Meeting Report: The Dallas Consensus Conference on Liver Transplantation for Alcohol Associated Hepatitis
Liver Transplantation. 2020;26(1):127-140
Liver transplantation (LT) for alcohol associated hepatitis (AH) remains controversial. We convened a consensus conference to examine various aspects of LT for AH. The goal was not to unequivocally endorse LT for AH; instead, it was to propose recommendations for programs that perform or plan to perform LT for AH. Criteria were established to determine candidacy for LT in the setting of AH and included the following: (1) AH patients presenting for the first time with decompensated liver disease that are nonresponders to medical therapy without severe medical or psychiatric comorbidities; (2) a fixed period of abstinence prior to transplantation is not required; and (3) assessment with a multidisciplinary psychosocial team, including a social worker and an addiction specialist/mental health professional with addiction and transplantation expertise. Supporting factors included lack of repeated unsuccessful attempts at addiction rehabilitation, lack of other substance use/dependency, acceptance of diagnosis/insight with a commitment of the patient/family to sobriety, and formalized agreement to adhere to total alcohol abstinence and counseling. LT should be avoided in AH patients who are likely to spontaneously recover. Short-term and longterm survival comparable to other indications for LT must be achieved. There should not be further disparity in LT either by indication, geography, or other sociodemographic factors. Treatment of alcohol-use disorders should be incorporated into pre- and post-LT care. The restrictive and focused evaluation process described in the initial LT experience for AH worldwide may not endure as this indication gains wider acceptance at more LT programs. Transparency in the selection process is crucial and requires the collection of objective data to assess outcomes and minimize center variation in listing. Oversight of program adherence is important to harmonize listing practices and outcomes.
Extracorporeal liver support in patients with liver failure: a systematic review and meta-analysis of randomized trials
Intensive Care Medicine. 2020;46(1):1-16
This systematic review and meta-analysis of randomized controlled trials (RCTs) aimed to examine the efficacy and safety of extracorporeal liver support (ECLS) in liver failure.
The MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases were searched from inception through March 13, 2019. Randomized control trials (RCTs) comparing ECLS to usual care in acute liver failure (ALF) or acute chronic liver failure (ACLF) were included. Included studies met the following criteria: (1) the study design was a randomized controlled trial (RCT); (2) the population were adults with ALF or ACLF; (3) the interventions were any form of artificial or bio-artificial ECLS; (4) the control group received supportive care not including ECLS; (5) the outcomes were all-cause mortality or liver-related mortality, bridging to liver transplant, improvement of HE and adverse events such as hypotension, bleeding, thrombocytopenia, line infection, and citrate toxicity.
A total of 25 randomized controlled trials, comprising 1796 patients were identified and used in this study.
The main outcomes explored were mortality, hepatic encephalopathy and adverse effects.
Up to 6 months
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
This is a systematic review and meta-anlaysis of 25 RCTs including a total of 1796 patients randomised to extra-corporeal liver support (ECLS) for acute liver failure or acute on chronic liver failure. Overall the review was conducted with several signs of good quality, by following the PRISMA statement and registering a protocol in advance. Multiple databases were searched and only RCTs were included. Report screening, data extraction and bias assessment were all completed in duplicate by 2 reviewers, another good indicator. Publication bias was assessed by funnel plot with Egger’s test. Among artificial systems, MARS (Teraklin AG, Germany, was the
most commonly used (8 studies) followed by Biologic-DT (HemoCleanse, Inc., USA, 5 studies), FPSA (Prometheus, Fresenius Medical Care, Germany, 2 studies), plasma exchange with hemoperfusion, whole blood exchange, and charcoal hemoperfusion (1 study each). Bio-artifcial modalities included extracorporeal liver assist device (ELAD, Vital Terapies Inc., USA, 3 studies) and HepatAssist (Circe Biomedical Inc., USA, 1 study). Twenty four studies reported mortality and in meta-analysis extra-corporeal liver support was associated with improved mortality, albeit potentially a very small effect (RR=0.84, 95%CI= 0.74-0.96), with low-moderate heterogeneity. The use of ECLS was associated with improved hepatic encephalopathy compared to usual care (RR=0.71; 95% CI= 0.60- 0.84), with low heterogeneity between studies, however some evidence of publication bias was suspected following funnel plot and Egger’s test (P=0.041). There was no significant differences in the risk of bleeding, hypotension or thrombocytopenia. The authors include a number of sensitivity analyses as well to explore the effect of type of liver failure, type of ECLS and study risk of bias, not finding any significant interaction. This is a thorough study overall and if the level of certainty in the conclusions is low, it is not the fault of the authors here. The results suggest that ECLS may reduce mortality and hepatic encephalopathy in acute and acute on chronic liver failure but the degree of benefit for each of the different types of system is not clear. Each of the included studies was small and RCTs using new technology in specific groups of patients are required.
PURPOSE Acute liver failure (ALF) and acute on chronic liver failure (ACLF) are associated with significant mortality and morbidity. Extracorporeal liver support (ECLS) devices have been used as a bridge to liver transplant; however, the efficacy and safety of ECLS are unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine the efficacy and safety of ECLS in liver failure. METHODS We searched MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials from inception through March 13, 2019. RCTs comparing ECLS to usual care in ALF or ACLF were included. We used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty of the evidence. RESULTS We identified 25 RCTs (1796 patients). ECLS use was associated with reduction in mortality (RR 0.84; 95% CI 0.74, 0.96, moderate certainty) and improvement in hepatic encephalopathy (HE) (RR 0.71; 95% CI 0.60, 0.84, low certainty) in patients with ALF or ACLF. The effect of ECLS on hypotension (RR 1.46; 95% CI 0.98, 2.2, low certainty), bleeding (RR 1.21; 95% CI 0.88, 1.66, moderate certainty), thrombocytopenia (RR 1.62; 95% CI 1.0, 2.64, very low certainty) and line infection (RR 1.92; 95% CI 0.11, 33.44, low certainty) was uncertain. CONCLUSIONS ECLS may reduce mortality and improve HE in patients with ALF and ACLF. The effect on other outcomes is uncertain. However, the evidence is limited by risk of bias and imprecision, and larger trials are needed to better determine the effect of ECLS on patient-important outcomes.
Comparing preferences of physicians and patients regarding the allocation of donor organs: A systematic review
Transplant Rev (Philadelphia). 2020;[record in progress]:100515
In order to improve the demand-supply-mismatch in transplantation medicine, policy makers have to think about adapting existing legal frameworks for donor organ allocation. This study aims to systematically review preferences of physicians as well as patients in the field of transplantation medicine. PubMed, Web of Science, EBSCO and PsycINFO were searched from January 2000 to December 2018 without language restrictions. Fourteen publications were identified, six aiming at physicians, seven focusing on patients and one on both groups. The criteria used in these studies to elicit preferences can be grouped into six different main categories, all deriving from the general principle of equality: "Effectiveness/Benefit", "Medical urgency", "Own fault", "Social value", "Medical background" and "Socio-demographic status". Whilst patients on the one hand show a high demand for equal access, outcome maximization and punishment for damaging behaviors, they would still allocate organs to people with very low survival chances. Physicians decide against equal access to transplantation in cases where clinical evidence is weighed more heavily, e.g. in the cases of ethnicity and sex. Also, they seem more informed regarding the involvement of medical factors and give less importance to those with uncertain effects on transplantation outcome, such as tissue or blood group match. It is important to continuously monitor preferences of all involved stakeholders in order to achieve fair and accessible transplantation systems.
Measurement of health-related quality of life in pediatric organ transplantation recipients: a systematic review of the PedsQL transplant module
Quality of Life Research. 2020;[record in progress]
OBJECTIVE To collect and assess the extant empirical literature assessing disease-specific health-related quality of life (HRQOL) in pediatric transplant recipients using the PedsQL 3.0 Transplant Module (PedsQL-TM) assessment. STUDY DESIGN A systematic search and review procedure was conducted of research reporting use and results of the PedsQL-TM with samples of pediatric heart, liver, kidney, and lung transplantation. Searches were conducted in nine scholarly databases and two additional sources to identify unpublished research. Multiple reviewers screened studies meeting inclusion criteria in accordance with PRISMA guidelines. RESULTS A final sample of nine studies reported findings for the PedsQL-TM with pediatric organ transplant recipients. Most studies relied on either kidney or liver transplant recipients from single pediatric transplant centers. Factor validity of the PedsQL-TM and inter-rater reliability (IRR) between patients and parents have not been adequately determined. Internal consistency reliability was found as acceptable or excellent across multiple studies. PedsQL-TM scores were found to vary with other HRQOL issues, yet few studies examined their association with medication adherence or posttransplant health outcomes. CONCLUSIONS With the goal of enhancing and sustaining HRQOL in pediatric organ transplant recipients, the need for a psychometrically valid and reliable measure of transplant-specific HRQOL is apparent. Research on the PedsQL-TM supports the promise of this measure although future efforts should be taken to examine measurement issues such as factor validity and IRR. Assessing transplant-specific HRQOL in these patients is paramount for their care and appropriate decision-making by patients, families, and the transplant team.
Information for transplant programs and OPOs regarding 2019 Novel Coronavirus
Guidance on the management of transplant recipients diagnosed with or suspected of having COVID19
The recent outbreak of a novel coronavirus (2019-nCoV) in Wuhan, Hubei Province, China and the finding of infection in many other countries including the United States has led to questions among transplant programs, Organ Procurement Organizations (OPOs) and patients. The Organ Procurement and Transplantation Network (OPTN) strives to provide up-to-date information to answer these questions and to provide guidance as needed. Accordingly, the OPTN Ad Hoc Donor Transmission Advisory Committee (DTAC), American Society of Transplantation (AST) and the American Society of Transplant Surgeons (ASTS), after careful review of information available from the Centers for Disease Control and Prevention (CDC), offers information to transplant programs and OPOs in light of these concerns. https://optn.transplant.hrsa.gov/news/information-for-transplant-programs-and-opos-regarding-2019-novel-coronavirus/
COVID-19: Clinical advice
This is a consensus opinion of a group of transplant professionals. The guidance is based on the sparse information available on transplant recipients in the literature and should be used in conjunction with local or national guidance. We understand that individual patients may need a bespoke plan but this is a general guideline which may help others when managing transplant recipients with, or suspected of having, COVID 19. All unwell transplant recipients should be discussed with their usual unit. This guidance does not cover cardiothoracic or small bowel transplant recipients. At the time of writing, there are no randomised controlled trials of additional therapy that show any benefit above standard supportive care. https://bts.org.uk/wp-content/uploads/2020/03/Clinical_management_transplant_recipients.pdf
Comparison of Ceftizoxime Plus Ampicillin-Sulbactam versus Gentamicin Plus Ampicillin-Sulbactam in the Prevention of Post-Transplant Early Bacterial Infections in Liver Transplant Recipients: A Randomized Controlled Trial
The general guidance is provided for clinical staff involved in facilitating organ donation in the UK. It provides links to COVID-19 Bulletins that are regularly published, guidance documents for deceased and living donation, and COVID-19 reporting forms. https://www.odt.nhs.uk/deceased-donation/covid-19-advice-for-clinicians/
Infection & Drug Resistance. 2020;13:89-98
Meta-analysis and Meta-regression of Survival After Liver Transplantation for Unresectable Perihilar Cholangiocarcinoma
Purpose: In this study, we aimed to compare the efficacy of combined ceftizoxime with ampicillin-sulbactam versus combined gentamicin with ampicillin-sulbactam as prophylactic antibiotic regimen in preventing early bacterial PTIs in liver TX recipients at a referral center. Patients and methods: All patients older than 18 years who had undergone liver TX at Abu-Ali Sina transplantation center in Shiraz, Iran from July 2018 to April 2019 were included in this study. In a single-blinded manner, the participants randomly received either combined intravenous ceftizoxime plus ampicillin-sulbactam (ceftizoxime group) or gentamicin plus ampicillin-sulbactam (gentamicin group) as prophylactic antibiotic regimen before the incision of the surgery, which was continued for 48 hrs after liver Tx. The rate and type of bacterial infections, length of hospital and intensive care unit (ICU) stay, mortality rate, and kidney function were assessed during 1 month following liver TX in the two groups. Results: Two hundred and thirty patients were divided into two groups. One patient in the gentamicin group and five in the ceftizoxime group were excluded due to emergency exploratory laparotomy within the first 3 days after transplantation. The rate of bacterial infections during the first month after transplantation was 25.4%. This rate was significantly lower in the gentamicin group (13.16%) in comparison to the ceftizoxime group (38.18%) (P value<0.01), based on the univariate logistic regression analysis. Length of ICU and hospital stay and also mortality rate were significantly lower in the gentamicin group (P value <0.01). There was no significant difference regarding kidney function between the two groups (P value = 0.16). Conclusion: Our results suggested that gentamicin can be considered as a promising agent in prophylactic antibiotic regimen for patients undergoing liver TX. Trial registration: The study was registered at the Iranian Registry of Clinical Trials (IRCT20120731010453N2; http://www.irct.ir/).
Annals of Surgery. 2020;24:24
OBJECTIVE To systematically review studies reporting survival data following neoadjuvant chemoradiation and orthotopic liver transplantation (NCR-OLT) for unresectable perihilar cholangiocarcinoma (pCC). BACKGROUND Despite survival improvements for other cancers, the prognosis of pCC remains dismal. Since publication of the Mayo protocol in 2000, increasing numbers of series globally are reporting outcomes after NCR-OLT. METHODS MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from January 2000 to February 2019. A meta-analysis of proportions was conducted, pooling 1, 3-, and 5-year overall survival and recurrence rates following NCR-OLT across centers. Per protocol and intention to treat data were interrogated. Meta-regression was used to evaluate PSC as a confounder affecting survival. RESULTS Twenty studies comprising 428 patients were eligible for analysis. No RCTs were retrieved; the majority of studies were noncomparative cohort studies. The pooled 1, 3-, and 5-year overall survival rates following OLT without neoadjuvant therapy were 71.2% (95% CI 62.2%-79.4%), 48.0% (95% CI 35.0%-60.9%), and 31.6% (95% CI 23.1%-40.7%). These improved to 82.8% (95% CI 73.0%-90.8%), 65.5% (95% CI 48.7%-80.5%), and 65.1% (95% CI 55.1%-74.5%) if neoadjuvant chemoradiation was completed. Pooled recurrence after 3 years was 24.1% (95% CI 17.9%-30.9%) with neoadjuvant chemoradiation, 51.7% (95% CI 33.8%-69.4%) without. CONCLUSIONS In unresectable pCC, NCR-OLT confers long-term survival in highly selected patients able to complete neoadjuvant chemoradiation followed by transplantation. PSC patients appear to have the most favorable outcomes. A high recurrence rate is of concern when considering extending national graft selection policy to pCC.