Reply to Spiess, B.D.; Houdijk, W.P.M. Comment on "Saner et al. The Yin and the Yang of Hemostasis in End-Stage Liver Disease. J. Clin. Med. 2023, 12, 5759".

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Use of Transesophageal Echocardiography for Liver Transplantation: A Global Comparison of Practice From the ILTS, SATA, and LICAGE.

BACKGROUND: Anesthesiologists frequently use intraoperative transesophageal echocardiography (TEE) to aid in the diagnosis and management of hemodynamic problems during liver transplantation (LT). Although the use of TEE in US centers continues to increase, data regarding international use are lacking. METHODS: This prospective, global, survey-based study evaluates international experience with TEE for LT. Responses from 252 LT (105 US and 147 non-US) centers representing 1789 anesthesiologists were analyzed. RESULTS: Routine use of TEE in the United States has increased in the last 5 y (from 37% to 47%), but only 21% of non-US LT anesthesiologists use TEE routinely. Lack of training (44% US versus 70% non-US) and equipment (9% non-US versus 34% US) were cited as obstacles. Most survey participants preferred not to perform a complete cardiac examination but rather use only 6 of 11 basic views. Although non-US LT anesthesiologists more frequently had additional clinical training than their US counterparts, they had less TEE experience (13% versus 44%) and less frequently, TEE certification (22% versus 35%). Most LT anesthesiologists agreed that TEE certification is essential for proficiency. Of all respondents, 89% agreed or strongly agreed that TEE provides valuable information needed for immediate clinical decision-making, and >86% agreed or strongly agreed that that information could not be derived from other sources. CONCLUSIONS: The use of TEE for LT surgery in the US LT centers is currently higher compared with non-US LT centers. This may become a standard monitoring modality during LT in the near future.

Navigating the Labyrinth: Intensive Care Challenges for Patients with Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) refers to the deterioration of liver function in individuals who already have chronic liver disease. In the setting of ACLF, liver damage leads to the failure of other organs and is associated with increased short-term mortality. Optimal medical management of patients with ACLF requires implementing complex treatment strategies, often in an intensive care unit (ICU). Failure of organs other than the liver distinguishes ACLF from other critical illnesses. Although there is growing evidence supporting the current approach to ACLF management, the mortality associated with this condition remains unacceptably high. In this review, we discuss considerations for ICU care of patients with ACLF and highlight areas for further research.

The Yin and the Yang of Hemostasis in End-Stage Liver Disease.

Patients with end-stage liver disease (ESLD) undergoing liver transplantation (LT) are prone to thromboses both while on the waiting list and in the perioperative period. This hypercoagulability is associated with significant endothelial dysfunction (ED) due to nitric oxide dysregulation. ED and increased thrombin generation are the main factors responsible for this hypercoagulability. Sepsis alone can significantly alter a patient's coagulation profile. In combination with ESLD, however, sepsis or septic shock are responsible for very complex changes. This makes both the assessment and management of coagulation in septic patients with ESLD very challenging. Viscoelastic testing (VET) is the preferred method of coagulation management in patients with cirrhosis because, as with standard laboratory testing, VET can assess the entire coagulation system including the interaction between both pro- and anticoagulants and platelets.

Anesthesia and Critical Care for the Prediction and Prevention for Small-for-size Syndrome: Guidelines from the ILTS-iLDLT-LTSI Consensus Conference.

BACKGROUND: During the perioperative period of living donor liver transplantation, anesthesiologists and intensivists may encounter patients in receipt of small grafts that puts them at risk of developing small for size syndrome (SFSS). METHODS: A scientific committee (106 members from 21 countries) performed an extensive literature review on aspects of SFSS with proposed recommendations. Recommendations underwent a blinded review by an independent expert panel and discussion/voting on the recommendations occurred at a consensus conference organized by the International Liver Transplantation Society, International Living Donor Liver Transplantation Group, and Liver Transplantation Society of India. RESULTS: It was determined that centers with experience in living donor liver transplantation should utilize potential small for size grafts. Higher risk recipients with sarcopenia, cardiopulmonary, and renal dysfunction should receive small for size grafts with caution. In the intraoperative phase, a restrictive fluid strategy should be considered along with routine use of cardiac output monitoring, as well as use of pharmacologic portal flow modulation when appropriate. Postoperatively, these patients can be considered for enhanced recovery and should receive proactive monitoring for SFSS, nutrition optimization, infection prevention, and consideration for early renal replacement therapy for avoidance of graft congestion. CONCLUSIONS: Our recommendations provide a framework for the optimal anesthetic and critical care management in the perioperative period for patients with grafts that put them at risk of developing SFSS. There is a significant limitation in the level of evidence for most recommendations. This statement aims to provide guidance for future research in the perioperative management of SFSS.

Liver Transplant Outcomes in Young Adults with Cirrhosis Related to Nonalcoholic Fatty Liver Disease.

BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NASH) and cryptogenic cirrhosis (CC) is constantly increasing in adolescents and young adults (AYAs). METHODS: In a retrospective UNOS database evaluation, we analyzed postoperative outcomes of AYAs with nonalcoholic NASH/CC undergoing LT between January 1st, 2003 and March 5th, 2021. After exclusions, 85,970 LT recipients, 393 (47.1%) AYAs with NASH/CC and 441 (52.9%) AYAs with other metabolic conditions, were analyzed. RESULTS: During the study period, the number of LTs performed for AYAs with NASH/CC increased from 4%-7% but decreased from 6.6%-5.3% compared to LTs performed for NASH/CC in all ages. In comparison to AYAs with other metabolic conditions, AYA LT recipients with NASH/CC had a higher prevalence of metabolic syndrome (MetS) components, including diabetes and increased body mass index (P < .0001 for both). Patient and graft survival in AYAs with NASH/CC were significantly lower in comparison to AYAs transplanted for other metabolic conditions (P < .0001) (Hazard Ratio = 1.93, P < .001). Patient survival in AYAs with NASH/CC was significantly better in comparison to older (40-65-year-old) patients with the same diagnosis (P = .01). CONCLUSIONS: Our study found that the overall number of LTs in AYAs with NASH increased significantly, but to a lesser degree compared to the older population with the same diagnosis. Outcomes after LT in AYAs with NASH/CC were worse compared to LT for other metabolic conditions, but significantly better in comparison to older patients. The prevalence of LT for NASH/CC in AYAs is growing. MetS may contribute to worse outcomes in AYAs.

Use or Misuse of Albumin in Critical Ill Patients.

Since 1940 albumin has been used worldwide and is widely available commercially since this time. However, a meta-analysis in 1998 challenged the use of albumin and identified a trend toward higher mortality in critically ill patients who had received albumin. Since then, many studies including multicenter randomized controlled trials have been carried out investigating the safety and efficacy of albumin treatment in different patient cohorts. In this context, patient cohorts that benefit from albumin were identified. However, particularly in non-liver patients, the use of albumin remains controversial. In our comprehensive review, we would like to highlight the most important studies in the recent 20 years and therefore offer an evidence-based outlook for the use of albumin for patients treated in the ICU.

International Liver Transplantation Society/Society for Advancement of Transplant Anesthesia Consensus Statement on Essential Attributes of a Liver Transplant Anesthesiologist.

BACKGROUND: We sought to establish consensus on the essential skills, knowledge, and attributes that a liver transplant (LT) anesthesiologist should possess in a bid to help guide the further training process. METHODS: Consensus was achieved via a modified Delphi methodology, surveying 15 identified international experts in the fields of LT anesthesia and critical care. RESULTS: Key competencies were identified in preoperative management and optimization of a potential LT recipient; intraoperative management, including hemodynamic monitoring; coagulation and potential crisis management; and postoperative intensive and enhanced recovery care. CONCLUSIONS: This article provides an essential guide to competency-based training of an LT anesthesiologist.

A brief history of liver transplantation and transplant anesthesia.

In this review, we describe the major milestones in the development of organ transplantation with a specific focus on hepatic transplantation. For many years, the barriers preventing successful organ transplantation in humans seemed insurmountable. Although advances in surgical technique provided the technical ability to perform organ transplantation, limited understanding of immunology prevented successful organ transplantation. The breakthrough to success was the result of several significant discoveries between 1950 and 1980 involving improved surgical techniques, the development of effective preservative solutions, and the suppression of cellular immunity to prevent graft rejection. After that, technical innovations and laboratory and clinical research developed rapidly. However, these advances alone could not have led to improved transplant outcomes without parallel advances in anesthesia and critical care. With increasing organ demand, it proved necessary to expand the donor pool, which has been achieved with the use of living donors, split grafts, extended criteria organs, and organs obtained through donation after cardiac death. Given this increased access to organs and organ resources, the number of transplantations performed every year has increased dramatically. New regulatory organizations and transplant societies provide critical oversight to ensure equitable organ distribution and a high standard of care and also perform outcome analyses. Establishing dedicated transplant anesthesia teams results in improved organ transplantation outcomes and provides a foundation for developing new standards for other subspecialties in anesthesiology, critical care, and medicine overall. Through a century of discovery, the success we enjoy at the present time is the result of the work of well-organized multidisciplinary teams following standardized protocols and thereby saving thousands of lives worldwide each year. With continuing innovation, the future is bright.

Decline in Functional Status While on the Waiting List Predicts Worse Survival After Lung Transplantation.

OBJECTIVES: To determine if decreases in the Karnofsky Performance Score (KPS) while on the waitlist predict decreased survival after lung transplantation (LTx). DESIGN: A retrospective evaluation of the United Network for Organ Sharing database. The KPS was evaluated at the time of listing for transplant and at the time of transplantation. Group I consisted of patients having a decrease in KPS during the time on the waiting list (from the time of listing to the time of transplant), and Group II consisted of patients whose KPS stayed the same or increased during the same period. The authors used propensity-score weighting for comparisons of these groups. SETTING: Retrospective observational database review. PARTICIPANTS: Adult patients undergoing lung transplantation. INTERVENTIONS: None. Patients were stratified according to a change in their KPS. MEASUREMENTS AND MAIN RESULTS: Patient and graft survival of patients with decreasing or not decreasing KPS were compared. Of the 27,558 subjects included in the analysis, 17,986 (65%) had worsening KPS, which was associated with worse graft (p = 0.0003) and patient (p = 0.0019) survival after LTx. Using multivariate regression, a decrease in KPS of ≥40 was associated with decreased survival, and an increase of ≥40 was associated with improved survival (HR = 1.245, 95% CI [1.181-1.312], p < 0.0001 and HR = 0.866, 95% CI [0.785, 0.955], respectively). Among patients with a KPS <40 at the time of transplant, those with a decrease in KPS of ≥40 had decreased graft and patient survival compared with those with a smaller decrease (p = 0.0002 and p = 0.0021, respectively). CONCLUSIONS: Deterioration of KPS on the waiting list for LTx is associated with significantly greater postoperative mortality in patients after LTx. These results should be taken into consideration when allocating organs. Strategies to increase or to prevent a decrease in KPS before LTx should be evaluated.

The Edge of Unknown: Postoperative Critical Care in Liver Transplantation.

Perioperative care of patients undergoing liver transplantation (LT) is very complex. Metabolic derangements, hypothermia, coagulopathy and thromboses, severe infections, and graft dysfunction can affect outcomes. In this manuscript, we discuss several perioperative problems that can be encountered in LT recipients. The authors present the most up-to-date information regarding predicting and treating hemodynamic instability, coagulation monitoring and management, postoperative ventilation strategies and early extubation, management of infections, and ESLD-related pulmonary complications. In addition, early post-transplant allograft dysfunction will be discussed.

Adult Renal Transplantation in a Patient 28 Years after Heart Transplantation as a Neonate for Hypoplastic Left Heart Syndrome.

We present a case of kidney transplantation in a 28-year-old patient who received a heart transplant at 7 weeks of age due to hypoplastic left heart syndrome. The patient's renal insufficiency was the result of chronic immunosuppression and hypertension. The almost 28-year-old graft demonstrated very good function. This patient represents as one of the longest pediatric cardiac graft recipients living without any significant functional limitations.

Multidrug-resistant infections in solid organ transplant recipients: a focus on risk factors, prevention, and treatment strategies.

Solid organ transplantation is the best therapeutic option for patients with end-stage organ disease and, according to the data from international registries, there has been a steady increase in numbers and results. However, post­transplant infections remain a fearsome complication with, in the last decade, an increasing incidence of episodes due to antibiotic­resistant bacteria and opportunistic agents. In this paper, we summarized the most relevant and updated knowledge concerning infections from multidrug­resistant germs in solid organ transplant recipients, focusing on risk factors, treatment and prevention strategies, and antimicrobial pharmacokinetics relevant to this population of patients.

Intraoperative transfusion management, antifibrinolytic therapy, coagulation monitoring and the impact on short-term outcomes after liver transplantation-A systematic review of the literature and expert panel recommendations.

BACKGROUND: Liver transplantation (LT) is frequently complicated by coagulopathy associated with end-stage liver disease (ESLD), that is, often multifactorial. OBJECTIVES: The objective of this systematic review was to identify evidence based intraoperative transfusion and coagulation management strategies that improve immediate and short-term outcomes after LT. METHODS: PRISMA-guidelines and GRADE-approach were followed. Three subquestions were formulated. (Q); Q1: transfusion management; Q2: antifibrinolytic therapy; and Q3: coagulation monitoring. RESULTS: Sixteen studies were included for Q1, six for Q2, and 10 for Q3. Q1: PRBC and platelet transfusions were associated with higher mortality. The use of prothrombin complex concentrate (PCC) and fibrinogen concentrate (FC) were not associated with reductions in intraoperative transfusion or increased thrombotic events. The use of cell salvage was not associated with hepatocellular carcinoma (HCC) recurrence or mortality. Cell salvage and transfusion education significantly decreased blood product transfusions. Q2: Epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA) were not associated with decreased blood product transfusion, improvements in patient or graft survival, or increases in thrombotic events. Q3: Viscoelastic testing (VET) was associated with decreased allogeneic blood product transfusion compared to conventional coagulation tests (CCT) and is likely to be cost-effective. Coagulation management guided by VET may be associated with increases in FC and PCC use. CONCLUSION: Q1: A specific blood product transfusion practice is not recommended (QOE; low | Recommendation; weak). Cell salvage and educational interventions are recommended (QOE: low | Grade of Recommendation: moderate). Q2: The routine use of antifibrinolytics is not recommended (QOE; low | Recommendation; weak). Q3: The use of VET is recommended (QOE; low-moderate | Recommendation; strong).

A decline in functional status while awaiting liver transplantation is predictive of increased post-transplantation mortality.

BACKGROUND: Functional status (FS) is dynamic and changes over time. We examined how changes in FS while awaiting liver transplantation influence post-transplant outcomes. METHODS: Data on adult liver transplants performed in the United States during the MELD era were obtained through September 2020. Patient and graft survival were compared between groups with no change or improved FS, and those with worsening FS. RESULTS: Of the 90,210 transplant recipients included in the analysis, 39,193 (43%) had worsening FS, which was associated with longer waiting-list time (187 vs. 329 days, p < 0.001) and worse patient survival after liver transplant (1858 vs. 1727 days, p < 0.001). A consistent and dose-dependent relationship was observed for each 10-point decrease in Karnofsky Performance Score and post-transplant survival. Multivariable regression analysis confirmed that a decline in FS was associated with worse patient survival (HR 1.15, p < 0.001). Similar findings were observed for graft survival. CONCLUSION: A decline in FS on the waiting-list is associated with significantly greater post-liver transplant mortality in recipients. These results should be taken into consideration when allocating organs and determining transplant candidacy. Strategies to optimize FS prior to transplantation should be prioritized as even subtle decreases in FS are associated with inferior post-transplantation outcomes.

Management of Patients With Non-alcoholic Steatohepatitis Undergoing Liver Transplantation: Considerations for the Anesthesiologist.

Non-alcoholic fatty liver disease (NAFLD) currently affects more than 25% of the world population and is rising. NAFLD can progress to non-alcoholic steatohepatitis that is associated with hepatic inflammation and fibrosis and can result in cirrhosis with subsequent liver failure. Non-alcoholic steatohepatitis (NASH) has now emerged as one of the leading etiologies for a liver transplant among adults in the United States. Given the rising incidence of liver transplants in patients with NASH-related cirrhosis, it is essential for anesthesiologists to be familiar with this condition as well as with NASH-related comorbidities and perioperative complications. Not only is NASH linked to metabolic syndrome, but it also is independently associated with cardiovascular disease, renal and thyroid dysfunction, obstructive sleep apnea (OSA), and a hypercoagulable state. The association with these conditions can affect the perioperative outcome of these patients, particularly because of increased mortality from major adverse cardiovascular events and sepsis. In order to decrease the perioperative morbidity and mortality of patients with NASH undergoing a liver transplant, a multidisciplinary approach to their perioperative management is essential, along with careful preoperative evaluation and aggressive intraoperative and postoperative monitoring. The focus of this review article is to provide a comprehensive overview of challenges associated with liver transplants in patients with NASH and to provide suggestions for appropriate patient selection and perioperative management.

Hyponatremia and Liver Transplantation: A Narrative Review.

Hyponatremia is a common electrolyte disorder in patients with end-stage liver disease (ESLD) and is associated with increased mortality on the liver transplantation (LT) waiting list. The impact of hyponatremia on outcomes after LT is unclear. Ninety-day and one-year mortality may be increased, but the data are conflicting. Hyponatremic patients have an increased rate of complications and longer hospital stays after transplant. Although rare, osmotic demyelination syndrome (ODS) is a feared complication after LT in the hyponatremic patient. The condition may occur when the serum sodium (sNa) concentration increases excessively during or after LT. This increase in sNa concentration correlates with the degree of preoperative hyponatremia, the amount of intraoperative blood loss, and the volume of intravenous fluid administration. The risk of developing ODS after LT can be mitigated by avoiding large perioperative increases in sNa concentration . This can be achieved through measures such as carefully increasing the sNa pretransplant, and by limiting the intravenous intra- and postoperative amounts of sodium infused. SNa concentrations should be monitored regularly throughout the entire perioperative period.

Excellent outcomes with liver transplantation in hepatopulmonary syndrome across pre-transplant PaO2 spectrum.

BACKGROUND & AIMS: Significantly worse survival has been reported in patients with hepatopulmonary syndrome (HPS) and partial pressure of arterial oxygen (PaO2) <45 mmHg undergoing liver transplantation. Long-term pre- and post-transplant outcomes based on degree of hypoxaemia were re-examined. METHODS: A retrospective analysis of 1,152 HPS candidates listed with an approved HPS model for end-stage liver disease (MELD) exception was performed. A Fine and Gray competing risks model was utilised to evaluate pre-transplant outcomes for PaO2 thresholds of <45, 45 to <60, and ≥60 mmHg. Post-transplant survival was analysed using the Kaplan-Meier method. RESULTS: Patients with a PaO2 <45 mmHg were significantly more likely to undergo transplantation (hazard ratio [HR] 1.51; 95% CI 1.12-2.03), whereas patients with higher MELD scores had lower hazard of transplant (HR 0.80, 95% CI 0.67-0.95, p = 0.011) and higher hazard of pre-transplant death (HR 2.29, 95% CI 1.55-3.37, p <0.001). Post-transplantation, patients with a PaO2 <45 mmHg had lower survival (p = 0.04) compared with patients with a PaO2 ≥45 to <50 mmHg, with survival curves significantly different at 2.6 years (75% survival compared with 86%) and median survival of 11.5 and 14.1 years, respectively. Cardiac arrest was a more likely (p = 0.025) cause of death for these patients. Cardiac arrest incidence in patients who died with a PaO2 >50 mmHg was 6.2%. CONCLUSIONS: Patients with a PaO2 <45 mmHg had a significantly higher rate of transplantation, and higher calculated MELD scores were associated with significantly higher pre-transplant mortality. Although post-transplant survival was lower in patients with a PaO2 <45 mmHg, the median survival was 11.5 years, and survival curves only became significantly different at 2.6 years. This suggests that patients with HPS do benefit from transplantation up to 2-3 years post-transplant regardless of the severity of pre-transplant hypoxaemia. LAY SUMMARY: A total of 1,152 patients with hepatopulmonary syndrome listed for liver transplant were analysed. Patients with a low PaO2 <45 mmHg had a high likelihood of transplantation. If associated with advanced liver disease, the mortality risk was higher for patients with hepatopulmonary syndrome on the wait list. After liver transplantation, patients with a PaO2 <45 mmHg had a lower survival, but this only became significant after 2.6 years, and the median survival was 11.5 years. This suggests that patients with hepatopulmonary syndrome do benefit from transplantation.

Plasminogen activator inhibitor is significantly elevated in liver transplant recipients with decompensated NASH cirrhosis.

BACKGROUND: Non-alcoholic fatty liver disease is a prohaemostatic state with abnormal primary, secondary and tertiary haemostasis. Plasminogen activator inhibitor (PAI)-1 is the best-established marker for prohaemostasis in non-alcoholic fatty liver disease. While epidemiological studies demonstrate decompensated non-alcoholic steatohepatitis (NASH) cirrhosis patients have increased rates of venous thromboembolism, including portal vein thrombosis, mechanistic studies have focused exclusively on patients without or with compensated cirrhosis. We aimed to characterizecharacterise PAI-1 levels in decompensated NASH cirrhosis. METHODS: PAI-1 level was measured in consecutive adult liver transplant recipients immediately prior to liver transplantation. Multivariable models were constructed using linear regression to assess factors related to PAI-1 level. RESULTS: Forty-six subjects with mean age 57 (IQR 53-62) years and Model for Endstage Liver Disease (MELD) score of 34 (IQR 30-40) were enrolled. Baseline characteristics were similar between NASH (n=10) and non-NASH (n=36) subjects except for rates of diabetes and hyperlipidaemia. Mean PAI-1 level was greater in NASH (53.9, 95% CI 33.3 to 74.5 mg/mL) when compared with non-NASH (36.1, 95% CI 28.7 to 43.5), p=0.040. NASH remained independently predictive of PAI-1 level prior to transplant on adjusted multivariable modelling (ß 40.13, 95% CI 14.41 to 65.86, p=0.003). CONCLUSIONS: PAI-1 level is significantly elevated in decompensated NASH cirrhosis independent of other pro-haemostatic factors. This may explain the greater rates of venous thromboembolism in decompensated NASH cirrhosis. Future study focusing on prevention of venous thromboembolism in this population is paramount to improve patient-oriented outcomes given the high morbidity and mortality of venous thromboembolism and the significant impact it has on transplant candidacy.