to 2010 in the United States (73)
Heart Lung Liver Kidney
DCD
DBD
5 2 45 154
4944 851 8120 6762
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perfusion (ESLP) provides a mechanism to evaluate the lung as well as improve lung function before transplantation through the resolution of edema. Cypel et al. (58) reported on 50 lung transplants after ESLP including 22 DCD donor lungs. The incidence of primary graft dysfunction, 30-day mortality (4% in the ESLP group and 3.5% in controls), and 1-year survival (87% in the ESLP group vs. 86% in controls) were similar in both groups. op den Dries et al. (59) performed ESP on four discarded human livers. Biochemical markers in the perfusion fluid reflected minimal hepatic injury and improving function. Lactate levels decreased to normal, reflecting active liver metabolism, and bile production was observed. Histological examination after 6 hr of perfusion showed preserved liver morphology without signs of hepatocellular ischemia, biliary injury, or sinusoidal injury. They concluded that ESLP was technically feasible and could allow assessment of graft viability, possible therapeutic interventions, and potential preconditioning. Peter Friend and the Oxford group (personal communication) performed eight liver transplants after pretransplant ESP with encouraging results. Nicholson and Hosgood (60) assessed the effect of ESP on kidneys from marginal donors. Eighteen ECD kidneys underwent a period of ESLP, using a plasma-free, red blood cellYbased solution immediately pretransplant, and their outcomes were compared with those of 47 ECD kidneys given static storage. The 1-week DGF rate was 1 (5.6%) of 18 in the ESLP group versus 17 (36.2%) of 47 in the cold storage group (P=0.014), with no difference in 1-year patient and graft survival. This technique was obviously feasible and safe and offered significant promise for improved kidney preservation. In the future, various ex vivo pharmacologic or molecular reparative strategies may further improve the ability to transplant DCD lungs and other solid organs.
recovery team and OR staff for an extended period may limit the applicability of this approach.
Strategies to Increase the Number of Usable DCD Organs Several modifications of DCD protocols have been examined to increase the number of donors yielding DCD organs.
Living Kidney Donation in DCD Candidates Current DCD protocols have significant problems: organs damaged from hypotension, hypoxia, or ischemia; failure of DCD donors to adequately progress to circulatory arrest resulting in no organ recovery, family disappointment, and lack of closure; requests to extend the waiting period for determination of death; and the structured approach to end-of-life care in the OR is traumatic and insensitive to the emotional needs of families. Extending living kidney donation to patients with severe irreversible brain injury who would otherwise qualify for DCD procedures (74) might modulate some of these problemsVa concept advanced in the lay literature and supported by DCD donor families (75). Nephrectomy would be performed as a controlled operative procedure in a person whose family previously consented to DNR and DCD. This option might provide a preferential alternative for some families of potential DNR/DCD donor. After nephrectomy, the donor would be returned to the ward for elective WLST and end-of-life care delivered by a combined primary care and palliative care team. The proposal does not violate the dead donor rule, because organ donation does not cause the donor’s demise, since it is a form of living kidney donation. Recovered kidneys would be less damaged, the recipients would fair better with less DGF, and the donor’s death, occurring hours (or days) later after elective WLST, in the absence of stress and urgency
Extension of the Waiting Time to Circulatory Arrest Most DCD protocols recommend a maximal period of 60 to 90 min from WLST to observe for circulatory arrest (14). Reid et al. (62) studied extending the cutoff time for recovery to a minimum of 4 hr. Of 173 potential DCD donors, 117 (67.6%) became donors, of which 90 (76.9%) arrested within 1 hr and an additional 27 (23.1%) donors arrested after 1 hr (8 by 2 hr, 11 more between 2 and 4 hr, and 8 more after 4 hr). The agonal phase (time from WLST to DOD) of all 173 potential donors was studied for the presence or absence of acidemia, lactic acidosis, hypotension for more than 30 min, hypoxia, oliguria, and the impact of these parameters on 3- and 12-month transplant outcomes determined by multivariate analysis. Longer agonal phases had greater donor instability, but increased agonal phase instability or its duration did not influence transplant outcome. Of 190 DCD kidneys transplanted, the 3and 12-month eGFRs were influenced independently by donor age and the 3-month eGFR was influenced by the cold ischemia time. Although extending the waiting time could increase the number of DCD kidneys, maintaining a
Re-evaluation of Timing and/or Declaration of Death The timing of the death declaration has been one of the most controversial parts of DCD protocols particularly as to whether the brain is irreversibly damaged after 5 min of circulatory arrest and, as such, whether DCD adheres to the dead donor ruleVthe guiding principle that the donor must be dead before organs are recovered (63Y67). Some ethicists (65) and clinicians (67) argue that the DCD donor is not dead, but rather in the process of dying; others emphasize the difference between ‘‘irreversible’’ and ‘‘permanent’’ cessation of cardiac function (68)Va crucial factor in end-of-life care. In one pediatric cardiac transplantation case, death was declared in two donors after 75 sec of circulatory arrest (69). Truog and Miller (70) advocated abandoning the dead donor rule and adopting a policy of fully informed consent for families of potential DCD candidates that would allow them to make an ethically acceptable decision as to the endof-life care of the decedent. Increased use of Pediatric DCD Organs Transplanted to Adult and Pediatric Recipients The pediatric community has been reticent to fully adopt DCD, and children are less likely to receive a DCD organ (Table 2). Three concerns regarding pediatric DCD donors are relevant (71): uncertainty about the potential for recovery of meaningful brain function in children, making decisions about WLST difficult; concerns over consent because children are less likely to have expressed a personal preference on donation; and insufficient scientific data on the duration of asystole required before organ recovery. Nevertheless, results from pediatric DCD renal transplants are acceptable (72, 73).
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imposed by current DCD protocols, would take place in a more sensitive and appropriate environment than the OR. This option might offer a desirable alternative to families of potential DNR/DCD donors. Depending on the family motivation, attitudes, and circumstances, DNR/DCD candidates who have donated a kidney in relation to imminent death could subsequently be considered for donation of other organs by standard DCD protocols. Legal concerns, primarily the family’s right to consent to this surgical procedure, and ethical considerations such as providing a foothold to circumvent the dead donor rule have been raised as challenges to this proposal (76). Others have claimed that the concept requires review and serious discussion among the transplant community (77). Involvement of the hospital ethics committee and the local OPO would provide further oversight and scrutiny for each donor as well as assurances for the surgical team and donor family.
Progress in utilization of DCD extrarenal organs should result from current scientific research to identify therapies that minimize organ injury and facilitate useful organ recovery. REFERENCES 1. 2. 3. 4. 5. 6. 7.
CONCLUSIONS
8.
Kidney and extrarenal organs suitable for transplantation are recovered from deceased donors after circulatory arrest throughout the world in increasing numbers (Table 3). Organ injury and failure of the donor to progress in an acceptable time limit DCD utilization. The number of usable DCD kidneys may be incrementally increased through the following:
9.
& & & &
utilization of donors declared dead beyond 1 hr after WLST, increased transplant of pediatric DCD organs, expanded use of NRP or ex situ organ resuscitation, or extending living kidney donation to potential DCD candidates before end-of-life care as a possible preferable alternative to DCD for some families.
TABLE 3. DCD donors recovered for transplant in the United States (January 1, 1996 to December 31, 2012)a Year
Donors Recovered
Kidneys Transplanted
Livers Transplanted
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Total
70 78 75 87 117 167 189 268 393 564 644 791 849 920 941 1055 1089 8297
107 116 110 148 175 249 306 411 566 795 1014 1171 1308 1385 1468 1766 1662 12657
12 17 24 23 39 67 79 112 184 272 289 306 277 289 269 270 260 2789
a
OPTN data assessed on April 4, 2013.
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10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
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