Intrahepatic Transcriptomics Differentiate Advanced Fibrosis and Clinical Outcomes in Adults With Fontan Circulation.

BACKGROUND: The molecular mechanisms underlying Fontan-associated liver disease (FALD) remain largely unknown. OBJECTIVES: This study aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. METHODS: This retrospective cohort study included adults with the Fontan circulation. Baseline clinical, laboratory, imaging, and hemodynamic data as well as a composite clinical outcome (CCO) were extracted from medical records. Patients were classified into early or advanced fibrosis. RNA was isolated from formalin-fixed paraffin-embedded liver biopsy samples; RNA libraries were constructed with the use of an rRNA depletion method and sequenced on an Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were performed with the use of DESeq2 and Metascape. RESULTS: A total of 106 patients (48% male, median age 31 years [IQR: 11.3 years]) were included. Those with advanced fibrosis had higher B-type natriuretic peptide levels and Fontan, mean pulmonary artery, and capillary wedge pressures. The CCO was present in 23 patients (22%) and was not predicted by advanced liver fibrosis, right ventricular morphology, presence of aortopulmonary collaterals, or Fontan pressures on multivariable analysis. Samples with advanced fibrosis had 228 upregulated genes compared with early fibrosis. Samples with the CCO had 894 upregulated genes compared with those without the CCO. A total of 136 upregulated genes were identified in both comparisons and were enriched in cellular response to cytokine stimulus or oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-ß signaling pathway, and vasculature development. CONCLUSIONS: Patients with FALD and advanced fibrosis or the CCO exhibited upregulated genes related to inflammation, congestion, and angiogenesis.

Super-massive transfusion during liver transplantation.

BACKGROUND: Massive hemorrhage and transfusion during liver transplantation (LT) present great challenges. We aimed to investigate the incidence and risk factors for super-massive transfusion (SMT) and survival outcome and factors that negatively affect survival in patients who received SMT during LT. STUDY DESIGN AND METHODS: We included adult patients undergoing LT from 2004 to 2019. SMT was defined as transfusion of ≥50 units of red blood cells (RBC) during LT. Independent risk factors were identified by multivariable logistic regression. Ninety-day survival was recorded and factors that negatively affected survival were analyzed by the Cox survival test. RESULTS: Of 2772 patients, 158 (5.6%) received SMT during LT. Mean RBC transfusion was 72.6 (±23.4) units with a maximum of 168 units. Four variables (MELD-Na score, previous upper abdominal surgery, portal vein thrombosis, and remote retransplant) were independent risk factors for SMT (odds ratio 1.800-8.274, 95% CI 1.008-16.685, all p < .005). The 90-day survival rate in SMT patients was 81.6%. Preoperative pulmonary hypertension and massive postreperfusion transfusion negatively affected 90-day survival (hazard ratio 2.658-4.633, 95% CI 1.144-10.130, and all p < .05). CONCLUSIONS: In this large retrospective study, we found that SMT occurred in a small percentage of patients and was associated with relatively satisfactory short-term survival. Identification of preoperative risk factors for SMT and factors that negatively affect survival improve our understanding of this unique LT patient population.

The Evolution of Redo Liver Transplantation Over 35 Years: Analysis of 654 Consecutive Adult Liver Retransplants at a Single Center.

OBJECTIVE: To examine liver retransplantation (ReLT) over 35 years at a single center. BACKGROUND: Despite the durability of liver transplantation (LT), graft failure affects up to 40% of LT recipients. METHODS: All adult ReLTs from 1984 to 2021 were analyzed. Comparisons were made between ReLTs in the pre versus post-model for end-stage liver disease (MELD) eras and between ReLTs and primary-LTs in the modern era. Multivariate analysis was used for prognostic modeling. RESULTS: Six hundred fifty-four ReLTs were performed in 590 recipients. There were 372 pre-MELD ReLTs and 282 post-MELD ReLTs. Of the ReLT recipients, 89% had one previous LT, whereas 11% had ≥2. Primary nonfunction was the most common indication in the pre-MELD era (33%) versus recurrent disease (24%) in the post-MELD era. Post-MELD ReLT recipients were older (53 vs 48, P = 0.001), had higher MELD scores (35 vs 31, P = 0.01), and had more comorbidities. However, post-MELD ReLT patients had superior 1, 5, and 10-year survival compared with pre-MELD ReLT (75%, 60%, and 43% vs 53%, 43%, and 35%, respectively, P < 0.001) and lower in-hospital mortality and rejection rates. Notably, in the post-MELD era, the MELD score did not affect survival. We identified the following risk factors for early mortality (≤12 months after ReLT): coronary artery disease, obesity, ventilatory support, older recipient age, and longer pre-ReLT hospital stay. CONCLUSIONS: This represents the largest single-center ReLT report to date. Despite the increased acuity and complexity of ReLT patients, post-MELD era outcomes have improved. With careful patient selection, these results support the efficacy and survival benefit of ReLT in an acuity-based allocation environment.

Intrahepatic transcriptomics differentiate advanced fibrosis and clinical outcomes in adults with the Fontan circulation.

Background: The molecular mechanisms underlying Fontan associated liver disease (FALD) remain largely unknown. We aimed to assess intrahepatic transcriptomic differences among patients with FALD according to the degree of liver fibrosis and clinical outcomes. Methods: This retrospective cohort study included adults with the Fontan circulation at the Ahmanson/UCLA Adult Congenital Heart Disease Center. Clinical, laboratory, imaging and hemodynamic data prior to the liver biopsy were extracted from medical records. Patients were classified into early (F1-F2) or advanced fibrosis (F3-F4). RNA was isolated from formalin-fixed paraffin embedded liver biopsy samples; RNA libraries were constructed using rRNA depletion method and sequencing was performed on Illumina Novaseq 6000. Differential gene expression and gene ontology analyses were carried out using DESeq2 and Metascape. Medical records were comprehensively reviewed for a composite clinical outcome which included decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, protein-losing enteropathy, chronic kidney disease stage 4 or higher, or death. Results: Patients with advanced fibrosis had higher serum BNP levels and Fontan, mean pulmonary artery and capillary wedge pressures. The composite clinical outcome was present in 23 patients (22%) and was predicted by age at Fontan, right ventricular morphology and presence of aortopulmonary collaterals on multivariable analysis. Samples with advanced fibrosis had 228 up-regulated genes compared to early fibrosis. Samples with the composite clinical outcome had 894 up-regulated genes compared to those without it. A total of 136 up-regulated genes were identified in both comparisons and these genes were enriched in cellular response to cytokine stimulus, response to oxidative stress, VEGFA-VEGFR2 signaling pathway, TGF-beta signaling pathway, and vasculature development. Conclusions: Patients with FALD and advanced liver fibrosis or the composite clinical outcome exhibit up-regulated genes including pathways related to inflammation, congestion, and angiogenesis. This adds further insight into FALD pathophysiology.

Intraoperative Hypotension and 30-D Mortality After Liver Transplantation.

Intraoperative hypotension (IOH) is common and associated with mortality in major surgery. Although patients undergoing liver transplantation (LT) have low baseline blood pressure, the relation between blood pressure and mortality in LT is not well studied. We aimed to determine mean arterial pressure (MAP) that was associated with 30-d mortality in LT. Methods: We performed a retrospective cohort study. The data included patient demographics, pertinent preoperative and intraoperative variables, and MAP using various metrics and thresholds. The endpoint was 30-d mortality after LT. Results: One thousand one hundred seventy-eight patients from 2013 to 2020 were included. A majority of patients were exposed to IOH and many for a long period. Eighty-nine patients (7.6%) died within 30 d after LT. The unadjusted analysis showed that predicted mortality was associated with MAP <45 to 60 mm Hg but not MAP <65 mm Hg. The association between MAP and mortality was further tested using adjustment and various duration cutoffs. After adjustment, the shortest durations for MAPs <45, 50, and 55 mm Hg associated with 30-d mortality were 6, 10, and 25 min (odds ratio, 1.911, 1.812, and 1.772; 95% confidence interval, 1.100-3.320, 1.039-3.158, and 1.008-3.114; P = 0.002, 0.036, and 0.047), respectively. Exposure to MAP <60 mm Hg up to 120 min was not associated with increased mortality. Conclusion: In this large retrospective study, we found IOH was common during LT. Intraoperative MAP <55 mm Hg was associated with increased 30-d mortality after LT, and the duration associated with postoperative mortality was shorter with lower MAP than with higher MAP.

Intraoperative High Tidal Volume Ventilation and Postoperative Acute Respiratory Distress Syndrome in Liver Transplant.

BACKGROUND: Mechanical ventilation plays an important role in perioperative management and patient outcomes. Although mechanical ventilation with high tidal volume (HTV) is injurious in patients in the intensive care unit, the effects of HTV ventilation in patients undergoing liver transplant (LT) has not been reported. The aim of this study was to determine if intraoperative HTV ventilation was associated with the development of acute respiratory distress syndrome (ARDS). METHODS: Patients undergoing LT between 2013 and 2018 at a tertiary medical center were reviewed. The tidal volume was recorded at 3 time points: after anesthesia induction, before liver reperfusion, and at the end of surgery. Patients were divided into 2 groups: HTV (>10 mL/kg predicted body weight [pBW]) and non-HTV (≤10 mL/kg pBW). The 2 groups were compared. Independent risk factors were identified by multivariable logistic models. RESULTS: Of 780 LT patients, 85 (10.9%) received HTV ventilation. Female sex and greater difference between actual body weight and pBW were independent risk factors for HTV ventilation. Patients who received HTV ventilation had a significantly higher incidence of ARDS (10.3% vs 3.9%; P = .01) than those who received non-HTV ventilation. CONCLUSIONS: In this retrospective study, we showed that HTV ventilation during LT was common and was associated with a higher incidence of ARDS. Therefore, tidal volume should be carefully selected during LT surgery. More studies using a prospective randomized controlled design are needed.

Optimal anesthetic conduct regarding immediate and short-term outcomes after liver transplantation - Systematic review of the literature and expert panel recommendations.

BACKGROUND: In the era of enhanced recovery after surgery, there is significant discussion regarding the impact of intraoperative anesthetic management on short-term outcomes following liver transplantation (LT), with no clear consensus in the literature. OBJECTIVES: To identify whether or not intraoperative anesthetic management affects short-term outcomes after liver transplantation. DATA SOURCES: Ovid MEDLINE, Embase, Scopus, Google Scholar, and Cochrane Central. METHODS: A systematic review following PRISMA guidelines was undertaken. The systematic review was registered on PROSPERO (CRD42021239758). An international expert panel made recommendations for clinical practice using the GRADE approach. RESULTS: After screening, 14 studies were eligible for inclusion in this systematic review. Six were prospective randomized clinical trials, three were prospective nonrandomized clinical trials, and five were retrospective studies. These manuscripts were reviewed to look at five questions regarding anesthetic care and its impact on short term outcomes following liver transplant. After review of the literature, the quality of evidence according to the following outcomes was as follows: intraoperative and postoperative morbidity and mortality (low), early allograft dysfunction (low), and hospital and ICU length of stay (moderate). CONCLUSIONS: For optimal short term outcomes after liver transplantation, the panel recommends the use of volatile anesthetics in preference to total intravenous anesthesia (TIVA) (Level of Evidence: Very low; Strength of Recommendation: Weak) and minimum alveolar concentration (MAC) versus bispectral index (BIS) for depth of anesthesia monitoring (Level of Evidence: Very low; Strength of Recommendation: Weak). Regarding ventilation and oxygenation, the panel recommends a restrictive oxygenation strategy targeting a PaO2 of 70-120 mmHg (10-14 kPa), a tidal volume of 6-8 ml/kg ideal body weight (IBW), administration of positive end expiratory pressure (PEEP) tailored to patient intraoperative physiology, and recruitment maneuvers. (Level of evidence: Very low; Strength of Recommendation: Strong). Finally, the panel recommends the routine use of antiemetic prophylaxis. (Level of evidence: low; Strength of Recommendation: Strong).

Combined Cardiothoracic Surgery and Liver Transplantation Versus Isolated Liver Transplantation.

OBJECTIVE: Combined cardiothoracic surgery and liver transplantation (cCSLT) recently increasingly has been used. Despite that, liver transplant immediately after cardiothoracic surgery has not been well-characterized. The authors aimed to compare perioperative management and postoperative outcomes between patients undergoing cCSLT and isolated liver transplantation (iLT). DESIGN: A retrospective study. SETTING: University tertiary medical center. PARTICIPANTS: Twenty-five cCSLT patients and 1091 iLT patients at a single institution from 2010 to 2017. INTERVENTIONS: Twenty-five cCSLT patients were compared with 100 randomly selected and 100 propensity-matched iLT patients. MEASUREMENTS AND MAIN RESULTS: All cCSLT patients underwent comprehensive preoperative evaluation by a multidisciplinary team. Of 25 cardiothoracic surgeries, heart transplant (n = 9) was most common, followed by coronary artery bypass grafting (n = 5) and lung transplant (n = 3). Intraoperative management of cCSLT was provided by 2 separate teams, one for cardiothoracic surgery and one for liver transplantation. Patients undergoing cCSLT often required cardiopulmonary bypass, an intra-aortic balloon pump, extracorporeal membrane oxygenation, or cardiac pharmacologic therapies and, additionally, needed more interventions including antifibrinolytic administration, venovenous bypass, massive blood transfusion, and platelet transfusions compared with iLT patients. Ninety-day survival rates were similar in the cCSLT (100%) and iLT groups (random iLT 87% and matched iLT 93%, log-rank test p = 0.089). CONCLUSIONS: Despite having end-stage liver disease and advanced cardiothoracic disorders and experiencing a complex intraoperative course, cCSLT patients had comparable 90-day survival to iLT patients. Comprehensive planning before transplant, optimal patient/donor selection, the multiple-team model, and meticulous intraoperative management are critical to the success of cCSLT.

Perioperative Considerations in Liver Transplantation.

Liver transplantation (LT) has the potential to cure patients with acute and chronic liver failure as well as a number of hepatic and biliary malignancies. Over time, due to the increasing demand for organs as well as improvements in the survival of LT recipients, patients awaiting LT have become sicker, and often undergo the procedure while critically ill. This trend has made the process of preoperative assessment and planning, intraoperative management, and postoperative management even more crucial to the success of LT programs. Multidisciplinary and specialized teams are essential and include anesthesiologists, surgeons, and intensivists. This article focuses on the preoperative evaluation, intraoperative care, and postoperative management of the liver transplant patient. Management relevant to the critically ill patient is discussed, with a focus on the management of postoperative cardiopulmonary conditions including the care of special populations such as those with hepatopulmonary syndrome and portopulmonary hypertension.

Accuracy of stress myocardial perfusion imaging to diagnose coronary artery disease in end stage liver disease patients.

Patients with end-stage liver disease (ESLD) who also have underlying coronary artery disease (CAD) may be at increased risk for undergoing hemodynamically challenging orthotopic liver transplantation. Noninvasive single-photon emission computed tomographic (SPECT) imaging is often used to determine whether a patient with ESLD has unsuspected CAD. The objective of this study was to determine the accuracy of SPECT imaging for detection of CAD in patients with ESLD. Patients with ESLD who underwent coronary angiography and SPECT imaging before orthotopic liver transplantation were analyzed retrospectively. The predictive accuracy of clinical risk factors was calculated and compared to the results of SPECT imaging. There were 473 SPECT imaging studies. Adenosine SPECT imaging had a sensitivity of 62%, specificity of 82%, positive predictive value of 30%, and negative predictive value of 95% for diagnosing severe CAD. Regadenoson SPECT imaging had a sensitivity of 35%, specificity of 88%, positive predictive value of 23%, and negative predictive value of 93% for diagnosing severe CAD. The accuracy of a standard risk factor analysis showed no statistical difference in predicting CAD compared with adenosine (sensitivity McNemar's p = 0.48, specificity McNemar's p = 1.00) or regadenoson (sensitivity McNemar's p = 0.77, specificity McNemar's p = 1.00) SPECT studies. In conclusion, the 2 pharmaceutical agents had low sensitivity but high specificity for diagnosing CAD. However, because the sensitivity of the test is low, the chances of missing patients with ESLD with CAD is high, making SPECT imaging an inaccurate screening test. A standard risk factor analysis as a predictor for CAD in patients with ESLD is less expensive, has no radiation exposure, and is as accurate as SPECT imaging.

Incidental intracardiac thromboemboli during liver transplantation: incidence, risk factors, and management.

Even though numerous cases of massive thromboemboli have been reported in the literature, intracardiac thromboemboli (ICTs) incidentally found during orthotopic liver transplantation (OLT) have not been examined. In this study, we retrospectively examined the incidence, risk factors, and management of incidental ICTs during OLT. After institutional review board approval, adult patients who underwent OLT between January 2004 and December 2008 at our center were reviewed. ICTs were identified and confirmed by the examination of OLT datasheets, anesthesia records, and recorded transesophageal echocardiography (TEE) clips. The clinical presentation, management, and outcomes of the patients with ICTs were reviewed. Risk factors were analyzed by multivariate logistic regression. During the study period, 426 of the 936 adult OLT patients (45.5%) underwent intraoperative TEE monitoring. Incidental ICTs were identified in 8 of these 426 patients (1.9%). Two ICTs occurred before reperfusion, and 6 ICTs occurred after reperfusion. The treatment was at the discretion of the treating physicians; however, none of the patients received an anticoagulant or thrombolytics. Multivariate analysis identified 2 independent risk factors for intraoperative incidental ICTs: the presence of symptomatic or surgically treated portal hypertension (a history of gastrointestinal bleeding, a transjugular intrahepatic portosystemic shunt procedure, or portocaval shunt surgery) before OLT and intraoperative hemodialysis (odds ratios of 4.05 and 7.29, respectively; P < 0.05 for both). In conclusion, incidental ICTs during OLT occurred at a rate of 1.9% and were associated with several preoperative and intraoperative risk factors. The use of TEE allows early identification, which may be important. Our management for incidental ICTs is described; however, no conclusions can be made about the optimal therapy.

Severe intraoperative hyperglycemia is independently associated with surgical site infection after liver transplantation.

BACKGROUND: Surgical site infection (SSI) is a common postoperative complication associated with increased morbidity and mortality in patients undergoing liver transplantation (LT). Although intraoperative hyperglycemia has been shown to be associated with adverse postoperative outcomes including overall infection rate in LT patients, a relationship between intraoperative hyperglycemia and SSI in LT has not been established. We sought to determine if intraoperative hyperglycemia was associated with SSI after LT. METHODS: Patients undergoing LT at our medical center between January 2004 and November 2007 were included in the study. Recipient, donor, and intraoperative variables including a variety of glucose indices were retrospectively analyzed. Independent risk factors of SSI were identified using a multivariate logistic regression model. RESULTS: Of 680 patients, 76 (11.2%) experienced postoperative SSIs. Among all intraoperative glucose indices analyzed, severe hyperglycemia (>or= 200 mg/dL) was independently associated with postoperative SSI (odds ratio [OR] 2.25, 95% confidence interval [CI] 1.26-4.03, P=0.006). Other independent risk factors include repeat surgery (OR 6.58, 95% CI 3.41-12.69, P<0.001), intraoperative administration of vasopressor (OR 3.14, 95% CI 1.65-5.95, P<0.001), preoperative mechanical ventilation (OR 3.01, 95% CI 1.70-5.33, P<0.001), and combined liver and kidney transplantation (OR 2.95, 95% CI 3.41-12.69, P<0.001). CONCLUSIONS: Severe, but not mild or moderate, intraoperative hyperglycemia is independently associated with postoperative SSI and should be avoided during LT surgery.