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To analyze the perioperative differences in a consecutive cohort of liver transplant recipients (LTRs) classified according to the indication of transplantation, and assess their impact upon early mortality 90 days after transplantation.A retrospective cohort study was carried out.A single university hospital.A total of 892 consecutive adult LTRs were included from January 1995 to December 2017. Recipients with acute liver failure, retransplantation or with grafts from non-brain death donors were excluded. Two cohorts were analyzed according to transplant indication: hepatocellular carcinoma (HCC-LTR) versus non-carcinoma (non-HCC-LTR).Recipient early mortality was the primary endpoint. The pretransplant recipient and donor characteristics, surgical time data and postoperative complications were analyzed as independent predictors.The crude early postoperative mortality rate related to transplant indication was 13.3% in non-HCC-LTR and 6.6% in HCC-LTR (non-adjusted HR=2.12, 95%CI=1.25-3.60; p=0.005). Comparison of the perioperative features between the cohorts revealed multiple differences. Multivariate analysis showed postoperative shock (HR=2.02, 95%CI=1.26-3.24; p=0.003), early graft vascular complications (HR=4.01, 95%CI=2.45-6.56; p0.001) and multiorgan dysfunction syndrome (HR=18.09, 95%CI=10.70-30.58; p0.001) to be independent predictors of mortality. There were no differences in early mortality related to transplant indication (adjusted HR=1.60, 95%CI=0.93-2.76; p=0.086).The crude early postoperative mortality rate in non-HCC-LTR was higher than in HCC-LTR, due to a greater incidence of postoperative complications with an impact upon mortality (shock at admission to intensive care and the development of multiorgan dysfunction syndrome).

Aims To identify pretransplant predictors of early mortality (90 days after transplantation) and evaluate their discriminating capacity in adult liver transplant recipients (LTRs). Design An observational, retrospective, nested cases–controls study from a consecutive cohort of LTRs was carried out. Setting University hospital. Patients All consecutive LTR between January 2003 and December 2016 were eligible for inclusion. Patients with acute liver failure, previous graft dysfunction, simultaneous multiple organ transplantation, non-heart beating donors, and those needing urgent retransplantation during the study period were excluded. The analysis comprised 471 patients. Main variables of interest Pretransplant characteristics were the main variables of interest. The LTR were grouped according to the dependent variable (early mortality). Multivariate logistic regression analysis was conducted to identify predictors of early mortality. The discriminating capacity of the models obtained was evaluated by comparing ROC curves (models versus MELD-Na). Results The MELD-Na score (OR = 1.069, 95% CI = 1.014–1.127), age >60 years (OR = 2.479, 95% CI = 1.226–5.015), and LTR height Conclusions In LTR due to decompensated cirrhosis, the MELD-Na score, age >60 years, and height

Resumen Objetivos Identificar predictores pretrasplante de mortalidad precoz (90 dias postrasplante) y evaluar su capacidad discriminante en receptores adultos de trasplante hepatico (RTH). Diseno Estudio observacional, retrospectivo, de casos y controles anidados sobre una cohorte consecutiva de RTH. Ambito Hospital Universitario. Pacientes Desde enero de 2003 a diciembre de 2016, todos los receptores adultos de trasplante hepatico fueron elegibles para inclusion. Fueron excluidos los RTH por fallo hepatico agudo, disfuncion de un injerto previo, trasplante simultaneo de organos, de donantes en asistolia, y aquellos que precisaron retrasplante durante el periodo de estudio. Para el analisis se incluyeron 471 pacientes. Principales variables de interes Las caracteristicas pretrasplante fueron las variables de interes. Los RTH fueron agrupados de acuerdo con la variable dependiente (mortalidad precoz). Los predictores se obtuvieron mediante analisis multivariante de regresion logistica. La capacidad discriminante de los modelos obtenidos se evaluo mediante comparacion de curvas ROC. Resultados Se identificaron como predictores independientes de mortalidad precoz: la puntuacion MELD-Na (OR=1,069; IC95%=1,014-1,127), la edad mayor de 60 anos (OR=2,479; IC95%= 1,226-5,015), y la estatura del RTH inferior a 163 cm (OR=4,092; IC95%=2,115-7,917), considerandose el motivo del trasplante (carcinoma hepatocelular o cirrosis descompensada) como variable de confusion. Conclusiones En los RTH por cirrosis descompensada, la puntuacion MELD-Na, la edad mayor de 60 anos y la estatura del receptor inferior a 163 cm son predictores independientes de mortalidad precoz. Esos predictores producen un modelo que clasifica a los pacientes significativamente mejor que el MELD-Na en relacion con la mortalidad precoz.

Carbapenemase-producing Enterobacterales and specifically Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) are rapidly spreading worldwide. The prognosis of ventilator-associated pneumonia (VAP) caused by KPC-Kp is not well known. Our study tries to assess whether ventilator-associated pneumonia caused by a KPC-Kp strain is associated with higher all-cause mortality than that caused by carbapenem-susceptible isolates. This is a retrospective cohort study of patients with VAP due to K. pneumoniae from a 35-bed polyvalent intensive care unit in a university hospital (>40,000 annual admissions) between January 2012 and December 2016. Adjusted multivariate analysis was used to study the association of KPC-Kp with 30-day all-cause mortality (Cox regression). We analyze 69 cases of K. pneumoniae VAP, of which 39 were produced by a KPC-Kp strain with high-level resistance to meropenem (MIC > 16 mg/ml). All-cause mortality at 30 days was 41% in the KPC-Kp group (16/39) and 33.3% in the carbapenem-susceptible cases (10/30). KPC-Kp etiology was not associated with higher mortality when controlled for confounders (adjusted hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.46 to 3.41). Adequate targeted therapy (HR, 0.03; 95% CI, Supported by Plan Nacional de I+D+i 2013 to 2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001; RD16/0016/0008). Cofinanced by the European Regional Development Regional Fund “A way to achieve Europe,” Operational Programme Smart Growth 2014 to 2020. B.G.-G. is a recipient of the “Río Hortega” grant by the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III.

(1) Background: The mammalian target of rapamycin (mTOR) pathway activation is critical for hepatocellular carcinoma (HCC) progression. We aimed to evaluate the mTOR tissue expression in liver transplant (LT) patients and to analyse its influence on post-LT outcomes. (2) Methods: Prospective study including a cohort of HCC patients who underwent LT (2012&ndash, 2015). MTOR pathway expression was evaluated in the explanted liver by using the &ldquo, PathScan Intracellular Signalling Array Kit&rdquo, (Cell Signalling). Kaplan-Meier and Cox regression analyses were performed to evaluate post-LT HCC recurrence. (3) Results: Forty-nine patients were included (average age 56.4 &plusmn, 6, 14.3% females). Phospho-mTOR (Ser2448) was over-expressed in peritumoral tissue as compared with tumoral tissue (&Delta, Signal 22.2%, p &lt, 0.001). The mTOR activators were also increased in peritumoral tissue (phospho-Akt (Thr308) &Delta, Signal 18.2%, p = 0.004, phospho-AMPKa (Thr172) &Delta, Signal 56.3%, p &lt, 0.001), as they were the downstream effectors responsible for cell growth/survival (phospho-p70S6K (Thr389) &Delta, Signal 33.3%, p &lt, 0.001 and phospho-S6RP (Ser235/236) &Delta, Signal 54.6%, p &lt, 0.001). MTOR expression was increased in patients with multinodular HCC (tumoral p = 0.01, peritumoral p = 0.001). Increased phospho-mTOR in tumoral tissue was associated with higher HCC recurrence rates after LT (23.8% vs. 5.9% at 24 months, p = 0.04). (4) Conclusion: mTOR pathway is over-expressed in patients with multinodular HCC and is it associated with increased post-LT tumour recurrence rates.

Background & aims Sirolimus should not be started within the first month after liver transplantation (LT) because of an increased risk of adverse outcomes. The evidence regarding everolimus is lacking but the manufacturer transposed the same warning. We aimed to evaluate the safety of everolimus started within the first month after LT. Methods A consecutive cohort 187 LT patients (2009–2013) with a tacrolimus-based immunosuppression was evaluated. Patients starting everolimus within the first month after LT (n = 33; 17.6%) were compared with those starting everolimus thereafter (n = 25; 13.4%) or not receiving everolimus (n = 129; 69%). The median follow-up after LT was 21 months (IQR 7–36). Prospective outcomes were evaluated by using Kaplan–Meier curves and Cox's regression. Results The incidence of hepatic artery thrombosis was not significantly different in patients early treated with everolimus when compared with the remaining cohort (0% vs 9.1%; p = 0.12). Other vascular complications occurred in 9.1% of patients with early everolimus vs 7.3% in the remaining cohort (p = 0.72). No wound healing complications were detected with early everolimus. There were similar rates of incisional hernia (p = 0.31), infections (p = 0.15), renal impairment (p = 0.37), and histologically-proven acute rejection (p = 0.24) between groups. The rates of hyperlipidemia were increased with early everolimus (29.9% vs 16.5% at 3 years; p = 0.018). Graft loss and mortality rates were similar between groups (p = 0.34 and p = 0.94 respectively), after adjusting for possible confounding factors. Conclusions Everolimus combined with reduced tacrolimus proved to be safe within the first month after LT. Future trials may be allowed to implement everolimus early after LT.

Ceftazidime-avibactam (CAZ-AVI) is a recently approved β-lactam–β-lactamase inhibitor combination with the potential to treat serious infections caused by carbapenem-resistant organisms. Few patients with such infections were included in the CAZ-AVI clinical trials, and clinical experience is lacking. We present a case series of patients with infections caused by carbapenem-resistant Enterobacteriaceae (CRE) or Pseudomonas aeruginosa (CRPa) who were treated with CAZ-AVI salvage therapy on a compassionate-use basis. Physicians who had prescribed CAZ-AVI completed a case report form. We used descriptive statistics to summarize patient characteristics and treatment outcomes. We used the Wilcoxon rank sum test and Fisher's exact test to compare patients by treatment outcome. The sample included 36 patients infected with CRE and two with CRPa. The most common infections were intra-abdominal. Physicians categorized 60.5% of patients as having life-threatening infections. All but two patients received other antibiotics before CAZ-AVI, for a median of 13 days. The median duration of CAZ-AVI treatment was 16 days. Twenty-five patients (65.8%) concurrently received other antibiotics to which their pathogen was nonresistant in vitro . Twenty-eight patients (73.7%, 95% confidence interval [CI], 56.9 to 86.6%) experienced clinical and/or microbiological cure. Five patients (20.8%) with documented microbiological cure died, whereas 10 patients (71.4%) with no documented microbiological cure died ( P = 0.01). In three-quarters of cases, CAZ-AVI (alone or combined with other antibiotics) cured infections caused by carbapenem-resistant organisms, 95% of which had failed previous therapy. Microbiological cure was associated with improved survival. CAZ-AVI shows promising clinical results for infections for which treatment options are limited.

Resumen Objetivo Describir la utilizacion de la oxigenacion por membrana extracorporea (ECMO) en la insuficiencia respiratoria refractaria Diseno Estudio prospectivo, observacional y multicentrico Ambito Servicios de Medicina Intensiva (SMI) de 148 hospitales espanoles Pacientes Enfermos ingresados entre las semanas 50-52 del 2010 y la 1-4 del 2011 con el diagnostico de gripe A (H1N1) que recibieron soporte respiratorio con ECMO Principales variables de interes: caracteristicas clinicas, gasometricas, complicaciones y supervivencia de los pacientes con ECMO Resultados Ingresaron 300 pacientes y se ventilaron 239 (79,6%). Solo cinco SMI disponian de la tecnica. Se indico la ECMO en nueve (3% del total y 3,2% de los ventilados). En el 77,7% se empleo previamente alguna tecnica de rescate frente a la hipoxemia. La canulacion mayoritaria fue veno-venosa (88,9%). Su colocacion fue precoz, tras una mediana de 4,5 dias de ventilacion mecanica. La duracion mediana de la asistencia fue de seis dias. Cuatro pacientes presentaron complicaciones asociadas a la ECMO. La mediana de estancia en el SMI y hospitalaria fue 17 y 29 dias respectivamente. En cinco pacientes (55,5%) se pudo retirar la asistencia con la ECMO. La supervivencia tanto del SMI como hospitalaria fue del 44,4%. Conclusiones El uso de la ECMO en la insuficiencia respiratoria refractaria en pacientes con gripe A (H1N1) es poco frecuente en nuestro pais. La supervivencia hospitalaria lograda con su uso permite considerarla como una posible tecnica de rescate en estos pacientes.

Objetivo: Describir la utilización de la oxigenación por membrana extracorpórea (ECMO) en la insuficiencia respiratoria refractaria Diseño: Estudio prospectivo, observacional y multicéntrico Ámbito: Servicios de Medicina Intensiva (SMI) de 148 hospitales españoles Pacientes: Enfermos ingresados entre las semanas 50-52 del 2010 y la 1-4 del 2011 con el diagnóstico de gripe A (H1N1) que recibieron soporte respiratorio con ECMO. Principales variables de interés: características clínicas, gasométricas, complicaciones y supervivencia de los pacientes con ECMO Resultados: Ingresaron 300 pacientes y se ventilaron 239 (79,6%). Solo cinco SMI disponían de la técnica. Se indicó la ECMO en nueve (3% del total y 3,2% de los ventilados). En el 77,7% se empleó previamente alguna técnica de rescate frente a la hipoxemia. La canulación mayoritaria fue veno-venosa (88,9%). Su colocación fue precoz, tras una mediana de 4,5 días de ventilación mecánica. La duración mediana de la asistencia fue de seis días. Cuatro pacientes presentaron complicaciones asociadas a la ECMO. La mediana de estancia en el SMI y hospitalaria fue 17 y 29 días respectivamente. En cinco pacientes (55,5%) se pudo retirar la asistencia con la ECMO. La supervivencia tanto del SMI como hospitalaria fue del 44,4%. Conclusiones: El uso de la ECMO en la insuficiencia respiratoria refractaria en pacientes con gripe A (H1N1) es poco frecuente en nuestro país. La supervivencia hospitalaria lograda con su uso permite considerarla como una posible técnica de rescate en estos pacientes. Objective: To describe the use of extracorporeal membrane oxygenation (ECMO) in refractory respiratory failure. Design: A prospective, observational, multi-center study was carried out. Setting: Intensive Care Units (ICU) in 148 Spanish hospitals. Patients: Subjects admitted during epidemic weeks 50-52 of 2010 and weeks 1-4 of 2011, receiving respiratory support with ECMO. Main variables of interest: Clinical and blood gas features, complications and survival of patients with ECMO. Results: Out of 300 ICU admitted patients, 239 (79.6%) were mechanically ventilated. ECMO was available in only 5 ICUs. Nine patients were treated with ECMO (3% of the total and 3.2% of the ventilated patients). In 77.7% of the cases some hypoxemia rescue technique was previously used. ECMO was initiated when ARDS proved refractory to standard treatment. ECMO therapy was started a median of 4.5 days after the onset of mechanical ventilation. The median duration of ECMO was 6 days. Veno-venous (VV) ECMO was the most frequent cannulation mode (88.9%). Four patients had complications associated with ECMO therapy. The median ICU and hospital stay was 17 and 29 days, respectively. In five patients (55.5%), ECMO assistance was satisfactory suspended. The ICU and hospital survival rate was 44.4%. Conclusions: The use of ECMO in refractory respiratory failure in patients with influenza A (H1N1) is rare in Spain. The hospital survival achieved with its use allows it to be regarded as a possible rescue technique in these patients.

The present article is an update of the literature on invasive fungal infections caused by filamentous fungi in critically ill patients. A multidisciplinary group of Spanish physicians with an interest in these infections organized a joint session and selected the most important papers produced lately in the field. Each article was analyzed and discussed by one of the members of the panel. Studies from the fields of causative microorganisms, epidemiology, and diagnosis are discussed; including the assessment of different strategies for the early identification and treatment of patients at risk of fungal infections by filamentous fungi in the intensive care unit setting.

The incidence of invasive mycoses following solid organ transplant (SOT) ranges from 5 to 42% depending on the organ transplanted. Despite the increasing impact of viral infections in SOT, fungal infections still have a main role in transplant recipients. In fact, they remain a common cause of morbidity and mortality in the early and late post-transplant periods. Aspergillus spp. and Candida spp. account for most IFI, but recent epidemiological and clinical studies suggest the emergence of mycelia fungi other than Aspergillus as well as resistant strains of Candida in these patients. Due to the difficulty in making a definitive diagnosis, the treatment is sometimes delayed or is not prescribed (post-mortem diagnosis). Serological and molecular detection of Aspergillus antigens or fungal DNA, in blood and/or BAL samples, may improve the diagnosis of pulmonary aspergillosis, but in SOT the sensitivity is variable and more studies are needed. Another pendent issue is antifungal prophylaxis in SOT recipients; it is unknown which is the best agent or the time duration, and in which receptors must be applied. Treatment combining AmB preparations, newer antifungal drugs, early surgical resection of infected tissue and discontinuation or modulation of immunosuppressive treatment can to be necessary in selected patients and in certain occasions, and all of them may improve prognosis of IFI. However, there are two main handicaps in the management of FI in transplant recipients: firstly, to establish an early diagnosis, secondly, delays in applying early treatment with antifungal drugs. Development of new early diagnostic tools more precise and well-designed multicenter evaluations of diagnostic methods and therapeutic regimens available at present are the important work in the next 3-5 years. This review highlights changing spectrum of invasive fungal infections, risk factors, antifungal prophylaxis, and treatment following SOT.

We conducted a prospective, randomized clinical trial among liver transplant patients to assess the efficacy and safety of weekly sulfadoxine/pyrimethamine compared with daily trimethoprim-sulfamethoxazole in the prevention of Pneumocystis carinii pneumonia. The studied drugs were given during 6 months after transplantation. One hundred twenty patients were included. None of the 60 patients receiving weekly sulfadoxine/pyrimethamine developed Pneumocystis carinii pneumonia, whereas two cases (3%) developed among the 60 patients who received trimethoprim-sulfamethoxazole. For both patients, the studied medication had been discontinued several weeks earlier because of adverse effects. No differences were observed in the incidence of adverse effects. We conclude that weekly sulfadoxine/pyrimethamine is as effective and safe as is daily trimethoprim-sulfamethoxazole in the prophylaxis of Pneumocystis carinii pneumonia after liver transplantation.

Postoperative Model for End-stage Liver Disease (MELD) values have never been assessed to predict very early (1 week) death after liver transplantation (OLT). We retrospectively reviewed 275 consecutive OLTs performed in 252 recipients reported in a prospective database. We calculated the MELD score (pre-MELD) and consecutive postoperative MELD (post-MELD) scores computed daily during the first postoperative week and on days 15 and 30 after OLT. Post-MELD scores from nonsurviving recipients displayed on a scatterplot of immediate probability of death were adjusted to the best goodness-of-fit curve, and, finally, depicted graphically as a receiver operating characteristic (ROC) curve. Nonsurviving recipients showed higher post-MELD scores: day 1: 23.5 versus 16.6 (P = .05); day 3: 25.1 versus 12.5 (P = .000); day 5: 25.7 versus 11.8 (P = .000); and day 7: 22.1 versus 10.2 (P = .000). Overall comparisons were performed using a time-dependent general linear regression model, revealing higher post-MELD scores for nonsurviving recipients, irrespective of postoperative time (P = .002). The best goodness-of-fit curve was displayed when adjusting to a theoretical exponential regression curve calculated as follows: Probability of dying within the first week (%) = 3.36 x e(0.079 x (post-MELD)) (r = .89; P = .000). The area under the ROC curve was 0.783 (95% confidence interval, 0.630-0.935; P = .001). The model had a positive predictive value of 82.3%, a negative predictive value of 33.1%, and an accuracy of 79.2%. In conclusion, this study corroborated the suggestion that the MELD score may serve as a reliable tool to assess very early death after OLT.

Received 8 October 2010; returned 9 November 2010; revised 2 December 2010; accepted 6 December 2010Objectives: The impact of oseltamivir on mortality in critically ill patients with 2009 pandemic influenza A(2009 H1N1) is not clear. The main objective of this study was to investigate the relationship between thetiming of antiviral administration and intensive care unit (ICU) outcomes.Methods: Prospective, observational study of a cohort of ICU patients with confirmed 2009 H1N1 infection.Clinical data, treatment and outcome were compared between patients receiving early treatment (ET) withoseltamivir, initiated within 2 days, and patients administered late treatment (LT), initiated after this timepoint.Multivariate analysis and propensity score were used to determine the effect of oseltamivir on ICU mortality.Results: Six hundred and fifty-seven patients were enrolled. Four hundred and four (61.5%) patients requiredmechanical ventilation (MV; mortality 32.6%). Among them, 385 received effective antiviral therapy andwere included in the study group. All patients received oseltamivir for a median duration of 10 days (interquar-tile range 8–14 days). Seventy-nine (20.5%) ET patients were compared with 306 LT patients. The two groupswere comparable in terms of main clinical variables. ICU length of stay (22.7+16.7 versus 18.4+14.2 days;P¼0.03), hospital length of stay (34.0+20.3 versus 27.2+18.2 days; P¼0.001) and MV days (17.4+15.2versus 14.0+12.4; P¼0.04) were higher in the LT group. ICU mortality was also higher in LT (34.3%) than inET (21.5%; OR¼1.9; 95% CI 1.06–3.41). A multivariate model identified ET (OR¼0.44; 95% CI 0.21–0.87) asan independent variable associated with reduced ICU mortality. These results were confirmed by propensityscore analysis (OR¼0.44; 95% CI 0.22–0.90; P,0.001).Conclusions: Our findings suggest that early oseltamivir administration was associated with favourableoutcomes among critically ill ventilated patients with 2009 H1N1 virus infection.Keywords: antiviral treatment, prognosis, pneumonia

S Grau,1 JC Pozo,2 E Romá,2 M Salavert,3 JA Barrueta,4 C Peral,4 I Rodriguez,5 D Rubio-Rodríguez,6 C Rubio-Terrés6 1Hospital del Mar (IMIM), Barcelona, 2Hospital Universitario Reina Sofía, Córdoba, 3Hospital Universitario y Politécnico La Fe, Valencia, 4Pfizer SLU, Alcobendas, 5Trial Form Support, Madrid, 6Health Value, Madrid, Spain Objective: To estimate the cost-effectiveness of three echinocandins (anidulafungin, caspofungin, and micafungin) and generic fluconazole in the treatment of nonneutropenic adult patients with candidemia and/or invasive candidiasis in intensive care units in Spain. Materials and methods: A decision-tree model was applied. The success and safety (hepatic and renal adverse effects) of first-line treatments were obtained from meta-analyses and systematic reviews of clinical trials. In the case of failure, a second-line treatment (liposomal amphotericin B after the echinocandins, or one of the echinocandins after fluconazole) was administered. The duration of the treatments (14 days total) was established by a panel of clinical experts using the Delphi method and according to Infectious Diseases Society of America guidelines. The cost of the medications and renal toxicity were considered. Deterministic and probabilistic sensitivity analysis using Monte Carlo simulations were carried out. Results: The total cost of the treatment of candidemia and/or invasive candidiasis with anidulafungin, caspofungin, micafungin, and fluconazole was €5,483, €5,968, €6,231, and €2,088, respectively. Anidulafungin was the dominant treatment (more effective, less expensive) compared to micafungin and caspofungin. The cost of achieving one more patient successfully treated with anidulafungin, caspofungin, and micafungin compared to fluconazole was €17,199, €23,962, and €27,339, respectively. The result remained stable, despite modification of the duration of the first-line and second-line treatments, as well as most of the dosing regimens. The probabilistic analysis also remained stable. Conclusion: In accordance with this economic study, anidulafungin would produce savings and would be the dominant treatment compared with micafungin and caspofungin in nonneutropenic adult patients with candidemia and/or invasive candidiasis in intensive care units in Spain. Keywords: invasive candidiasis, candidemia, anidulafungin, micafungin, caspofungin, fluconazole, cost-effectiveness analysis