Ilynn G. Bulatao

Events in procurement as risk factors for ischemic cholangiopathy in liver transplantation using donation after cardiac death donors

The use of donation after cardiac death (DCD) liver grafts is controversial because of the overall increased rates of graft loss and morbidity, which are mostly related to the consequences of ischemic cholangiopathy (IC). In this study, we sought to determine the factors leading to graft loss and the development of IC and to compare patient and graft survival rates for recipients of DCD liver grafts and recipients of donation after brain death (DBD) liver grafts in a large series at a single transplant center. Two hundred liver transplants with DCD donors were performed between 1998 and 2010 at Mayo Clinic Florida. Logistic regression models were used in the univariate and multivariate analyses of predictors for the development of IC. Additional analyses using Cox regression models were performed to identify predictors of graft survival and to compare outcomes for DCD and DBD graft recipients. In our series, the patient survival rates for the DCD and DBD groups at 1, 3, and 5 years was 92.6%, 85%, and 80.9% and 89.8%, 83.0%, and 76.6%, respectively (P = not significant). The graft survival rates for the DCD and DBD groups at 1, 3, and 5 years were 80.9%, 72.7%, and 68.9% and 83.3%, 75.1%, and 68.6%, respectively (P = not significant). In the DCD group, 5 patients (2.5%) had primary nonfunction, 7 patients (3.5%) had hepatic artery thrombosis, and 3 patients (1.5%) experienced hepatic necrosis. IC was diagnosed in 24 patients (12%), and 11 of these patients (5.5%) required retransplantation. In the multivariate analysis, the asystole‐to‐cross clamp duration [odds ratio = 1.161, 95% confidence interval (CI) = 1.021‐1.321] and African American recipient race (odds ratio = 5.374, 95% CI = 1.368‐21.103) were identified as significant factors for predicting the development of IC (P < 0.05). This study has established a link between the development of IC and the asystole‐to‐cross clamp duration. Procurement techniques that prolong the nonperfusion period increase the risk for the development of IC in DCD liver grafts. Liver Transpl 18:101–112, 2012.

Asystole to cross‐clamp period predicts development of biliary complications in liver transplantation using donation after cardiac death donors

This study sought to determine the procurement factors that lead to development of intrahepatic bile duct strictures (ITBS) and overall biliary complications in recipients of donation after cardiac death (DCD) liver grafts. Detailed information for different time points during procurement (withdrawal of support; SBP < 50 mmHg; oxygen saturation <30%; mandatory wait period; asystole; incision; aortic cross clamp) and their association with the development of ITBS and overall biliary complications were examined using logistic regression. Two hundred and fifteen liver transplants using DCD donors were performed between 1998 and 2010 at Mayo Clinic Florida. Of all the time periods during procurement, only asystole‐cross clamp period was significantly different between patients with ITBS versus no ITBS (P = 0.048) and between the patients who had overall biliary complications versus no biliary complications (P = 0.047). On multivariate analysis, only asystole‐cross clamp period was significant predictor for development of ITBS (P = 0.015) and development of overall biliary complications (P = 0.029). Hemodynamic changes in the agonal period did not emerge as risk factors. The results of the study raise the possibility of utilizing asystole‐cross‐clamp period in place of or in conjunction with donor warm ischemia time in determining viability or quality of liver grafts.

Use of liver grafts from donation after cardiac death donors for recipients with hepatitis C virus

Hepatitis C virus (HCV) infection is the most common indication for orthotopic liver transplantation in the United States. Although studies have addressed the use of expanded criteria donor organs in HCV+ patients, to date the use of liver grafts from donation after cardiac death (DCD) donors in HCV+ patients has been addressed by only a limited number of studies. This retrospective analysis was undertaken to study the outcomes of DCD liver grafts used in HCV+ recipients. Seventy‐seven HCV+ patients who received DCD liver grafts were compared to 77 matched HCV+ patients who received donation after brain death (DBD) liver grafts and 77 unmatched non‐HCV patients who received DCD liver grafts. There were no differences in 1‐, 3‐, and 5‐year patient or graft survival among the groups. Multivariate analysis showed that the Model for End‐Stage Liver Disease score [hazard ratio (HR) = 1.037, 95% confidence interval (CI) = 1.006‐1.069, P = 0.018] and posttransplant cytomegalovirus infection (HR = 3.367, 95% CI = 1.493‐7.593, P = 0.003) were significant factors for graft loss. A comparison of the HCV+ groups for fibrosis progression based on protocol biopsy samples up to 5 years post‐transplant did not show any difference; in multivariate analysis, HCV genotype 1 was the only factor that affected progression to stage 2 fibrosis (genotype 1 versus non‐1 genotypes: HR = 2.739, 95% CI = 1.047‐7.143, P = 0.040). In conclusion, this match‐controlled, retrospective analysis demonstrates that DCD liver graft utilization does not cause untoward effects on disease progression or patient and graft survival in comparison with DBD liver grafts in HCV+ patients. Liver Transpl 17:641‐649, 2011.

Is a mandatory intensive care unit stay needed after liver transplantation? Feasibility of fast‐tracking to the surgical ward after liver transplantation

The continuation of hemodynamic, respiratory, and metabolic support for a variable period after liver transplantation (LT) in the intensive care unit (ICU) is considered routine by many transplant programs. However, some LT recipients may be liberated from mechanical ventilation shortly after the discontinuation of anesthesia. These patients might be appropriately discharged from the postanesthesia care unit (PACU) to the surgical ward and bypass the ICU entirely. In 2002, our program started a fast‐tracking program: select LT recipients are transferred from the operating room to the PACU for recovery and tracheal extubation with a subsequent transfer to the ward, and the ICU stay is completely eliminated. Between January 1, 2003 and December 31, 2007, 1045 patients underwent LT at our transplant program; 175 patients were excluded from the study. Five hundred twenty‐three of the remaining 870 patients (60.10%) were fast‐tracked to the surgical ward, and 347 (39.90%) were admitted to the ICU after LT. The failure rate after fast‐tracking to the surgical ward was 1.90%. The groups were significantly different with respect to the recipient age, the raw Model for End‐Stage Liver Disease (MELD) score at the time of LT, the recipient body mass index (BMI), the retransplantation status, the operative time, the warm ischemia time, and the intraoperative transfusion requirements. A multivariate logistic regression analysis revealed that the raw MELD score at the time of LT, the operative time, the intraoperative transfusion requirements, the recipient age, the recipient BMI, and the absence of hepatocellular cancer/cholangiocarcinoma were significant predictors of ICU admission. In conclusion, we are reporting the largest single‐center experience demonstrating the feasibility of bypassing an ICU stay after LT. Liver Transpl 18:361–369, 2012.

Inferior long-term outcomes of liver-kidney transplantation using donation after cardiac death donors: Single-center and organ procurement and transplantation network analyses

Limited data are available for outcomes of simultaneous liver‐kidney (SLK) transplantation using donation after cardiac death (DCD) donors. The outcomes of 12 DCD‐SLK transplants and 54 SLK transplants using donation after brain death (DBD) donors were retrospectively compared. The baseline demographics were similar for the DCD‐SLK and DBD‐SLK groups except for the higher liver donor risk index for the DCD‐SLK group (1.8 ± 0.4 versus 1.3 ± 0.4, P = 0.001). The rates of surgical complications and graft rejections within 1 year were comparable for the DCD‐SLK and DBD‐SLK groups. Delayed renal graft function was twice as common in the DCD‐SLK group. At 1 year, the serum creatinine levels and the iothalamate glomerular filtration rates were similar for the groups. The patient, liver graft, and kidney graft survival rates at 1 year were comparable for the groups (83.3%, 75.0%, and 82.5% for the DCD‐SLK group and 92.4%, 92.4%, and 92.6% for the DBD‐SLK group, P = 0.3 for all). The DCD‐SLK group had worse patient, liver graft, and kidney graft survival at 3 years (62.5%, 62.5%, and 58.9% versus 90.5%, 90.5%, and 90.6%, P = 0.03 for all) and at 5 years (62.5%, 62.5%, and 58.9% versus 87.4%, 87.4%, and 87.7%, P < 0.05 for all). An analysis of the Organ Procurement and Transplantation Network database showed inferior 1‐ and 5‐year patient and graft survival rates for DCD‐SLK patients versus DBD‐SLK patients. In conclusion, despite comparable rates of surgical and medical complications and comparable kidney function at 1 year, DCD‐SLK transplantation was associated with inferior long‐term survival in comparison with DBD‐SLK transplantation. Liver Transpl 20:728‐735, 2014.

Proteinuria following sirolimus conversion is associated with deterioration of kidney function in liver transplant recipients.

Background The role of sirolimus (SRL) conversion in the preservation of kidney function in liver transplant (LT) recipients with calcineurin inhibitor (CNI) nephrotoxicity is unclear. Methods Data on 102 LT recipients with deteriorating kidney function after CNI exposure who were later converted to SRL were retrospectively reviewed. Kidney function was assessed using serum creatinine and estimated glomerular filtration rate (eGFR) at time of conversion and serially thereafter. The primary endpoint was stabilization or improvement of kidney function as assessed by eGFR at last recorded follow-up compared with eGFR at the time of conversion. Result After a median (interquartile range) of 3.1 (1.6–4.5) years of follow-up, serum creatinine decreased from 1.9±0.8 to 1.8±0.7 mg/dL (P=0.25) and eGFR increased from 40.8±16.7 to 44.3±20.0 mL/min (P=0.03). During the same time period, 24-hr urinary protein excretion increased from median (interquartile range) of 72 (0–155) to 382 (169–999) mg/day (P=0.0001). Sixty-five (64%) patients achieved the primary endpoint and 37 (36%) experienced deterioration in kidney function. Independent predictors of deterioration of kidney function after SRL conversion were development of proteinuria ≥1000 mg/day (odds ratio [OR]: 3.3, confidence interval [CI]: 1.1–9.5 P=0.03), post-LT diabetes (OR: 4.2, CI: 1.6–11.1, P=0.004), and higher eGFR at time of conversion (OR: 1.6, CI: 1.2–2.2, P=0.003). Conclusion Improvement or stabilization of kidney function occurred in the majority of LT recipients converted to SRL for CNI nephrotoxicity. Proteinuria ≥1000 mg/day, post-LT diabetes, and higher baseline eGFR were independent predictors of kidney function loss after SRL conversion.

Avoiding Stay in the Intensive Care Unit After Liver Transplantation: A Score to Assign Location of Care

Select liver transplantation (LT) recipients in our program are transferred from operating room to postanesthesia care unit for recovery and extubation with transfer to the ward, completely eliminating an intensive care unit (ICU) stay. Developing a reliable method to determine patients suitable for fast‐tracking would be of practical benefit to centers considering this practice. The aim of this study was to create a fast‐tracking probability score that could be used to predict successful assignment of care location after LT. Recipient, donor and operative characteristics were assessed for independent association with successful fast‐tracking to create a probability score. Of the 1296 LT recipients who met inclusion criteria, 704 (54.3%) were successfully fast‐tracked and 592 (45.7%) were directly admitted to the ICU after LT. Based on nine readily available variables at the time of LT, we created a scoring system that classified patients according to the likelihood of being successfully fast‐tracked to the surgical ward, with an area under the curve (AUC) of 0.790 (95% CI: 0.765–0.816). This score was validated in an independent group of 372 LT with similar AUC. We describe a score that can be used to predict successful fast‐tracking immediately after LT using readily available clinical variables.

Radiologic Characterization of Ischemic Cholangiopathy in Donation-After-Cardiac-Death Liver Transplants and Correlation With Clinical Outcomes.

OBJECTIVE The purpose of this study was to define the cholangiographic patterns of ischemic cholangiopathy and clinically silent nonanastomotic biliary strictures in donation-after-cardiac-death (DCD) liver grafts in a large single-institution series. We also examined the correlation of the radiologic findings with laboratory data and clinical outcomes. MATERIALS AND METHODS Data were collected for all DCD liver transplants at one institution from December 1998 to December 2011. Posttransplant cholangiograms were obtained during postoperative weeks 1 and 3 and when clinically indicated. Intrahepatic biliary strictures were classified by anatomic distribution and chronologic development. Radiologic findings were correlated with laboratory data and with 1-, 3-, and 5-year graft and patient survival rates. RESULTS A total of 231 patients received DCD grafts. Cholangiograms were available for 184 of these patients. Postoperative cholangiographic findings were correlated with clinical data and divided into the following three groups: A, normal cholangiographic findings with normal laboratory values; B, radiologic abnormalities and cholangiopathy according to laboratory values; and C, radiologic abnormalities without laboratory abnormalities. Group B had four distinct abnormal cholangiographic patterns that were predictive of graft survival. Group C had mild nonprogressive multifocal stenoses and decreased graft and patient survival rates, although cholangiopathy was not detected in these patients according to laboratory data. CONCLUSION Patterns and severity of nonanastomotic biliary abnormalities in DCD liver transplants can be defined radiologically and correlate with clinical outcomes. Postoperative cholangiography can depict the mild biliary abnormalities that occur in a subclinical manner yet cause a marked decrease in graft and patient survival rates in DCD liver transplants.

Agonal period in donation after cardiac death donors

Sirs, We read with great interest the letter by Blok et al. [1] regarding our recently published article on liver transplantation using liver grafts from donation after cardiac death (DCD) donors [2]. We agree with Blok and colleagues that there is currently no worldwide consensus on the definition of warm ischemia times (WIT). While more data are emerging from individual transplant programs, readers should pay attention to the varying definitions of WIT (i.e. time points between withdrawal of life support and aortic cross clamp). As the experience in using liver grafts from DCD donors increases especially from high volume programs with relatively uniform protocols-, we believe a clearer picture of the events during procurement will continue to emerge. As one of the largest transplant programs regularly using liver grafts from DCD donors, our rate of biliary complications from ischemic injury has been lower compared with other reports from transplant programs in the US. Our observation of different procurement practices in individual transplant programs combined with a significant difference in rates of ischemic-type biliary injuries between our and others’ experience motivated us to analyze our procurement data. Our DCD practice started in 1998 and continues to be a significant part of our practice. The analyses in our paper comprised of data collected between 1998 and 2010. We took systolic blood pressure less than 50 mmHg as measure points for several reasons: 1. We based our analysis on a previous study published in 2008 by Ho et al. [3]. That study examined DCD donor postextubation hypotension and subsequent liver and kidney graft outcomes (reference 18 in our paper). To the best of our knowledge, this paper was first to report that the interval between systolic blood pressure of less than 50 mmHg to aortic flush was the best predictive test for their composite end-point. However, because of low number of liver grafts used in that analysis, a concrete recommendation was not given. Therefore, with a much larger data from 215 liver transplants using DCD donors, we aimed to bring granularity to this issue. 2. ASTS recommendations published in 2009 states that “Controlled DCD liver transplantation beyond the following time frames may be associated with increased complications: True warm ischemia time (interval between significant ischemic insult, such as a drop in mean arterial blood pressure below 60 mmHg, and initiation of perfusion) longer than 20–30 min” [4]. There are two problems with this specific recommendation: First, in contrary to the above mentioned recommendations, the authors referenced a study published in 2005 by Muiesan et al. (reference 37 in ASTS recommended guidelines) which actually takes warm ischemia time as the interval from systolic blood pressure of less than 50 mmHg to aortic perfusion [5]. Second, the authors of ASTS recommendations put themselves in a relatively noncommittal situation with their wording by suggesting some of the time frames “may be associated with increased complications”. 3. ASTS recommendations do not include oxygen saturation as one of the criteria. In our experience, pulse oxymetry (usually measured at upper extremity finger) is not a reliable method of measuring oxygen saturation overall and at the end-organ level (liver in this specific paper). In fact, our analysis did not identify oxygen saturation <30% as a significant factor for development of ischemic-type biliary strictures and overall biliary complications. We sincerely appreciate the interest in our paper. We hope that this letter clarifies the reasons behind our analysis.