In an attempt to bridge the gap between organ donor supply and demand, effort has been made over the last decade to reevaluate the use of donation after circulatory death (DCD) organs, resulting in a significant increase in the number of DCD liver donors used in the United Kingdom. In 2016, the number of DCD liver donors increased by 23% to 296, whereas transplants from DCD donors increased by 16% to 206, giving the United Kingdom one of the highest DCD usage rates in Europe.1
Although well-selected DCD donor livers transplanted into selected recipients can achieve outcomes comparable to donation after brain death (DBD),2-4 overall outcomes from DCD donor liver transplantation (LT) remain inferior to those of DBD donors.5-7 Callaghan et al7 analyzed the outcome of DCD LT across the United Kingdom performed between January 2005 and December 2010 and demonstrated twice the risk of graft loss and death within 3 years of transplant for recipients of DCD livers compared to DBD donors. Furthermore, a wide variation in the impact of using DCD livers on graft outcomes and recipient mortality across the 7 UK transplant centers was observed.
Studies have demonstrated several donor factors associated with graft loss and biliary complications in DCD LT, including prolonged donor warm ischemia time (WIT) and cold ischemia time (CIT), time from asystole to cold perfusion, increasing donor age and weight, and rate of systolic blood pressure decline in the first 10 minutes of treatment withdrawal.8-12 Nevertheless, there continues to be a drive to expand the selection criteria for DCD donors to include advancing age, comorbidity, and degree of steatosis/liver injury. As a result, organ procurement practices must ensure the detrimental effect of warm and cold ischemia is minimized if the potential complications of ischemic cholangiopathy, primary nonfunction (PNF), and rates of retransplantation are to be improved from DCD donors. Most recently a UK DCD Risk Score has been proposed incorporating several donor and recipient variables and predicting graft survival.13 However, this study did not evaluate the specific impact of hepatectomy time (HT) in DCD donors on short- and long-term outcomes after LT. Indeed, no large-volume data exist to provide recommendations on HT and its impact on outcomes of DCD LT.
In this study, we analyze the impact of the HT on PNF, 90-day and longer-term graft survival after DCD donor LT in a large UK-wide cohort to inform best practices.
MATERIALS AND METHODS
The study was approved by the UK National Health Service institutional review board. Using data from the UK Transplant Registry, prospectively maintained by NHS Blood and Transplant, we identified all adult patients (age >18 y) receiving a first whole LT in the United Kingdom between January 1, 2001, and August 31, 2015 from a DCD donor. Eligibility for transplantation in the UK is based on the United Kingdom Model for End-Stage Liver Disease (UKELD) scoring system. A score >49 enables a patient to be listed but scores less than can be listed under a variant category. It was originally derived in 2008 from the Model for End-Stage Liver Disease (MELD) score but incorporates the serum sodium level.14 Follow-up ceased in September 2015. Patients receiving domino, emergency (“super urgent”), or multiorgan transplant were excluded. Donors were all Maastricht Category III. Livers from DCD donors were allocated locally, and centers chose recipients according to local criteria. A cohort of DBD donor recipients in the same period was included to allow comparison of long-term outcomes.
Withdrawal of Life Support Treatment, Declaration of Death, and Stand down
Location of treatment withdrawal was either in the intensive care unit or theater complex environment, depending on the donor center practices. Administration of heparin or vasodilators and predissection of femoral vessels before death is prohibited by law in the United Kingdom and was therefore not performed. Death was declared after cardiorespiratory arrest with a minimum interval of 5-minute “no touch time.” Criteria for DCD donor selection and acceptable postwithdrawal hemodynamic parameters varied among the liver transplant centers but were broadly based on the experience of Muiesan et al.15 Majority consensus in the United Kingdom is to stand down if the functional WIT exceeds 30 minutes.16 The functional WIT is defined as the time from systolic of 50 mm Hg or less or oxygen saturations of 70% or less, depending on which observation occurred first, to time of aortic cannulation.
Organ Procurement Techniques
All UK liver procurement centers use a super-rapid recovery technique with some modifications between centers.17 In brief, this involves making an abdominal incision, aortic cannulation, venting of blood from the infrahepatic inferior vena cava (IVC), commencement of perfusion, and then either application of a supraceliac aortic clamp before opening the chest and venting the suprahepatic IVC or applying the aortic clamp in the chest and venting the suprahepatic IVC (and/or reapplying the aortic clamp in the thorax and remove the supraceliac if placed.) If the pancreas is not being retrieved, portal perfusion is performed either directly via the portal vein or via the inferior mesenteric vein; if the pancreas is also being retrieved, portal perfusion is performed directly via the portal vein. One center practices a thoracoabdominal incision and venting first the suprahepatic IVC before aortic perfusion. Abdominal organs were procured in sequence of liver, pancreas (or liver-pancreas en bloc), and kidneys.
The preservation fluid type, bag pressure, and the use of dual perfusion techniques varied over the early study period but more contemporary UK guidelines and the establishment of the National Organ Retrieval Service (NORS) in 2010 stipulate using aortic perfusion at a pressure of 200 mm Hg and portal perfusion under gravity alone.18 For in-situ perfusion, 4 L (aortic) and 2 L (portal) University of Wisconsin (UW) with 20 000 IU heparin/L are used.17 Once perfusion has started, the gall bladder is flushed until clear of bile, followed by copious in situ flushing of the bile duct with chilled (4°C) normal saline. Sterile crushed ice is placed around the organs to be retrieved. On the back-bench after hepatectomy the portal vein (500 mL), hepatic artery (250 mL), and bile duct (250 mL) are flushed further with chilled UW, whereas other abdominal organs are procured. The liver is then bagged for cold static storage and placed in an ice box.
If need be, a fresh frozen trucut liver biopsy is taken to assess degree of steatosis or to exclude donor pathology. DCD liver steatosis >30% would commonly lead to organ discard, as would a severely steatotic liver on visual inspection. Implant techniques vary across the UK centers. The majority of livers were reperfused via the portal vein but some transplant surgeons advocate the artery first approach to reperfusion to minimize biliary ischemia in DCD donors.
Graft loss was defined as retransplantation or death, regardless of perceived graft function at the time of death. Hepatectomy time was defined as the time from initiation of aortic perfusion to the end of the hepatectomy. Cold ischemia time was defined as the duration from the start of cold perfusion of the liver in the donor to organ removal from ice immediately before implantation. Primary nonfunction was defined as a patient requiring listing for urgent regraft with graft dysfunction on days 0–7 after LT with at least 2 of the following: >10 000; INR >3.0; arterial lactate >3 mmol/L; absence of bile production.
Pearson’s χ2 test was used to identify differences between categorical variables and Student t test or Mann-Whitney test for differences between continuous variables. Risk factors for PNF were analyzed using the Pearson χ2 test for univariate analysis and logistic regression for multivariate analysis. Variables with a P value < 0.05 in the univariate analysis were entered into a forward stepwise logistic regression to identify risk factors for PNF after LT. Graft survival after transplantation was estimated using the Kaplan-Meier method. Multivariate analysis was performed using Cox regression (stepwise forward model) for donor variables reaching significance on univariate analysis that impacted upon graft survival, and statistical significance was taken at the 5% level.
In total 1112 first elective adult LT from DCD donors between January 1, 2001, and August 31, 2015 met inclusion criteria. The numbers of transplants from DCD donors have consistently increased over the years with almost doubling of numbers from 2006 (28) to 2007 (52), then 100 in 2010, and by the end of 2014, 167 DCD donor liver transplants were performed (Figure S1, SDC,http://links.lww.com/TP/B652).
Donor, Recipient, and Operative Characteristics
In the study cohort, the mean age, male sex, and BMI of donors was 44.7 years (SD, 16), 667 (61%), and 25 (SD 4.7), respectively. The cause of death was trauma 173 (16%), stroke 568 (51%), anoxia 266 (24%), and other 105 (9.4%). In 889 of 1112 cases in which the organ appearance was recorded, the organ was categorized as “healthy” in 573 (64%) and “suboptimal” in 316 (36%). The donor liver was reported to have conventional arterial anatomy in 774 (70%) of 1108 cases and to have variable degrees of steatosis (mild-moderate) in 35%. In 1038 (93%) cases, there was multiple organ procurement, and the most common organs to be taken with the liver were kidney (93%), pancreas (39%), and lung (11%). The majority (>98%) of liver procurement used UW preservation solution with aortic and portal perfusion. Donor operative details are shown in Table 1 and recipient details in Supplementary Table A.
Impact of the UK NORS
In April 2010, a NORS was established in the United Kingdom, and the cohort was divided into periods before and after April 2010. Differences in retrieval practice in the 2 periods are shown in Supplementary Table B. Specifically, the donor and recipient age, use of “suboptimal” livers, steatosis, and the number of pancreas procured at the same time have all increased. The asystole to liver in ice box time, HT and time taken to put the liver into ice box from liver being declared out of body, incidence of capsular damage, and livers subjected to longer CIT have all increased since 2010. However, there has been no statistical difference in long-term survival outcomes between the 2 periods (data not shown).
PNF, Biliary Complications, Short-, and Long-term Survival
In the study group, the incidence of PNF was 40 (4%), of which 5 patients died within the first postoperative week. Thirty-five patients received a regraft from a DBD donor. Analyses of variables associated with PNF are shown in Table 2. On univariate analysis, HT >60 minutes, CIT >8 hours, and UKELD>62 were all associated with PNF. On multivariate analysis only CIT >8 hours. (hazard ratio [HR], 2.186; 95% confidence interval [CI], 1.113–4.294; P = 0.023) and HT >60 minutes (HR, 3.669; 95% CI, 1.363–9.873; P = 0.01) were independently correlated with PNF.
In total, graft loss secondary to biliary complications was 25 (2.2%). No further data in the registry were available to detail biliary complications, such as ischemic cholangiopathy, anastomotic and nonanastomotic strictures, and the need for biliary reconstruction and other interventions.
Overall 90-day, 1-, 3-, and 5-year graft survival in DCD LT was 91.2%, 86.5%, 80.9%, and 77.7% (compared with a DBD cohort of first elective recipients of a whole liver graft in the same period [n = 7221] 94%, 91%, 86.6%, and 82.6%, respectively [P < 0.001]), Figure S2 (SDC,http://links.lww.com/TP/B652).
In the study cohort, 220 (19.8%) DCD grafts failed. Causes for graft loss included: PNF, 40 (4%); acute vascular occlusion, 26 (2.3%); recurrent disease, 26 (2.3%); biliary complications, 25 (2.2%); chronic rejection, 9 (0.8%,); vascular occlusion, 3 (0.3%); nonthrombotic infarction, 2 (0.2%); ductopeanic rejection, 2 (0.2%); recipient died but graft still functioning at time of death, 48 (4.3%); and unknown, 43 (3.9%). One hundred and seven of the 220 grafts lost had failed within 90 days. In addition to the 40 cases of PNF, the other main causes for early failure (<90 days) were 23 acute vascular occlusions, 6 biliary complications, 18 deaths with functioning grafts, and 20 cases due to “other causes.”
On univariate analysis, factors associated with early graft loss (<90 days) were withdrawal to asystole time, HT longer than 60 minutes, CIT longer than 8 hours, and recipient BMI (Supplementary Table C). Hepatectomy time longer than 60 minutes remained the only significant factor (HR, 3.287; 95% CI, 1.335–8.096; P = 0.010) on multivariate analysis.
An analysis of factors associated with longer-term graft survival is shown in Table 3. Donor age (40–49 y; HR, 1.890; 95% CI, 1.192–2.997; P = 0.007) and (50-59 y; HR, 1.659; 95% CI, 1.051–2.619; P = 0.030), CIT >8 hours (HR, 1.384; 95% CI, 1.043–1.830; P = 0.049), HT >60 minutes (HR, 1.953; 95% CI, 1.242–3.070; P = 0.004), “suboptimal” appearance judged by the operating surgeon (HR, 1.562; 95% CI, 1.142–2.136; P = 0.005), and previous recipient abdominal surgery (HR, 1.911; 95% CI, 1.298–2.900; P = 0.009) were significant in univariate analysis. In multivariate analysis, the only donor factors that remained independently significant and correlate with graft loss were HT >60 minutes, donor older than 45 years, and CIT >8 hours. Recipient factors, including previous abdominal surgery, remained a significant factor associated with graft loss.
Donor factors associated with a prolonged HT (>60 min) were concomitant retrieval of pancreas (P < 0.01) or lungs (P = 0.021) and aberrant anatomy (Table 4). Donor BMI did not influence HT.
Graft survival stratified by HT is shown in Figure 1. There was a significant difference in graft loss with HT >60 minutes compared with <30 minutes (P = 0.003). One-year graft survival for HT <60 minutes and >60 minutes was 87.5% and 82.2%, respectively, whereas 3-year graft survival was 77% and 68%, respectively (P = 0.028). In a subanalysis, the combination of HT >60 minutes, donor older than 45 years, and CIT >8 hours conferred significantly poorer long-term graft outcomes compared with those with 2 or less of these risk factors (Figure 2).
This is the first study on a large cohort of DCD donors to demonstrate the negative impact of HT on short and long-term outcomes after LT. Hepatectomy time >60 minutes and CIT >8 hours were associated with a greater incidence of PNF. Hepatectomy time >60 minutes was correlated with increased risk of graft loss within 90 days. Hepatectomy time >60 minutes, donor age (>45 y), CIT (>8 h), and previous recipient surgery (a surrogate marker of prolonged cold ischemia time) are associated with poorer long-term overall graft survival.
Although there are data demonstrating the negative impact of extraction time on outcomes in kidney transplantation,19 the only study published analyzing the effect of HT during liver organ procurement of a pooled DCD and DBD donor group showed increased times for DCD compared with DBD donors and HT to be independently associated with transplant loss (adjusted HR, 1.03 for every 10-min increase).18 Additionally, factors including DCD, donor age, and CIT were all found to be associated with poorer long-term outcome. The magnitude of HT effect was comparable to the effect of each hour of additional CIT (adjusted HR, 1.04). In this study that focuses on >1100 DCD donors, the median HT was less than the previous study, and the magnitude effect of HT on PNF and long-term graft loss was significantly greater than CIT.
The nature and severity of the ischemic and procurement insult on a DCD liver is different than that of a DBD donor. Cold preservation is preceded by a period of warm ischemia during treatment withdrawal, progression to asystole, and during hepatectomy itself, despite topical cooling. Thorough analysis of the warm ischemic duration for livers from DCD donors in this study is limited by the lack of data on donor cardiorespiratory parameters after treatment withdrawal. Some controlled DCD donors have prolonged periods of cardiorespiratory stability before dying rapidly and the duration of hypotension or hypoxia may have a greater impact on subsequent graft viability than the actual duration from treatment withdrawal to cardiac arrest or cold perfusion.20,21 Nevertheless, in controlled animal studies, duration of warm ischemia exacerbates the injury to the liver and biliary system during subsequent cold ischemia.22,23
In multiorgan procurement, aortic and portal perfusion is typically completed within 10 to 15 minutes after which cold organ flush ceases and only topical cooling occurs during hepatectomy phase, which may result in degrees of rewarming as extraction times increases.24 This insult may be exacerbated as the criteria for acceptance of donors expands; as the procurement surgeon increasingly is faced with donors with increased BMI, previous abdominal surgery, and lung/heart and pancreas donation adding to the complexity of the surgery. Opinion has existed for many years in the United Kingdom that HT should be <45 minutes to limit the liver injury, despite the lack of objective data. In this study, the median HT was 35 minutes and supports this target.
Transplanted livers from DCD donors are particularly susceptible to biliary complications, most commonly ischemic cholangiopathy. This is a result of damage to the biliary epithelium sustained predominantly during warm ischemia.9 Published rates of cholangiopathy range between 2.5% and 20% in single-center reports25-27 and graft loss due to biliary complications was 2.2% in this study. This small number did not allow a robust multivariate analysis to explore the impact of HT. The true figure is likely to be higher in the United Kingdom and represents the problem of retrospective analysis of registry data, particularly the reporting of complications. This is disappointing, as biliary complications and their consequences remain the Achilles heel of DCD LT and require detailed study to understand and improve outcomes. The median asystole to cold perfusion time was 13 (8–18) minutes in the United Kingdom and is longer than studies reported in the United States, as there is an established 5-minute “no touch time” after asystole in the United Kingdom. In addition, treatment withdrawal mainly takes place in intensive care units at present, with variable distances to the operating theaters. Recent meta-analysis data support withdrawal in the operating theater environment to improve DCD liver transplant outcomes, such as ischemic cholangiopathy,28 and there is now a drive to establish withdrawal in the theater environment across the United Kingdom.
After hepatectomy, standard practice is to flush the graft on the back-bench before putting in the ice box. Data in this study show that a further period of 33 minutes (IQR, 24–44 min) occurs after portal/aortic flush where the liver remains is cold preservation fluid in a bowl on the back-bench before actually being secured in the transport icebox. This is the time in which the surgeon proceeds with procurement of other abdominal organs and splits the pancreas and liver if retrieved en bloc. Although the fluid is cold there is risk of insidious warming till placed in the icebox and over the study period the time to ice box has increased as more abdominal organs are being procured. Thus, the authors support the proposal to achieve a “1 hour knife to skin and liver placement in the ice box” time as a target and standard of best practice.
Although cold preservation reduces liver metabolism to low levels, it does not stop anaerobic metabolism and morphological changes in the DCD liver as a result of proteolytic modification of extracellular matrix and collapse of the endothelial glycocalyx, promoting ischemia-reperfusion injury by facilitating endothelial activation and leukocyte adherence.29-32 Furthermore, ATP depletion during cold storage results in detachment of cholangiocytes from the basal membrane and can lead to cholangiopathy33,34 with a number of clinical studies showing the negative impact of prolonged CIT in outcomes after transplantation.10,35-37 In this study, the median CIT was 7 hours and grafts with times >8 hours were associated with poorer outcomes in concurrence with published studies.26,38-40 Normothermic machine and regional perfusion technologies are emerging as an alternative to cold storage and ameliorate some of the disadvantages of current DCD procurement techniques while also allowing viability tests. However, long-term data are awaited before it potentially makes any significant change to practice.41-45
Since the establishment of the NORS in April 2010, there have been continuous developments in standardizing operating protocols for NORS personnel. In this time donors have become older, livers “suboptimal” to visual inspection, with more concomitant pancreas and lung procurement, and there have been increases in capsular injury and HTs. Reasons for increased HT are multifactorial but in this study HT >60 minutes was observed in multiorgan (pancreas, lung) procurement and in cases of aberrant anatomy. This may suggest that other factors, such as intraoperative performance and surgical experience, have a significant role. This is an important parameter to optimize as HT >60 minutes have been shown to be associated with a higher incidence of PNF, graft loss, and the need for retransplantation.
Data on the seniority and experience of the surgeon performing DCD retrieval are not captured in this registry, but it can be inferred that before 2010, the vast majority of DCD operations in the United Kingdom were by senior transplant surgeons in fewer and more selected local donors, compared with the contemporary era of multiorgan donors with a wider variation of operating surgeon seniority. This may have an important role in the procurement of more marginal DCD donors where timely procurement is critical.
A number of limitations inherent in a retrospective analysis of registry data and confounding factors contributing to the outcomes of DCD LT exist in this study. Recipient factors were not the focus of this study but increasing implantation time was associated with a greater incidence of PNF and previous recipient abdominal surgery (a surrogate marker for increased cold ischemia time) conferred poor long-term graft survival. Nevertheless, the large number of donor DCD cases and attempts to focus on a recipient group which does not include regrafts, emergency “super urgent,” or multiorgan transplants across all centers in the United Kingdom does provide valuable information to stimulate further investigation into the impact of HT. Although the data do not evaluate retrieval surgeon experience, it is clear that experienced surgeons are required for DCD liver procurement and that procurement training needs to be optimized to ensure HT are minimized.
In conclusion, this is the first report in a large data set to highlight the negative impact of prolonged HT on outcomes on DCD LT. In prolonged hepatectomy, there is likely to be insufficient cooling and then rewarming of the graft, with the initiation of the cascade of ischemic injury to the donor liver. Although HT beyond 60 minutes is not in itself a contraindication for utilization, it is an important variable that should be taken into account as part of a multifactorial assessment with established prognostic donor factors, such as age, CIT, and the appearance of the liver. More agonal phase data are required to better inform and define warm ischemia limits but the focus in the DCD setting should still remain on limiting ischemic times by withdrawing treatment in theater, having experienced surgeons perform timely procurement, continuing cold perfusion for longer in lung procurement, transferring the liver to the ice box as soon as possible after flushing on the back bench, early dispatch, and optimizing CIT with effective communication with recipient teams.
National Health Service Blood and Transplant for the provision of the national data and all the UK Liver Transplanters.
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