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Background: To assess the impact of attaining aggressive beta-lactam pharmacokinetic/pharmacodynamic (PK/PD) targets on clinical efficacy in critical orthotopic liver transplant (OLT) recipients with documented early Gram-negative infections., Methods: OLT recipients admitted to the post-transplant ICU between June 2021 and May 2024 having documented Gram-negative infections treated with targeted therapy continuous infusion (CI) beta-lactams, and undergoing therapeutic drug monitoring (TDM)-guided beta-lactam dosing adjustment in the first 72 hours were prospectively enrolled. Free steady-state concentrations (fCss) of beta-lactams (BL) and/or of beta-lactamase inhibitors (BLI) were calculated, and aggressive PK/PD target attainment was measured. Multivariate logistic regression analyses were performed for testing independent variables associated with 30-day resistance occurrence., Results: Fifty critical OLT recipients were treated with CI beta-lactam in mono- (n=34) or in combination (n=16) therapy for documented Gram-negative infections (46% hospital-acquired/ventilator-associated pneumonia). Combination therapy was selected more frequently for treating intraabdominal infections (P=0.03) and was associated with lower attainment of aggressive PK/PD target (P=0.03). No significant difference in clinical/microbiological outcome emerged between mono- and combination therapy. Four patients (8.0%) developed 30-day resistance occurrence. At multivariate analysis, failure in attaining an aggressive beta-lactam PK/PD target emerged as the only independent predictor of 30-day resistance development (OR 14.33; 95% CI 1.46-140.53; P=0.02)., Conclusions: Attaining an aggressive PK/PD target of CI beta-lactams in critical OLT recipients treated for documented Gram-negative infections could represent an effective strategy for minimizing the risk of 30-day resistance occurrence to the selected beta-lactam., (© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: To analyse the biliary pharmacokinetics/pharmacodynamics (PK/PD) of continuous infusion (CI) meropenem-vaborbactam (MEM-VBM) in a case series of orthotopic liver transplant (OLT) recipients being treated for Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) related biliary tract infections (BTIs) or as preemptive therapy of KPC-Kp rectal colonization., Methods: Critical OLT recipients receiving CI MEM-VBM (2 g/2 g q8h over 8 h) because of KPC-Kp related BTIs or as preemptive therapy of KPC-Kp rectal colonization, having Kehr's tube positioned and undergoing simultaneous therapeutic drug monitoring of MEM and VBM in plasma and bile were retrospectively assessed. Bile-to-plasma ratio of free steady-state concentrations (fCss) of MEM and VBM was used for assessing biliary penetration. Optimal joint MEM-VBM PK/PD target attainment was defined as MEM fCss/MIC ratio >4 coupled with VBM free area under time-concentration curve (fAUC)/threshold concentration (CT) ratio >24., Results: Overall, four critical OLT recipients were included. Median bile-to-plasma ratio was 0.32 for MEM (range 0.21-0.79) and 0.40 for VBM (range 0.20-0.77). Biliary MEM-VBM joint PK/PD target attainment was optimal in 3/4 OLT recipients and quasi-optimal in the other one., Conclusions: The 1:1 proportion between MEM and VBM concentrations was maintained unchanged in the bile, allowing us to assume that the efficacy of MEM-VBM may be appropriate even in the treatment of BTIs. CI administration was an effective strategy for attaining aggressive biliary joint PK/PD targets against pathogens with an MIC up to 2 mg/L., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Venovenous bypass (VVB) use during liver transplantation (LT) is notably variable among the centres and it is actually restricted to surgically complex cases, severely unstable recipients or grafts from high-risk donors. Historically, VVB was associated with the classical LT with caval cross clamping, while not much is known about the safety of this technique applied to piggyback LT. This retrospective observational study evaluated the effects of VVB applied to piggyback LT on mortality, hospital outcomes, postoperative graft and other organ dysfunction. We retrospectively collected data about recipient status, surgical complexity and graft quality of all the piggyback LTs performed at the Transplant Unit of IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy, from January 2012 to December 2022. A propensity score (PS) was built taking into account the variables possibly associated with either VVB choice and the investigated outcomes with the average treatment overlap method. PS-weighted general linear models (GLMs) were developed to investigate the adjusted effect of VVB use on the selected outcomes. The final analysis included 874 LT cases, of whom 74 (8.5%) underwent VVB. The effective sample sizes after PS-weighting were 280.2 and 64.3 patients in the no-VVB and VVB groups, respectively. PS-weighted GLMs did not show any differences regarding hospital and graft-related outcomes. However, significantly higher odds ratios for serum creatinine > 2 mg/dL and AKIN stage 2 or 3 during the first 24 h after ICU admission together with a higher renal replacement therapy need during ICU stay were reported for VVB exposure in the weighted analyses. This study suggests similar mortality and length of stay but a higher risk for postoperative acute kidney injury in patients undergoing piggyback LT with VVB., (© 2024. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Purpose: A preoperative point-of-care neck ultrasound, carried out during preoperative airway evaluation by extending the scans to the regions close to the larynx and trachea, can allow for the rapid identification of unknown pathologies or abnormalities in a cost-effective and non-invasive manner. This prospective, observational study examines a series of ultrasound findings in structures close to the airway, made through preoperative point-of-care neck ultrasound in a cohort of 230 patients., Methods: We conducted a prospective observational study, enrolling 230 adult patients selected for elective abdominal surgery. The primary goal was to verify the predictive role of airway ultrasound in identifying difficult airways, while the secondary goal was to evaluate structures close to the airway such as jugular veins, carotid arteries, thyroid gland and soft tissues., Results: Overall, preoperative point-of-care neck ultrasound proved to be an effective and reliable method of obtaining details about local or systemic pathologies, which could affect perioperative care. For example, the exam consistently revealed the presence of carotid plaques or venous congestion, which could be used to best determine the patient's cardiovascular risk or to instigate further investigations. It also allowed for more accurate central venous catheter placement planning and better airway management and it warned about possible thyroid or neoplastic pathologies that would have otherwise remained unknown. In some cases, information from preoperative point-of-care neck ultrasound has even led to modifications in perioperative therapy., Conclusion: Preoperative point-of-care neck ultrasound is fast, inexpensive, and non-invasive, and it can be easily performed by a properly trained professional during the preoperative airway ultrasound evaluation. It can be considered as a new preoperative assessment tool., (© 2023. Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB).)

Background & Aims: The aim of this study was to investigate gut microbiome (GM) dynamics in relation to carbapenem-resistant Enterobacterales (CRE) colonization, CRE infection, and non-CRE infection development within 2 months after liver transplant (LT)., Methods: A single-center, prospective study was performed in patients undergoing LT from November 2018 to January 2020. The GM was profiled through 16S rRNA amplicon sequencing of a rectal swab taken on the day of transplantation, and fecal samples were collected weekly until 1 month after LT. A subset of samples was subjected to shotgun metagenomics, including resistome dynamics. The primary endpoint was to explore changes in the GM in the following groups: (1) CRE carriers developing CRE infection (CRE_I); (2) CRE carriers not developing infection (CRE_UI); (3) non-CRE carriers developing microbial infection (INF); and (4) non-CRE carriers not developing infection (NEG)., Results: Overall, 97 patients were enrolled, and 91 provided fecal samples. Of these, five, nine, 22, and 55 patients were classified as CRE_I, CRE_UI, INF, and NEG, respectively. CRE_I patients showed an immediate and sustained post-LT decrease in alpha diversity, with depletion of the GM structure and gradual over-representation of Klebsiella and Enterococcus . The proportions of Klebsiella were significantly higher in CRE_I patients than in NEG patients even before LT, serving as an early marker of subsequent CRE infection. CRE_UI patients had a more stable and diverse GM, whose compositional dynamics tended to overlap with those of NEG patients., Conclusions: GM profiling before LT could improve patient stratification and risk prediction and guide early GM-based intervention strategies to reduce infectious complications and improve overall prognosis., Impact and Implications: Little is known about the temporal dynamics of gut microbiome (GM) in liver transplant recipients associated with carbapenem-resistant Enterobacterales (CRE) colonization and infection. The GM structure and functionality of patients colonized with CRE and developing infection appeared to be distinct compared with CRE carriers without infection or patients with other microbial infection or no infection and CRE colonization. Higher proportions of antimicrobial-resistant pathogens and poor representation of bacteria and metabolic pathways capable of promoting overall host health were observed in CRE carriers who developed infection, even before liver transplant. Therefore, pretransplant GM profiling could improve patient stratification and risk prediction and guide early GM-based intervention strategies to reduce infectious complications and improve overall prognosis., Competing Interests: The authors of this study declare that they do not have any conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Author(s).)

(1) Objectives: To describe the attainment of optimal pharmacokinetic/pharmacodynamic (PK/PD) targets in orthotopic liver transplant (OLT) recipients treated with continuous infusion (CI) beta-lactams optimized using a real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program during the early post-surgical period. (2) Methods: OLT recipients admitted to the post-transplant intensive care unit over the period of July 2021-September 2023, receiving empirical or targeted therapy with CI meropenem, piperacillin-tazobactam, meropenem-vaborbactam, or ceftazidime-avibactam optimized using a real-time TDM-guided ECPA program, were retrospectively retrieved. Steady-state beta-lactam (BL) and/or beta-lactamase inhibitor (BLI) plasma concentrations (C ss ) were measured, and the C ss /MIC ratio was selected as the best PK/PD target for beta-lactam efficacy. The PK/PD target of meropenem was defined as being optimal when attaining a f C ss /MIC ratio > 4. The joint PK/PD target of the BL/BLI combinations (namely piperacillin-tazobactam, ceftazidime-avibactam, and meropenem-vaborbactam) was defined as being optimal when the f C ss /MIC ratio > 4 of the BL and the f C ss /target concentration (C T ) ratio > 1 of tazobactam or avibactam, or the f AUC/C T ratio > 24 of vaborbactam were simultaneously attained. Multivariate logistic regression analysis was performed for testing potential variables that were associated with a failure in attaining early (i.e., at first TDM assessment) optimal PK/PD targets. (3) Results: Overall, 77 critically ill OLT recipients (median age, 57 years; male, 63.6%; median MELD score at transplantation, 17 points) receiving a total of 100 beta-lactam treatment courses, were included. Beta-lactam therapy was targeted in 43% of cases. Beta-lactam dosing adjustments were provided in 76 out of 100 first TDM assessments (76.0%; 69.0% decreases and 7.0% increases), and overall, in 134 out of 245 total ECPAs (54.7%). Optimal PK/PD target was attained early in 88% of treatment courses, and throughout beta-lactam therapy in 89% of cases. Augmented renal clearance (ARC; OR 7.64; 95%CI 1.32-44.13) and MIC values above the EUCAST clinical breakpoint (OR 91.55; 95%CI 7.12-1177.12) emerged as independent predictors of failure in attaining early optimal beta-lactam PK/PD targets. (4) Conclusion: A real-time TDM-guided ECPA program allowed for the attainment of optimal beta-lactam PK/PD targets in approximately 90% of critically ill OLT recipients treated with CI beta-lactams during the early post-transplant period. OLT recipients having ARC or being affected by pathogens with MIC values above the EUCAST clinical breakpoint were at high risk for failure in attaining early optimal beta-lactam PK/PD targets. Larger prospective studies are warranted for confirming our findings.

Background: Postoperative pulmonary complications (PPCs) significantly contribute to postoperative morbidity and mortality. We conducted a study to determine the incidence of PPCs after major elective abdominal surgery and their association with early and 1-year mortality in patient without pre-existing respiratory disease., Methods: We conducted a multicenter observational prospective clinical study in 40 Italian centers. 1542 patients undergoing elective major abdominal surgery were recruited in a time period of 14 days and clinically managed according to local protocol. The primary outcome was to determine the incidence of PPCs. Further, we aimed to identify independent predictors for PPCs and examine the association between PPCs and mortality., Results: PPCs occurred in 12.6% (95% CI 11.1-14.4%) of patients with significant differences among general (18.3%, 95% CI 15.7-21.0%), gynecological (3.7%, 95% CI 2.1-6.0%) and urological surgery (9.0%, 95% CI 6.0-12.8%). PPCs development was associated with known pre- and intraoperative risk factors. Patients who developed PPCs had longer length of hospital stay, higher risk of 30-days hospital readmission, and increased in-hospital and one-year mortality (OR 3.078, 95% CI 1.825-5.191; P<0.001)., Conclusions: The incidence of PPCs in patients without pre-existing respiratory disease undergoing elective abdominal surgery is high and associated with worse clinical outcome at one year after surgery. General surgery is associated with higher incidence of PPCs and mortality compared to gynecological and urological surgery.

Extracorporeal membrane oxygenation (ECMO) is a rescue therapy for cardiovascular collapse during and after liver transplantation (LT). According to the most recent guidelines, patients with severe cardiomyopathy are excluded from LT because of high-mortality risk during surgery. Intraoperative ECMO support could give these patients the opportunity to undergo LT by reducing the risk of heart failure and reperfusion syndrome. In this case report, we present a case of veno-arterial ECMO (VA-ECMO) support started before LT surgery in a patient with severe pulmonary hypertension, mitral valve steno-insufficiency, and right heart dysfunction. The presence of severe heart disease would have contraindicated LT, but simultaneous liver cirrhosis contraindicated mitral valve surgery, leaving the patient locked in a "Catch-22" state. The best solution was to perform LT with VA-ECMO support before, during, and after the surgery to reduce cardiac load and possible heart failure. LT was performed with good hemodynamic stability and the patient was successfully weaned from ECMO a few hours after surgery. At the 6 month follow-up, normal liver and kidney functions were recorded as well as an overall improvement of heart function; the patient successfully underwent mitral valve replacement and tricuspid annuloplasty 10 months after transplant and is now in good condition., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

An essential means of collecting more abdominal donor organs is controlled donation after circulatory death (cDCD). The organs are typically preserved during cDCD using the abdominal normothermic regional perfusion (A-NRP) technique to recirculate oxygenated blood flow following cardiac arrest and the withdrawal of life support. One of the challenges of A-NRP is ensuring the correct vascular devices' positionings, specifically extracorporeal membrane oxygenation cannulae and aortic balloons, typically achieved through fluoroscopy with or without contrast agents. Here, we present a case report in which transesophageal echocardiography (TEE) helped the transplant team to effectively procure viable abdominal organs from a cDCD donor in the shortest time frame, as minimizing time is one of the most crucial factors in maintaining organ viability. TEE use leads to a more effective and efficient A-NRP procedure with limited complications. In addition, it allows us to observe the circulation of both the thoracic and part of the abdominal organs using one fast exam. This case is the first report describing TEE as a primary guide and useful tool for DCD donors. However, prospective studies are needed to confirm that TEE could be used as standard practice during all DCD organ retrieval procedures.

Assessment of glomerular filtration rate (GFR) is necessary for dose adjustments of beta-lactam that are excreted by the kidneys, such as meropenem. The aim of this study was to compare the daily dose of 24 h-continuous infusion (CI) meropenem when GFR was calculated by means of measured creatinine clearance (mCL CR ) or estimated by the CKDEPI (eGFR CKDEPI ), Cockcroft-Gault (eGFR CG ), and MDRD (eGFR MDRD ) equations. Adult critically ill patients who underwent therapeutic drug monitoring (TDM) for the assessment of 24 h-CI meropenem steady state concentration (Css) and for whom a 24 h-urine collection was performed were retrospectively enrolled. Meropenem clearance (CL M ) was regressed against mCL CR , and meropenem daily dose was calculated based on the equation infusion rate = daily dose/CL M . eGFR CKDEPI , eGFR CG , and eGFR CKDEPI were regressed against mCL CR in order to estimate CL M . Forty-six patients who provided 133 meropenem Css were included. eGFR CKDEPI overestimated mCL CR up to 90 mL/min, then mCL CR was underestimated. eGFR CG and eGFR MDRD overestimated mCL CR across the entire range of GFR. In critically ill patients, dose adjustments of 24 h-CI meropenem should be based on mCL CR . Equations for estimation of GFR may lead to gross under/overestimates of meropenem dosages. TDM may be highly beneficial, especially for critically ill patients with augmented renal clearance.

Liver Transplantation (LT) has become the gold standard treatment for End-Stage Liver Disease (ESLD). One of the main strategies to manage life-threatening complications, such as cardio-respiratory failure, is Extracorporeal Membrane Oxygenation (ECMO) in the peri-transplantation period, with different configurations of the technique and in combination with other extracorporeal care devices such as Continuous Renal Replacement Therapy (CRRT). This retrospective study includes three clinical cases of planned ECMO support strategies in LT and evaluates their application compared with current literature exploring PubMed/Medline. The three LT supported with ECMO and CRRT were performed at IRCCS Polyclinic S. Orsola-Malpighi, Bologna. All three cases of patients with compromised organ function analysed produced positive outcomes. The planned use of ECMO and CRRT support in peri-transplantation has allowed the patients to overcome contraindications and successfully undergo LT. In recent years, only a few reports have documented successful LT outcomes performed with intraoperative ECMO in critically ESLD patients. However, the management of LT with ECMO and/or CRRT assistance is an emerging challenge, with the need for more published evidence on this topic to guide treatment choices in patients with severe, acute and reversible respiratory and cardiovascular failure after LT.

Background: Hemodynamic instability (HDI) is common during liver transplantation (LT); veno-venous bypass (VVB) is a tool used in selected cases to ensure hemodynamic stability and for surgical needs. Transesophageal echocardiography (TEE) allows the transplant team to identify the causes of HDI and to guide therapies. We present a case series of four patients showing the valuable role of TEE during LT in VVB., Methods: We report four explicative cases of TEE use in LT with VVB performed at IRCCS Azienda Ospedaliero-Universitaria di Bologna. Four transplants were performed between 2016 and 2022., Results: Many authors have highlighted the diagnostic value of TEE during LT in the case of HDI. However, its specific role during LT with VVB is poorly described. This paper illustrates multiple potential uses of TEE in LT with VVB: TEE as a guide for catheterization and optimal cannula positioning, TEE as a tool for intraoperative Patent Foramen Ovale management, TEE as help for anticoagulation therapy and finally, TEE as support when evaluating bypass efficiency and correcting hypovolemia., Conclusion: TEE is a useful instrument during LT with VVB. However, further studies are needed to assess the suitable applications of TEE during LT in patients with HDI requiring VVB. TEE should be part of the anesthetist's cultural background.

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., (© 2022 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Introduction: Liver transplantation (LT) is the only effective treatment for acute-on-chronic liver failure (ACLF), but it is limited by organ availability. This study aims to identify predictive factors of mortality for LT candidates based on parameters measured at the admission into the ICU., Methods: Sixty-four patients diagnosed with ACLF, admitted consecutively into ICU between 2015 and 2019, were retrospectively enrolled in the study. Data were assessed using univariate and multivariate regression analyses to identify risk factors for inhospital mortality and 1-year mortality., Results: A total of 67% of patients were diagnosed with ACLF grade 3, and 25 and 8% with grades 2 and 1. Thirty percent received LT with a 1-year mortality rate of 16%, whereas for nontransplanted patients it reached 90%. Clinical features were compared according to transplant eligibility. In the univariate analysis model, lung failure (HR, 3.01; 95% CI, 1.48-6.09; P = 0.002), high lactate levels (HR, 1.03; 95% CI, 1.02-1.04; P < 0.001) and CLIF-ACLF score (HR, 1.04; 95% CI, 1.01-1.09; P = 0.026) were independently correlated to increased inhospital mortality. LT reduced mortality risk (HR, 0.16; 95% CI, 0.04-0.72; P = 0.016)., Conclusion: Lung failure, CLIF-ACLF score and blood lactate levels at admission were the only statistically significant independent predictors of inhospital mortality, more accurate in determining transplant success than ACLF grade., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: COVID-19-related acute respiratory distress syndrome (ARDS) is characterized by the presence of signs of microvascular involvement at the CT scan, such as the vascular tree in bud (TIB) and the vascular enlargement pattern (VEP). Recent evidence suggests that TIB could be associated with an increased duration of invasive mechanical ventilation (IMV) and intensive care unit (ICU) stay. The primary objective of this study was to evaluate whether microvascular involvement signs could have a prognostic significance concerning liberation from IMV., Material and Methods: All the COVID-19 patients requiring IMV admitted to 16 Italian ICUs and having a lung CT scan recorded within 3 days from intubation were enrolled in this secondary analysis. Radiologic, clinical and biochemical data were collected., Results: A total of 139 patients affected by COVID-19 related ARDS were enrolled. After grouping based on TIB or VEP detection, we found no differences in terms of duration of IMV and mortality. Extension of VEP and TIB was significantly correlated with ground-glass opacities (GGOs) and crazy paving pattern extension. A parenchymal extent over 50% of GGO and crazy paving pattern was more frequently observed among non-survivors, while a VEP and TIB extent involving 3 or more lobes was significantly more frequent in non-responders to prone positioning., Conclusions: The presence of early CT scan signs of microvascular involvement in COVID-19 patients does not appear to be associated with differences in duration of IMV and mortality. However, patients with a high extension of VEP and TIB may have a reduced oxygenation response to prone positioning., Trial Registration: NCT04411459., (© 2022. Italian Society of Medical Radiology.)

Introduction: optimal treatment of Gram-negative infections in critically ill patients is challenged by changing pathophysiological conditions, reduced antimicrobial susceptibility and limited therapeutic options. The aim of this study was to assess the impact of maximizing Css/MIC ratio on efficacy of continuous infusion (CI) meropenem in treating documented Gram-negative infections in critically ill patients and to perform a population pharmacokinetic/pharmacodynamic analysis to support treatment optimization. Materials and Methods: Classification and regression tree (CART) analysis was used to identify whether a cutoff of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) (Css/MIC) ratio correlated with favorable clinical outcome. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. The probability of target attainment (PTA) of the identified Css/MIC ratio was calculated by means of Monte Carlo simulations. Cumulative fraction of response (CFRs) were calculated against common Enterobacterales, P. aeruginosa and A. baumannii as well. Results: a total of 74 patients with 183 meropenem Css were included. CART analysis identified a Css/MIC ratio ≥4.63 as cutoff value significantly associated with favorable clinical outcomes. Multivariate regression analysis confirmed the association [OR (95%CI): 20.440 (2.063-202.522); p < 0.01]. Creatinine clearance (CL CR ) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that, across different classes of renal function, dosages of meropenem ranging between 0.5 and 2 g q6h over 6 h (namely by CI) may grant PTAs of Css/MIC ratios ≥4.63 against susceptible pathogens with an MIC up to the EUCAST clinical breakpoint of 2 mg/L. The CFRs achievable with these dosages were very high (>90%) against Enterobacterales across all the classes of renal function and against P. aeruginosa among patients with CL CR < 30 ml/min/1.73 m 2 , and quite lower against A. baumannii . Discussion: our findings suggest that Css/MIC ratio ≥4.63 may be considered the pharmacodynamic target useful at maximizing the efficacy of CI meropenem in the treatment of Gram-negative infections in critically ill patients. Dosages ranging between 0.5 g q6h and 2 g q6h by CI may maximize the probability of favorable clinical outcome against meropenem-susceptible Gram-negative pathogens among critically ill patients having different degrees of renal function ., Competing Interests: FP has participated in speaker bureaus for Angelini, Basilea Pharmaceutica, Gilead, Hikma, Merck Sharp and Dohme, Nordic Pharma, Pfizer and Sanofi Aventis, and in advisory boards for Angelini, Basilea, Pharmaceutica, Correvio, Gilead, Hikma, Merck Sharp and Dohme, Nordic Pharma, Novartis, Pfizer, Shionogi and Thermo-Fisher, outside the submitted work. PV has served as a consultant for bioMérieux, Gilead, Merck Sharp and Dohme, Nabriva, Nordic Pharma, Pfizer, Thermo-Fisher, and Venatorx, and received payment for serving on the speaker’s bureaus for Correvio, Gilead, Merck Sharp and Dohme, Nordic Pharma, and Pfizer, outside the submitted work. MG has received personal fees from Angelini, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cojutti, Gatti, Rinaldi, Tonetti, Laici, Mega, Siniscalchi, Giannella, Viale and Pea.)

Background: Health-related quality of life (HRQoL) impairment is often reported among COVID-19 ICU survivors, and little is known about their long-term outcomes. We evaluated the HRQoL trajectories between 3 months and 1 year after ICU discharge, the factors influencing these trajectories and the presence of clusters of HRQoL profiles in a population of COVID-19 patients who underwent invasive mechanical ventilation (IMV). Moreover, pathophysiological correlations of residual dyspnea were tested., Methods: We followed up 178 survivors from 16 Italian ICUs up to one year after ICU discharge. HRQoL was investigated through the 15D instrument. Available pulmonary function tests (PFTs) and chest CT scans at 1 year were also collected. A linear mixed-effects model was adopted to identify factors associated with different HRQoL trajectories and a two-step cluster analysis was performed to identify HRQoL clusters., Results: We found that HRQoL increased during the study period, especially for the significant increase of the physical dimensions, while the mental dimensions and dyspnea remained substantially unchanged. Four main 15D profiles were identified: full recovery (47.2%), bad recovery (5.1%) and two partial recovery clusters with mostly physical (9.6%) or mental (38.2%) dimensions affected. Gender, duration of IMV and number of comorbidities significantly influenced HRQoL trajectories. Persistent dyspnea was reported in 58.4% of patients, and weakly, but significantly, correlated with both DLCO and length of IMV., Conclusions: HRQoL impairment is frequent 1 year after ICU discharge, and the lowest recovery is found in the mental dimensions. Persistent dyspnea is often reported and weakly correlated with PFTs alterations., Trial Registration: NCT04411459., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Emerging data suggest that more aggressive beta-lactam PK/PD targets could minimize the occurrence of microbiological failure and/or resistance development. This study aims to assess whether a PK/PD target threshold of continuous infusion (CI) beta-lactams may be useful in preventing microbiological failure and/or resistance development in critically ill patients affected by documented Gram-negative infections., Methods: Patients admitted to intensive care units from December 2020 to July 2021 receiving continuous infusion beta-lactams for documented Gram-negative infections and having at least one therapeutic drug monitoring in the first 72 h of treatment were included. A receiver operating characteristic (ROC) curve analysis was performed using the ratio between steady-state concentration and minimum inhibitory concentration (C ss /MIC) ratio as the test variable and occurrence of microbiological failure as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated. Independent risk factors for the occurrence of microbiological failure were investigated using logistic regression., Results: Overall, 116 patients were included. Microbiological failure occurred in 26 cases (22.4%). A C ss /MIC ratio ≤ 5 was identified as PK/PD target cut-off with sensitivity of 80.8% (CI 60.6-93.4%) and specificity of 90.5% (CI 74.2-94.4%), and with an AUC of 0.868 (95%CI 0.793-0.924; p < 0.001). At multivariate regression, independent predictors of microbiological failure were C ss /MIC ratio ≤ 5 (odds ratio [OR] 34.54; 95%CI 7.45-160.11; p < 0.001) and Pseudomonas aeruginosa infection (OR 4.79; 95%CI 1.11-20.79; p = 0.036)., Conclusions: Early targeting of CI beta-lactams at C ss /MIC ratio > 5 during the treatment of documented Gram-negative infections may be helpful in preventing microbiological failure and/or resistance development in critically ill patients.

Purpose: The onset of the coronavirus disease 19 (COVID-19) pandemic in Italy induced a dramatic increase in the need for intensive care unit (ICU) beds for a large proportion of patients affected by COVID-19-related acute respiratory distress syndrome (ARDS). The aim of the present study was to describe the health-related quality of life (HRQoL) at 90 days after ICU discharge in a cohort of COVID-19 patients undergoing invasive mechanical ventilation and to compare it with an age and sex-matched sample from the general Italian and Finnish populations. Moreover, the possible associations between clinical, demographic, social factors, and HRQoL were investigated., Methods: COVID-19 ARDS survivors from 16 participating ICUs were followed up until 90 days after ICU discharge and the HRQoL was evaluated with the 15D instrument. A parallel cohort of age and sex-matched Italian population from the same geographic areas was interviewed and a third group of matched Finnish population was extracted from the Finnish 2011 National Health survey. A linear regression analysis was performed to evaluate potential associations between the evaluated factors and HRQoL., Results: 205 patients answered to the questionnaire. HRQoL of the COVID-19 ARDS patients was significantly lower than the matched populations in both physical and mental dimensions. Age, sex, number of comorbidities, ARDS class, duration of invasive mechanical ventilation, and occupational status were found to be significant determinants of the 90 days HRQoL. Clinical severity at ICU admission was poorly correlated to HRQoL., Conclusion: COVID-19-related ARDS survivors at 90 days after ICU discharge present a significant reduction both on physical and psychological dimensions of HRQoL measured with the 15D instrument., Trial Registration: NCT04411459., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Prone positioning (PP) has been used to improve oxygenation in patients affected by the SARS-CoV-2 disease (COVID-19). Several mechanisms, including lung recruitment and better lung ventilation/perfusion matching, make a relevant rational for using PP. However, not all patients maintain the oxygenation improvement after returning to supine position. Nevertheless, no evidence exists that a sustained oxygenation response after PP is associated to outcome in mechanically ventilated COVID-19 patients. We analyzed data from 191 patients affected by COVID-19-related acute respiratory distress syndrome undergoing PP for clinical reasons. Clinical history, severity scores and respiratory mechanics were analyzed. Patients were classified as responders (≥ median PaO 2 /FiO 2 variation) or non-responders (< median PaO 2 /FiO 2 variation) based on the PaO 2 /FiO 2 percentage change between pre-proning and 1 to 3 h after re-supination in the first prone positioning session. Differences among the groups in physiological variables, complication rates and outcome were evaluated. A competing risk regression analysis was conducted to evaluate if PaO 2 /FiO 2 response after the first pronation cycle was associated to liberation from mechanical ventilation., Results: The median PaO 2 /FiO 2 variation after the first PP cycle was 49 [19-100%] and no differences were found in demographics, comorbidities, ventilatory treatment and PaO 2 /FiO 2 before PP between responders (96/191) and non-responders (95/191). Despite no differences in ICU length of stay, non-responders had a higher rate of tracheostomy (70.5% vs 47.9, P = 0.008) and mortality (53.7% vs 33.3%, P = 0.006), as compared to responders. Moreover, oxygenation response after the first PP was independently associated to liberation from mechanical ventilation at 28 days and was increasingly higher being higher the oxygenation response to PP., Conclusions: Sustained oxygenation improvement after first PP session is independently associated to improved survival and reduced duration of mechanical ventilation in critically ill COVID-19 patients.

Transplant programs have been severely disrupted by the COVID-19 pandemic. Italy was one of the first countries with the highest number of deaths in the world due to SARS-CoV-2. Here we propose a management model for the reorganization of liver transplant (LT) activities and policies in a local intensive care unit (ICU) assigned to liver transplantation affected by restrictions on mobility and availability of donors and recipients as well as health personnel and beds. We describe the solutions implemented to continue transplantation activities throughout a given pandemic: management of donors and recipients' LT program, ICU rearrangement, healthcare personnel training and monitoring to minimize mortality rates of patients on the waiting list. Transplantation activities from February 22, 2020, the data of first known COVID-19 case in Italy's Emilia Romagna region to June 30, 2020, were compared with the corresponding period in 2019. During the 2020 study period, 38 LTs were performed, whereas 41 were performed in 2019. Patients transplanted during the COVID-19 pandemic had higher MELD and MELD-Na scores, cold ischaemia times, and hospitalization rates (p < 0.05); accordingly, they spent fewer days on the waitlist and had a lower prevalence of hepatocellular carcinoma (p < 0.05). No differences were found in the provenance area, additional MELD scores, age of donors and recipients, BMI, re-transplant rates, and post-transplant mortality. No transplanted patients contracted COVID-19, although five healthcare workers did. Ultimately, our policy allowed us to continue the ICU's operations by prioritizing patients hospitalized with higher MELD without any case of transplant infection due to COVID-19.

Background: A large proportion of patients with coronavirus disease 2019 (COVID-19) develop severe respiratory failure requiring admission to the intensive care unit (ICU) and about 80% of them need mechanical ventilation (MV). These patients show great complexity due to multiple organ involvement and a dynamic evolution over time; moreover, few information is available about the risk factors that may contribute to increase the time course of mechanical ventilation.The primary objective of this study is to investigate the risk factors associated with the inability to liberate COVID-19 patients from mechanical ventilation. Due to the complex evolution of the disease, we analyzed both pulmonary variables and occurrence of non-pulmonary complications during mechanical ventilation. The secondary objective of this study was the evaluation of risk factors for ICU mortality., Methods: This multicenter prospective observational study enrolled 391 patients from fifteen COVID-19 dedicated Italian ICUs which underwent invasive mechanical ventilation for COVID-19 pneumonia. Clinical and laboratory data, ventilator parameters, occurrence of organ dysfunction, and outcome were recorded. The primary outcome measure was 28 days ventilator-free days and the liberation from MV at 28 days was studied by performing a competing risks regression model on data, according to the method of Fine and Gray; the event death was considered as a competing risk., Results: Liberation from mechanical ventilation was achieved in 53.2% of the patients (208/391). Competing risks analysis, considering death as a competing event, demonstrated a decreased sub-hazard ratio for liberation from mechanical ventilation (MV) with increasing age and SOFA score at ICU admission, low values of PaO 2 /FiO 2 ratio during the first 5 days of MV, respiratory system compliance (C RS ) lower than 40 mL/cmH 2 O during the first 5 days of MV, need for renal replacement therapy (RRT), late-onset ventilator-associated pneumonia (VAP), and cardiovascular complications.ICU mortality during the observation period was 36.1% (141/391). Similar results were obtained by the multivariate logistic regression analysis using mortality as a dependent variable., Conclusions: Age, SOFA score at ICU admission, C RS , PaO 2 /FiO 2 , renal and cardiovascular complications, and late-onset VAP were all independent risk factors for prolonged mechanical ventilation in patients with COVID-19., Trial Registration: NCT04411459., Competing Interests: Competing interestsThe authors have no conflict of interest to declare., (© The Author(s) 2020.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Post-reperfusion syndrome during orthotopic liver transplantation, which definition best predicts postoperative graft failure and recipient mortality?, Purpose: Post-reperfusion syndrome (PRS) is a serious complication of liver transplantation, at present two main definitions are in use, and they differ both clinically and temporally. The primary objective of this study was to evaluate these two definitions as risk factors for post-transplantation mortality and primary graft non-function., Materials and Methods: We conducted a retrospective observational study on 794 patients undergoing orthotopic liver transplantation at our university hospital. The presence of PRS was evaluated according to both definitions and correlated with the end points: three months mortality, primary graft non-function (PGNF) and the combined outcome of the two., Results: Both definitions proved to be independent risk factors for three months mortality and the combined outcome. The definition according to Aggarwal et al. was also an independent risk factor for PGNF when adjusted for the propensity score. The Hilmi definition, despite being more comprehensive, did not improve the predictivity of the Aggarwal definition for the evaluated outcomes., Conclusions: PRS proved to be an independent risk factor for post-transplantation mortality and occurrence of PGNF. The pathophysiological mechanisms of this entity are still not fully understood and preventive strategies could help in reducing patients and graft losses., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: To evaluate the potential benefits and risks of the use of epidural anaesthesia within an enhanced recovery protocol in this specific subpopulation., Methods: A retrospective review was conducted, including all cirrhotic patients who underwent open liver resection between January 2013 and December 2015 at Bologna University Hospital. Patients with an abnormal coagulation profile contraindicating the placement of an epidural catheter were excluded from the analysis. The control group was composed by patients refusing epidural anaesthesia., Results: Of the 183 cirrhotic patients undergoing open liver resections, 57 had contraindications to the placement of an epidural catheter; of the remaining 126, 86 patients received general anaesthesia and 40 combined anaesthesia. The two groups presented homogeneous characteristics. Intraoperatively the metabolic data did not differ between the two groups, whilst the epidural group had a lower mean arterial pressure (P = 0.041) and received more colloid infusions (P = 0.007). Postoperative liver and kidney function did not differ significantly. Length of mechanical ventilation (P = 0.003) and hospital stay (P = 0.032) were significantly lower in the epidural group. No complications related to the epidural catheter placement or removal was recorded., Conclusion: The use of Epidural Anaesthesia within a fast track protocol for cirrhotic patients undergoing liver resections had a positive impact on the patient's outcomes and comfort as demonstrated by a significantly lower length of mechanical ventilation and hospital stay in the epidural group. The technique appears to be safely manageable in this fragile population even though these results need confirmation in larger studies.

This review aims at evaluating the existing evidence regarding post reperfusion syndrome, providing a description of the pathophysiologic mechanisms involved and possible management and preventive strategies. A PubMed search was conducted using the MeSH database, "Reperfusion" AND "liver transplantation" were the combined MeSH headings; EMBASE and the Cochrane library were also searched using the same terms. 52 relevant studies and one ongoing trial were found. The concept of post reperfusion syndrome has evolved through years to a multisystemic disorder. The implications of the main organ, recipient and procedure related factors in the genesis of this complex syndrome are discussed in the text as the novel pharmacologic and technical approaches to reduce its incidence. However the available evidence about risk factors, physiopathology and preventive measures is still confusing, the presence of two main definitions and the numerosity of possible confounding factors greatly complicates the interpretation of the studies.

Aim: To evaluate the currently available evidence on thoracic epidural anesthesia effects on splanchnic macro and microcirculation, in physiologic and pathologic conditions., Methods: A PubMed search was conducted using the MeSH database. Anesthesia, Epidural was always the first MeSH heading and was combined by boolean operator AND with the following headings: Circulation, Splanchnic; Intestines; Pancreas and Pancreatitis; Liver Function Tests. EMBASE, Cochrane library, ClinicalTrials.gov and clinicaltrialsregister.eu were also searched using the same terms., Results: Twenty-seven relevant studies and four ongoing trials were found. The data regarding the effects of epidural anesthesia on splanchnic perfusion are conflicting. The studies focusing on regional macro-hemodynamics in healthy animals and humans undergoing elective surgery, demonstrated no influence or worsening of regional perfusion in patients receiving thoracic epidural anesthesia (TEA). On the other hand most of the studies focusing on micro-hemodynamics, especially in pathologic low flow conditions, suggested that TEA could foster microcirculation., Conclusion: The available studies in this field are heterogeneous and the results conflicting, thus it is difficult to draw decisive conclusions. However there is increasing evidence deriving from animal studies, that thoracic epidural blockade could have an important role in modifying tissue microperfusion and protecting microcirculatory weak units from ischemic damage, regardless of the effects on macro-hemodynamics.