Safety and anti-HCV effect of prolonged intravenous silibinin in HCV genotype 1 subjects in the immediate liver transplant period.

BACKGROUND & AIMS: Reinfection of the graft is the rule in patients with HCV cirrhosis undergoing liver transplantation, and HCV-RNA reaches pre-transplantation levels within the first month. Short-term intravenous silibinin monotherapy is safe and shows a potent in vivo anti-HCV effect. We aimed at evaluating the safety and antiviral effect of prolonged intravenous silibinin, started immediately before liver transplantation. METHODS: Single centre, prospective, pilot study, to assess the safety and effect on HCV-RNA kinetics during at least 21 days of intravenous silibinin monotherapy (20 mg/kg/day) in 9 consecutive HCV genotype 1 subjects, in comparison to a control, non-treated group of 7 consecutive prior transplanted subjects under the same immunosuppressive regimen (basiliximab, steroids, delayed tacrolimus, micophenolate). RESULTS: Intravenous silibinin led to significant, maintained and progressive HCV-RNA decreases (mean HCV-RNA drop at week 3, -4.1 ± 1.3 log(10)IU/ml), and lack of viral breakthrough during administration. Four patients (44%) reached negative HCV-RNA, maintained during silibinin treatment, vs. none in the control group, but HCV-RNA relapsed in all of them after a median of 21 days (16-28), following silibinin withdrawal. Partial responders to silibinin showed marked decreases in HCV-RNA when compared to controls, but lower than complete responders. There were no clinical adverse effects, and silibinin led to asymptomatic transient hyperbilirubinemia (week 2, 4.2 ± 2.2 vs. 2.5 ± 3.6 mg/dl; p=0.02). CONCLUSIONS: Prolonged intravenous silibinin monotherapy was safe in the immediate liver transplantation period, leading to a potent and time dependent antiviral effect and lack of HCV-RNA breakthrough during administration. However, HCV-RNA rebounded after withdrawal, and silibinin monotherapy did not avoid reinfection of the graft.

Intravenous Ascorbic Acid for the Prevention of Postreperfusion Syndrome in Orthotopic Liver Transplantation: Protocol for a Randomized Controlled Trial.

BACKGROUND: Liver transplantation is the last therapeutic option for patients with end-stage liver disease. Postreperfusion syndrome (PRS), defined as a fall in mean arterial pressure of more than 30% within the first 5 minutes after reperfusion of at least 1 minute, can occur in liver transplantation as a deep hemodynamic instability with associated hyperfibrinolysis immediately after reperfusion of the new graft. Its incidence has remained unchanged since it was first described in 1987. PRS is related to ischemia-reperfusion (I/R) injury, whose pathophysiology involves the release of several mediators from both the donor and the recipient. The antioxidant effect of ascorbic acid has been studied in resuscitating patients with septic shock and burns. Even today, there are publications with conflicting results, and there is a need for further studies to confirm or rule out the usefulness of this drug in this group of patients. The addition of ascorbic acid to preservation solutions used in solid organ transplantation is under investigation to harness its antioxidant effect and mitigate I/R injury. Since PRS could be considered a manifestation of I/R injury, we believe that the possible beneficial effect of ascorbic acid on the occurrence of PRS should be investigated. OBJECTIVE: The aim of this randomized controlled trial is to assess the benefits of ascorbic acid over saline in the development of PRS in adult liver transplantation. METHODS: We plan to conduct a single-center randomized controlled trial at the Hospital Universitario Ramón y Cajal in Spain. A total of 70 participants aged 18 years or older undergoing liver transplantation will be randomized to receive either ascorbic acid or saline. The primary outcome will be the difference between groups in the incidence of PRS. The randomized controlled trial will be conducted under conditions of respect for fundamental human rights and ethical principles governing biomedical research involving human participants and in accordance with the international recommendations contained in the Declaration of Helsinki and its subsequent revisions. RESULTS: The enrollment process began in 2020. A total of 35 patients have been recruited so far. Data cleaning and analysis are expected to occur in the first months of 2024. Results are expected around the middle of 2024. CONCLUSIONS: We believe that this study could be particularly relevant because it will be the first to analyze the clinical effect of ascorbic acid in liver transplantation. Moreover, we believe that this study fills an important gap in the knowledge of the potential benefits of ascorbic acid in the field of liver transplantation, particularly in relation to PRS. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database 2020-000123-39; https://tinyurl.com/2cfzddw8; ClinicalTrials.gov NCT05754242; https://tinyurl.com/346vw7sm. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50091.

Health-related quality of life and stress-related disorders in COVID-19 ICU survivors: Are they worse than with other causes of ARDS?

Background: There are insufficient data regarding the impact of acute respiratory distress syndrome related to coronavirus disease 2019 (C-ARDS) - caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) - on health-related quality of life (HRQoL) and the occurrence of stress-related disorders in coronavirus disease 2019 (COVID-19) intensive care unit (ICU) survivors. The aim of this study is to assess HRQoL and the occurrence of stress-related disorders (acute stress disorder [ASD] and post-traumatic stress disorder [PTSD]) in C-ARDS ICU survivors at 1 and 6 months following hospital discharge. Methods: This prospective observational study included 90 patients treated for C-ARDS between March and May 2020 in the ICU and discharged alive from the hospital. All patients included in the study were contacted by telephone 1 month and 6 months post-hospital discharge to assess the presence of symptoms of stress-related disorders and HRQoL using the 8-item Treatment Outcome Post-traumatic Stress Disorder scale (TOP-8) and 36-item Short Form survey (SF-36). We performed univariate analyses to evaluate differences between patients who developed stress and those who did not. We also compared SF-36 scores in our sample with data from the general Spanish population and from cohorts of non-C-ARDS and severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) survivors. Results: There are 24.1% of patients showed symptoms of ASD; in 13.5% of cases the symptoms persisted 6 months later. Risk factors for the development of symptoms of ASD and PTSD are younger age, female sex, obesity, a previously diagnosed psychiatric disease and disease severity at ICU admission (P < 0.05). HRQoL was greatly affected by C-ARDS; however, there was improvement on all scales of the SF-36 at the 6-month follow-up (P < 0.05). The mean SF-36 score of our sample was higher than those previously reported in non-C-ARDS survivors (P < 0.05) for physical functioning (78.0 vs. 52.0), role functioning/physical (51.0 vs. 31.0), bodily pain (76.1 vs. 57.0), vitality (58.6 vs. 48.0), social function (72.6 vs. 63.0) and role emotional (77.4 vs. 55.0), except on the general health scale. C-ARDS survivors also scored better than SARS-CoV-1 survivors on all scales except for body pain (P < 0.05). Conclusions: The impact of C-ARDS on HRQoL is substantial, with frequent occurrence of PTSD symptoms. Patients are heavily affected in all areas of health in the first month of post-hospital discharge but show a dramatic improvement within 6 months, especially in terms of physical health.

Study protocol for an observational cohort evaluating incidence and clinical relevance of perioperative elevation of high-sensitivity troponin I and N-terminal pro-brain natriuretic peptide in patients undergoing lung resection.

INTRODUCTION: Myocardial injury after non-cardiac surgery has been defined as myocardial injury due to ischaemia, with or without additional symptoms or ECG changes occurring during or within 30 days after non-cardiac surgery and mainly diagnosed based on elevated postoperative cardiac troponin (cTn) values. In patients undergoing thoracic surgery for lung resection, only postoperative cTn elevations are seemingly not enough as an independent predictor of cardiovascular complications. After lung resection, troponin elevations may be regulated by mechanisms other than myocardial ischaemia. The combination of perioperative natriuretic peptide measurement together with high-sensitivity cTns may help to identify changes in ventricular function during thoracic surgery. Integrating both cardiac biomarkers may improve the predictive value for cardiovascular complications after lung resection. We designed our cohort study to evaluate perioperative elevation of both high-sensitivity troponin I (hs-TnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients undergoing lung resection and to establish a risk score for major cardiovascular postoperative complications. METHODS AND ANALYSIS: We will conduct a prospective, multicentre, observational cohort study, including 345 patients undergoing elective thoracic surgery for lung resection. Cardiac biomarkers such as hs-TnI and NT-proBNP will be measured preoperatively and at postoperatively on days 1 and 2. We will calculate a risk score for major cardiovascular postoperative complications based on both biomarkers' perioperative changes. All patients will be followed up for 30 days after surgery. ETHICS AND DISSEMINATION: All participating centres were approved by the Ethics Research Committee. Written informed consent is required for all patients before inclusion. Results will be disseminated through publication in peer-reviewed journals and presentations at national or international conference meetings. TRIAL REGISTRATION NUMBER: NCT04749212.

Protective Role of the Portocaval Shunt in Liver Transplantation.

BACKGROUND: Advances in medical management and surgical technique have resulted in stepwise improvements in early post-transplant survival rates. Modifications in the surgical technique, such as the realization of the portocaval shunt (PCS), could influence survival rates. The aim of this study was to evaluate the mortality rate for 12 months after liver transplantation, analyzing the causes and risk factors related to its development and assessing the impact that PCS could have on them. METHODS: A total of 231 recipients were included in the retrospective, longitudinal, and nonrandomized study. RESULTS: The overall survival of the transplant was 85.2% (197 patients). The most frequent cause of death was infection (38.2%), followed by the multiorgan failure of multiple etiology (23.5%). Most of the risk factors related to mortality correspond to variables of the postoperative period. The results of the multivariate analysis identified the main risk factors for death: the presence of surgical complications and the need for renal replacement therapy. In contrast, the performance of PCS exerted a protective effect, reducing the probability of death by 70%. CONCLUSIONS: Despite the good results obtained in several studies, there is still debate regarding the benefit of its realization. In our study, PCS was a factor associated with a reduction in mortality, with a markedly lower probability of adverse events. However, we agree with other authors on the need for larger and randomized studies to adequately determine the validity of such results.

False-positive results of Aspergillus galactomannan antigenemia in liver transplant recipients.

BACKGROUND: Aspergillus galactomannan (GM) antigenemia is an early marker of invasive aspergillosis (IA), but may yield false-positive results. A prospective study, testing GM periodically in serum samples of liver transplant recipients, was performed. METHODS: An index more than or equal to 0.5 were considered positive. Positive GM in samples from patients without any other criteria of proven or probable IA was considered as false-positive. The test was performed weekly during the first month after transplantation. RESULTS: Three patients developed IA. In total, 414 serum samples from 85 liver transplant recipients were analyzed. Mean number of samples per patient (out of those who could be assessed) was 4.8. The number of false-positive GM samples was 40 (9.6%), corresponding to 28 patients. The frequency of false-positive results in samples obtained during the first week posttransplantation was 36% (27 of 75), significantly higher than the number of false-positive samples obtained after the first week (3.8%; 13 of 339; P<0.001). Multivariate analysis showed that antibacterial prophylaxis with ampicillin was the only independent factor associated with a false-positive result. Different vials of beta-lactam antibiotics were tested for GM. We obtained a positive GM value (>0.5) in four of the six vials of ampicillin, in three of the six vials of piperacillin-tazobactam, in none of the six vials of cefotaxime, and in none of the six controls. CONCLUSIONS: The present study suggests that the administration of ampicillin as antibacterial prophylaxis during the first days after transplantation could be a possible cause of false-positive GM results.

Analysis of renal function in the immediate postoperative period after partial liver transplantation.

Although renal dysfunction is common after liver transplantation, postoperative renal function after split liver transplantation (SLT) has not been well studied. Renal function immediately after surgery was analyzed retrospectively in 16 patients that received a SLT (SLT group). The results were compared with corresponding data from 31 matched patients that received a full-size liver transplant (FSLT group) during the same period. Serum creatinine (SCr) was measured before surgery, and, after transplantation, daily during the first week and at days 14, 21, and 28. Renal dysfunction (RD) was defined as the requirement for renal replacement therapy (RRT) or a 100% increase in SCr if the basal value had been <1.0 mg/dL or a 50% increase in SCr if the basal value had been >1.0 mg/dL. SCr had to be at least 1.5 mg/dL for a diagnosis of RD to be considered. The classification of RD was: mild, SCr 1.5-2.4 mg/dL; moderate, SCr 2.5-4.0 mg/dL; or severe, SCr >4.0 mg/dL (the requirement for RRT). Both donor and recipient age and cold ischemia time were lower in the SLT group than in the FSLT group (P < 0.05). Length of surgery was longer in the SLT group (P < 0.05). There were no significant differences between groups with respect to Model for End-Stage Liver Disease scores, the need for transfusions, the length of admission to the intensive care unit (ICU), survival rate, individual severity index, or sepsis-related organ failure assessment scores at the time of diagnosing RD. Immunosuppression regimens were similar in both groups. RD developed in 82% of SLT patients, but in only 58% of FSLT patients (P = not significant [NS]). Among SLT patients, RD (23.0% mild, 15.5% moderate, and 61.5% severe) was more severe (P = 0.007) than in FSLT patients (63.1% mild, 15.8% moderate, and 24.1% severe). The requirement for RRT in the SLT group (43.7%) was significantly greater (P < 0.05) than that in the FSLT group (12.9%). This finding may be due to the different incidence of sepsis in the 2 groups (SLT 37.5% vs. FSLT 9.7%; P < 0.05). In conclusion, although the number of patients studied was small, our data suggest a higher incidence of RD and a greater requirement for RRT in patients that receive a split liver graft than in those that receive a full size liver graft.