See Editorial on Page 751
Orthotopic liver transplantation is universally accepted as the treatment of choice for patients with end-stage chronic liver disease and acute liver failure. The procedure is highly successful, and survival rates greater than 90% at 1 year are routinely reported. This high success rate has led to an increased demand for liver grafts and has resulted in an increasing disparity between the number of patients listed for liver transplantation and the number of donors. The procurement of donation after circulatory determination of death (DCDD) liver grafts is now actively promoted as a means of increasing the available donor pool and bridging the evolving disparity between the number of patients on the waiting list and the number of transplants performed.
In the United Kingdom, liver transplantation using donation after circulatory determination of death organs has increased steadily over the last few years and now accounts for 20% of UK transplant activity (100 of 524 transplants in 2010-2011 according to National Health Service Blood and Transplant1). There are, however, concerns about this increase. First, graft survival is worse, primarily because of the high incidence of ischemic cholangitis and nonanastomotic biliary stricturing; in addition, primary nonfunction is much more common. Both lead to retransplantation, usually with a graft from a brain-dead donor.2-4 Second, although the use of DCDD liver grafts has significantly increased, the total number of liver transplants performed has not increased proportionately. Why the number of donation after brain death (DBD) donors has fallen when the number of DCDD donors is increasing is far from clear; this may be partially related to changes in neurosurgical practice. Only a minority of DCDD donors in the United Kingdom are brain stem–dead at the time of treatment withdrawal, and an unanswerable question is how many potential DCDD donors would eventually become brain-dead if treatment withdrawal did not take place.5
To determine whether the use of DCDD grafts versus DBD grafts has a negative impact on both the outcome of orthotopic liver transplantation and its associated costs, we retrospectively studied all DCDD transplant patients at our center during a fixed time period and compared these patients to a cohort of patients who were matched for factors predictive of mortality [etiology, age, and Model for End-Stage Liver Disease (MELD) score] and received DBD grafts during the same time period. We perform 60 to 80 transplants per year at our center.
PATIENTS AND METHODS
Specific ethical approval was not required for this study because the data were collected routinely, and consent for the use of anonymized data for audit purposes was obtained from all patients before transplantation. This is a retrospective analysis of data already collected during each operation; as such, no additional blood samples or clinical investigations were required. In addition, none of the patients can be identified from the published information.
Data were collected from all patients undergoing elective liver transplantation with full-size DCDD donor grafts at the Royal Free Hospital between January 2008 and August 2009 (all recipients in this study were first-time recipients of whole liver grafts). Demographic and perioperative data for DBD patients were collected retrospectively from a prospectively collected database and were compared to the data for a control group of patients receiving DCDD grafts; they were matched for age, etiology, and disease severity (as assessed by the MELD score). Intraoperative data, including hemodynamic variability, blood gas analysis, thromboelastography (TEG), and transfusion requirements, were analyzed by stage (dissection, anhepatic, and reperfusion). Postoperative intensive therapy unit (ITU) data, including vasopressor requirements, ventilator use (hours), renal support [continuous venovenous hemofiltration (CVVHF)], and total ITU length of stay, were also collected.
Surgical Retrieval and Implantation Techniques
The technique used for retrieval from the donor was a modification of the Pittsburgh super-rapid technique as described by Casavilla et al.6 The retrieval team waited up to 60 minutes after extubation before they stood down. During this time, the blood pressure and oxygen saturation were observed. The donor warm ischemia time was defined as the time from a systolic blood pressure of 50 mm Hg and/or an oxygen saturation less than 70%. In general, a warm ischemia time in excess of 30 minutes precluded graft retrieval. After a 5-minute standoff period, the distal end of the aorta was cannulated through a midline laparotomy, and organ perfusion was initiated with the abdomen cooled by a topical iced slush. Approximately 5 L of University of Wisconsin solution was perfused, with the first 2 bags containing 20,000 units of heparin. Immediately after perfusion, the vena cava was vented, and the sternum was divided to cross-clamp the descending aorta. A further modification was made in some of the later retrievals, as described by Muiesan et al.7 (the vena cava was vented first to prevent congestion of the liver before aortic cannulation). In some cases, the portal vein was cannulated and perfused during the retrieval, but in the majority of the cases, portal vein perfusion took place on the back bench after hepatectomy. The organ was stored in University of Wisconsin solution and was transferred back to the recipient center for early implantation. DCDD livers were not accepted when the period of warm ischemia was >30 minutes.
DBD liver retrieval took longer because more extensive warm dissection took place in preparation for the cross-clamping and subsequent cold dissection. Portal venous cannulation was also more likely. For the implantation, there were no differences in the surgical techniques between the 2 groups. Before the release of the suprahepatic caval clamp, the liver graft was flushed through the portal vein with 4.5% albumin (500 mL for a liver of normal size and 1000 mL for a large liver). If the effluent fluid was blood-stained, more flush solution was administered. With experience, we modified our protocol to routinely use higher volumes of flush solution in DCDD and other extended criteria grafts.
In our approach to the DCDD program, we adopted conservative measures, and the recipient procedure was not started until the recipient's surgeon was satisfied that the liver was transplantable. This was determined by communication with the donor's surgeon after the liver was cold-perfused and inspected on the bench, or if there was sufficient doubt about the suitability of the organ, the recipient surgeon inspected the liver himself.
The baseline characteristics of the patients are expressed as medians and interquartile ranges (IQRs). Comparisons between groups were performed by chi-square analysis. Noncategorical variables were compared with the Mann-Whitney U test. The level of significance was set at P = 0.05. All data were analyzed with SPSS 10.1.
Sixteen matched pairs of DBD and DCDD recipients who received liver transplants during an 18-month period were compared.
The patient demographics were similar, and there were no statistically significant differences in age or MELD score (Table 1). Similarly to other large centers, the median cold ischemia time for DCDD grafts was significantly shorter (397 versus 488 minutes, P = 0.02). The median cold ischemia time at our center was 8.5 hours (range = 3-15 hours). The baseline TEG coagulation profiles were comparable; there were nonsignificant differences in the reaction time, maximum amplitude, and lysis 30 index. All other demographic information, the etiologies, and the MELD scores were similar, and a matched cohort was produced according to the study design.
Table 1. Comparison of the 2 Groups By Recipient and Donor Demographics
|Age (years)*||54 (41-61)||52 (43-57)|
|Sex (%)|| || |
|Cause of liver failure (n)|| || |
| ALC and HCC||3||3|
| ALC and HCVC||4||4|
| ALC, HCVC, and HCC||1||1|
| Primary sclerosing cholangitis||1||1|
| Primary biliary cirrhosis||1||1|
|MELD score*||18 (13.5-21)||16.5 (13-20)|
|Cold ischemia time (minutes)*||397 (361-423)||488 (431-589)†|
Patients receiving DCDD grafts were more likely to have postreperfusion syndrome (PRS), which was defined as a decrease in the systolic arterial pressure below 100 mm Hg occurring immediately after reperfusion and persisting for 5 minutes or more.8-10 The median duration of PRS despite active interventions with vasopressors was significantly longer in the DCDD cohort [45 minutes (range = 30-64 minutes)] versus the matched DBD group (0 minutes, P < 0.001). Patients with DCDD grafts required ongoing noradrenaline support to maintain their blood pressure for approximately twice as long [20.5 hours (range = 12-37 hours)] as those receiving DBD grafts [9.5 hours (range = 5-16 hours), P = 0.002].
Coagulation and Transfusion
At the baseline, there were no significant differences in the TEG parameters (the reaction time and the maximum amplitude) between the groups, and there was no evidence of fibrinolysis (clot lysis index < 10) or any heparin effect (the native reaction time was 50% greater than the heparinase reaction time; Table 2). By reperfusion, 7 of the 16 DCDD patients had developed TEG evidence of fibrinolysis (Clot Lysis Index (CLI) > 15%), whereas none of the 16 DBD patients had. Tranexamic acid was given to 7 of the 16 DCDD recipients but to none of the 16 DBD recipients; aprotinin was given to 5 DCDD recipients and 4 DBD recipients. Immediately after reperfusion, TEG demonstrated a heparin effect in the majority of the patients (14 of the 16 DCDD recipients and 15 of the 16 DBD recipients). By the end of the procedure, a heparin effect was still apparent in the DCDD patients (14/16), but it had spontaneously disappeared in most of the DBD patients (6/16, P = 0.01).
Table 2. Comparison of the Intraoperative TEG Profiles of the 2 Groups
|Base reaction time (mins)*||16.6 (13.9-22.5)||17.5 (12.5-28)||0.89|
|Base maximum amplitude (mm)*||54.8 (37.8-60.2)||43 (29.9-53.4)||0.06|
|Base lysis 30 index (%)*||0 (0-0)||0 (0-0)||0.99|
|Reperfusion lysis 30 index (%)*||17 (0-61.1)||0 (0-2.3)||0.002|
|Heparin effect at end of case (%)||88||38||0.01|
Although statistical significance was not reached, there was a clear trend of increased red blood cell and component transfusions in the DCDD cohort (6.7 U of total red blood cells, 1.18 U of platelets, and 5.25 U of fresh frozen plasma) versus the DBD cohort (3.9 U of total red blood cells, 1.05 U of platelets, and 5.125 U of fresh frozen plasma).
Patients in the DCDD group tended to have higher lactate levels at the end of the case and also 24 hours later; in addition, the rate at which lactate levels returned to normal was much slower (Table 3. There was a statistically significant difference in the peak aspartate aminotransferase (AST) levels recorded (P = 0.007)
Table 3. Comparison of Lactate Clearance and AST Levels in the 2 Groups
|Lactate at end of case (mmol/l)*||3.31 (3.0-4.25)||2.51 (2.1-2.63)||0.12|
|Lactate at 24 hours (mmol/l)*||2.89 (0.6-5.7)||1.27 (0.84-1.7)||0.12|
|Mean fall in lactate (%)||12.7||49.4||0.69|
|Peak AST within 24 hours (U/L)*||2434 (900-4171)||803 (356-1615)||0.007|
Respiratory and Renal Support
Patients receiving DCDD grafts required mechanical ventilatory support for significantly longer than DBD patients; in addition, their length of stay in the intensive care unit was nearly twice as long (Table 4). Nineteen percent of the DCDD patients required renal replacement therapy (RRT), whereas no patients in the DBD group did.
Table 4. Comparison of Postoperative Variables of the 2 Groups
|Vasopressor (hours)*||20.5 (12-37)||9.5 (5-16)||0.002|
|Ventilator (hours)*||22 (10-113)||11 (7-19)||0.03|
|ITU length of stay (days)*||3.75 (2.5-6.5)||2 (1.5-3.5)||0.02|
Graft and Patient Survival
Graft survival at 3 months was lower in the DCDD cohort (14/16) versus the DBD cohort (16/16, P = 0.26), and a statistically significant difference was reached for graft survival at 12 months (12/16 in the DCDD group versus 16/16 in the DBD group, P = 0.03; Table 5). The 2 graft failures within 3 months were attributed to primary nonfunction. Another 2 grafts failed within 12 months: one patient suffered from ischemic cholangiopathy and underwent retransplantation, and another patient suffered from chronic rejection and subsequently died. Fifteen of the 16 DCDD recipients (94%) were alive at 12 months, whereas all 16 DBD recipients (100%) were (P = 0.31).
Table 5. Comparison of Graft and Recipient Survival
|Graft survival at 3 months (%)||88||100||0.26|
|Graft survival at 12 months (%)||75||100||0.03|
|Patient survival at 12 months (%)||94||100||0.31|
The cost of an ITU bed was £1200 to £1700 per 24 hours; the length of stay and hence the costs for the DCDD cohort (3.75 days and £4500-£6375) were approximately twice those of the DBD group (2 days and £2400-£3400).11-13
It has been calculated that the median cost of CVVHF is £32,400. The 3 patients who required RRT, therefore, cost the trust an additional £97,200.
The degree to which the use of DCDD grafts affects graft and patient survival is controversial. In the large single-center experience published by the Mayo Clinic group, graft survival and patient survival were not significantly different between DCDD recipients (n = 108) and DBD recipients (n = 1328).14 In contrast, using registry data, Selck et al.15 reported that recipients of DCDD grafts had higher early graft failure and retransplant rates than DBD recipients, even though DCDD recipients had lower MELD scores and a less urgent status at the time of transplantation. The difference between the findings of these 2 studies provokes some interesting observations. First, because of the perceived inherent risk attached to the use of DCDD grafts, these grafts are possibly being selectively used in lower risk patients. This may explain why outcomes in terms of overall survival with DCDD and DBD grafts are similar in some studies (ie, recipients of DCDD grafts with lower MELD scores do as well as patients receiving DBD grafts with higher MELD scores). Second, if the use of DCDD grafts is associated with an increased risk of early complications, then the use of DCDD grafts could increase the costs associated with liver transplantation. Work published by the Mayo group in 2012 again showed no significant differences in the survival of DCDD and DBD patients, but poorer graft survival was suggested (10% of the 200 patients who received a donation after cardiac death graft required early retransplantation).16
A recent publication by the Leeds group examined the outcomes of 39 DCDD recipients and 39 DBD recipients who were matched for a variety of pretransplant variables predictive of mortality.17 This study confirmed that the patients receiving DCDD grafts had outcomes inferior to those of the matched DBD recipients. In addition to poorer graft and patient survival, the use of DCDD grafts was also associated with increased early complications and thus potentially increased use of perioperative resources. In a retrospective, multicenter study, Salvalaggio et al.18 estimated that DCDD organs had the greatest impact on the donor risk index and conferred an increased cost of $20,769 in comparison with organs from brain-dead donors.
In this study, in comparison with patients who were matched for disease etiology and severity and underwent orthotopic liver transplantation with a DBD graft, DCDD recipients had more profound perioperative hemodynamic instability and a prolonged need for vasopressor support. They were also much more likely to develop aggressive fibrinolysis after graft reperfusion that required treatment with antifibrinolytic agents. Both the persistence of a marked heparin effect and the much reduced rate at which lactate levels fell were indicative of poorer graft function. In addition, the patients who received DCDD grafts required ventilatory support for much longer, and 19% required RRT. Overall, the length of stay in the intensive care unit was approximately twice as long. The rate of graft survival was lower at 3 months in the DCDD cohort (14/16) versus the DBD cohort (16/16, P = 0.26), and a statistically significant difference was reached for graft survival at 12 months (12/16 in the DCDD group versus 16/16 in the DBD group, P = 0.03). Two of the failures were attributed to primary nonfunction (ie, ischemic cholangiopathy and chronic rejection). Fifteen of the 16 DCDD recipients (94%) were alive at 12 months, whereas all 16 DBD recipients (100%) were (P = 0.31). The patient with chronic rejection died.
Jay et al.19 recently showed that higher rates of graft failure and biliary complications translate into markedly increased direct medical care costs for DCDD recipients. The development of ischemic biliary complications and retransplantation were associated with 53% and 107% increases, respectively, in costs 1 year after transplantation. DCDD costs remained significantly higher than DBD costs even after adjustments for recipient disease severity as measured by the MELD score.
In our series, there was evidence that the DCDD grafts sustained more ischemic damage than the DBD grafts; the AST levels were much higher, and the blood lactate levels took longer to fall. AST levels after transplantation have long been recognized as a sensitive marker of hepatic preservation injury and the extent of hepatocellular damage.20, 21 In one study,22 the extent of injury was classified according to the peak levels of serum AST during the first 72 hours after transplantation as minor (AST < 1000 U/L), moderate (1000-5000 U/L), or severe (>5000 U/L). The median peak AST level in our DCDD cohort was 2434 U/L. Lactate is normally converted into pyruvate by the healthy liver via the Cori cycle. The higher lactate levels at the end and the slower fall in the blood concentration in the DCDD patients may represent a slow postimplantation recovery due to graft damage. Ischemia/reperfusion injury to the liver is more of a problem with DCDD grafts. Cellular injury during the initial warm ischemia phase before cold perfusion is thought to be particularly significant. The rapid depletion of adenosine triphosphate from cells during the warm ischemia phase causes cellular acidosis and a loss of membrane integrity. It has been demonstrated that prolonged warm ischemia times are associated with increased biliary complications and an increased incidence of primary nonfunction.23, 24
The significant reperfusion instability noted in the DCDD transplants required greater amounts of vasopressor support for a longer time. Noradrenaline has been shown to reduce renal25, 26 and splanchnic blood flow.27 Prolonged therapy has the potential to cause acute, subacute, and chronic secondary organ damage, which has both patient morbidity and medical cost sequelae. Notably, 3 of the DCDD patients required RRT. Reperfusion of the DCDD grafts was in many cases associated with profound hyperfibrinolysis requiring treatment with tranexamic acid. Hyperfibrinolysis can cause an increased risk of bleeding and transfusion requirements.28 Explosive hyperfibrinolysis has been described after liver graft reperfusion,29-31 and studies have also shown a link between fibrinolysis occurring at this stage and the severity of PRS.32 Typically, upon reperfusion of the transplanted organ, there is a clear heparin effect visible by TEG, and this generally resolves rapidly and spontaneously.33 The persistence of a heparin effect, as seen in our DCDD cohort, is a further indication of poor initial graft function.
Since our initial experience with DCDD grafts, we now have a separate protocol for extended criteria grafts. When it is appropriate, we routinely monitor perioperative hemodynamic changes with transesophageal echocardiography. We aim for a serum potassium level no higher than 4.0 mmol/L immediately before reperfusion, and we aggressively treat higher levels with insulin and dextrose. If the base deficit is >10 mmol/L, this is corrected with sodium bicarbonate, and ionized calcium levels are maintained at 1.0 mmol/L or higher. Tranexamic acid (2 g) is given immediately after reperfusion. A low-dose noradrenaline infusion (if it is not already in use for maintaining the mean arterial blood pressure and systemic vascular resistance) is turned on and is run before reperfusion. We also have immediately available two 10-mL syringes of epinephrine (in concentrations of 10 and 100 μg/mL) and an epinephrine infusion (4 mg/50 mL)
Although patient deaths in the ITU result from heterogeneous underlying pathophysiologies, there is good evidence that the length of time on a mechanical ventilator is an independent mortality risk factor and leads to extra financial outlays.34-36 Our results show a clear increase in the need for ventilatory and renal support in the DCDD cohort. CVVHF is associated with substantial manpower and disposable costs (nurses, doctors, vascular access, and dialysate) as well as long-term kidney-related morbidity. It has been calculated that the median costs are £3600 for patients not requiring RRT and £32,400 for those receiving RRT.37 The causes of renal failure are multifactorial and include preoperative function, intraoperative fluid shifts and hemodynamic compromise, postoperative bleeding, and sepsis. The more profound PRS may have contributed to the increased rate of renal failure and the increased need for RRT seen in the DCDD cohort.
Data from the US Scientific Registry of Transplant Recipients and UK Transplant point to significant additional costs associated with DCDD donors due to the fruitless mobilization of retrieval teams.38 In the United States, only 63% of potential DCDD donor livers are recovered, and only 71% of these livers are transplanted (a 55% discard rate). For DBD livers, the recovery rate is 90%, and the transplant rate for recovered grafts is 82% (a 26% discard rate). Low rates of retrieval by procurement teams are often due to the fact that the donor does not progress to asystole and/or there is an extended period of profound hypotension that exceeds acceptable time limits. It has been shown that prolonged severe hypotension in the donor in the postextubation period is a better predictor of subsequent organ function than the time from extubation to asystole.39 In the United Kingdom in 2008-2009, 80 of 118 retrieved DCDD organs (68%) were used for a transplant, whereas 527 of 559 DBD organs (94%) were.
Using matched recipient pairing, we have demonstrated that there are different perioperative and early postoperative courses for DCDD and DBD liver transplants. The overall quality of DCDD grafts is poorer; as a result, the length of the ITU stay and the need for multiorgan support are increased, and this has significant financial and resource implications. In a recent editorial, Skaro et al.40 noted that the transplantation of livers with a high donor risk index provides a survival benefit to candidates with high MELD scores but not to candidates with low MELD scores. This seems relevant to our UK practice, which currently selects patients with low MELD scores for DCDD grafts because it is felt that they have more physiological reserve and less comorbidity and will better tolerate more significant ischemia/reperfusion injury. As we have shown by matching recipients with similar MELD scores, patients who receive DCDD grafts have a stormier and consequently more costly perioperative course.
Most centers report graft survival rates below those with DBD grafts. This is mostly due to the high retransplantation rate, which is due to the increased rates of primary nonfunction, vascular complications, and nonanastomotic biliary strictures. The Netherlands started its DCDD program more than 10 years ago, and its survival figures for DCDD grafts were inferior to those for DBD grafts; however, this difference was significantly reduced when the Netherlands began to use DCDD grafts according to predefined and restrictive donor acceptance criteria. In addition, the retrieval teams were mobilized only if the potential donor was expected to develop cardiorespiratory arrest within 1 hour of the cessation of mechanical respiratory support (as determined by a scoring system developed for the purpose).41 All patients and their families should be given the option of organ donation as a component of end-of-life care; however, most will also want the option of this decision resulting in the donation of an organ that is in the best possible condition for the recipient. This is not something that we can currently guarantee when donation follows cardiac arrest occurring as a result of profound hypotension and/or hypoxia. Perhaps it would be better for us to maximize opportunities to facilitate donation from DBD donors rather than focus our efforts on expanding a donor pool that has already led to significantly increased costs associated with transplantation and generally results in grafts of inferior quality.
Although resource utilization has previously been examined for DCDD liver grafts, as far as we know, what is generally discussed is the cost of futile retrieval efforts as well as the long-term costs associated with ischemic cholangitis, imaging, readmission, and retransplantation. Our intention for this article is not to compare long-term outcomes and ways to improve them but instead to highlight that there are significant perioperative resource implications to the use of these grafts. Although the numbers in this retrospective study are small, it is a single-center study using recipients matched for age, liver disease etiology, and MELD score to demonstrate any differences in perioperative outcomes with DCDD and DBD grafts. This difference may on face value appear to be interesting only to the liver transplant community, but centers that are considering starting DCDD programs should be aware of the significantly increased costs (short- and long-term) associated with doing so. Also, intensivists should be in possession of all available facts when they are discussing organ donation with relatives; this is particularly relevant if the potential donor is already brain-dead or is likely to become so in hours. In comparison with DBD, the donation of the liver after circulatory determination of death (which may be offered as an alternative) will potentially result in inferior graft function.
We do not want to give the impression that DCDD livers should not be used in any circumstances because this would potentially lead to a number of patients dying while they are waiting for a liver. Indeed, current evidence suggests that on the basis of MELD mortality rates, a cohort of patients will have a survival benefit that outweighs the biliary complication rate and the increased utilization of resources.
What we do believe is that because of the current impetus for promoting the utilization of DCDD grafts, the implications require a careful consideration of the real benefits. It is essential that DCDD not be seen as a like-for-like alternative to DBD and that every effort be made to increase the number of donations from brain-dead patients as a first resort.