Invasive aspergillosis causes high mortality in critically ill patients, particularly those with viral pneumonitis receiving extracorporeal membrane oxygenation. Achieving effective voriconazole exposure in this setting is difficult, and existing data on drug concentrations during extracorporeal support are inconsistent. To characterize voriconazole pharmacokinetics in adults receiving extracorporeal membrane oxygenation and evaluate the influence of CYP2C19 genotype on drug exposure. This single-center prospective observational study included adults treated with intravenous voriconazole for suspected or confirmed aspergillosis during extracorporeal support. Serial plasma samples were analyzed using population pharmacokinetic modeling to describe drug disposition and simulate dosing regimens. Thirty-one patients (median age 40 years, mean weight 87 kilograms) provided 131 plasma samples; 61% carried reduced-function CYP2C19 variants. Voriconazole concentrations varied widely, with subtherapeutic levels increasing from 28% on days 1-5 to 47% by days 6-10. A dual-pathway model incorporating an early, rapidly decaying circuit sequestration process followed by a logistic rise in intrinsic clearance from 6.2 to 22.3 liters per h best described the data. Intermediate or poor metabolizers had 36% lower late-phase clearance, though genotype effects were estimated with substantial uncertainty. Simulations indicated that standard dosing achieved therapeutic concentrations in only half of patients at 48 h, declining sharply by day 7. Voriconazole clearance during extracorporeal membrane oxygenation is time-varying, with evidence of early circuit sequestration and later metabolic recovery influenced by CYP2C19 genotype. Early and repeated monitoring is required to maintain effective antifungal exposure. Time-varying clearance should inform dosing of voriconazole and other hepatically metabolized agents during extracorporeal support.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04868188.

Background: Bleeding and thrombosis are major complications of veno-venous (VV) extracorporeal membrane oxygenation (ECMO). Objectives: To assess thrombosis, major bleeding (MB), and 180-day survival in patients supported by VV-ECMO between the first (March 1 to May 31, 2020) and second (June 1, 2020, to June 30, 2021) waves of the COVID-19 pandemic.Methods: An observational study of 309 consecutive patients (aged >= 18years) with severe COVID-19 supported by VV-ECMO was performed in 4 nationally commissioned ECMO centers in the United Kingdom.Results: Median age was 48 (19-75) years, and 70.6% were male. Probabilities of survival, thrombosis, and MB at 180 days in the overall cohort were 62.5% (193/309), 39.8% (123/309), and 30% (93/309), respectively. In multivariate analysis, an age of >55 years (hazard ratio [HR], 2.29; 95% CI, 1.33-3.93; P = .003) and an elevated creatinine level (HR, 1.91; 95% CI, 1.19-3.08; P = .008) were associated with increased mortality. Correction for duration of VV-ECMO support, arterial thrombosis alone (HR, 3.0; 95% CI, 1.5-5.9; P = .002) or circuit thrombosis alone (HR, 3.9; 95% CI, 2.4-6.3; P < .001) but not venous thrombosis increased mortality. MB during ECMO had a 3-fold risk (95% CI, 2.6-5.8, P < .001) of mortality. The first wave cohort had more males (76.7% vs 64%; P = .014), higher 180-day survival (71.1% vs 53.3%; P = .003), more venous thrombosis alone (46.4% vs 29.2%; P = .02), and lower circuit thrombosis (9.2% vs 28.1%; P < .001). The second wave cohort received more steroids (121/150 [80.6%] vs 86/159 [54.1%]; P < .0001) and tocilizumab (20/150 [13.3%] vs 4/159 [2.5%]; P = .005).Conclusion: MB and thrombosis are frequent complications in patients on VV-ECMO and significantly increase mortality. Arterial thrombosis alone or circuit thrombosis alone increased mortality, while venous thrombosis alone had no effect. MB during ECMO support increased mortality by 3.9-fold.

CORONAVIRUS DISEASE 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a complex multisystem disorder primarily characterized by pulmonary involvement.1 Although lung injury leading to acute severe respiratory failure is the most feared clinical presentation of COVID-19, cardiac complications in patients without underlying heart disease also could be a feature of the syndrome and range from 20% to 30%.2-4 Right ventricular (RV) dysfunction (RVD) seems to be particularly common (20%-39%) in the COVID-19 patient group and often remains undiagnosed.

COVID-19 is a prothrombotic condition and a major focus of attention has been to reduce thrombosis in order to improve outcomes. Extracorporeal membrane oxygenation (ECMO) triggers contact activation of coagulation, platelet dysfunction and systemic anticoagulation which may contribute to both thrombosis and bleeding complications.Methods: Multicentre observational study of mortality, thrombosis, and bleeding complications in 152 consecutive patients (≥18 years) supported with VV ECMO during the first wave of the COVID-19 pandemic (1st of March 2020 to 31st of May 2020) from four nationally commissioned UK ECMO centres.Findings: Of 152 patients, mortality during ECMO up to 120 days was 21.1% (32/152) whilst overall all cause in- hospital mortality up to 143 days from ECMO initiation was 25.7% (39/152). Median duration on ECMO was 17 days (interquartile range [IQR] 11-29.7). On multivariate analysis, mortality increased with age (Hazard ratio [HR] 1.09 [95% CI 1.03 - 1.14]), P=0.002. Rates of major bleeding and thrombosis during ECMO were 25.0% (38/152) and 17.1% (26/152). Presence of major bleeding prior to or at initiation of ECMO and intracranial haemorrhage during ECMO conferred 3.65 ([95% CI 1.16 - 11.48], P=0.027) and 6.92 ([95% CI 2.66 - 18.02], <0.0001) folds risks of death respectively during ECMO. Heparin induced thrombocytopenia was diagnosed in 16/152 (10.52%) of the patients and was independently associated with 4-fold increased risk of developing thrombosis (CI1.78-7.21), P=0.002. Thrombosis, coagulation and laboratory parameters did not predict mortality.Interpretation: Although thrombosis is a major complication in patients with COVID-19, major bleeding was frequent and independently associated with increased mortality. Despite a high incidence of major bleeding and thrombosis, both overall and 120-day mortality in this cohort of patients supported with ECMO were better than reported from international registries.Funding Statement: Bayer plc supported the study by providing the investigator-initiated funding to setup the multicentre database of the study.Declaration of Interests: DJA received funding from Bayer plc to setup the multicentre database of the study as an investigator-initiated funding. Other authors have no conflict of interest to declare.Ethics Approval Statement: The study was approved by the human research authority (HRA) and health and care Research Wales (HCRW) and the local Caldicott Guardian at Scotland (reference number: 20/HRA/1785). All patients lacked capacity, and the need for individual informed consent was waived because of observational nature of the study. Data was collected from patient clinical records by the treating medical team with no breach of privacy or anonymity.

Bleeding and thrombosis are major complications in patients supported with extracorporeal membrane oxygenation (ECMO). In this multicentre observational study of 152 consecutive patients (≥18 years) with severe COVID‐19 supported by veno‐venous (VV) ECMO in four UK commissioned centres during the first wave of the COVID‐19 pandemic (1 March to 31 May 2020), we assessed the incidence of major bleeding and thrombosis and their association with 180‐day mortality. Median age (range) was 47 years (23–65) and 75% were male. Overall, the 180‐day survival was 70·4% (107/152). The rate of major bleeding was 30·9% (47/152), of which intracranial bleeding (ICH) was 34% (16/47). There were 96 thrombotic events (63·1%) consisting of venous 44·7% [68/152 of which 66·2% were pulmonary embolism (PE)], arterial 18·6% (13/152) and ECMO circuit thrombosis 9·9% (15/152). In multivariate analysis, only raised lactate dehydrogenase (LDH) at the initiation of VV ECMO was associated with an increased risk of thrombosis [hazard ratio (HR) 1·92, 95% CI 1·21‐3·03]. Major bleeding and ICH were associated with 3·87‐fold (95% CI 2·10–7·23) and 5·97‐fold [95% confidence interval (CI) 2·36–15·04] increased risk of mortality and PE with a 2·00‐fold (95% CI1·09–3·56) risk of mortality. This highlights the difficult balancing act often encountered when managing coagulopathy in COVID‐19 patients supported with ECMO.

with biventricular failure and multiple-systemic organ compromise. The development of post-implantation acute respiratory failure with profound hypoxic lung injury has previously been reported. Veno-venous (VV) as well as VA ECMO has been successfully used in case studies as a suitable strategy to enable adequate oxygenation whilst allowing time for recovery of lung function. We have reviewed our experience. Methods: Single-centre, case series review of patients who required VV ECMO in conjunction with the TAH (Syncardia, USA). Results: The underlying etiology of cardiac dysfunction included: dilated cardiomyopathy; myocarditis; biventricular failure postvalvular surgical intervention, and biventricular failure following ascending aortic dissection repair. 4 patients were bridged to TAH on VA ECMO, with average treatment duration of 6 days; all these patients were intubated. Prior to ECMO cannulation, the average FiO2:PaO2 ratio was 56 (49–73.9) associated with a significant deterioration in respiratory mechanics with increased plateau inspiratory pressures (28-36cmH2O), and reduction in tidal volumes (217-400cc) and lung compliance. All of the patients had bilateral pulmonary infiltrates on chest radiographs. In four patients VV ECMO support was initiated prior to leaving theatre and in the other after 11 hours on ITU. In all cases the indication was refractory and severe hypoxemia. One patient had a Protek Duo cannula (Cardiac Assist, Pittsburgh, PA, USA), the others had two-cannula configurations. ECMO support was weaned off successfully in 4 patients after significant improvement in respiratory function, with an average treatment duration of 152h. One patient developed multi-organ failure and both TAH and VV ECMO support was withdrawn. Conclusions: The mechanism of this acute lung injury would appear to have multiple contributing factors including pre-existing lung injury, pulmonary edema secondary to mechanical obstruction of venous return during chest closure, and reperfusion lung injury. Additionally, pre-implantation VA ECMO support may mask pre-existing lung pathology. There were no additional operative factors or prolonged cardiopulmonary bypass times that may suggest a reason for deterioration in lung function. We describe our experience after TAH implantation and how VV ECMO was successfully weaned off in 4 out of 5 patient with resolution of the acute lung pathology. CCMCritical Care MedicineCrit Care Med0090-3493Lippincott Williams & WilkinsHagerstown, MDCCM

Elderly patients and patients chronically treated with corticosteroids often have thin and inelastic skin. Traumatic skin lacerations, especially of the pretibial area, are particularly difficult to treat in these patients, due to skin retraction and fragility. Suture/Steri-Strip Combination for the Management of Lacerations in Thin-Skinned IndividualsJournal of Emergency MedicineVol. 40Issue 3PreviewThe closure of lacerations in thin-skinned patients often presents a challenge to emergency physicians; skin contracture and inflamed, edematous wounds prevent easy opposition of wound edges, thereby preventing simple closure. Full-Text PDF

BACKGROUND & AIMS:One-year survival in cirrhosis ranges from 1 to 57% depending on the clinical stage. Accurate sub-classification has important prognostic implications but there is no stage beyond cirrhosis using current qualitative histological systems. We compared the performance of all histological semi-quantitative and quantitative methods specifically developed for sub-classifying cirrhosis that have been described to date, with collagen proportionate area (CPA), to evaluate how well they distinguish patients with and without hepatic clinical decompensation at presentation, and in predicting future decompensating events. METHODS:We included consecutive patients with a histological diagnosis of cirrhosis that had a suitable liver biopsy between 2003 and 2007. We used semi-quantitative histological scoring systems proposed by Laennec, Kumar, and Nagula. We also measured quantitatively nodule size, septal width and fibrous tissue expressed in CPA. RESULTS:Sixty-nine patients, mean age 52.3±11years, mean MELD 11.8±5.8, median follow-up 56months. Main aetiologies were alcohol (38%) and hepatitis C (27.5%). Twenty-four patients (34.8%) had had a previous episode of clinical decompensation. Amongst the 45 patients who were compensated, 11 (24%) decompensated on follow-up. In Cox regression, amongst all histological parameters, CPA was the only variable independently associated with clinical decompensation up to the time of biopsy, with an odds ratio that ranged from 1.245 to 1.292. Furthermore, only CPA was significantly associated with future decompensation (OR: 1.117, 95% CI 1.020-1.223; p=0.017). CONCLUSIONS:Cirrhosis can be accurately sub-classified using quantification of fibrosis with CPA, and furthermore CPA is the only independent predictor of clinical decompensation amongst all other histological sub-classification systems described to date.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the beneficial and harmful effects of drugs improving insulin resistance for non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis.

Digital image analysis of collagen assessment of progression of fibrosis in recurrent HCV after liver transplantationJournal of HepatologyVol. 58Issue 5PreviewHistological assessment of fibrosis progression is currently performed by staging systems which are not continuous quantitative measurements. We aimed at assessing a quantitative measurement of fibrosis collagen proportionate area (CPA), to evaluate fibrosis progression and compare it to Ishak stage progression. Full-Text PDF In the authors’ list, the name Emmanuel Tsochatzis was incorrectly spelled as Emmanuel T. Sochatzis. The Publisher apologizes for this. The corrected list of authors is placed above. In the authors’ list, the name Emmanuel Tsochatzis was incorrectly spelled as Emmanuel T. Sochatzis. The Publisher apologizes for this. The corrected list of authors is placed above.

Traditional radiotherapy is only effective in treating hepatocellular cancer (HCC) in doses above 50Gy, but this is above the recommended liver radiation exposure of about 35Gy, which is an important limitation making this treatment unsuitable for routine clinical practice. Trans-arterial radio-embolisation (TARE), consists of delivery of compounds linked to radio-emitter particles which end up in hepatic end-arterioles or show affinity for the neoplasm itself, allowing localised delivery of doses beyond 120Gy. These are well tolerated in patients treated with this type of internal radiation therapy. TARE for HCC is used for palliative treatment of advanced disease which cannot be treated in other ways, or for tumour down-staging before liver transplantation, or as adjuvant therapy for surgically resected HCC. Tumour response after TARE is between 25% and 60% if assessed by using RECIST criteria, and 80% by EASL criteria. In this review we outline the advantages and limitations of radio-emitter therapy including 131-I, 90-Y and 188-Re. We include several observational, and all comparative studies using these compounds. In particular we compare TARE to trans-arterial chemo-embolisation and other intra-arterial techniques.

Background & Aims: Histological assessment of fibrosis progression is currently performed by staging systems which are not continuous quantitative measurements. We aimed at assessing a quantitative measurement of fibrosis collagen proportionate area (CPA), to evaluate fibrosis progression and compare it to Ishak stage progression.Methods: We studied a consecutive cohort of 155 patients with recurrent HCV hepatitis after liver transplantation (LT), who had liver biopsies at one year and were subsequently evaluated for progression of fibrosis using CPA and Ishak staging, and correlated with clinical decompensation. The upper quartile of distribution of fibrosis rates (difference in CPA or Ishak stage between paired biopsies) defined fast fibrosers.Results: Patients had 610 biopsies and a median follow-up of 116 (18-252) months. Decompensation occurred in 29 (18%) patients. Median Ishak stage progression rate was 0.42 units/year: (24 (15%) fast fibrosers). Median CPA fibrosis progression rate was 0.71%/year (36 (23%) fast fibrosers). Clinical decompensation was independently associated by Cox regression only with CPA (p = 0.007), with AUROCs of 0.81 (95% CI 0.71-0.91) compared to 0.68 (95% CI 0.56-0.81) for Ishak stage.Fast fibrosis defined by CPA progression was independently associated with histological de novo hepatitis (OR: 3.77), older donor age (OR: 1.03) and non-use/discontinuation of azathioprine before 1 year post-LT (OR: 3.85), whereas when defined by Ishak progression, fast fibrosers was only associated with histological de nova hepatitis.Conclusions: CPA fibrosis progression rate is a better predictor of clinical outcome than progression by Ishak stage. Histological de nova hepatitis, older donor age and non-use/discontinuation of azathioprine are associated with rapid fibrosis progression in recurrent HCV chronic hepatitis after liver transplantation. (c) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Collagen proportionate area (CPA) has a better correlation with hepatic venous pressure gradient (HVPG) than with Ishak stage. Liver stiffness measurement (LSM) is proposed as non invasive marker of portal hypertension/disease progression. Our aim was to compare LSM and CPA with Ishak staging in chronic viral hepatitis, and HVPG in HCV hepatitis after transplantation.

AIMS:Little information is available regarding the distribution of fibrosis within cirrhotic livers. We measured collagen in cirrhotic explants to determine if fibrosis differs (i) between left (L) and right (R) lobes, and (ii) between different aetiologies.METHODS AND RESULTS:Ten cases each of common aetiologies of cirrhosis were studied: alcoholic liver disease (ALD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), hepatitis C virus (HCV) and hepatitis B virus (HBV). A total of 120 tissue blocks (one block each from L and R lobes) were studied. Collagen was measured as collagen proportionate area (CPA), i.e. the proportion of the tissue sections stained by picro-Sirius red. L and R lobes contained similar amounts of fibrosis (r = 0.788; P < 0.0001) with good agreement between L and R lobes (Bland-Altman analysis, R lobe bias = 1.35%). Median CPA across all aetiologies (R plus L lobes) was 21.5%, (L = 8-40%, R = 10-47%). There was more fibrosis in ALD (30%, 15-47%) than PBC (23.5%, 16-34%) and PSC (22.5%, 8-33%), which in turn showed more than AIH (18.5%, 10-40%), HCV (17%, 13-31%) and HBV (16.5%, 8-30%).CONCLUSIONS:At the time of transplantation cirrhotic livers have different ranges of collagen proportionate area, according to aetiology. R lobe fibrosis corresponds with L lobe fibrosis. The range of fibrosis within each aetiological group could be useful for prognostic subclassification.

Clinical outcomes of recurrent hepatitis C virus after liver transplantation are difficult to predict. We evaluated collagen proportionate area (CPA), a quantitative histological index, at 1 year with respect to the first episode of clinical decompensation. Patients with biopsies at 1 year after liver transplantation were evaluated by Ishak stage/grade, and biopsy samples stained with Sirius red for digital image analysis were evaluated for CPA. Cox regression was used to evaluate variables associated with first appearance of clinical decompensation. Receiver operating characteristic (ROC) curves were also used. A total of 135 patients with median follow-up of 76 months were evaluated. At 1 year, median CPA was 4.6% (0.2%-36%) and Ishak stage was 0-2 in 101 patients, 3-4 in 23 patients, and 5-6 in 11 patients. Decompensation occurred in 26 (19.3%) at a median of 61 months (15-138). Univariately, CPA, tacrolimus monotherapy, and Ishak stage/grade at 1 year were associated with decompensation; upon multivariate analysis, only CPA was associated with decompensation (P = 0.010; Exp(B) = 1.169; 95%CI, 1.037-1.317). Area under the ROC curve was 0.97 (95%CI, 0.94-0.99). A cutoff value of 6% of CPA had 82% sensitivity and 95% specificity for decompensation. In the 89 patients with hepatic venous pressure gradient (HVPG) measurement, similar results were obtained. When both cutoffs of CPA > 6% and HVPG ≥ 6 mm Hg were used, all patients decompensated. Thus, CPA at 1-year biopsy after liver transplantation was highly predictive of clinical outcome in patients infected with hepatitis C virus who underwent transplantation, better than Ishak stage or HVPG.

POSTERSvascular liver disorders (p = ns).During the follow up (31.5±33 months), the latter group experienced a complete resolution of ascites and normalization of liver function; on the contrary, in the 5 patients with underlying liver disease only 3 had partial resolution of ascites.There were three deaths out of 5 patients in the patients with underlying liver disease compared to 1 death among 8 patients with vascular liver disorders.Conclusions: LT recipients with portal hypertension due to allograft dysfunction had a poor outcome in the absence of retransplantation and portal decompression provides only marginal clinical benefit.On the contrary, TIPS if indicated for the presence of vascular liver disease after LT seems to be effective and provide long term-benefit.