Balancing the scales: achieving the optimal beta-lactam to beta-lactamase inhibitor ratio with continuous infusion piperacillin/tazobactam against extended spectrum beta-lactamase producing Enterobacterales.

Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against Enterobacterales. Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively. A population pharmacokinetic approach was used to select the best kidney function model predictive of TZP clearance (CL). The probability of target attainment (PTA), cumulative fraction of response (CFR) and the ratio between piperacillin and tazobactam were computed to identify optimal dosage regimens by continuous infusion across kidney function. This study included 257 critically ill patients (79.3% male) with intra-abdominal, bloodstream, and hospital-acquired pneumonia infections in 89.5% as the primary indication. The median (min-max range) age, body weight, and estimated glomerular filtration rate (eGFR) were 66 (23-93) years, 75 (39-310) kg, and 79.2 (6.4-234) mL/min, respectively. Doses of up to 22.5 g/day were used to optimize TZP based on TDM. The 2021 chronic kidney disease epidemiology equation in mL/min best modeled TZP CL. The ratio of piperacillin:tazobactam increased from 6:1 to 10:1 between an eGFR of <20 mL/min and >120 mL/min. At conventional doses, the PTA is below 90% when eGFR is ≥100 mL/min. Daily doses of 18 g/day and 22.5 g/day by CI are expected to achieve a >80% CFR when eGFR is 100-120 mL/min and >120-160 mL/min, respectively. Inadequate piperacillin and tazobactam exposure is likely in patients with eGFR ≥ 100 mL/min. Dose regimen adjustments informed by TDM should be evaluated in this specific population.

The role of cold ischemia time and hypothermic perfusion in predicting early hepatocellular carcinoma recurrences after liver transplantation.

AIM: The aim of the study was to identify predictors of early tumor recurrence in patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). METHODS: Retrospective cohort study in 237 consecutive liver recipients with HCC between 2016 and 2021. Multivariate logistic analysis was performed to identify predictors of early HCC recurrences. The impact of hypothermic-oxygenated perfusion (HOPE) on outcome was analyzed after propensity score weighting. RESULTS: Early recurrences were observed in 15 cases. Microvascular invasion (OR 3.737, 95% CI 1.246-11.206, p = 0.019) and cold ischemia time (OR 1.155, 95% CI 1.001-1.333, p = 0.049) were independently associated with a lower risk of HCC recurrences. After balancing for relevant variables, patients in the HOPE group had lower rates of tumor recurrence (weighted OR 0.126, 95% CI 0.016-0.989, p = 0.049) and higher recurrence free survival (weighted HR 0.132, 95% CI 0.017-0.999, p = 0.050). CONCLUSION: Reducing cold ischemia time and graft perfusion with HOPE can lead to lower rates of early HCC recurrences and higher recurrence-free survival.

Beyond the Concepts of Elder and Marginal in DCD Liver Transplantation: A Prospective Observational Matched-Cohort Study in the Italian Clinical Setting.

Donation after circulatory determination of death (DCD) is a valuable strategy to increase the availability of grafts for liver transplantation (LT). As the average age of populations rises, the donor pool is likely to be affected by a potential increase in DCD donor age in the near future. We conducted a prospective cohort study to evaluate post-transplantation outcomes in recipients of grafts from elderly DCD donors compared with younger DCD donors, and elderly donors after brainstem determination of death (DBD). From August 2020 to May 2022, consecutive recipients of deceased donor liver-only transplants were enrolled in the study. DCD recipients were propensity score matched 1:3 to DBD recipients. One-hundred fifty-seven patients were included, 26 of whom (16.6%) were transplanted with a DCD liver graft. After propensity score matching and stratification, three groups were obtained: 15 recipients of DCD donors ≥75 years, 11 recipients of DCD donors <75 years, and 28 recipients of DBD donors ≥75 years. Short-term outcomes, as well as 12 months graft survival rates (93.3%, 100%, and 89.3% respectively), were comparable among the groups. LT involving grafts retrieved from very elderly DCD donors was feasible and safe in an experienced high-volume center, with outcomes comparable to LTs from younger DCD donors and age-matched DBD donors.

Hypothermic oxygenated perfusion in extended criteria donor liver transplantation-A randomized clinical trial.

Hypothermic Oxygenated Perfusion (HOPE) of the liver can reduce the incidence of early allograft dysfunction (EAD) and failure in extended criteria donors (ECD) grafts, although data from prospective studies are very limited. In this monocentric, open-label study, from December 2018 to January 2021, 110 patients undergoing transplantation of an ECD liver graft were randomized to receive a liver after HOPE or after static cold storage (SCS) alone. The primary endpoint was the incidence of EAD. The secondary endpoints included graft and patient survival, the EASE risk score, and the rate of graft or other graft-related complications. Patients in the HOPE group had a significantly lower rate of EAD (13% vs. 35%, p = .007) and were more frequently allocated to the intermediate or higher risk group according to the EASE score (2% vs. 11%, p = .05). The survival analysis confirmed that patients in the HOPE group were associated with higher graft survival one year after LT (p = .03, log-rank test). In addition, patients in the SCS group had a higher re-admission and overall complication rate at six months, in particular cardio-vascular adverse events (p = .04 and p = .03, respectively). HOPE of ECD grafts compared to the traditional SCS preservation method is associated with lower dysfunction rates and better graft survival.

Prediction models for carbapenem-resistant Enterobacterales carriage at liver transplantation: A multicenter retrospective study.

BACKGROUND: Carbapenem-resistant Enterobacterales (CRE) colonisation at liver transplantation (LT) increases the risk of CRE infection after LT, which impacts on recipients' survival. Colonization status usually becomes evident only near LT. Thus, predictive models can be useful to guide antibiotic prophylaxis in endemic centres. AIMS: This study aimed to identify risk factors for CRE colonisation at LT in order to build a predictive model. METHODS: Retrospective multicentre study including consecutive adult patients who underwent LT, from 2010 to 2019, at two large teaching hospitals. We excluded patients who had CRE infections within 90 days before LT. CRE screening was performed in all patients on the day of LT. Exposure variables were considered within 90 days before LT and included cirrhosis complications, underlying disease, time on the waiting list, MELD and CLIF-SOFA scores, antibiotic use, intensive care unit and hospital stay, and infections. A machine learning model was trained to detect the probability of a patient being colonized with CRE at LT. RESULTS: A total of 1544 patients were analyzed, 116 (7.5%) patients were colonized by CRE at LT. The median time from CRE isolation to LT was 5 days. Use of antibiotics, hepato-renal syndrome, worst CLIF sofa score, and use of beta-lactam/beta-lactamase inhibitor increased the probability of a patient having pre-LT CRE. The proposed algorithm had a sensitivity of 66% and a specificity of 83% with a negative predictive value of 97%. CONCLUSIONS: We created a model able to predict CRE colonization at LT based on easy-to-obtain features that could guide antibiotic prophylaxis.

Expert clinical pharmacological advice may make an antimicrobial TDM program for emerging candidates more clinically useful in tailoring therapy of critically ill patients.

BACKGROUND: Therapeutic drug monitoring (TDM) may represent an invaluable tool for optimizing antimicrobial therapy in septic patients, but extensive use is burdened by barriers. The aim of this study was to assess the impact of a newly established expert clinical pharmacological advice (ECPA) program in improving the clinical usefulness of an already existing TDM program for emerging candidates in tailoring antimicrobial therapy among critically ill patients. METHODS: This retrospective observational study included an organizational phase (OP) and an assessment phase (AP). During the OP (January-June 2021), specific actions were organized by MD clinical pharmacologists together with bioanalytical experts, clinical engineers, and ICU clinicians. During the AP (July-December 2021), the impact of these actions in optimizing antimicrobial treatment of the critically ill patients was assessed. Four indicators of performance of the TDM-guided real-time ECPA program were identified [total TDM-guided ECPAs July-December 2021/total TDM results July-December 2020; total ECPA dosing adjustments/total delivered ECPAs both at first assessment and overall; and turnaround time (TAT) of ECPAs, defined as optimal (< 12 h), quasi-optimal (12-24 h), acceptable (24-48 h), suboptimal (> 48 h)]. RESULTS: The OP allowed to implement new organizational procedures, to create a dedicated pathway in the intranet system, to offer educational webinars on clinical pharmacology of antimicrobials, and to establish a multidisciplinary team at the morning bedside ICU meeting. In the AP, a total of 640 ECPAs were provided for optimizing 261 courses of antimicrobial therapy in 166 critically ill patients. ECPAs concerned mainly piperacillin-tazobactam (41.8%) and meropenem (24.9%), and also other antimicrobials had ≥ 10 ECPAs (ceftazidime, ciprofloxacin, fluconazole, ganciclovir, levofloxacin, and linezolid). Overall, the pre-post-increase in TDM activity was of 13.3-fold. TDM-guided dosing adjustments were recommended at first assessment in 61.7% of ECPAs (10.7% increases and 51.0% decreases), and overall in 45.0% of ECPAs (10.0% increases and 35.0% decreases). The overall median TAT was optimal (7.7 h) and that of each single agent was always optimal or quasi-optimal. CONCLUSIONS: Multidisciplinary approach and timely expert interpretation of TDM results by MD Clinical Pharmacologists could represent cornerstones in improving the cost-effectiveness of an antimicrobial TDM program for emerging TDM candidates.

Overcoming challenges in patient selection and monitoring in combined heart and kidney transplantation.

Combined heart-kidney transplantation (HKT) is a growing therapeutic strategy in patients with advanced heart failure (HF) and concomitant chronic kidney disease (CKD). Although patients with advanced HF and need for chronic haemodialysis have a clear indication for combined HKT, challenges to current practice lie in identifying those patients with severely depressed kidney function, which will not recover kidney function after restoration of appropriate haemodynamic conditions following heart transplantation (HT) alone. Because of the paucity of available organs, maximisation of kidney graft utility whilst minimising the operative risks associated with combined transplantation is mandatory. The benefits of HKT go beyond the mere restoration of kidney function. Data from registry analysis show that HKT improves overall survival in patients with CKD, as compared to heart transplant only, and it is associated with reduced incidence of heart allograft rejection, likely through the promotion of host immune tolerance mechanisms. In patients not requiring chronic dialysis, kidney-after-heart strategy may be explored, instead of combined HKT, in particular when the aetiology of CKD is unclear. This indeed allows for monitoring and gaging of indications for combined transplantation in the postoperative period. This approach however should be matched with priority listing for kidney transplantation given the high waitlist mortality in heart transplant recipients with associated CKD. The use of kidney machine perfusion may represent an additional tool to optimise the outcome of HKT, allowing more time to stabilise the patient after HT surgery.

Heterotopic segmental liver transplantation on splenic vessels after splenectomy with delayed native hepatectomy after graft regeneration: A new technique to enhance liver transplantation.

We describe a patient with liver metastases from colorectal cancer treated with chemotherapy and hepatic resection, who developed unresectable multifocal liver recurrence and who received liver transplantation using a novel planned technique: heterotopic transplantation of segment 2-3 in the splenic fossa with splenectomy and delayed hepatectomy after regeneration of the transplanted graft. We transplanted a segmental liver graft after in-situ splitting without any impact on the waiting list, as it was previously rejected for pediatric and adult transplantation. The volume of the graft was insufficient to provide liver function to the recipient, so we performed this novel operation. The graft was anastomosed to the splenic vessels after splenectomy, and the native liver portal flow was modulated to enhance graft regeneration, leaving the native recipient liver intact. The volume of the graft doubled during the next 2 weeks and the native liver was removed. After 8 months, the patient lives with a functioning liver in the splenic fossa and without abdominal tumor recurrence. This is the first case reported of a segmental graft transplanted replacing the spleen and modulating the portal flow to favor graft growth, with delayed native hepatectomy.

Complex Liver Transplantation Using Venovenous Bypass With an Atypical Placement of the Portal Vein Cannula.

In liver transplantation (LT) medical literature, venovenous bypass (VVB) with the interposition of a venous graft attached to the inferior mesenteric vein (IMV) or to the splenic vein (SV) has not been reported previously. Here, we report the decompression of the portomesenteric compartment in 2 patients with complex cases of orthotopic LT. A femoroaxillary percutaneous VVB was installed prior to abdominal opening to decompress massive collateral veins in the abdominal wall. In the first patient, the IMV was connected to a donor vein graft with a lateroterminal anastomosis, and the distal part of the vein graft was cannulated and connected to the VVB. In the second patient, because of the excessive size of the spleen, it was necessary to perform a splenectomy to gain sufficient space in the abdomen to implant the new liver. The SV was connected to a donor vein graft with a terminoterminal anastomosis, and the distal part of the vein graft was cannulated and connected to the VVB. In both patients, the decompression of the portomesenteric compartment was crucial to reduce portal hypertension and to access the hepatic hilum, where the dissection was very complex due to previous major surgeries. In conclusion, VVB with the interposition of a venous graft attached to the IMV or to the SV during LT is a safe and simple technique, and it may be useful for patients needing VVB with no standard access to the portal compartment, particularly in the case of severe portal hypertension and re-LTs.

The Role of Ex Situ Hypothermic Oxygenated Machine Perfusion and Cold Preservation Time in Extended Criteria Donation After Circulatory Death and Donation After Brain Death.

Hypothermic oxygenated machine perfusion (HOPE) has the potential to counterbalance the detrimental consequences of cold and warm ischemia time (WIT) in both donation after brain death (DBD) and donation after circulatory death (DCD). Herein we investigated the protective effects of HOPE in extended criteria donor (ECD) DBD and overextended WIT DCD grafts. The present retrospective case series included 50 livers subjected to end-ischemic HOPE or dual DHOPE in 2 liver transplantation (LT) centers from January 2018 to December 2019. All DCD donors were subjected to normothermic regional perfusion before organ procurement. Results are expressed as median (interquartile range [IQR]). In the study period, 21 grafts were derived from overextended WIT DCD donors (total WIT 54 [IQR, 40-60] minutes and 75% classified as futile), whereas 29 were from ECD DBD. A total of 3 biliary complications and 1 case of ischemia-type biliary lesion were diagnosed. The rate of early allograft dysfunction (EAD) was 20%, and those patients had higher Comprehensive Complication Index scores. Through a changing point analysis, cold preservation time >9 hours was associated with prolonged hospital stays (P = 0.02), higher rates of EAD (P = 0.009), and worst post-LT complications (P = 0.02). Logistic regression analyses indicated a significant relationship between cold preservation time and EAD. No differences were shown in terms of the early post-LT results between LTs performed with DCD and DBD. Overall, our data are fully comparable with benchmark criteria in LT. In conclusion, the application of DHOPE obtained satisfactory and promising results using ECD-DBD and overextended DCD grafts. Our findings indicate the need to reduce cold preservation time also in the setting of DHOPE, particularly for grafts showing poor quality.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory diagnostic tests are not routinely performed by most laboratories, accounting for common misdiagnosis. Factors predictive of progression and appropriate tests for monitoring are still undefined. Several treatment options showed promising results in restoring the biochemical imbalance of MNGIE. The lack of controlled studies with appropriate follow-up accounts for the limited evidence informing diagnostic and therapeutic choices. The International Consensus Conference (ICC) on MNGIE, held in Bologna, Italy, on 30 March to 31 March 2019, aimed at an evidence-based consensus on diagnosis, prognosis, and treatment of MNGIE among experts, patients, caregivers and other stakeholders involved in caring the condition. The conference was conducted according to the National Institute of Health Consensus Conference methodology. A consensus development panel formulated a set of statements and proposed a research agenda. Specifically, the ICC produced recommendations on: (a) diagnostic pathway; (b) prognosis and the main predictors of disease progression; (c) efficacy and safety of treatments; and (f) research priorities on diagnosis, prognosis, and treatment. The Bologna ICC on diagnosis, management and treatment of MNGIE provided evidence-based guidance for clinicians incorporating patients' values and preferences.

Restoration of portal flow with varix in liver transplantation for patients with total portal vein thrombosis: An effective strategy in the largest center experience.

INTRODUCTION: Postoperative complications and worse prognosis still burden liver transplantations (LT) with complex portal vein thrombosis (CPVT). When an engorged left gastric vein (LGV) is present, the portal inflow is restorable with an anastomosis between the graft portal vein and the LGV of the recipient. We analyzed short- and long-term results of this procedure in 12 LT with CPVT. METHODS: Between 2005 and 2019, 55 patients with CPVT underwent LT. We applied this technique in 12 patients. In six cases, we placed a vascular graft to obtain a tension-free structure. We evaluated patency, short- and long-term results. RESULTS: No intraoperative complication was observed. The median duration of LT, blood transfusion, deceased donor age, and MELD score of the recipients were 7 h, 1250 mL, 72 years, and 19. Seven patients were affected by hepatocellular carcinoma. No major complications or PVT recurrence were observed. One patient required a liver re-transplantation for primary non-functioning syndrome. The mean hospital stay was 20 days. The actuarial patient survival was 85% with a mean FU of 4 years. The two late deaths were due to hepatocellular carcinoma recurrence and sepsis for cholangitis. CONCLUSIONS: This technique in presence of both CPVT and engorged LGV is feasible and safe for patients, with good short- and long-term results.

Breakthrough invasive fungal infection after liver transplantation in patients on targeted antifungal prophylaxis: A prospective multicentre study.

OBJECTIVE: To investigate the rate of and the risk factors for breakthrough-IFI (b-IFI) after orthotopic liver transplantation (OLT) according to the new definition proposed by Mycoses-Study-Group-Education-and-Research-Consortium (MSG-ERC) and the European-Confederation-of-Medical-Mycology (ECMM). METHODS: Multicenter prospective study of adult patients who underwent OLT at three Italian hospitals, from January 2015 to December 2018. Targeted antifungal prophylaxis (TAP) protocol was developed and shared among participating centers. Follow-up was 1-year after OLT. B-IFI was defined as infection occurring during exposure to antifungal prophylaxis. Risk factors for b-IFI were analyzed among patients exposed to prophylaxis by univariable analysis. RESULTS: We enrolled 485 OLT patients. Overall compliance to TAP protocol was 64.3%, 220 patients received antifungal prophylaxis, 172 according to TAP protocol. Twenty-nine patients were diagnosed of IFI within 1 year after OLT. Of them, 11 presented with b-IFI within 17 (IQR 11-33) and 16 (IQR 4-30) days from OLT and from antifungal onset, respectively. Then out of 11 patients with b-IFI were classified as having high risk of IFI and were receiving anti-mould prophylaxis, nine with echinocandins and one with polyenes. Comparison of patients with and without b-IFI showed significant differences for prior Candida colonization, need of renal replacement therapy after OLT, re-operation, and CMV infection (whole blood CMV-DNA >100 000 copies/mL). Although non-significant, a higher rate of b-IFI in patients on echinocandins was observed (8.2% vs 1.8%, P = .06). CONCLUSIONS: We observed 5% of b-IFI among OLT patients exposed to antifungal prophylaxis. The impact of echinocandins on b-IFI risk in this setting should be further explored.

Removal of Bilirubin with a New Adsorbent System: In Vitro Kinetics.

BACKGROUND/AIMS: Many potentially toxic molecules accumulate in the blood during hepatic dysfunction. In clinical practice, it is very difficult to remove bilirubin, the most widely studied toxin, and particularly the unconjugated form, strongly albumin-bound. The aim of this in vitro study was to assess irreversible bilirubin adsorption as a protein-bound compound marker, using Cytosorb® (Cytosorbents Corp.), a new hemoadsorption device designed to remove cytokines. METHODS: We performed 4 in vitro experiments, dynamic and static, with different albumin-bilirubin solutions. RESULTS: All experiments showed the resin's ability to break the albumin-bilirubin complex (Experiment 1, 2), leading to efficient bilirubin removal for 24 h (Removal Rate: 90% Experiment 3) with minimal albumin loss. No sign of bilirubin release from the charged resin was detected (Experiment 4). CONCLUSION: Cytosorb® seems a promising artificial liver support, thanks to its ability to adsorb bilirubin and its proven ability to modulate the cytokines involved in hepatic dysfunction.

Intracranial Hemorrhage Diagnosed with Transcranial Ultrasound in a Comatose, Postliver Transplant Patient.

Transcranial ultrasound is a well validated diagnostic technique used to assess cerebral perfusion or to detect structural damage in intensive care unit patients. We report a case of an intracranial hemorrhage first suspected during a trans-cranial Doppler assessment of a postorthotopic liver transplant patient. The patient was at considerable risk of bleeding, due to a primary graft nonfunction, but he had also elevated ammonium levels, justifying the comatose state, and no focal neurological deficits. The clinical conditions were unstable, making the transportation to the radiology suite at elevated risk. The hemorrhage was identified by B-mode ultrasound before the development of focal neurological signs or alterations in the middle cerebral artery Doppler flow and optical nerve sheath diameter. We suggest that transcranial B-mode ultrasound may prove useful as a monitoring tool in selected patients, also providing early clinical suspicion for the onset of intracranial hemorrhage even before the development of intracranial hypertension or focal neurological deficits.

Preliminary experience of sequential use of normothermic and hypothermic oxygenated perfusion for donation after circulatory death kidney with warm ischemia time over the conventional criteria - a retrospective and observational study.

Donation after circulatory death (DCD) is a potential source of reducing organ demand. In Italy, DCD requires a 20-min no-touch period that prolongs warm ischemia and increases delayed graft function (DGF) risk and graft loss. We report here our preliminary experience of sequential use of normothermic regional perfusion (NRP), as standard procedure, and hypothermic oxygenated perfusion (HOPE), as an experimental technique of organ preservation, in 10 kidney transplants (KT) from five DCD Maastricht III with extensive functional warm ischemia time (fWIT) up to 325 min. During NRP, renal function tests were evaluated to accept organs which were retrieved according to standard fashion with biopsy. While waiting for pathology and cross-match results, organs were preserved with HOPE through pressure- and temperature-controlled arterial pulsatile flow. All grafts with Karpinski score ≤4 were used for conventional single KT with mean cold ischemia time of 584 ± 167 min and mean fWIT of 151 ± 132 min. At the end of HOPE, lactate levels increased significantly in all cases with DGF (P = 0.0095), which were 3/10 (30%). No primary nonfunctions were recorded, and all patients had sCr < 1.5 mg/dl at 6-month post-KT. NRP and HOPE for DCD may overcome fWIT limits safely, and lactate during HOPE predicts DGF.

Early infections in the intensive care unit after liver transplantation-etiology and risk factors: A single-center experience.

BACKGROUND: Infectious complications represent one of the main causes of perioperative morbidity and mortality of liver transplant recipients. The primary objective of this retrospective observational study was to evaluate incidence and etiology of early (within 1 month from surgery and occurring in the intensive care unit [ICU]) postoperative infections as well as donor- and recipient-related risk factors. METHODS: The data of 280 patients undergoing 299 consecutive liver transplant procedures from January 2012 to December 2015 were extracted from the Italian ICU registry database and hospital registries. Perioperative risk factors, etiology of infections, and antibiotic susceptibility of isolated microorganisms were taken into consideration. RESULTS: Global incidence of postoperative infections was 21%. Pneumonia was the most frequent infection and, globally, gram-negative bacteria were the most common agents. Septic shock was present in 22% of infection cases and hospital mortality was higher in patients with postoperative infection. Preoperative chronic obstructive pulmonary disease, malnutrition, preoperative ascites, encephalopathy, and early re-transplantation were significantly associated to post orthotopic LT infections. CONCLUSION: Infections represent a major cause of early postoperative morbidity and mortality. The impact of single risk factors and the results of their preoperative management should be further investigated in order to reduce the incidence and evolution of postoperative infections.