The role of an integrated referral program for patients with liver disease: A network between hub and spoke centers.

INTRODUCTION: Access to Liver transplantation (LT) can be affected by several barriers, resulting in delayed referral and increased risk of mortality due to complications of the underlying liver disease. AIM: To assess the clinical characteristics and outcomes of patients with acute or chronic liver disease referred using an integrated referral program. MATERIALS AND METHODS: An integrated referral program was developed in 1 October 2017 based on email addresses and a 24/7 telephone availability. All consecutive adult patients with liver disease referred for the first time using this referral program were prospectively collected until 1 October 2021. Characteristics and outcomes of inpatients were compared with a historical cohort of patients referred without using the integrated referral program (1 October 2015-1 October 2017). Patients were further divided according to pre- and post-Covid-19 pandemic. RESULTS: Two hundred eighty-one referred patients were considered. End stage liver disease was the most common underlying condition (79.3%), 50.5% of patients were referred as inpatients and 74.7% were referred for LT evaluation. When inpatient referrals (n = 142) were compared with the historical cohort (n = 86), a significant increase in acute liver injury due to drugs/herbals and supplements was seen (p = 0.01) as well as an increase in End stage liver disease due to alcohol-related liver disease and NASH, although not statistically significant. A significant increase in referrals for evaluation for Trans-jugular intrahepatic portosystemic shunt placement was seen over time (5.6% vs. 1%; p = 0.01) as well as for LT evaluation (84.5% vs. 81%; p = 0.01). Transplant-free survival was similar between the study and control groups (p = 0.3). The Covid-19 pandemic did not affect trends of referrals and patient survival. CONCLUSIONS: The development of an integrated referral program for patients with liver disease can represent the first step to standardize already existing referral networks between hub and spoke centers. Future studies should focus on the timing of referral according to different etiologies to optimize treatment options and outcomes.

Role of nonneoplastic PVT in the natural history of patients with cirrhosis and first diagnosis of HCC.

BACKGROUND AND AIMS: HCC can increase the risk of nonneoplastic PVT in cirrhosis. However, the natural history of PVT and its prognostic role in HCC patients are unknown. APPROACH AND RESULTS: Consecutive HCC patients with cirrhosis undergoing laparoscopic ablation were retrospectively evaluated and followed up to 36 months. HCC and PVT characteristics and evolution were reviewed. PVT was categorized according to lumen occupancy (≤50%, >50% <100%, and = 100%) and extension to other veins. The evolution of thrombosis was considered at 1 year from diagnosis. Variables associated with the presence of PVT and evolution patterns were analyzed, as well as their impact on survival. In all, 750 patients were included, 88 of whom had PVT. On multivariate analysis, the occurrence of PVT at HCC diagnosis was associated with pretreatment total tumor volume ( p < 0.001) and clinically significant portal hypertension ( p = 0.005). During the follow-up, 46 de novo PVT occurred, 27/46 (58.7%) in the presence of a viable tumor. Among 115 PVT diagnosed in the presence of HCC, 83 had available radiological follow-up, and 22 were anticoagulated. The "complete/progressive" evolution pattern was associated with nonresponse to HCC treatment in non-anticoagulated patients. The presence of PVT was independently associated with lower overall survival, particularly when progressive or occlusive ( p < 0.001). A higher competing risk of death emerged for "complete and progressive" PVT, both for HCC-related ( p < 0.001) and non-HCC-related ( p = 0.002) death. CONCLUSIONS: HCC represents an independent risk factor for the occurrence and progression of PVT in cirrhosis. Since progressive and occlusive PVT seems to be an independent factor associated with mortality, screening and prompt treatment of this complication should be considered.

Impact of bacterial infections prior to liver transplantation on post-transplant outcomes in patients with cirrhosis.

Background & Aims: Bacterial infections are frequent in patients with cirrhosis and increase the risk of death and drop-out from liver transplant (LT) waiting list. In patients with bacterial infections, LT is frequently delayed because of the fear of poor outcomes. We evaluated the impact of pre-LT infections on post-LT complications and survival. Methods: From 2012 to 2018, consecutive patients transplanted at the Hospital of Padua were identified and classified in two groups: patients surviving an episode of bacterial infection within 3 months before LT (study group) and patients without infections before LT (control group). Post-LT outcomes (complications, new infections, survival) were collected. Results: A total of 466 LT recipients were identified (study group n = 108; control group n = 358). After LT, the study group had a higher incidence of new bacterial (57% vs. 20%, p <0.001) and fungal infections (14% vs. 5%, p = 0.001) and of septic shock (8% vs. 2%, p = 0.004) than the control group. Along with the model for end-stage liver disease (MELD) score and alcohol-related cirrhosis, bacterial infection pre-LT was an independent predictor of post-LT infections (odds ratio = 3.92; p <0.001). Nevertheless, no significant difference was found in 1-year (88% vs. 89%, p = 0.579) and 5-year survival rates (76% vs. 75%, p = 0.829) between the study group and control group. Within the study group, no association was found between the time elapsed from infection improvement/resolution to LT and post-LT outcomes. Conclusions: Patients with pre-LT infections have a higher risk of new bacterial and fungal infections and of septic shock after LT. However, post-LT survival is excellent. Therefore, as soon as the bacterial infection is improving/resolving, transplant should not be delayed, but patients with pre-transplant bacterial infections require active surveillance for infections after LT. Impact and Implications: Bacterial infections increase mortality and delay transplant in patients with cirrhosis awaiting liver transplantation (LT). Little is known about the impact of adequately treated infections before LT on post-transplant complications and outcomes. The study highlights that pre-LT infections increase the risk of post-LT infections, but post-LT survival rates are excellent despite the risk. These findings suggest that physicians should not delay LT because of concerns about pre-LT infections, but instead should actively monitor these patients for infections after surgery.

Acute kidney injury after liver transplantation, perioperative risk factors, and outcome: prospective observational study of 1681 patients (OLTx Study).

BACKGROUND: Acute kidney injury (AKI) represents a frequent complication after orthotopic liver transplantation (OLT). This study aimed to evaluate early postoperative AKI incidence during the first 72 h after OLT, perioperative risk factors, and AKI impact on survival. METHODS: From January 2011 to December 2013, 1681 patients underwent OLT in 19 centers and were enrolled in this prospective cohort study. RESULTS: According to RIFLE criteria, AKI occurred in 367 patients, 21.8% (R: 5.8%, I: 6.4%, F: 4.8%, L: 4.8%). Based on multivariate analysis, intraoperative risk factors for AKI were: administration of 5-10 RBCs (OR 1.8, 95% CI 1.3-2.7), dopamine use (OR 1.6, 95% CI 1.2-2.3), post-reperfusion syndrome (OR 1.5, 95% CI 1.0-2.3), surgical complications (OR 2.0, 95% CI 1.3-3.0), and cardiological complications (OR 2.2, 95% CI 1.2-4.0). Postoperative risk factors were: norepinephrine (OR 1.4, 95% CI 1.0-2.0), furosemide (OR 4.2, 95% CI 3.0-5.9), more than 10 RBCs transfusion, (OR 3.7, 95% CI 1.4-10.5), platelets administration (OR 1.6, 95% CI 1.1-2.4), fibrinogen administration (OR 3.0, 95% CI, 1.5-6.2), hepatic complications (OR 4.6, 95% CI 2.9-7.5), neurological complications (OR 2.4, 95% CI 1.5-3.7), and infectious complications (OR 2.7, 95% CI 1.8-4.3). NO-AKI patients' 5-year survival rate was higher than AKI patients (68.06, 95% CI 62.7-72.7 and 81.2, 95% CI 78.9-83.3, P<0.001). CONCLUSIONS: AKI still remains an important risk factor for morbidity and mortality after OLT. Further research to develop new strategies aimed at preventing or minimizing post-OLT AKI is needed.

Liver transplantation for severe alcoholic hepatitis: A multicenter Italian study.

There is increasing evidence that early liver transplantation (eLT), performed within standardized protocols can improve survival in severe alcoholic hepatitis (sAH). The aim of the study was to assess outcomes after eLT for sAH in four Italian LT centers and to compare them with non-responders to medical therapy excluded from eLT. Patients admitted for sAH (2013-2019), according to NIAAA criteria, were included. Patients not responding to medical therapy were placed on the waiting list for eLT after a strict selection. Histological features of explanted livers were evaluated. Posttransplant survival and alcohol relapse were evaluated. Ninety-three patients with severe AH were evaluated (65.6% male, median [IQR] age: 47 [42-56] years). Forty-five of 93 patients received corticosteroids, 52 of 93 were non-responders and among these, 20 patients were waitlisted. Sixteen patients underwent LT. Overall, 6-, 12-, and 24-month survival rates were 100% significantly higher compared with non-responders to medical therapy who were denied LT (45%, 45%, and 36%; p < .001). 2/16 patients resumed alcohol intake, one at 164 days and one at 184 days. Early LT significantly improves survival in sAH non-responding to medical therapy, when a strict selection process is applied. Further studies are needed to properly assess alcohol relapse rates.

Recent Advances in the Management of Acute Variceal Hemorrhage.

Gastrointestinal bleeding is one of the most relevant causes of death in patients with cirrhosis and clinically significant portal hypertension, with gastroesophageal varices being the most frequent source of hemorrhage. Despite survival has improved thanks to the standardization on medical treatment aiming to decrease portal hypertension and prevent infections, mortality remains significant. In this review, our goal is to discuss the most recent advances in the management of esophageal variceal hemorrhage in cirrhosis with specific attention to the treatment algorithms involving the use of indirect measurement of portal pressure (HVPG) and transjugular intrahepatic portosystemic shunt (TIPS), which aim to further reduce mortality in high-risk patients after acute variceal hemorrhage and in the setting of secondary prophylaxis.

Colon Rectal Liver Metastases: The Role of the Liver Transplantation in the Era of the Transplant Oncology and Precision Medicine.

The development of liver metastases in colon rectal cancer has a strong impact on the overall survival (OS) of the patient, with a 5-year survival rate of 5% with palliative treatment. Surgical resection combined with pharmacological treatment can achieve a 5-year OS rate of 31-58%. However, in only 20% of patients with colon rectal liver metastases (CRLMs), liver resection is feasible. In highly selected patients, recent trials and studies proved that liver transplantation (LT) for non-resectable CRLM is a surgical option with an excellent long-term OS. The paper aims to review the indications and outcome of LT for CRLMs, with a special focus on immunosuppressive therapy and the management of local and extrahepatic recurrence after LT.

Coronary artery calcium on standard chest computed tomography predicts cardiovascular events after liver transplantation.

AIMS: Cardiac complications are a leading cause of mortality after orthotopic liver transplantation (LT) and pre-operative risk stratification is challenging. We evaluated whether coronary artery calcium (CAC) score calculated on a standard (non-thin layer, non-ECG gated) chest computed tomography (CT) predicted cardiac outcome after LT. METHODS: We included a consecutive series of LT recipients who underwent pre-operative cardiac evaluation including stress-testing or cardiac catheterization in high-risk patients. Patients with a history of coronary artery disease or coronary revascularization were excluded. The CAC score was calculated from the chest CT routinely performed before LT. CAC values were not available at the time of pre-transplant cardiac evaluation and did not affect LT eligibility. The primary end-point included peri-operative arrhythmic cardiac arrest and sustained ventricular arrhythmias; heart failure, myocardial infarction and cardiac death within 1-year after LT. RESULTS: The study population consisted of 301 patients (median age 56 years, 76% males). At chest CT, 49% had CAC = 0; 27% had CAC = 1-99, 15% had CAC = 100-399 and 9% CAC > 400. The primary end-point incidence increased from 7% in patients with CAC = 0 to 27% in patients with CAC > 400 (p = 0.007). At multivariable analysis including traditional risk factors, CAC remained an independent predictor of cardiac events (p = 0.01). CONCLUSIONS: CAC score calculated on a standard chest CT stratified the risk of cardiac events in patients who underwent LT after negative pre-transplant cardiac evaluation. These findings suggest that evaluation of CAC from a standard chest CT performed for other reasons can be used as an early cardiac risk stratification tool before LT.

Liver Transplantation for T2 Hepatocellular Carcinoma during the COVID-19 Pandemic: A Novel Model Balancing Individual Benefit against Healthcare Resources.

The COVID-19 pandemic caused temporary drops in the supply of organs for transplantation, leading to renewed debate about whether T2 hepatocellular carcinoma (HCC) patients should receive priority during these times. The aim of this study was to provide a quantitative model to aid decision-making in liver transplantation for T2 HCC. We proposed a novel ethical framework where the individual transplant benefit for a T2 HCC patient should outweigh the harm to others on the waiting list, determining a "net benefit", to define appropriate organ allocation. This ethical framework was then translated into a quantitative Markov model including Italian averages for waiting list characteristics, donor resources, mortality, and transplant rates obtained from a national prospective database (n = 8567 patients). The net benefit of transplantation in a T2 HCC patient in a usual situation varied from 0 life months with a model for end-stage liver disease (MELD) score of 15, to 34 life months with a MELD score of 40, while it progressively decreased with acute organ shortage during a pandemic (i.e., with a 50% decrease in organs, the net benefit varied from 0 life months with MELD 30, to 12 life months with MELD 40). Our study supports the continuation of transplantation for T2 HCC patients during crises such as COVID-19; however, the focus needs to be on those T2 HCC patients with the highest net survival benefit.

Adjunctive IgM-enriched immunoglobulin therapy with a personalised dose based on serum IgM-titres versus standard dose in the treatment of septic shock: a randomised controlled trial (IgM-fat trial).

INTRODUCTION: In patients with septic shock, low levels of circulating immunoglobulins are common and their kinetics appear to be related to clinical outcome. The pivotal role of immunoglobulins in the host immune response to infection suggests that additional therapy with polyclonal intravenous immunoglobulins may be a promising option in patients with septic shock. Immunoglobulin preparations enriched with the IgM component have largely been used in sepsis, mostly at standard dosages (250 mg/kg per day), regardless of clinical severity and without any dose adjustment based on immunoglobulin serum titres or other biomarkers. We hypothesised that a personalised dose of IgM enriched preparation based on patient IgM titres and aimed to achieve a specific threshold of IgM titre is more effective in decreasing mortality than a standard dose. METHODS AND ANALYSIS: The study is designed as a multicentre, interventional, randomised, single-blinded, prospective, investigator sponsored, two-armed study. Patients with septic shock and IgM titres <60 mg/dL will be randomly assigned to an IgM titre-based treatment or a standard treatment group in a ratio of 1:1. The study will involve 12 Italian intensive care units and 356 patients will be enrolled. Patients assigned to the IgM titre-based treatment will receive a personalised daily dose based on an IgM serum titre aimed at achieving serum titres above 100 mg/dL up to discontinuation of vasoactive drugs or day 7 after enrolment. Patients assigned to the IgM standard treatment group will receive IgM enriched preparation daily for three consecutive days at the standard dose of 250 mg/kg. The primary endpoint will be all-cause mortality at 28 days. ETHICS AND DISSEMINATION: The study protocol was approved by the ethics committees of the coordinating centre (Comitato Etico dell'Area Vasta Emilia Nord) and collaborating centres. The results of the trial will be published within 12 months from the end of the study and the steering committee has the right to present them at public symposia and conferences. TRIAL REGISTRATION DETAILS: The trial protocol and information documents have received a favourable opinion from the Area Vasta Emilia Nord Ethical Committee on 12 September 2019. The trial protocol has been registered on EudraCT (2018-001613-33) on 18 April 2018 and on ClinicalTrials.gov (NCT04182737) on 2 December 2019.

Mechanical thrombectomy in a pediatric patient with sedation aided by contralateral intra-arterial propofol injection: feasibility in an extreme condition.

Pediatric patients undergoing mechanical thrombectomy may be challenging for the anesthesiologists as regards the best anesthetic choice, especially if concomitant to severe comorbidities such as heart failure. A 16-year-old patient affected by arrhythmogenic right ventricle dysplasia/cardiomyopathy underwent mechanical thrombectomy. He was not eligible for deep sedation or general anesthesia since he has been suffering from severe heart failure. The patient stillness was obtained by intra-arterial injection of propofol from the contralateral internal carotid artery. The procedure has been well tolerated, without cardiorespiratory impairment. The case stresses the growing importance to tailor a proper anesthesiologic plan during mechanical thrombectomy, especially in extreme conditions.

Recommendations from the Italian intersociety consensus on Perioperative Anesthesia Care in Thoracic surgery (PACTS) part 1: preadmission and preoperative care.

INTRODUCTION: Anesthetic care in patients undergoing thoracic surgery presents specific challenges that necessitate standardized, multidisciplionary, and continuously updated guidelines for perioperative care. METHODS: A multidisciplinary expert group, the Perioperative Anesthesia in Thoracic Surgery (PACTS) group, comprising 24 members from 19 Italian centers, was established to develop recommendations for anesthesia practice in patients undergoing thoracic surgery (specifically lung resection for cancer). The project focused on preoperative patient assessment and preparation, intraoperative management (surgical and anesthesiologic care), and postoperative care and discharge. A series of clinical questions was developed, and PubMed and Embase literature searches were performed to inform discussions around these areas, leading to the development of 69 recommendations. The quality of evidence and strength of recommendations were graded using the United States Preventative Services Task Force criteria. RESULTS: Recommendations for preoperative care focus on risk assessment, patient preparation (prehabilitation), and the choice of procedure (open thoracotomy vs. video-assisted thoracic surgery). CONCLUSIONS: These recommendations should help pulmonologists to improve preoperative management in thoracic surgery patients. Further refinement of the recommendations can be anticipated as the literature continues to evolve.

Continuous stellate ganglion block in delayed cerebral ischemia: A possible supplementary approach to traditional therapy?

Delayed Cerebral Ischemia (DCI) is a major contributor to morbidity and mortality after SAH. Currently the prevention of vasospasm and DCI relies on nimodipine administration and on maintaining an adequate cerebral perfusion pressure. We report a patient with initial DCI after SAH in which stellate ganglion block (SGB) was performed after nimodipine administration. Firstly the procedure was characterized by a iv and intra-arterial nimodipine administration which did not result into a normal perfusion pattern. Therefore a single-shot stellate ganglion block was performed, as suggested in literature. Because of the not sufficient but promising perfusion improvement, we decided to deliver a continuous ganglion block (cSGB) for 5 days. Consequently a further improvement of the cerebral perfusion on CTPerfusion and Real Time Angiographic Perfusion Assessment was registered. In order to treat cerebral vasospasm, SGB is known to be a further valuable treatment, despite its temporary effect. However the continuous use of SGB during initial DCI has never been described before.

Recommendations from the Italian intersociety consensus on Perioperative Anesthesa Care in Thoracic surgery (PACTS) part 2: intraoperative and postoperative care.

INTRODUCTION: Anesthetic care in patients undergoing thoracic surgery presents specific challenges that require a multidisciplinary approach to management. There remains a need for standardized, evidence-based, continuously updated guidelines for perioperative care in these patients. METHODS: A multidisciplinary expert group, the Perioperative Anesthesia in Thoracic Surgery (PACTS) group, was established to develop recommendations for anesthesia practice in patients undergoing elective lung resection for lung cancer. The project addressed three key areas: preoperative patient assessment and preparation, intraoperative management (surgical and anesthesiologic care), and postoperative care and discharge. A series of clinical questions was developed, and literature searches were performed to inform discussions around these areas, leading to the development of 69 recommendations. The quality of evidence and strength of recommendations were graded using the United States Preventive Services Task Force criteria. RESULTS: Recommendations for intraoperative care focus on airway management, and monitoring of vital signs, hemodynamics, blood gases, neuromuscular blockade, and depth of anesthesia. Recommendations for postoperative care focus on the provision of multimodal analgesia, intensive care unit (ICU) care, and specific measures such as chest drainage, mobilization, noninvasive ventilation, and atrial fibrillation prophylaxis. CONCLUSIONS: These recommendations should help clinicians to improve intraoperative and postoperative management, and thereby achieve better postoperative outcomes in thoracic surgery patients. Further refinement of the recommendations can be anticipated as the literature continues to evolve.

[Pulse pressure variation guided fluid therapy during kidney transplantation: a randomized controlled trial]. / Reposição de volume orientada pela variação da pressão de pulso durante transplante renal: estudo randomizado controlado.

PURPOSE: Kidney transplantation is the gold-standard treatment for end stage renal disease. Although different hemodynamic variables, like central venous pressure and mean arterial pressure, have been used to guide volume replacement during surgery, the best strategy still ought to be determined. Respiratory arterial Pulse Pressure Variation (PPV) is recognized to be a good predictor of fluid responsiveness for perioperative hemodynamic optimization in operating room settings. The aim of this study was to investigate whether a PPV-guided fluid management strategy is better than a liberal fluid strategy during kidney transplantation surgeries. Identification of differences in urine output in the first postoperative hour was the main objective of this study. METHODS: We conducted a prospective, single blind, randomized controlled trial. We enrolled 40 patients who underwent kidney transplantation from deceased donors. Patients randomized in the PPV Group received fluids whenever PPV was higher than 12%, patients in the Free Fluid Group received fluids following our institutional standard care protocol for kidney transplantations (10mL.kg-1.h-1). RESULTS: Urinary output was similar at every time-point between the two groups, urea was statistically different from the third postoperative day with a peak at the fourth postoperative day and creatinine showed a similar trend, being statistically different from the second postoperative day. Urea, creatinine and urine output were not different at the hospital discharge. CONCLUSION: PPV-guided fluid therapy during kidney transplantation significantly improves urea and creatinine levels in the first week after kidney transplantation surgery.

Pulse pressure variation guided fluid therapy during kidney transplantation: a randomized controlled trial / Reposição de volume orientada pela variação da pressão de pulso durante transplante renal: estudo randomizado controlado

Abstract Purpose: Kidney transplantation is the gold-standard treatment for end stage renal disease. Although different hemodynamic variables, like central venous pressure and mean arterial pressure, have been used to guide volume replacement during surgery, the best strategy still ought to be determined. Respiratory arterial Pulse Pressure Variation (PPV) is recognized to be a good predictor of fluid responsiveness for perioperative hemodynamic optimization in operating room settings. The aim of this study was to investigate whether a PPV guided fluid management strategy is better than a liberal fluid strategy during kidney transplantation surgeries. Identification of differences in urine output in the first postoperative hour was the main objective of this study. Methods: We conducted a prospective, single blind, randomized controlled trial. We enrolled 40 patients who underwent kidney transplantation from deceased donors. Patients randomized in the "PPV" group received fluids whenever PPV was higher than 12%, patients in the "free fluid" group received fluids following our institutional standard care protocol for kidney transplantations (10 mL.kg-1. h-1). Results: Urinary output was similar at every time-point between the two groups, urea was statistically different from the third postoperative day with a peak at the fourth postoperative day and creatinine showed a similar trend, being statistically different from the second postoperative day. Urea, creatinine and urine output were not different at the hospital discharge. Conclusion: PPV guided fluid therapy during kidney transplantation significantly improves urea and creatinine levels in the first week after kidney transplantation surgery.

Resumo Objetivo: Transplante renal é o tratamento padrão-ouro na doença renal em estágio terminal. Embora diferentes variáveis hemodinâmicas, tais como pressão venosa central e pressão arterial média, têm sido usadas para orientar a estratégia de reposição volêmica durante a cirurgia, a melhor estratégia ainda não foi determinada. A Variação da Pressão de Pulso (VPP) durante o ciclo respiratório é reconhecida como um bom preditor da resposta à infusão de volume para otimização hemodinâmica perioperatória no centro cirúrgico. O objetivo do estudo foi estudar se a estratégia de reposição de volume orientada por VPP é melhor do que a estratégia liberal de reposição de volume durante cirurgia de transplante renal. O principal objetivo do estudo foi identificar diferença no débito urinário na primeira hora do pós-operatório. Método: Realizamos estudo prospectivo, unicego, randomizado, controlado. Incluímos 40 pacientes submetidos a transplante renal de doador cadáver. Pacientes randomizados para o Grupo VPP receberam volume quando a VPP estava acima de 12%, e os pacientes no Grupo Reposição Liberal receberam volume de acordo com o nosso protocolo institucional padrão de assistência para transplante renal (10 mL.kg-1.h-1). Resultados: O débito urinário foi semelhante em todos os tempos nos dois grupos, a ureia foi estatisticamente diferente a partir do terceiro dia do pós-operatório com pico no quarto dia do pós-operatório e a creatinina apresentou tendência semelhante, tornando-se estatisticamente diferente a partir do segundo dia do pós-operatório. Ureia, creatinina e débito urinário não estavam diferentes na alta hospitalar. Conclusões: A terapia orientada por VPP durante transplante renal melhorou de forma significativa os níveis de ureia e creatinina na primeira semana pós-transplante renal.