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).

Liver transplantation in Jehovah's witnesses: 13 consecutive cases at a single institution.

BACKGROUND: Jehovah's Witnesses represent a tremendous clinical challenge when indicated to liver transplantation because they refuse blood transfusion on religious grounds and the procedure is historically associated with potential massive peri-operative blood loss. We herein describe a peri-operative management pathway with strategies toward a transfusion-free environment with the aim not only of offering liver transplant to selected Jehovah's Witnesses patients but also, ultimately, of translating this practice to all general surgical procedures. METHODS: This is a retrospective review of prospective medical records of JW patients who underwent LT at our Institution. The peri-operative multimodal strategy to liver transplantation in Jehovah's Witnesses includes a pre-operative red cell mass optimization package and the intra-operative use of normovolemic haemodilution, veno-venous bypass and low central venous pressure. RESULTS: In a 9-year period, 13 Jehovah's Witness patients received liver transplantation at our centre representing the largest liver transplant program from deceased donors in Jehovah's Witnesses patients reported so far. No patient received blood bank products but 3 had fibrinogen concentrate and one tranexamic acid to correct ongoing hyper-fibrinolysis. There were 4 cases of acute kidney injury (one required extracorporeal renal replacement treatment) and one patient needed vasoactive medications to support blood pressure for the first 2 postoperative days. Two patients underwent re-laparotomy. Finally, of the 13 recipients, 12 were alive at the 1 year follow-up interview and 1 died due to septic complications. CONCLUSIONS: Our experience confirms that liver transplantation in selected Jehovah's Witnesses patients can be feasible and safe provided that it is carried out at a very experienced centre and according to a multidisciplinary approach.

Dual aortic and portal perfusion at procurement prevents ischaemic-type biliary lesions in liver transplantation when using octogenarian donors: a retrospective cohort study.

Several risk factors for ischaemic-type biliary lesions (ITBL) after liver transplantation (LT) have been identified, but the role of portal vein perfusion at graft procurement is still unclear. This was a prospective study on double aortic and portal perfusion (DP) of liver grafts stratified by donor's decade (<60 yo; 60-69 yo; 70-79 yo and ≥80 yo) versus similar historical cohorts of primary, adult grafts procured with single aortic perfusion (SP) only. The primary study aim was to assess the role of DP on the incidence of ITBL. There was no difference in the incidence of overall biliary complications according to procurement technique for recipients of grafts <80 years. A higher incidence of ITBL was observed for patients receiving grafts ≥80 years and perfused through the aorta only (1.9 vs. 13.4%; P = 0.008). When analysing octogenarian grafts, donor male gender (HR = 6.4; P = 0.001), haemodynamic instability (HR = 4.9; P = 0.008), and type-2 diabetes mellitus (DM2) (HR = 3.0; P = 0.03) were all independent risk factors for ITBL, while double perfusion at procurement (HR = 0.1; P = 0.04) and longer donor intensive care unit (ICU) stay (HR = 0.7; P = 0.04) were protective factors. Dual aortic and portal perfusion has the potential to reduce post-transplant ITBL incidence for recipients of octogenarian donor grafts. Larger series are needed to confirm this preliminary experience.

Metformin intoxication: Vasopressin's key role in the management of severe lactic acidosis.

Vasopressin is a potent vasopressor used for improving organ perfusion during cardiac arrest, septic and catecholamine-resistant shock; with reference to this, it is useful for the treatment of vasoplegic shock because, restoring organ perfusion pressure by contraction of vascular smooth muscle through a non-catecholamine receptor pathway, it can be employed when catecholamines are ineffective. A 49-yr-old woman was admitted to the Emergency Department after having intentionally taken 95.2g of metformin, 1.6g of pioglitazone and 40 UI of insulin glargine in a suicide attempt. Despite fluid resuscitation, CVVHDF (continuous veno-venous hemodiafiltration) treatment, norepinephrine and epinephrine infusion, she developed a severe lactic acidosis and a catecholamines-refractive vasodilatory shock. Only the vasopressin infusion, in association with catecholamines, gradually stabilized the patient's hemodynamic status.

Red blood cell exchange as an approach for treating a case of severe tacrolimus overexposure.

Immunosuppressive medication dosing errors are not unfrequent and may present a number of challenges to transplant clinicians. Tacrolimus (TAC) is a widely used immunosuppressant with a narrow therapeutic index and potential severe side effects, including neurotoxicity and kidney injury. We herein report a case of 60-year-old woman who underwent deceased-donor liver transplantation at our center and due to inadvertent TAC overexposure was admitted to the Intensive Care Unit because of severe neurologic impairment, kidney injury and arterial hypotension. This case was challenging because TAC is largely bound to erythrocytes, has a high molecular weight, is highly lipophilic, has a high distribution volume and cannot be removed by hemodialysis or plasmapheresis. Based on these considerations, we decided to replace TAC-saturated erythrocytes with blood-bank red cells with the aim to accelerate its clearance. The treatment was effective in decreasing TAC whole blood trough levels within the therapeutic ranges with a significant improvement of the patient's clinical status. Red-blood cell exchange is a potentially safe and effective means of managing severe and symptomatic TAC toxicity.

Risk analysis of ischemic-type biliary lesions after liver transplant using octogenarian donors.

The use of octogenarian donors to increase the donor pool in liver transplantation (LT) is controversial because advanced donor age is associated with a higher risk of ischemic-type biliary lesions (ITBL). The aim of this study was to investigate retrospectively the role of a number of different pre-LT risk factors for ITBL in a selected population of recipients of octogenarian donor grafts. Between January 2003 and December 2013, 123 patients underwent transplantation at our institution with deceased donor grafts from donors of age ≥80 years. Patients were divided into 2 groups based on the presence of ITBL in the posttransplant course. Exclusion criteria were retransplantations, presence of vascular complications, and no availability of procurement liver biopsy. A total of 88 primary LTs were included, 73 (83.0%) with no posttransplant ITBLs and 15 (17.0%) with ITBLs. The median follow-up after LT was 2.1 years (range, 0.7-5.4 years). At multivariate analysis, donor hemodynamic instability (hazard ratio [HR], 7.6; P = 0.005), donor diabetes mellitus (HR, 9.5; P = 0.009), and donor age-Model for End-Stage Liver Disease (HR, 1.0; P = 0.04) were risk factors for ITBL. Transplantation of liver grafts from donors of age ≥80 years is associated with a higher risk for ITBL. However, favorable results can be achieved with accurate donor selection. Donor hemodynamic instability, a donor history of diabetes mellitus, and allocation to higher Model for End-Stage Liver Disease score recipient all increase the risk of ITBL and are associated with worse graft survival when octogenarian donors are used. Liver Transplantation 22 588-598 2016 AASLD.

A web-based Italian survey of current trends, habits and beliefs in hemodynamic monitoring and management.

Significant evidence outlines that the management of the high-risk surgical patient with perioperative hemodynamic optimization leads to significant benefits. This study aimed at studying the current practice of hemodynamic monitoring and management of Italian anesthesiologists. An invitation to participate in a web-based survey was published on the web site of the Società Italiana di Anestesia Analgesia Rianimazione Terapia Intensiva. Overall, 478 questionnaires were completed. The most frequently used monitoring techniques was invasive blood pressure (94.1 %). Cardiac output was used in 41.3% of the cases mainly throughout less-invasive methods. When cardiac output was not monitored, the main reason given was that other surrogate techniques, mainly central venous oxygen saturation (40.5%). Written protocols concerning hemodynamic management in high-risk surgical patients were used by the 29.1% of the respondents. 6.3% of the respondents reported not to be aware if such document was available at their institution. 86.3% of the respondents reported that they usually optimize high risk patients but to use blood flow assessment rarely (39.7%). The most used parameter in clinical practice to assess the effects of volume loading were an increase in urine output and arterial blood pressure together with a decrease in heart rate and blood lactates. The 45.1% or the respondents outlined that hemodynamic optimization in the high risk patients is of major clinical value. Our study outlines an important gap between available evidence and clinical practice emphasizing the need for a better awareness, more information and knowledge on the specific topic.

Intravenous fenoldopam for early acute kidney injury after liver transplantation.

PURPOSE: Acute kidney injury remains a serious complication after orthotopic liver transplantation. To date, several 'renal-protective' agents have been explored in this setting but with conflicting and disappointing results. Therefore, our aim is to evaluate the effects of fenoldopam in liver transplant patients with an established renal injury. METHODS: In this prospective study, intravenous fenoldopam 0.1 µg/kg/min was administered to consecutive liver transplant patients with postoperative (within 7 days from surgery) stage 2 acute kidney injury (AKI) according to the Acute Kidney Injury Network classification. Actual glomerular filtration rate (GFR; calculated by the iohexol plasma clearance), serum creatinine (SCr) and cystatin C (SCyC) were used to assess the effect of the medication on the patients. RESULTS: During the study, 295 patients underwent liver transplant. Fifty-one patients (17.6%) met the inclusion criteria and the data from 48 patients were analysed. SCr and SCyC levels decreased (p < 0.001 after 48 h; p < 0.0001 after 72 h) and GFR increased (p < 0.001 after 24 h; p < 0.0001 after 72 h). When compared to a cohort of comparable patients with AKI from our historical series, the patients in the present study showed better SCr and SCyC levels. It was not necessary to discontinue the infusion of fenoldopam in any patient because of the occurrence of adverse events potentially attributable to it. CONCLUSION: We showed that fenoldopam was capable of improving some renal function parameters in postoperative liver transplantation patients with on-going AKI. This preliminary study now sets the stage for a multicenter, randomized, placebo-controlled trial in order to provide definite evidence.

Pain management in liver transplant recipients: a focus on current and future strategies.

Liver transplantation is the only curative treatment option for patients with end-stage liver disease. Anesthesiologists and intensivists are fully involved in this procedure due to the perioperative care focus on hemodynamic, respiratory and metabolic support. However, quite surprisingly, postoperative pain management does not have clinical primary consideration in this class of patients due to a combination of factors including the thought that liver transplantation recipients have less pain and require lower doses of analgesics than patients who undergo other types of major abdominal surgery. Other factors contribute to make the management of postoperative pain somewhat complex in this class of patients: 1) drug pharmacokinetics and metabolism by the new liver is not predictable; 2) the multifactorial nature of liver graft recovery; and 3) the alterations of homeostasis, including circulatory, respiratory and metabolic vulnerability, in the days postoperative period. As a result, post-liver transplantation analgesia is underestimated not only from the clinical point of view but also in the literature and only a few papers deal with the management of postoperative pain in this particular class of patients. Thus, in the experts' opinion paper we aimed to report the possible strategies for managing post-LT pain with a focus on opioids alternatives and possible future developments in this particular clinical setting also in the view that improvements in perioperative care have made it possible to adopt fast track and Enhanced Recovery After Surgery-oriented protocols also in this class of patients.

Landiolol for heart rate control in patients with septic shock and persistent tachycardia. A multicenter randomized clinical trial (Landi-SEP).

PURPOSE: Excessive tachycardia in resuscitated septic shock patients can impair hemodynamics and worsen patient outcome. We investigated whether heart rate (HR) control can be achieved without increased vasopressor requirements using the titratable highly selective, ultra-short-acting ß1-blocker landiolol. METHODS: This randomized, open-label, controlled trial was conducted at 20 sites in 7 European countries from 2018 to 2022 and investigated the efficacy and safety of landiolol in adult patients with septic shock and persistent tachycardia. Patients were randomly assigned to receive either landiolol along with standard treatment (n = 99) or standard treatment alone (n = 101). The combined primary endpoint was HR response (i.e., HR within the range of 80-94 beats per minute) and its maintenance without increasing vasopressor requirements during the first 24 h after treatment start. Key secondary endpoints were 28-day mortality and adverse events. RESULTS: Out of 196 included septic shock patients, 98 received standard treatment combined with landiolol and 98 standard treatment alone. A significantly larger proportion of patients met the combined primary endpoint in the landiolol group than in the control group (39.8% [39/98] vs. 23.5% [23/98]), with a between-group difference of 16.5% (95% confidence interval [CI]: 3.4-28.8%; p = 0.013). There were no statistically significant differences between study groups in tested secondary outcomes and adverse events. CONCLUSION: The ultra-short-acting beta-blocker landiolol was effective in reducing and maintaining HR without increasing vasopressor requirements after 24 h in patients with septic shock and persistent tachycardia. There were no differences in adverse events and clinical outcomes such as 28-day mortality vs. standard of care. The results of this study, in the context of previous trials, do not support a treatment strategy of stringent HR reduction (< 95 bpm) in an unselected septic shock population with persistent tachycardia. Further investigations are needed to identify septic shock patient phenotypes that benefit clinically from HR control.

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.

Use of an intraoperative veno-venous bypass during liver transplantation: an observational, single center, cohort study.

BACKGROUND: As previous studies demonstrated conflicting results, we investigated the hemodynamic and renal outcomes of the intra-operative use of a veno-venous bypass during liver transplantation. METHODS: The intraoperative levels of mean artery pressure, cardiac index, inferior vena cava and renal perfusion pressures were compared in liver transplant patients receiving or not the bypass. RESULTS: We enrolled 38 patients: 20 with the bypass and 18 without. No differences characterized the two groups regarding gender (P=0.95), age (P=0.32), BMI (P=0.09), liver disease indicating LT and preoperative serum creatinine levels. Patients with the bypass received more intraoperative fluids (crystalloids and colloids) but with no difference in terms of intraoperative blood products and vasopressors requirements (P=0.33). After clamping of the inferior vena cava, patients with the bypass showed higher mean artery pressure. Simultaneously, pressure in the inferior vena cava below the clamp level sharply increased vs. baseline (P<0.0001) independently of the use of the bypass and remained high until clamp release. Consequently, renal perfusion pressure dropped abruptly (P<0.0001) after vena cava clamping and returned to baseline only upon clamp removal. Overall, 18 subjects developed postoperative acute kidney injury which was equally distributed between patients with (n=9) or without (N.=8) the bypass. CONCLUSIONS: Our data suggest that the use of a veno-venous bypass fails to release the increased renal venous backflow from inferior vena cava clamping resulting in renal congestion with reduced renal perfusion pressure.

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.

The prevention of pressure injuries in the positioning and mobilization of patients in the ICU: a good clinical practice document by the Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI).

BACKGROUND: The aim of this document is to support clinical decision-making concerning positioning and mobilization of the critically ill patient in the early identification and resolution of risk factors (primary prevention) and in the early recognition of those most at risk (secondary prevention). The addresses of this document are physicians, nurses, physiotherapists, and other professionals involved in patient positioning in the intensive care unit (ICU). METHODS: A consensus pathway was followed using the Nominal Focus Group and the Delphi Technique, integrating a phase of focused group discussion online and with a pre-coded guide to an individual phase. A multidisciplinary advisory board composed by nine experts on the topic contributed to both the phases of the process, to reach a consensus on four clinical questions positioning and mobilization of the critically ill patient. RESULTS: The topics addressed by the clinical questions were the risks associated with obligatory positioning and therapeutic positions, the effective interventions in preventing pressure injuries, the appropriate instruments for screening for pressure injuries in the ICU, and the cost-effectiveness of preventive interventions relating to ICU positioning. A total of 27 statements addressing these clinical questions were produced by the panel. Among the statements, nine provided guidance on how to manage safely some specific patients' positions, including the prone position; five suggested specific screening tools and patients' factors to consider when assessing the individual risk of developing pressure injuries; five gave indications on mobilization and repositioning; and eight focused on the use of devices, such as positioners and preventive dressings. CONCLUSIONS: The statements may represent a practical guidance for a broad public of healthcare professionals involved in the management of critically ill patients.

Guidelines for Perioperative Care for Liver Transplantation: Enhanced Recovery After Surgery (ERAS) Recommendations.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) is a multimodal, evidence-based, program of care developed to minimize the response to surgical stress, associated with reduced perioperative morbidity and hospital stay. This study presents the specific ERAS Society recommendations for liver transplantation (LT) based on the best available evidence and on expert consensus. METHODS: PubMed and ClinicalTrials.gov were searched in April 2019 for published and ongoing randomized clinical trials on LT in the last 15 y. Studies were selected by 5 independent reviewers and were eligible if focusing on each validated ERAS item in the area of adult LT. An e-Delphi method was used with an extended interdisciplinary panel of experts to validate the final recommendations. RESULTS: Forty-three articles were included in the systematic review. A consensus was reached among experts after the second round. Patients should be screened for malnutrition and treated whenever possible. Prophylactic nasogastric intubation and prophylactic abdominal drainage may be omitted, and early extubation should be considered. Early oral intake, mobilization, and multimodal-balanced analgesia are recommended. CONCLUSIONS: The current ERAS recommendations were elaborated based on the best available evidence and endorsed by the e-Delphi method. Nevertheless, prospective studies need to confirm the clinical use of the suggested protocol.

Evaluation of a new software version of the FloTrac/Vigileo (version 3.02) and a comparison with previous data in cirrhotic patients undergoing liver transplant surgery.

BACKGROUND: Reliable cardiac output monitoring is particularly useful in the cirrhotic patient undergoing liver transplant surgery, because cirrhosis of the liver is associated with a vasodilated and high output state, known as cirrhotic cardiomyopathy, that challenges the reliability of pulse contour cardiac output technology. The contractility of the ventricle in cirrhosis is impaired, which is tolerated even though the ejection fraction and cardiac output are elevated because of the low peripheral resistance. However, during surgery the cirrhotic patient can decompensate because of the physiological changes and stress of surgery. Recently, we showed that the FloTrac/Vigileo™ failed to perform in cirrhotic patients undergoing transplant surgery. In response, the company upgraded their software. Therefore, we have assessed the accuracy and reliability of this new third-generation (version 3.02) FloTrac/Vigileo algorithm software in the same setting. METHODS: The cardiac index was measured simultaneously by single-bolus thermodilution (CI(TD)), using a pulmonary artery catheter, and pulse contour analysis, using the FloTrac/Vigileo (CI(V)). Readings were made at 10 time points during and after liver transplant surgery in 21 patients. Comparisons with data from our 2009 study, which used second-generation (version 01.10) software, were also made. RESULTS: Our new data show that version 3.02 software significantly reduced the adverse effect on pulse contour cardiac output reading bias in low peripheral resistance states, and thus improves the overall precision and trending ability of the system. Regression analysis between CI(TD) and CI(V) showed that the correlation was moderate (r =0.67, 95% confidence interval, 0.40 to 0.86). The Bland and Altman analysis showed that bias was 0.4 L.min(-1) · m(-2), and the percentage error was 52% (95% confidence interval, 49% to 55%). Trending ability of the new software also was improved but was still well below the current benchmarks. CONCLUSION: The new software (version 3.02) provided substantial improvements over the previous versions with better overall precision and trending ability. Further algorithm refinements will increase this technology's reliability to be extensively used in the highly complex setting of cirrhotic patients undergoing liver transplantation.

Safety Analysis of 13 Suspicious Deaths in Intensive Care: Ergonomics and Forensic Approach Compared.

OBJECTIVES: Thirteen suspicious deaths occurred in an intensive care unit of Tuscany, Italy, in 2015. All patients developed sudden unexplained coagulopathy leading to severe bleeding. None of them had been prescribed heparin, but supertherapeutic concentrations of heparin were found. After a nurse was arrested on suspicion of murdering Human Factor and Ergonomics (HF/E) experts received a mandate to identify system failures. According to the judgment of the Court of First Instance on April 2019, the nurse was found guilty. METHODS: The HF/E group used a two-pronged safety analysis: understanding the conditions in which the healthcare practitioners were working in the period when the suspicious deaths emerged and reviewing the clinical records. RESULTS: Fourteen patients admitted to the intensive care unit in 2014 and 2015 were selected on the basis of markedly abnormal coagulation tests (n = 13) or a family member's complaint (n = 1). In 13 cases, a massive, abrupt hemorrhage in the presence of an unexpected abnormality of coagulation tests occurred, whereas the fourteenth patient had the only prolongation of coagulation markers without bleeding. All cases examined classified as adverse events related to a coagulation disorder. Human factor and ergonomics analysis identified a number of latent and active failures that contributed to the event and provided a set of important recommendations for safety improvement. CONCLUSIONS: When presented with a manifest, albeit suspected, wrongdoing with lethal consequences for patients, forensic investigators and safety investigators have distinctly different goals and methods. We believe that a memorandum of understanding between HF/E and forensic investigative teams provides an operative framework for allowing co-existence and fosters collaboration. The pursuit of safe care as a new emerging right for patients and balancing the right to legal justice with the right to safer healthcare merit further investigation and discussion.