Cardiac Adverse Events and Remdesivir in Hospitalized Patients with Coronavirus Disease 2019 (COVID-19): A Post Hoc Safety Analysis of the Randomized DisCoVeRy Trial.

BACKGROUND: We aimed to evaluate the cardiac adverse events (AEs) in hospitalized patients with Coronavirus Disease 2019 (COVID-19) receiving remdesivir plus standard of care (SoC) compared to SoC alone (control), as an association was noted in some cohort studies and disproportionality analyses of safety databases. METHODS: This post-hoc safety analysis is based on data from the multicenter, randomized, open-label, controlled DisCoVeRy trial in hospitalized patients with COVID-19 (NCT04315948). Any first AE occurring between randomization and day 29 in the modified intention-to-treat (mITT) population randomized to either remdesivir or control group was considered. Analysis was performed using Kaplan-Meier survival curves and Kaplan-Meier estimates were calculated for event rates. RESULTS: Cardiac AEs were reported in 46 (11.2%) of 410 and 48 (11.3%) of 423 patients in the mITT population (n = 833) enrolled in the remdesivir and control groups, respectively. The difference between both groups was not significant (HR 1.0, 95% CI 0.7-1.5, p = 0.98), even when evaluating serious and non-serious cardiac AEs separately. The majority of reports in both groups were of arrhythmic nature (remdesivir, 84.8%; control, 83.3%) and were associated with a favorable outcome. There was no significant difference between remdesivir and control groups in the occurrence of different cardiac AE subclasses, including arrhythmic events (HR 1.1, 95% CI: 0.7-1.7, p = 0.68). CONCLUSIONS: Remdesivir treatment was not associated with an increased risk of cardiac AEs, whether serious or not, and regardless of AE severity, compared to control, in patients hospitalized with moderate or severe COVID-19. This is consistent with the results of other randomized controlled trials and meta-analyses.

Cardiac Tamponade Complicating Extracorporeal Membrane Oxygenation: An Extracorporeal Life Support Organization Registry Analysis.

OBJECTIVES: Cardiac tamponade is a potentially life-threatening complication during extracorporeal membrane oxygenation (ECMO). In this study, the authors assessed the incidence, patient characteristics, and risk factors for mortality of cardiac tamponade during ECMO. DESIGN: The authors queried the Extracorporeal Life Support Organization (ELSO) Registry from 1997 to 2021 for all adults with cardiac tamponade as a reported complication during ECMO. PARTICIPANTS: Cardiac tamponade was reported in 2,176 (64% men; 53.8 ± 0.33 years) of 84,430 adults (2.6%). MEASUREMENTS AND MAIN RESULTS: Venoarterial ECMO was the main configuration (78%), followed by venovenous ECMO (VV ECMO) (18%), for cardiac (67%), pulmonary (21%) support, and extracorporeal cardiopulmonary resuscitation (ECPR) (12%). Percutaneous cannulation was performed in 51%, with the femoral vein and femoral artery as the most common sites for drainage and return cannulae, with dual-lumen cannulae in 39% of VV ECMO. Hospital survival was lower (35% v 49%; p < 0.01) when compared with that of all adults from the ELSO Registry. In multivariate analysis, age, aortic dissection and/or rupture, COVID-19, ECPR, pre-ECMO renal-replacement therapy, and prone position are associated with hospital mortality, whereas ECMO for pulmonary support is associated with hospital survival. Similarly, renal, cardiovascular, metabolic, neurologic, and pulmonary complications occurred more frequently in nonsurvivors. CONCLUSIONS: Cardiac tamponade is a rare complication during ECMO that, despite being potentially reversible, is associated with high hospital mortality. Venoarterial ECMO is the most common configuration. ECMO for pulmonary support was associated with higher survival, and ECPR was associated with higher mortality. In these patients, other ECMO-related complications were frequently reported and associated with hospital mortality.

Ultrasonography to Access Diaphragm Dysfunction and Predict the Success of Mechanical Ventilation Weaning in Critical Care: A Narrative Review.

INTRODUCTION: Weaning failure is common in mechanically ventilated patients, and whether ultrasound (US) can predict weaning outcome remains controversial. This review aims to evaluate the diaphragmatic function measured by US as a predictor of weaning outcome. METHODS: PubMed was searched to identify original articles about the use of diaphragmatic US in ICU patients. A total of 61 citations were retrieved initially; available data of 26 studies were included in this review. RESULTS: To assess diaphragmatic dysfunction in adults, six studies evaluated excursion, five evaluated thickening fraction, and both in nine. Despite heterogeneity in the diagnostic accuracy of diaphragm US among the studies, the sonographic indices showed good diagnostic performance for predicting weaning outcome. CONCLUSIONS: Diaphragmatic US can be a useful and accurate tool to detect diaphragmatic dysfunction in critically ill patients and predict weaning outcome.

Evaluation of urinary cysteinyl leukotrienes as biomarkers of severity and putative therapeutic targets in COVID-19 patients.

BACKGROUND: Cysteinyl leukotrienes (CysLT) are potent inflammation-promoting mediators, but remain scarcely explored in COVID-19. We evaluated urinary CysLT (U-CysLT) relationship with disease severity and their usefulness for prognostication in hospitalized COVID-19 patients. The impact on U-CysLT of veno-venous extracorporeal membrane oxygenation (VV-ECMO) and of comorbidities such as hypertension and obesity was also assessed. METHODS: Blood and spot urine were collected in "severe" (n = 26), "critically ill" (n = 17) and "critically ill on VV-ECMO" (n = 17) patients with COVID-19 at days 1-2 (admission), 3-4, 5-8 and weekly thereafter, and in controls (n = 23) at a single time point. U-CysLT were measured by ELISA. Routine markers, prognostic scores and outcomes were also evaluated. RESULTS: U-CysLT did not differ between groups at admission, but significantly increased along hospitalization only in critical groups, being markedly higher in VV-ECMO patients, especially in hypertensives. U-CysLT values during the first week were positively associated with ICU and total hospital length of stay in critical groups and showed acceptable area under curve (AUC) for prediction of 30-day mortality (AUC: 0.734, p = 0.001) among all patients. CONCLUSIONS: U-CysLT increase during hospitalization in critical COVID-19 patients, especially in hypertensives on VV-ECMO. U-CysLT association with severe outcomes suggests their usefulness for prognostication and as therapeutic targets.

Treatment of invasive candidiasis in the era of Candida resistance.

PURPOSE OF REVIEW: The increasing incidence of drug-resistant Candida brings a new challenge to the treatment of invasive candidiasis. Although cross-resistance among azoles and echinocandins was generally uncommon, reports of multidrug-resistant (MDR) Candida markedly increased in the last decade. The purpose of this review is to understand mechanisms and risk factors for resistance and how to tackle antifungal resistance. RECENT FINDINGS: The paper describes the action of the three main classes of antifungals - azoles, echinocandins and polyenes - and Candida's mechanisms of resistance. The current evolution from cross-resistance to multiresistance among Candida explains the modern glossary - multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) - imported from bacteria. MDR Candida most commonly involves acquired resistance in species with intrinsic resistance, therefore it mostly involves C. glabrata, C. parapsilosis, C. krusei, C guilliermondii or C. auris , which is intrinsically multidrug resistant. Finally, strategies to tackle antifungal resistance became clearer, ideally implemented through antifungal stewardship. SUMMARY: Avoiding antifungal's overuse and selecting the best drug, dose and duration, when they are needed, is fundamental. Knowledge of risk factors for resistance, microbiological diagnosis to the species, use of susceptibility test supported by antifungal stewardship programs help attaining effective therapy and sustaining the effectiveness of the current antifungal armamentarium.

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. METHODS: Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. RESULTS: Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49-69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI - 0.1% [- 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (- 3.2% [- 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. CONCLUSION: This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 ).

Creatinine Clearance in Acute Brain Injury: A Comparison of Methods.

BACKGROUND: Currently, the measurement of glomerular filtration rate is very complex and costly, so its daily evaluation is performed using endogenous markers, of which creatinine is the most frequently used. It allows the estimation of glomerular filtration rate by means of its clearance or by formulas based on its serum and urine concentration. Augmented renal clearance (ARC) is frequent among critically ill patients and is defined as creatinine clearance (CrCl) > 130 ml/min/1.73 m2. The aim of this study was to compare measured CrCl (MCC) and estimated CrCl obtained with the Cockcroft-Gault formula (CG), the Modification of Diet in Renal Disease Study equation (MDRD), and the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) in patients with severe traumatic brain injury and nontraumatic subarachnoid hemorrhage. The second aim was to assess the incidence of ARC in this population of neurocritical patients. METHODS: This was a prospective, observational, single center study from a cohort of 74 patients admitted to the neurocritical intensive care unit due to traumatic brain injury or subarachnoid hemorrhage. Serum creatinine (at 7 a.m.) and a 6-h urine collection were analyzed, and CrCl was measured and estimated by using CG, MDRD, and CKD-EPI. The intraclass correlation coefficient (ICC) was evaluated for each pair, and Bland-Altman plots were used to assess clinical significance. RESULTS: Among 74 patients, the median age was 53 (interquartile range [IQR] 36-65), and the median Glasgow Coma Scale score at admission was 6. The median MCC at admission was 176 (IQR 135-214). The medians of CG, MDRD and CKD-EPI were, respectively, 129 ml/min/1.73 m2 (IQR 95-176), 158 (IQR 115-202), and 116 (97-132). An ICC was applied to evaluate the correlation between MCC and estimated methods and showed a weak correlation between MCC and estimated CrCl obtained with the three different methods. The strongest ICC statistical correlation was found between MCC and MDRD, and the weakest correlation was found between MCC and CKD-EPI. Bland-Altman plots showed that differences between each pair were not clinically acceptable. ARC was present in 78% of measurements, using MCC. A weak correlation was observed between MCC and calculated CrCl. CG, MDRD, and CKD-EPI overestimated MCC when MCC ≤ 130 ml/min/1.73 m2 and underestimated it when MCC > 130 ml/min/1.73 m2. CONCLUSIONS: In this population, there was a weak statistical correlation between measured and estimated methods. In patients with ARC, formulas underestimated MCC. MCC should probably be the preferred methodology for renal function assessment in the clinical setting to better adjust drug dosage and guarantee drug effectiveness.

Effect of remdesivir on viral dynamics in COVID-19 hospitalized patients: a modelling analysis of the randomized, controlled, open-label DisCoVeRy trial.

BACKGROUND: The antiviral efficacy of remdesivir in COVID-19 hospitalized patients remains controversial. OBJECTIVES: To estimate the effect of remdesivir in blocking viral replication. METHODS: We analysed nasopharyngeal normalized viral loads from 665 hospitalized patients included in the DisCoVeRy trial (NCT04315948; EudraCT 2020-000936-23), randomized to either standard of care (SoC) or SoC + remdesivir. We used a mathematical model to reconstruct viral kinetic profiles and estimate the antiviral efficacy of remdesivir in blocking viral replication. Additional analyses were conducted stratified on time of treatment initiation (≤7 or >7 days since symptom onset) or viral load at randomization (< or ≥3.5 log10 copies/104 cells). RESULTS: In our model, remdesivir reduced viral production by infected cells by 2-fold on average (95% CI: 1.5-3.2-fold). Model-based simulations predict that remdesivir reduced time to viral clearance by 0.7 days compared with SoC, with large inter-individual variabilities (IQR: 0.0-1.3 days). Remdesivir had a larger impact in patients with high viral load at randomization, reducing viral production by 5-fold on average (95% CI: 2.8-25-fold) and the median time to viral clearance by 2.4 days (IQR: 0.9-4.5 days). CONCLUSIONS: Remdesivir halved viral production, leading to a median reduction of 0.7 days in the time to viral clearance compared with SoC. The efficacy was larger in patients with high viral load at randomization.

Different epidemiology of bloodstream infections in COVID-19 compared to non-COVID-19 critically ill patients: a descriptive analysis of the Eurobact II study.

BACKGROUND: The study aimed to describe the epidemiology and outcomes of hospital-acquired bloodstream infections (HABSIs) between COVID-19 and non-COVID-19 critically ill patients. METHODS: We used data from the Eurobact II study, a prospective observational multicontinental cohort study on HABSI treated in ICU. For the current analysis, we selected centers that included both COVID-19 and non-COVID-19 critically ill patients. We performed descriptive statistics between COVID-19 and non-COVID-19 in terms of patients' characteristics, source of infection and microorganism distribution. We studied the association between COVID-19 status and mortality using multivariable fragility Cox models. RESULTS: A total of 53 centers from 19 countries over the 5 continents were eligible. Overall, 829 patients (median age 65 years [IQR 55; 74]; male, n = 538 [64.9%]) were treated for a HABSI. Included patients comprised 252 (30.4%) COVID-19 and 577 (69.6%) non-COVID-19 patients. The time interval between hospital admission and HABSI was similar between both groups. Respiratory sources (40.1 vs. 26.0%, p < 0.0001) and primary HABSI (25.4% vs. 17.2%, p = 0.006) were more frequent in COVID-19 patients. COVID-19 patients had more often enterococcal (20.5% vs. 9%) and Acinetobacter spp. (18.8% vs. 13.6%) HABSIs. Bacteremic COVID-19 patients had an increased mortality hazard ratio (HR) versus non-COVID-19 patients (HR 1.91, 95% CI 1.49-2.45). CONCLUSIONS: We showed that the epidemiology of HABSI differed between COVID-19 and non-COVID-19 patients. Enterococcal HABSI predominated in COVID-19 patients. COVID-19 patients with HABSI had elevated risk of mortality. Trial registration ClinicalTrials.org number NCT03937245 . Registered 3 May 2019.

Depressive and Anxiety Symptoms in Severe COVID-19 Survivors: A Prospective Cohort Study.

The coronavirus disease 2019 (COVID-19) has rapidly spread worldwide, leading to increased concerns about long-term patients' neuropsychiatric consequences. This study aims to describe the presence of depressive and anxiety symptoms in severe COVID-19 survivors and to identify associated baseline, in-hospital and post-discharge factors. This study is part of the MAPA longitudinal project conducted with severe COVID-19 patients admitted in Intensive Care Medicine Department (ICMD) of a University Hospital (CHUSJ) in Porto, Portugal. Patients with ICMD length of stay ≤ 24 h, terminal illness, major auditory loss or inability to communicate at follow-up assessment were excluded. All participants were assessed by telephone post-discharge (median = 101 days), with a comprehensive protocol assessing depressive and anxiety symptoms, cognition, Intensive Care Unit (ICU) memories recall and health-related quality of life. Out of a sample of 56 survivors (median age = 65; 68% males), 29% and 23% had depressive and anxiety symptoms, respectively. Depressive and anxiety symptoms were significantly more prevalent among younger survivors and were associated with cognitive complaints, emotional and delusions ICU memories and fear of having COVID-19 sequelae, sleep problems and pain after discharge (all p < 0.05). An important proportion of these survivors suffers from depression and anxiety symptoms post-discharge, namely younger ones and those who reported more cognitive complaints, ICU memories, fear of having COVID-19 sequelae, sleep problems and pain. These findings highlight the importance of psychological consequences assessment and planning of appropriate and multidisciplinary follow-up care after hospitalization due to COVID-19.

Brain Multimodal Monitoring in Severe Acute Brain Injury: Is It Relevant to Patient Outcome and Mortality?

INTRODUCTION: Advanced multimodal monitoring (MMM) of the brain is recommended as a tool to manage severe acute brain injury in intensive care units (ICUs) and prevent secondary lesions. The aim of this study was to determine if MMM has implications for patient outcome and mortality. METHODS: We analyzed data on 389 patients admitted with a subarachnoid hemorrhage (SAH) or traumatic brain injury (TBI) to two general ICUs and one neurocritical care ICU (NCCU) between March 2014 and October 2016, and their subsequent outcomes. RESULTS: The study population consisted of 259 males and 130 females. Group 1, which comprised 69 patients with MMM admitted to the NCCU, was compared with group 2, which comprised patients managed without MMM. With the exceptions of the Simplified Acute Physiology Score (SAPS II) and Glasgow Coma Scale (GCS) scores, there were no differences between the two groups. Group 1 had significantly better outcomes at ICU discharge, at 28 days, and at 3 months, and also had a lower mortality rate (P < 0.05). When outcomes were adjusted for SAPS II scores, patients who had MMM had better outcomes (odds ratios 0.215 at ICU discharge, 0.234 at 28 days, 0.338 at 3 months, and 0.474 at 6 months) but no difference in mortality. CONCLUSION: Use of MMM in patients with SAH or TBI is associated with better outcomes and should be considered in the management of these patients.

Cardiac Tamponade Complicating Extracorporeal Membrane Oxygenation: A Single-Centre Experience.

BACKGROUND: Cardiac tamponade is a potential complication during extracorporeal membrane oxygenation (ECMO). METHOD: This study assessed the incidence, clinical presentation, therapeutic approach, and outcome of cardiac tamponade at a single ECMO centre during a 10-year period. RESULTS: Cardiac tamponade occurred in 11 adults (seven men; age 53 years [range, 48-60]) of 566 patients (1.9%), after 10 days (range, 3-16) of ECMO support: eight veno-venous (VV) and three veno-arterial (VA). Cardiac tamponade was suspected due to haemodynamic deterioration or collapse, and was confirmed by bedside echocardiography. In five of eight VV-ECMO (62%) patients, circulatory arrest ensued and immediate VA-ECMO conversion was performed. Definitive treatment of cardiac tamponade consisted of surgical pericardiotomy in 10 cases: sternotomy (n=8), left minithoracotomy (n=1) and subxiphoid approach (n=1); and pericardiocentesis in one patient. Cardiovascular perforation repair was performed in five patients: two right atrium, two superior vena cava and one pulmonary artery. In the remaining six patients, cardiac tamponade was associated with recent cardiac surgery (n=2), prolonged cardiopulmonary resuscitation (n=1), thoracic trauma (n=1), myopericarditis (n=1), and acute myocardial infarction (n=1). Nine (9) patients (82%) were weaned from ECMO (20 days [range, 11-25]) and eight patients (73%) survived intensive care unit (ICU) (29 days [range, 26-61]) and hospital (34 days [range, 29-81]). CONCLUSION: Cardiac tamponade is a rare but life-threatening complication during both VV-ECMO and VA-ECMO. Echocardiography plays a major role in timely diagnosis and treatment. Immediate conversion to VA-ECMO when circulatory collapse ensued and emergency sternotomy for cardiovascular perforation repair gave favourable outcomes in a high proportion of patients.

High impact of COVID-19 in long-term care facilities, suggestion for monitoring in the EU/EEA, May 2020.

Residents in long-term care facilities (LTCF) are a vulnerable population group. Coronavirus disease (COVID-19)-related deaths in LTCF residents represent 30-60% of all COVID-19 deaths in many European countries. This situation demands that countries implement local and national testing, infection prevention and control, and monitoring programmes for COVID-19 in LTCF in order to identify clusters early, decrease the spread within and between facilities and reduce the size and severity of outbreaks.

Biomarkers of fungal lung infection.

PURPOSE OF REVIEW: The incidence of lung fungal infections, namely invasive pulmonary aspergillosis (IPA) and mucormycosis, is increasing in neutropenic and nonneutropenic patients. As they are a major cause of death, early diagnosis and antifungal therapy are crucial for outcome. The role of biomarkers in the management of this infections is the scope of this review. RECENT FINDINGS: Galactomannan in bronchoalveolar lavage shows the best discriminatory power for IPA diagnosis. At baseline, serum galactomannan may be useful to predict outcome and its kinetics may be informative to assess response to antifungal therapy. Recent standardization of PCR technology brought some improvements in IPA and mucormycosis diagnosis. Several new biomarkers are currently under investigation, but none showed a better performance than current available biomarkers. To improve diagnostic accuracy, a combination of biomarkers, including galactomannan, has been proposed. SUMMARY: Biomarkers may play an important role in the early diagnosis of fungal lung infections and in prognostic assessment and response monitoring, but more research is needed to determine the best strategy for their clinical use.

Incidence and outcome of invasive candidiasis in intensive care units (ICUs) in Europe: results of the EUCANDICU project.

BACKGROUND: The objective of this study was to assess the cumulative incidence of invasive candidiasis (IC) in intensive care units (ICUs) in Europe. METHODS: A multinational, multicenter, retrospective study was conducted in 23 ICUs in 9 European countries, representing the first phase of the candidemia/intra-abdominal candidiasis in European ICU project (EUCANDICU). RESULTS: During the study period, 570 episodes of ICU-acquired IC were observed, with a cumulative incidence of 7.07 episodes per 1000 ICU admissions, with important between-center variability. Separated, non-mutually exclusive cumulative incidences of candidemia and IAC were 5.52 and 1.84 episodes per 1000 ICU admissions, respectively. Crude 30-day mortality was 42%. Age (odds ratio [OR] 1.04 per year, 95% CI 1.02-1.06, p < 0.001), severe hepatic failure (OR 3.25, 95% 1.31-8.08, p 0.011), SOFA score at the onset of IC (OR 1.11 per point, 95% CI 1.04-1.17, p 0.001), and septic shock (OR 2.12, 95% CI 1.24-3.63, p 0.006) were associated with increased 30-day mortality in a secondary, exploratory analysis. CONCLUSIONS: The cumulative incidence of IC in 23 European ICUs was 7.07 episodes per 1000 ICU admissions. Future in-depth analyses will allow explaining part of the observed between-center variability, with the ultimate aim of helping to improve local infection control and antifungal stewardship projects and interventions.

Outcome and Management of Refractory Respiratory Failure With Timely Extracorporeal Membrane Oxygenation: Single-Center Experience With Legionella Pneumonia.

OBJECTIVE:: To analyze the management and outcome of patients with refractory respiratory failure complicating severe Legionella pneumonia rescued with extracorporeal membrane oxygenation (ECMO) in our Center. DESIGN AND SETTING:: Observational study of patients with refractory respiratory failure treated with ECMO in Hospital S.João (Porto, Portugal), between November 2009 and September 2016. PARTICIPANTS:: A total of 112 patients rescued with ECMO, of which 14 had Legionella pneumonia. RESULTS:: Patients with Legionella pneumonia were slightly older than patients with acute respiratory failure of other etiologies (51 [48-56] vs 45 [35-54]), but with no significant differences in acute respiratory failure severity between groups: Pao2/Fio2 ratio 67 (60-75) versus 69 (55-85) and Respiratory Extracorporeal Membrane Oxygenation Survival Prediction score 4 (1-5) versus 2 (-1-4), respectively. Legionella pneumonia was associated with earlier ECMO initiation (days of invasive mechanical ventilation [IMV] before ECMO: 2.0 [1.0-4.0] vs 5.0 [2.0-9.5]). After IMV adjustment to "lung rest" settings, this group presented higher respiratory system (RS) static compliance (28.7 [18.8-37.4] vs 16.0 [10.0-20.8] mL/cmH2O) but required higher ECMO support (blood flow 5.0 [4.3-5.4] vs 4.2 [3.6-4.8]). Patients with Legionella pneumonia had shorter IMV (16 [14-23] vs 27 [20-42] days) and lower incidence of intensive care unit nosocomial infections (35.7% vs 64.3%), with a trend to higher hospital survival (85.7% vs 62.2%; P = .13). CONCLUSION:: In Legionella pneumonia complicated by refractory respiratory failure, ECMO support allowed patient stabilization under lung protective ventilation and high survival rates. Timely ECMO referral should be considered for Legionella pneumonia failing conventional treatment.

Aspergillus and other respiratory fungal infections in the ICU: diagnosis and management.

PURPOSE OF REVIEW: Filamentous fungi respiratory infections, namely because of Aspergillus, Mucorales, Fusarium, or Scedosporium, show rising incidence and occur more in populations which are not classically immunosuppressed. This and their persistent dismal prognosis are the focus of this review. RECENT FINDINGS: Both an early diagnosis, rooted on a high level of suspicion and based on clinical picture, radiology, cultural microbiological exams, fungal biomarkers, PCR and biopsy, and an early therapy, including immunorecovery, whenever possible, good antifungal selection, and surgery for source control, are paramount to maximize the outcome in these diseases. An evolving antifungal armamentarium and a more Pharmacokinetics/Pharmacodynamics-based antifungal prescription may help to improve the prognosis. SUMMARY: Improved awareness of these infections may increase the level of suspicion, promoting early diagnosis and treatment, ideally supported with expert stewardship.

MicroRNA-155 Amplifies Nitric Oxide/cGMP Signaling and Impairs Vascular Angiotensin II Reactivity in Septic Shock.

OBJECTIVES: Septic shock is a life-threatening clinical situation associated with acute myocardial and vascular dysfunction, whose pathophysiology is still poorly understood. Herein, we investigated microRNA-155-dependent mechanisms of myocardial and vascular dysfunction in septic shock. DESIGN: Prospective, randomized controlled experimental murine study and clinical cohort analysis. SETTING: University research laboratory and ICU at a tertiary-care center. PATIENTS: Septic patients, ICU controls, and healthy controls. Postmortem myocardial samples from septic and nonseptic patients. Ex vivo evaluation of arterial rings from patients undergoing coronary artery bypass grafting. SUBJECTS: C57Bl/6J and genetic background-matched microRNA-155 knockout mice. INTERVENTIONS: Two mouse models of septic shock were used. Genetic deletion and pharmacologic inhibition of microRNA-155 were performed. Ex vivo myographic studies were performed using mouse and human arterial rings. MEASUREMENTS AND MAIN RESULTS: We identified microRNA-155 as a highly up-regulated multifunctional mediator of sepsis-associated cardiovascular dysfunction. In humans, plasma and myocardial microRNA-155 levels correlate with sepsis-related mortality and cardiac injury, respectively, whereas in murine models, microRNA-155 deletion and pharmacologic inhibition attenuate sepsis-associated cardiovascular dysfunction and mortality. MicroRNA-155 up-regulation in septic myocardium was found to be mostly supported by microvascular endothelial cells. This promoted myocardial microvascular permeability and edema, bioenergetic deterioration, contractile dysfunction, proinflammatory, and nitric oxide-cGMP-protein kinase G signaling overactivation. In isolate cardiac microvascular endothelial cells, microRNA-155 up-regulation significantly contributes to LPS-induced proinflammatory cytokine up-regulation, leukocyte adhesion, and nitric oxide overproduction. Furthermore, we identified direct targeting of CD47 by microRNA-155 as a novel mechanism of myocardial and vascular contractile depression in sepsis, promoting microvascular endothelial cell and vascular insensitivity to thrombospondin-1-mediated inhibition of nitric oxide production and nitric oxide-mediated vasorelaxation, respectively. Additionally, microRNA-155 directly targets angiotensin type 1 receptor, decreasing vascular angiotensin II reactivity. Deletion of microRNA-155 restored angiotensin II and thrombospondin-1 vascular reactivity in LPS-exposed arterial rings. CONCLUSIONS: Our study demonstrates multiple new microRNA-155-mediated mechanisms of sepsis-associated cardiovascular dysfunction, supporting the translational potential of microRNA-155 inhibition in human septic shock.

Pharmacokinetics-pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics in critically ill patients.

Antimicrobials are among the most important and commonly prescribed drugs in the management of critically ill patients and beta-lactams are the most common antibiotic class used. Critically ill patient's pathophysiological factors lead to altered pharmacokinetics and pharmacodynamics of beta-lactams.A comprehensive bibliographic search in PubMed database of all English language articles published from January 2000 to December 2017 was performed, allowing the selection of articles addressing the pharmacokinetics or pharmacodynamics of beta-lactam antibiotics in critically ill patients.In critically ill patients, several factors may increase volume of distribution and enhance renal clearance, inducing high intra- and inter-patient variability in beta-lactam concentration and promoting the risk of antibiotic underdosing. The duration of infusion of beta-lactams has been shown to influence the fT > minimal inhibitory concentration and an improved beta-lactam pharmacodynamics profile may be obtained by longer exposure with more frequent dosing, extended infusions, or continuous infusions.The use of extracorporeal support techniques in the critically ill may further contribute to this problem and we recommend not reducing standard antibiotic dosage since no drug accumulation was found in the available literature and to maintain continuous or prolonged infusion, especially for the treatment of infections caused by multidrug-resistant bacteria.Prediction of outcome based on concentrations in plasma results in overestimation of antimicrobial activity at the site of infection, namely in cerebrospinal fluid and the lung. Therefore, although no studies have assessed clinical outcome, we recommend using higher than standard dosing, preferably with continuous or prolonged infusions, especially when treating less susceptible bacterial strains at these sites, as the pharmacodynamics profile may improve with no apparent increase in toxicity.A therapeutic drug monitoring-guided approach could be particularly useful in critically ill patients in whom achieving target concentrations is more difficult, such as obese patients, immunocompromised patients, those infected by highly resistant bacterial strains, patients with augmented renal clearance, and those undergoing extracorporeal support techniques.