Orthotopic liver transplantation (OLT) is the treatment of choice for patients with life-threatening chronic and acute liver disease, hepatocarcinoma, and several metabolic diseases. Over the years, favorable outcomes have been achieved with this procedure, leading to an increasing number of candidates on the waiting list. However, the number of liver grafts is not sufficient to treat all patients who need an OLT. In Spain, 1247 OLTs were performed in 2017, and 3% of OLT candidates died on the waiting list, taking into account that 11.2% of patients were removed from the waiting list because they were too sick to be transplanted.1 Thus, access to liver transplantation is limited by organ shortage.
Aiming to mitigate liver graft shortage and thus decrease waiting list mortality, many OLT teams have proposed expanding the number of available grafts using livers from marginal or extended-criteria donors. This is a poorly defined group that primarily includes living-related and old liver donors; donors with hypernatremia, prolonged intensive care unit (ICU) stay, vasoactive drug requirements, or positive serology for viral hepatitis B or C; livers with a prolonged cold ischemia time or steatosis; and grafts from split livers or donations after circulatory death (DCDs).2-8 Circulatory death is defined as the cessation of peripheral blood flow by the absence of peripheral pulses and blood pressure,9 and a DCD is classified as controlled (cDCD or Maastricht type 3) and uncontrolled DCD (uDCD). Type 2 uDCD is defined as a donation from a patient who had a witnessed cardiac arrest outside of the hospital and underwent unsuccessful cardiopulmonary resuscitation (CPR). In type 3 cDCD, the organs may be recovered after a death declaration from patients with irreversible brain injury or respiratory failure from whom treatment was withdrawn.10 Type 3 cDCDs are mostly used for OLTs in Belgium, the Netherlands, the United Kingdom, Sweden, and the United States. In Spain, the use of type 3 cDCDs is increasing, but the focus is primarily on the use of type 2 uDCDs.11-13 Recently, a short multicenter French study reported the use of type 2 uDCDs.14 This type of donation requires significant effort from out-of-hospital emergency services and hospital staff such as ICU staff, transplant coordinators, and transplant surgeons. In an earlier, short follow-up series of 20 OLTs, our team reported using type 2 uDCDs that were maintained with normothermic extracorporeal membrane oxygenation (NECMO).13 The aim of the present study was to analyze our 10-year experience using liver grafts from type 2 uDCDs, comparing post-OLT complications and recipient outcomes with a control group of patients who received liver grafts from donations after brain death (DBDs). To our knowledge, this series represents the largest reported experience using type 2 uDCDs.
PATIENTS AND METHODS
Study Population and Study Design
From April 1986 to December 2016, a total of 1876 patients, including adults and children, underwent OLTs at “Doce de Octubre” University Hospital. The first OLT using an uDCD liver was performed in January 2006. From this date to December 2016, 680 OLTs were performed using DBDs, and 75 OLTs were performed using DCD livers (case group A). Control group B comprised a sample of 265 patients who received a liver graft from a DBD during the same period. Group B patients were selected after applying the following exclusion criteria: liver graft macrosteatosis >30%, donors older than 70 years, partial (reduced, split, and living-related donors) or combined transplants, retransplantation, recipients older than 70 years or HIV seropositive, and transplants for acute liver failure. There was a chronologic correlation between the cases and controls. A retrospective case-controlled study comparing case group A and control group B was performed.
This study was closed for follow-up at the end of February 2018, with a minimal follow-up of 14 months after OLT. All transplant recipients were periodically followed by surgeons of the Abdominal Organ Transplantation Unit. This study was approved by the institutional review board.
Protocol for Type 2 Uncontrolled Donation After Circulatory Death
Our protocol for type 2 uDCD was established by our transplant team in 200513 and is similar to others previously reported in Spain.11,12 After unrecovered cardiac arrest was diagnosed, emergency medical services went to the scene and initiated CPR using a chest compression system and endotracheal tube. The donor was transferred to our hospital, and according to Spanish law, death was confirmed by the absence of cardiac function and spontaneous respiration after cessation of CPR maneuvers during a period of 5 minutes. Once death was confirmed, chest compression and pulmonary ventilation were reinitiated. In Spain, the law permits donor vessel cannulation and initiation of NECMO and heparin anticoagulation without consent from the family or a judge. Cannulation of the femoral artery and vein in the right groin region was performed, and a Fogarty balloon catheter was introduced into the contralateral femoral artery and inflated at the supraceliac aorta to exclude the thoracic organs from the circuit. These maneuvers ensured an adequate blood supply to the liver and kidneys that enables their use for transplant. At that moment, transplant coordinators were engaged to obtain family consent or permission from a judge for organ donation. If consent was obtained and there was no contraindication for donation, the procurement process continued. The period of cardiac arrest needed to be <15 minutes. Pre-NECMO warm ischemia time was defined as the period from cardiac arrest to regional perfusion (the sum of cardiac arrest and CPR periods). According to our protocol, the elapsed time from advanced CPR to initiation of NECMO must be <150 minutes. Thus, the maximum period allowed of pre-NECMO warm ischemia time was less than or equal to 165 minutes.
The donors were maintained in NECMO for a maximum period of 300 minutes before initiation of organ perfusion with the preservation solution (Celsior or Belzer). During this time, several hematological, liver function, and acid-base parameters were periodically determined (every 30 min on NECMO). The pump flow is maintained between 2.5 and 3.5 L/min, temperature between 36° and 37.5°C, and pH between 7.1 and 7.4 with the administration of 1/6 M sodium bicarbonate. Anticoagulation doses of heparin (3 mg/kg) were administered when the donor death was declared and repeated every 90 minutes at doses of 1.5 mg/kg during NECMO maintenance.
Criteria for uDCD Liver Graft Acceptance
For uDCD donors to be accepted for transplant, the maximum levels of transaminases needed to be <4 times the upper limit of normal values. The following other conditions were needed for liver graft acceptance: donors aged 14–55 years; absence of alcoholic disease, drug addiction, signs of a violent death or abdominal trauma; and no history of cancer, hepatitis B or C, or HIV infection.
During organ procurement, other macroscopic conditions before and after cold perfusion were considered for liver acceptance, such as good general appearance, consistency and vascularization of the liver, and absence of signs of ischemia of the gallbladder, choledochus, or intestine. We routinely carried out a liver biopsy before cold perfusion in all type 2 uDCD livers and discarded the graft when it showed fibrosis or ≥30% macrosteatosis. In DBD donors, we performed a biopsy on all liver grafts that showed macroscopic abnormalities (steatosis, color, hard consistency, and edema).
Type 2 uDCD liver grafts were also not used when the time periods established in the protocol (Figure 1) were exceeded.
The NECMO system was maintained until organ perfusion began with Belzer or Celsior solution. Organ procurement was exclusively performed by our transplant team, using a standard rapid technique.15
Candidate Information and Transplant Technique
All accepted candidates for OLT were previously informed about the possibility of receiving a liver from a uDCD donor and possible associated risks. Livers from uDCD donors were usually offered to all candidates but avoided in patients with a previous history of abdominal surgery, model for end-stage liver disease (MELD) score >30, or candidates for retransplantation. Patients who signed the informed consent were included on both waiting lists (for uDCD and DBD liver grafts). Recipient hepatectomy was performed without venous-venous bypass, using the vena cava–sparing technique (piggy-back). In most cases, biliary reconstruction was carried out by an end-to-end choledochocholedochostomy without a T-tube.
Donor and Pre-OLT Recipient Variables
We evaluated variables related to donor maintenance and liver function test evolution of uDCD donors after confirmation of circulatory death. We also compared variables common to both types of donors: age, gender, body mass index, cause of death, vasopressor use, ICU stay, cardiac arrest, transaminases, steatosis, preservation injury, and cold and recipient warm ischemia times. Pre-OLT recipient variables were also compared in both groups: age, gender, body mass index, OLT indication, MELD score, hematological and liver function tests, and serum levels of albumin, creatinine, and sodium.
Perioperative Variables, Morbidity/Mortality, and Patient and Graft Survivals
We analyzed the following perioperative variables: biliary reconstruction techniques, hemoderivative transfusions, liver graft function parameters on the 7th and 30th day after OLT, immunosuppression, ICU and hospital stay, post-OLT complications (biliary, arterial, primary nonfunction [PNF], rejection, infection, and retransplantation), hospital mortality, and patient and graft survivals. We defined PNF as the necessity of retransplantation within 10 days of implantation or death from a nonfunctioning graft.16 Nonanastomotic biliary strictures (NABS) were defined as any stricture, dilation, or irregularity of the intrahepatic or extrahepatic bile ducts of the liver (hilum), whereas anastomotic biliary strictures (ABS) were defined as lesions localized at the site of anastomosis.17 Mixed biliary strictures (MBS) were defined as lesions that affected biliary anastomosis, hepatic hilum, or intrahepatic bile ducts. To establish the true impact of uDCD transplant on the development of biliary complications, we excluded cases of hepatic artery thrombosis from the uDCD and control groups because hepatic artery thrombosis is a well-known cause of biliary complications.
Biliary strictures were suspected when an alteration of liver function tests or ultrasonography findings was identified, and were primarily confirmed magnetic resonance imaging cholangiography.
Acute renal failure was defined as an increase in serum creatinine greater than or equal to 0.5 mg/dL or >50% of the baseline value.18
The immunosuppressive regimen comprised tacrolimus and prednisone. Steroids were usually discontinued between 3 and 6 months after OLT. Tacrolimus trough levels were maintained at 10–15 ng/mL during the first month, 8–12 ng/mL from the second month to the sixth month, and 5–8 ng/mL thereafter. Mild episodes of acute rejection were treated with increasing doses of tacrolimus. Moderate or severe episodes were initially treated with 1 g methylprednisolone intravenously for 3 days and steroid recycling. In the rare cases of steroid-resistant rejection, thymoglobulin or basiliximab were added. When renal dysfunction or adverse events related to tacrolimus (nephrotoxicity, hypertension, diabetes) were evident, we decreased the doses of tacrolimus and added mycophenolate mofetil to the immunosuppressive regimen.
Quantitative variables were expressed as mean values and SD or as medians and range. Qualitative variables were expressed as percentages. Differences in properties between qualitative variables were assessed by chi-square test or Fisher’s exact test, as appropriate. Comparisons of quantitative variables were made by t-test or Mann-Whitney U test regarding normality. Graft and patient survivals were estimated using the Kaplan-Meier method. Comparisons of survival curves were performed using the log-rank test. All donor and recipient variables with P less than 0.10 in the univariate analysis were subsequently investigated in a multivariate analysis using Cox’s regression model to evaluate the association between variables present at the baseline evaluation and patient and graft survival. Results were expressed as hazard ratios and 95% confidence intervals. A P <0.05 was considered statistically significant. Analysis of these data were performed using SPSS Statistics Version 24.
A total of 256 uDCD donors were cannulated. Evaluation and interoperative exploration of liver grafts were performed during <300 minutes of connection to NECMO. Seventy-five (29.3%) livers were accepted for OLT (Figure 2), and 181 (70.7%) livers were discarded primarily due to liver ischemia, elevated transaminases, family refusal, low pump flow, and steatosis (Table 1).
The parameters of uDCD donors while under NECMO maintenance are shown in Table 2. Mean pre-NECMO warm ischemia time was 130 ± 21.5 minutes, and mean pump flow during maintenance of uDCD livers under NECMO was 3790 ± 425 mL/min. Donor characteristics are shown in Table 3. Uncontrolled DCD donors were significantly younger than DBD donors (41.7 ± 9.7 y versus 47.8 ± 14.9 y; P = 0.001). In addition, both groups had more male donors, but only the uDCD group showed a statistically significant difference. The rates of macrosteatosis, macrosteatosis, and preservation injury were similar in both donor groups. Although the mean values of cold ischemia time were similar in both groups, mean recipient warm ischemia time was significantly shorter in the uDCD group (62 ± 14 min versus 70 ± 36 min; P = 0.010).
Recipient characteristics are shown in Table 4. The mean age of uDCD recipients was significantly higher than that of DBD recipients (58.8 ± 7.7 y versus 54.7 ± 10.1 y; P = 0.000). Regarding OLT indications, uDCDs were more frequently used in recipients with hepatocarcinoma and HCV cirrhosis. The mean value of the MELD score was similar in both recipient groups. The waiting list period was significantly shorter for uDCD recipients than for DBD recipients (160 ± 91 days versus 240 ± 165 days; P = 0.037). The mean platelet count was the only parameter that was significantly lower in uDCD recipients.
Perioperative Variables, Immunosuppression, and Morbidity/Mortality
As shown in Table 5, choledochocholedochostomy without T-tube was the most common technique used for biliary reconstruction without significant differences between the groups. The amount of intraoperative transfusions of PRBC, platelets, fresh frozen plasma, and fibrinogen were significantly higher in uDCD recipients.
No significant differences were observed in liver function parameters, such as glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, gamma-glutamyl transpeptidase, and bilirubin, on the 7th and 30th day post-OLT between the groups. The use of immunosuppressive drugs was also similar in both groups.
The length of ICU stay was similar in both groups. The length of hospital stay was longer in uDCD recipients, but this difference did not reach statistical significance.
The rate of PNF was significantly higher in uDCD recipients (6 cases, 8%) than in DBD recipients (4 cases, 1.5%) (P = 0.031). The overall rate of biliary complications was significantly higher (P = 0.001) in uDCD recipients (23 cases, 30.6%) than in DBD recipients (32 cases, 12.1%). After further analyzing these complications, we found a statistically significant higher rate of NABS in uDCD recipients (12 cases, 16%) than in DBD recipients (8 cases, 3%) (P = 0.018). In addition, we found a statistically significant higher rate of ABS in uDCD recipients (5 cases, 6.7%) than in DBD recipients (5 cases, 1.9%) (P = 0.040). However, the rates of MBS and biliary leakage were not different between the groups. The median time from OLT to the diagnosis of NABS was 3 months in the uDCD group and 3.6 months in the DBD group (P = 0.999). Meanwhile, the median time from OLT to the diagnosis of ABS was 4.5 months in the uDCD group and 6.5 months in the DBD group (P = 0.680).
The acute rejection rate was significantly lower in the uDCD group than in the DBD group (24% versus 35.5%; P = 0.044). The rate of hepatic artery thrombosis was 4% (3 cases) in the uDCD group and 3.4% (9 cases) in the DBD group (P = 0.732). Of the 3 hepatic artery thrombosis cases in the uDCD group, 2 developed biliary complications (1 ABS and 1 MBS) and one remained asymptomatic. In the DBD group, 4 patients developed biliary complications (2 ABS and 2 NABS), 3 patients were retransplanted for hepatic artery thrombosis, and 2 patients died.
Other complications such as chronic rejection and infection did not show significant differences between the groups. Post-OLT (30th day) mortality was similar in both groups (5.3% in uDCD group versus 6.4% in DBD group; P = 0.794). The rate of retransplantation was significantly higher (P = 0.028) in the uDCD group (12%) than in the DBD group (4.5%). Retransplantation was performed in 6 cases of the uDCD group and 2 cases of the DBD group due to PNF and in 3 cases of the uDCD group and 1 case of the DBD group due to NABS. Patients who underwent retransplantation for other reasons are described in Table 5. Thirteen patients of the uDCD group with NABS or MBS were managed by percutaneous transhepatic biliary dilation, endoscopic retrograde cholangiopancreatography dilation or Roux-en-Y hepaticojejunostomy. The patients were followed for a mean period of 63.5 ± 2.3 months.
As shown in Figure 3, patient and graft survival were lower in uDCD recipients, but only the difference in graft survival was statistically significant. Thus, overall 1-, 3-, and 5-year patient survival rates were 82.7%, 73.0% and 71.5%, respectively, in uDCD recipients and 89.0%, 83.7%, and 78.8%, respectively, in DBD recipients (P = 0.180). Meanwhile, 1-, 3-, and 5-year graft survival rates were 73.3%, 65.1%, and 63.6% in uDCD recipients and 87.1%, 81.9%, and 76.5%, respectively, in DBD recipients (P = 0.013).
When we divided this study in 2 periods (first period: from January 2006 to December 2012; second period: from January 2013 to December 2016), we observed an improved but not statistically significant 1- and 3-year patient survival during the second period (second period: 85% and 80%; first period: 80% and 70.3%; P = 0.299), as well as an improved graft survival (second period: 80% and 75%; first period: 70% and 62%).
Multivariate analysis showed that independent risk factors for patient and graft survival were intraoperative transfusion of >6 units of PRBC and recipients older than 60 years (Table 6).
Similar to other reports,14,19 our requirements for accepting uDCD liver grafts for OLT were as follows: donor age between 14 and 55 years; an estimated preresuscitation cardiac arrest of <15 minutes; CPR during a maximum period of 150 minutes; time in NECMO under 5 hours; level of transaminases <4 times the upper-level limit; liver macrosteatosis <30%; absence of alcoholism, drug addiction, violent death, or abdominal trauma; and no history of cancer, HCV, HBV, or HIV infection. Exceptionally, liver grafts initially showing higher values of transaminases were accepted if the transaminase levels progressively decrease while the donor is maintained in pump. Other important conditions for uDCD liver acceptance are normal consistency of the liver and absence of signs of ischemia of the liver, gallbladder, and intestines. Whereas initially donors were maintained on NECMO for <4 hours, as previously reported,13,14,19 in recent years, we extended this period up to 5 hours and obtained the same results as maintaining during <4 hours. As other authors have reported,19 our primary reasons for excluding 181 donors on NECMO were ischemic liver, progressive elevation of transaminases during connection to NECMO, family refusal, and pump flow <2 L/min.
As in the prior series,11,19 our study’s uDCD donors were significantly younger than the DBD donors, and the most frequent causes of uDCD donor death were heart arrhythmias and myocardial infarction. By contrast, cerebrovascular events and trauma were the most frequent causes in DBD donors, showing statistically significant differences between the donor groups. We systematically performed a liver biopsy in all uDCD donors and DBD donors with abnormal consistency and macroscopic appearance of the livers and discarded grafts with >30% macrosteatosis or fibrosis. Mean cold ischemia time was similar in both groups (<7 h), but mean recipient warm ischemia time was significantly lower in uDCD donors. Celsior preservation solution was used in approximately 80% of donors in both groups and is currently our solution of choice because of having a lower viscosity than Belzer solution. Previous reports have shown a lower incidence of NABS when livers are preserved with low-viscosity solutions.17,20
The mean age of uDCD recipients was 58.8 years, which was significantly higher than that of DBD recipients. In other reports,11,14,19 the mean age of uDCD recipients was between 55 and 56 years. Due to poor results, we currently recommend avoiding the use of uDCD livers for recipients older than 60 years. Similar to other series, hepatocarcinoma, HCV, and alcoholic cirrhosis were our most frequent indications for using uDCD livers.11,19 A recent multicenter report used uDCD livers almost exclusively (90%) in patients with hepatocarcinoma, with 46% of those patients being outside of the Milan criteria.14 In our experience, the use of uDCD livers confers an advantage for the recipients, given that the period on the waiting list is significantly shorter than on the conventional DBD list, as reported by other centers.14
Because of the extended period of cardiac arrest and ischemia that uDCD donors experience, the recipients of these liver grafts develop hyperfibrinolysis, and it is therefore unnecessary to add fibrinolytic agents.21 The mean global transfusion rate was significantly higher in our recipients of uDCD livers than those of DBD livers. However, nowadays the necessity of hemoderivative transfusion has dramatically decreased, primarily due to better selection and management of donors and recipients. In spite of severe stress endured by uDCD livers during the cardiorespiratory arrest and ischemia periods, we did not find significant differences between the groups regarding the recovery of liver function parameters on the 7th and 30th day post-OLT.
Among previous series investigating uDCD livers, the rates of PNF ranged between 5% and 25%.11,13,14,19,22,23 Six (8%) patients in our uDCD group (re-OLT in all) and 4 (1.5%) in the DBD group (re-OLT in 2) developed PNF. The mechanism of PNF is usually related to several factors, such as a prolonged period of cardiocirculatory arrest, cold and warm ischemia, inadequate pump flow or venous return during NECMO, and severe liver macrosteatosis. In the procurement, the presence of ischemic necrosis of the gallbladder, common bile duct, or intestines is usually related with PNF, and consequently, the uDCD livers in this scenario must be discarded. Similar with other series,23 in our experience the use of uDCD livers was not associated with a higher incidence of hepatic artery thrombosis than the use of DBD livers.
Three interconnected mechanisms for NABS have been described, namely cold and warm ischemia-reperfusion injury, injury induced by cytotoxic bile salts, and immune-mediated injury.24,25 Focusing on experiences using cDCD livers, a cold ischemia time >8–10 hours has been significantly associated with NABS,26,27 whereas a donor warm ischemia time >30 minutes has been associated with graft loss.28,29 Considering that old livers are more susceptible to warm and cold ischemia-reperfusion injury than young livers, some transplant teams decline the use of cDCD livers older than 60 years because of a significantly increased risk of NABS.29 However, other studies have obtained similar results in terms of graft survival and incidence of NABS when comparing the use of cDCD livers older than 60 years and younger than 60 years.30,31 The overall rate of biliary complications is 13%–50% for recipients of cDCD livers24,30,32-35 and 10%–30% for recipients of DBD livers.30,35-37 Our overall rate of biliary complications was 30.6% in recipients of uDCD livers and 10.6% in recipients of DBD livers. Specifically, our incidence of NABS (16%) and ABS (6.7%) lesions in recipients of uDCD livers was significantly higher than in recipients of DBD livers, and the incidence of MBS was similar in both groups. The rate of NABS in recipients of uDCD livers has been reported to be between 7.5% and 25%.14,19,22,23
The rate of acute rejection was significantly lower in our recipients of uDCD livers, a finding previously reported by other authors.11 Other post-OLT complications such as chronic rejection, acute renal failure, or infections showed similar rates in both groups. In agreement with several other series, the rates of retransplantation were significantly higher in recipients of uDCD than recipients of DBD livers, and the most frequent causes were PNF, ischemic cholangiopathy, and hepatic artery thrombosis, which ranged from 15% to 25% of cases.11,13,14,22 Our retransplantation rate of 12% in uDCD recipients is similar to those series. Nine patients of our uDCD group underwent retransplantation due to PNF or NABS. The remaining 13 patients of the uDCD group who developed NABS or MBS were successfully managed by percutaneous transhepatic biliary, endoscopic retrograde cholangiopancreatography dilations, or Roux-en-Y hepaticojejunostomy.
As in this study, other teams have also reported higher ICU and hospital stays in recipients of uDCD livers.11,22 In prior reports,11,13,14,19,22 no differences in 1-year patient survival were found between recipients of uDCD or DBD livers (higher than 80% in both groups), but 1-year graft survival was significantly lower in recipients of uDCD livers (range, 55%–70%).11,13,14,19,22 Our study is the first one to report 1-, 3-, and 5-year patient and graft survival and show similar patient survival in the uDCD and DBD groups but significantly lower graft survival in the uDCD group.
When the recipients of uDCD livers were divided into 2 groups, we observed better patient and graft survival, although without significant differences in patients who underwent OLT in the last 4 years. We attribute these results to improved donor selection and donor and recipient perioperative management.
Multivariate analysis showed that the only independent risk factors for patient and graft survival were intraoperative transfusion >6 units of PRBC and recipient age older than 60 years.
In summary, the use of uDCD livers is a complex process that helps increase the donor pool. Careful selection of these donors can provide 5-year patient survival comparable to that obtained with DBD livers. However, 5-year graft survival is significantly lower in uDCD livers, and recipients of them have higher incidences of biliary complications and PNF.
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