Improvement in survival after transplantation for critically ill patients with cirrhosis in the United States.

BACKGROUND: There is considerable debate over the indication of liver transplantation (LT) for critically ill patients with cirrhosis, in part due to their potentially poor post-LT prognosis. AIM: We analyzed the epidemiology and outcome of liver transplantation (LT) for critically ill patients with cirrhosis over 4 time periods of 4 years. METHODS: We included adult patients who underwent liver transplant alone between 2005 and 2020 using the United Network for Organ Sharing registry database. We defined critically ill patients with cirrhosis as being in the intensive care unit with one or more of the following characteristics at the time of LT: (i) grade III/IV hepatic encephalopathy, (ii) mechanical ventilation, (iii) dialysis, (iv) vasopressors. RESULTS: A total of 85,594 LT recipients were included, 5,827 (6.8%) of whom were classified as being critically ill with cirrhosis at the time of LT. The number and percentage of critically ill LT recipients with cirrhosis increased over the study period: 819 (4.3%) in 2005-2008 vs. 2,067 (7.9%) in 2017-2020 p<0.001. There was a 17% absolute increase in 1-year survival after LT: 72.5% in 2005-2008 vs. 89.5% in 2017-2020, p<0.001. The one-year post-LT survival gap between critically ill and non-critically ill patients with cirrhosis narrowed over the study period: 16.7 percentage points in 2005-2008 vs. 4.6 percentage points in 2017-2020. The year of LT was independently associated with lower one-year post-LT mortality (HR (95%CI): 0.92 (0.91-0.93) p<0.001). CONCLUSION: The absolute number and relative percentage of LT recipients who were critically ill increased over time, as did one-year post-LT survival. Meanwhile, the gap in survival between this group of patients and non-critically ill patients with cirrhosis decreased, but persisted. Cautious access to selected LT candidates that are critically ill may be warranted, provided the gap in survival with non-critically ill patients remains as small as possible.

Intensive care management of acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a clinical syndrome defined by an acute deterioration of the liver function associated with extrahepatic organ failures requiring intensive care support and associated with a high short-term mortality. ACLF has emerged as a major cause of mortality in patients with cirrhosis and chronic liver disease. ACLF has a unique pathophysiology in which systemic inflammation plays a key role; this provides the basis of novel therapies, several of which are now in clinical trials. Intensive care unit (ICU) therapy parallels that applied in the general ICU population in some organ failures but has peculiar differential characteristics in others. Critical care management strategies and the option of liver transplantation (LT) should be balanced with futility considerations in those with a poor prognosis. Nowadays, LT is the only life-saving treatment that can radically improve the long-term prognosis of patients with ACLF. This narrative review will provide insights on the current understanding of ACLF with emphasis on intensive care management.

The novel SALT-M score predicts 1-year post-transplant mortality in patients with severe acute-on-chronic liver failure.

BACKGROUND & AIMS: Twenty-eight-day mortality ranges from 30-90% in patients with acute-on-chronic liver failure grades 2/3 (severe ACLF). Though liver transplantation (LT) has demonstrated a survival benefit, the scarcity of donor organs and uncertainty regarding post-LT mortality among patients with severe ACLF may cause hesitancy. We developed and externally validated a model to predict 1-year post-LT mortality in severe ACLF, called the Sundaram ACLF-LT-Mortality (SALT-M) score, and estimated the median length of stay (LoS) after LT (ACLF-LT-LoS). METHODS: In 15 LT centers in the US, we retrospectively identified a cohort of patients with severe ACLF transplanted between 2014-2019, followed up to Jan'2022. Candidate predictors included demographics, clinical and laboratory values, and organ failures. We selected predictors in the final model using clinical criteria and externally validated them in two French cohorts. We provided measures of overall performance, discrimination, and calibration. We used multivariable median regression to estimate LoS after adjusting for clinically relevant factors. RESULTS: We included 735 patients, of whom 521 (70.8%) had severe ACLF (120 ACLF-3, external cohort). The median age was 55 years, and 104 with severe ACLF (19.9%) died within 1-year post-LT. Our final model included age >50 years, use of 1/≥2 inotropes, presence of respiratory failure, diabetes mellitus, and BMI (continuous). The c-statistic was 0.72 (derivation) and 0.80 (validation), indicating adequate discrimination and calibration based on the observed/expected probability plots. Age, respiratory failure, BMI, and presence of infection independently predicted median LoS. CONCLUSIONS: The SALT-M score predicts mortality within 1-year after LT in patients with ACLF. The ACLF-LT-LoS score predicted median post-LT stay. Future studies using these scores could assist in determining transplant benefits. IMPACT AND IMPLICATIONS: Liver transplantation (LT) may be the only life-saving procedure available to patients with acute-on-chronic liver failure (ACLF), but clinically instability can augment the perceived risk of post-transplant mortality at 1 year. We developed a parsimonious score with clinically and readily available parameters to objectively assess 1-year post-LT survival and predict median length of stay after LT. We developed and externally validated a clinical model called the Sundaram ACLF-LT-Mortality score in 521 US patients with ACLF with 2 or ≥3 organ failure(s) and 120 French patients with ACLF grade 3. The c-statistic was 0.72 in the development cohort and 0.80 in the validation cohort. We also provided an estimation of the median length of stay after LT in these patients. Our models can be used in discussions on the risks/benefits of LT in patients listed with severe ACLF. Nevertheless, the score is far from perfect and other factors, such as patient's preference and center-specific factors, need to be considered when using these tools.

Additional value of interleukin-6 level to predict histopathological features of hepatocellular carcinoma before liver transplantation.

BACKGROUND & AIMS: Inflammatory biomarkers are increasingly used as outcome predictors in the field of oncology and liver transplantation for HCC, but no study has shown the prognostic value of IL6 after LT. The goal of this study was to evaluate the predictive value of IL-6 on histopathological features of HCC on explant, its predictive value on recurrence risk and its additional value to other scores and inflammatory markers at the time of transplantation. METHODS: From 2009 to 2019, all adults transplanted with a first liver graft and diagnosed with HCC on the explant analysis were retrospectively included (n = 229). Only patients who had a pre-LT IL6 level determination were analysed in this study (n = 204). RESULTS: High IL-6 level at transplantation was associated with a significantly higher risk of vascular invasion (15% vs 6%; p = 0.023), microsatellitosis (11% vs 3%; p = 0.013), lower rate of histological response both in terms of complete response (2% vs 14%, p = 0.004) and of necrosis (p = 0.010). Patients with pre-LT IL-6 level > 15 ng/ml had a lower overall and cancer-specific survival (p = 0.013). Recurrence-free survival was lower in patients with IL-6 > 15 ng/ml with a 3-year recurrence-free survival of 88% versus 78% (p = 0.034). IL6 levels were significantly higher in patients with early recurrence compared to patients without (p = 0.002) or with late recurrence (p = 0.044). CONCLUSIONS: IL6 level at transplantation is an independent predictor of pejorative histological features of HCC and is associated to the risk of recurrence.

Location and allocation: Inequity of access to liver transplantation for patients with severe acute-on-chronic liver failure in Europe.

There is growing evidence that liver transplantation (LT) is the most effective treatment for acute-on-chronic liver failure grade-3 (ACLF-3). This study examines whether and how this evidence translates into practice by analyzing the variability in intensive care unit (ICU) admissions, listing strategies, and LT activity for patients with ACLF-3 across transplantation centers in Europe. Consecutive patients who were admitted to the ICU with ACLF-3, whether or not they were listed and/or transplanted with ACLF-3, between 2018 and 2019 were included across 20 transplantation centers. A total of 351 patients with ACLF-3 were included: 33 had been listed prior to developing ACLF-3 and 318 had not been listed at the time of admission to the ICU. There was no correlation between the number of unlisted patients with ACLF-3 admitted to the ICU and the number listed or transplanted while in ACLF-3 across centers. By contrast, there was a correlation between the number of patients listed and the number transplanted while in ACLF-3. About 21% of patients who were listed while in ACLF-3 died on the waiting list or were delisted. The percentage of LT for patients with ACLF-3 varied from 0% to 29% for those transplanted with decompensated cirrhosis across centers (average = 8%), with an I2 index of 68% (95% confidence interval, 49%-80%), showing substantial heterogeneity among centers. The 1-year survival for all patients with ACLF-3 was significantly higher in centers that listed and transplanted more patients with ACLF-3 (>10 patients) than in centers that listed and transplanted fewer: 36% versus 20%, respectively (p = 0.012). Patients with ACLF-3 face inequity of access to LT across Europe. Waitlisting strategies for patients with ACLF-3 influence their access to LT and, ultimately, their survival.

Immunosuppression in patients with grade 3 acute-on-chronic liver failure at transplantation: A practice analysis study.

Transplantation for patients with acute-on-chronic liver failure grade 3 (ACLF3) has encouraging results with 1-year-survival of 80-90%. These patients with multiple organ failure meet the conditions for serious alterations of drug metabolism and increased toxicity. The goal of this study was to identify immunosuppression-dependent factors that affect survival. This retrospective monocentric study was conducted in patients with ACLF3 consecutively transplanted between 2007 and 2019. The primary endpoint was 1-year survival. Secondary endpoints were overall survival, treated rejection, and surgical complications. Immunosuppression was evaluated as to type of immunosuppression, post-transplant introduction timing, trough levels, and trough level intra-patient variability (IPV). One hundred patients were included. Tacrolimus IPV < 40% (P = .019), absence of early tacrolimus overdose (P = .033), use of anti-IL2-receptor antibodies (P = .034), and early mycophenolic acid introduction (P = .038) predicted 1-year survival. Treated rejection was an independent predictor of survival (P = .001; HR 4.2 (CI 95%: 1.13-15.6)). Early everolimus introduction was neither associated with higher rejection rates nor with more surgical complications. Management of immunosuppression in ACLF3 critically ill patients undergoing liver transplantation is challenging. Occurrence and treatment of rejection impacts on survival. Early introduction of mTOR inhibitor seems safe and efficient in this situation.

Pre-operative CT scan helps predict outcome after liver transplantation for acute-on-chronic grade 3 liver failure.

OBJECTIVES: The aim of this study was to identify the prognostic value of pre-operative imaging to predict post-transplantation survival in critically ill cirrhotic patients with severe acute-on-chronic liver failure (ACLF). METHODS: Patients with grade 3 ACLF who underwent liver transplantation between January 2010 and January 2020 and with available contrast-enhanced abdominal computed tomography (CT) performed less than 3 months before LT were retrospectively included (n = 82). Primary endpoint was 1-year mortality. Imaging parameters (sarcopenia, liver morphology and volumetry, and signs of portal hypertension) were screened and tested to build a prognostic score. RESULTS: In the multivariate analysis, three independent CT-derived prognostic factors were found: splenomegaly (p = 0.021; HR = 5.6 (1.29-24.1)), liver atrophy (p = 0.05; HR = 2.93 (1.01-10.64)), and vena cava diameter ratio (p < 0.0001; HR = 12.7 (3.4-92)). A simple prognostic score was proposed, based on the presence of splenomegaly (5 points), liver atrophy (5 points), and vena cava diameter ratio < 0.2 (12 points). A cutoff at 10 points distinguished a high-risk group (score > 10) from a low-risk group (score ≤ 10) with 1-year survival of 27% vs. 67% respectively (p < 0.001). It was found to be an independent predictive factor in association with the Transplantation for ACLF3 Model (TAM) score. CONCLUSION: Pre-transplantation contrast-enhanced abdominal CT has a significant impact on selection of patients in ACLF3 in order to predict 1-year survival after LT. KEY POINTS: • Splenomegaly, liver atrophy, and vena cava diameter ratio are independent CT-derived prognostic factors after transplantation for severe acute-on-chronic liver failure. • A simple CT-based prognostic score is an independent predictive factor, complementary to clinical and biological parameters. • The use of the CT-derived score allows stratification based on 1-year mortality for patients with otherwise uncertain prognosis with clinical and biological parameters alone.

Pretransplant Intensive Care Unit Management and Selection of Grade 3 Acute-on-Chronic Liver Failure Transplant Candidates.

The aim of this study is to report on the liver transplantation (LT) activity and posttransplant outcome, over time, of patients with grade 3 acute-on-chronic liver failure (ACLF-3) in a single transplant center performing a large number of LTs for patients with ACLF-3. It aims at showing how pre-LT intensive care unit (ICU) management impacts post-LT outcomes, in particular through monitoring the transplantation for ACLF-3 model (TAM) score. A total of 100 patients who had ACLF-3 at the time of LT between 2007 and 2019 were included retrospectively. The cohort was divided in 2 periods, with 50 patients in each period. There was an increase in the number of patients with ACLF-3 who received an LT during the course of the study period and significantly higher 1-year post-LT survival rates in the second period compared with the first period (86% versus 66%, respectively; P = 0.02). Interestingly, patients during both periods had similar severity profiles and scores apart from a significantly lower number of patients with TAM scores >2 at the time of LT in the second period compared with the first period (1 [2%] versus 11 [22%], respectively; P ≤ 0.01). In addition, patients whose clinical condition improved in the ICU (with a TAM score downstaged between admission and LT) had significantly higher post-LT survival rates than those whose TAM score stayed the same or increased: 88% versus 70%, respectively (P = 0.04). This study shows a learning curve in LT for patients with ACLF-3, with optimized ICU management and patient selection leading to increased numbers of LTs for patients with ACLF-3 and improved post-LT outcomes. It also delineates how the TAM score can be used to identify the optimal transplantability window for patients with ACLF-3.

Liver transplantation for critically ill cirrhotic patients: Results from the French transplant registry.

This study describes the population of cirrhotic patients who were transplanted from the ICU in France, identifying pre-transplant risk factors of post-transplant mortality and describing geographic variations in ICU transplant activity. Cirrhotic patients transplanted between 2008 and 2018 were included through the national transplant registry. The demographic, clinical and biological characteristics of the patients transplanted from the ICU were compared to cirrhotic patients who were transplanted from home or from the hospital. Risk factors of post-transplant one-year mortality were identified in uni- and multivariable analysis within the population transplanted from the ICU. Funnel plots were used to illustrate center-specific differences in ICU transplant activity. 1,047 cirrhotic patients were transplanted from the ICU during the study period. While the national rate of transplants performed from the ICU was 14.3% the absolute number and the rate of cirrhotic patients transplanted from the ICU varied significantly from one center to another, ranging from 6.6% to 22.8% (p < 0.05). Three recipient-associated independent risk factors one-year post-LT mortality were identified in the population transplanted from the ICU: age > 50 years (HR 1.65, 95%CI 1.16-2.36), p = 0.005), diabetes (HR 1.46, 95%CI 1.07-1.98, p = 0.02) and intubation (HR2.12, 95%CI 1.62-2.78), p < 0.001). Donor age was also independently associated with mortality (HR 1.01, 95%CI 1.01-1.02, p < 0.001). Funnel plots showed significant differences in the proportion of patients transplanted from the ICU and the distribution of risk factors across French transplant centers, especially the inclination to transplant intubated patients. This study underlines the increased post-transplant mortality among cirrhotic patients transplanted from the ICU. It identifies four clinically pertinent independent risk factors associated with post-transplant mortality in this specific sub-group of transplant candidates. Finally, it illustrates how diverse the landscape of liver transplantation for critically ill cirrhotic patients is across a single country, despite a unified allocation algorithm.

Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: Results of the ELITA/EF-CLIF collaborative study (ECLIS).

BACKGROUND & AIMS: Liver transplantation (LT) has been proposed as an effective salvage therapy even for the sickest patients with acute-on-chronic liver failure (ACLF). This large collaborative study was designed to assess the current clinical practice and outcomes of patients with ACLF who are wait-listed for LT in Europe. METHODS: This was a retrospective study including 308 consecutive patients with ACLF, listed in 20 centres across 8 European countries, from January 2018 to June 2019. RESULTS: A total of 2,677 patients received a LT: 1,216 (45.4%) for decompensated cirrhosis. Of these, 234 (19.2%) had ACLF at LT: 58 (4.8%) had ACLF-1, 78 (6.4%) had ACLF-2, and 98 (8.1%) had ACLF-3. Wide variations were observed amongst countries: France and Germany had high rates of ACLF-2/3 (27-41%); Italy, Switzerland, Poland and the Netherlands had medium rates (9-15%); and the United Kingdom and Spain had low rates (3-5%) (p <0.0001). The 1-year probability of survival after LT for patients with ACLF was 81% (95% CI 74-87). Pre-LT arterial lactate levels >4 mmol/L (hazard ratio [HR] 3.14; 95% CI 1.37-7.19), recent infection from multidrug resistant organisms (HR 3.67; 95% CI 1.63-8.28), and renal replacement therapy (HR 2.74; 95% CI 1.37-5.51) were independent predictors of post-LT mortality. During the same period, 74 patients with ACLF died on the waiting list. In an intention-to-treat analysis, 1-year survival of patients with ACLF on the LT waiting list was 73% for ACLF-1 or -2 and 50% for ACLF-3. CONCLUSION: The results reveal wide variations in the listing of patients with ACLF in Europe despite favourable post-LT survival. Risk factors for mortality were identified, enabling a more precise prognostic assessment of patients with ACLF. LAY SUMMARY: Acute-on-chronic liver failure (ACLF) is a severe clinical condition for which liver transplantation is an effective therapeutic option. This study has demonstrated that in Europe, referral and access to liver transplantation (LT) for patients with ACLF needs to be harmonised to avoid inequities. Post-LT survival for patients with ACLF was >80% after 1 year and some factors have been identified to help select patients with favourable outcomes.

Acute-onset delirium in intensive care COVID patients: association of imperfect brain repair with foodborne micro-pollutants.

BACKGROUND AND PURPOSE: COVID-19 affects the brain in various ways, amongst which delirium is worrying. An assessment was made of whether a specific, long-lasting, COVID-19-related brain injury develops in acute respiratory distress syndrome patients after life-saving re-oxygenation. METHODS: Ten COVID+ patients (COVID+) with unusual delirium associated with neuroimaging suggestive of diffuse brain injury and seven controls with non-COVID encephalopathy were studied. The assessment took place when the intractable delirium started at weaning off ventilation support. Brain magnetic resonance imaging (MRI) was performed followed by standard cerebrospinal fluid (CSF) analyses and assessment of CSF erythropoietin concentrations (as a marker for the assessment of tissue repair), and of non-targeted CSF metabolomics using liquid chromatography high resolution mass spectrometry. RESULTS: Patients were similar as regards severity scores, but COVID+ were hospitalized longer (25 [11.75; 25] vs. 9 [4.5; 12.5] days, p = 0.03). On admission, but not at MRI and lumbar puncture performance, COVID+ were more hypoxic (p = 0.002). On MRI, there were leptomeningeal enhancement and diffuse white matter haemorrhages only in COVID+. In the latter, CSF erythropoietin concentration was lower (1.73 [1.6; 2.06] vs. 3.04 [2.9; 3.91] mIU/ml, p = 0.01), and CSF metabolomics indicated (a) increased compounds such as foodborne molecules (sesquiterpenes), molecules from industrialized beverages and micro-pollutants (diethanolamine); and (b) decreased molecules such as incomplete breakdown products of protein catabolism and foodborne molecules (glabridin). At 3-month discharge, fatigue, anxiety and depression as well as MRI lesions persisted in COVID+. CONCLUSIONS: Some COVID+ are at risk of a specific delirium. Imperfect brain repair after re-oxygenation and lifestyle factors might influence long-lasting brain injuries in a context of foodborne micro-pollutants.

Organ allocation in the age of the algorithm: avoiding futile transplantation - utility in allocation.

PURPOSE OF REVIEW: This review describes and questions the evolution of allocation systems from local team decisions in the 20th century to patient-oriented allocation using complex algorithm predicting transplant benefit. RECENT FINDINGS: The opening years of the 2000s have seen the implementation of prioritization scores aiming at increasing transparency and reducing waitlist mortality. The 2010s have underlined the necessity of drawing the upper limits of how sick a patient can be while still ensuring acceptable survival. More complex algorithms evaluating transplant benefit have been implemented in allocation systems to take this issue into account. SUMMARY: Allocation algorithms are becoming more and more complex, integrating numerous parameters from both donor and recipient to achieve optimal matching. The limitations of implementing these complex algorithms are represented by the evermoving waiting list demography, geographic disparities between recipients and donors, team policy adaptation to rule changes, and implicit biases within the transplant community. Survival as the only metric by which to define benefit may be seen as restrictive; quality of life may be a fruitful measure for better defining benefit in organ transplantation in the future.

Liver transplantation for critically ill cirrhotic patients: Stratifying utility based on pretransplant factors.

The aim of this study was to produce a prognostic model to help predict posttransplant survival in patients transplanted with grade-3 acute-on-chronic liver failure (ACLF-3). Patients with ACLF-3 who underwent liver transplantation (LT) between 2007 and 2017 in 5 transplant centers were included (n = 152). Predictors of 1-year mortality were retrospectively screened and tested on a single center training cohort and subsequently tested on an independent multicenter cohort composed of the 4 other centers. Four independent pretransplant risk factors were associated with 1-year mortality after transplantation in the training cohort: age ≥53 years (P = .044), pre-LT arterial lactate level ≥4 mml/L (P = .013), mechanical ventilation with PaO2 /FiO2  ≤ 200 mm Hg (P = .026), and pre-LT leukocyte count ≤10 G/L (P = .004). A simplified version of the model was derived by assigning 1 point to each risk factor: the transplantation for Aclf-3 model (TAM) score. A cut-off at 2 points distinguished a high-risk group (score >2) from a low-risk group (score ≤2) with 1-year survival of 8.3% vs 83.9% respectively (P < .001). This model was subsequently validated in the independent multicenter cohort. The TAM score can help stratify posttransplant survival and identify an optimal transplantation window for patients with ACLF-3.