Publications by authors named "Ricard Ferrer"

115 Publications

Consequences of ICU Readmission After Lung Transplantation: Beyond the Early Postoperative Period.

Arch Bronconeumol 2021 Mar 18. Epub 2021 Mar 18.

Department of Intensive Care, Vall d'Hebron University Hospital, Barcelona, Spain; Shock, Organ Dysfunction, and Resuscitation Research Group, Vall d'Hebron Research Institute, Barcelona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBER), Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.arbres.2021.03.007DOI Listing
March 2021

Pleth variability index may predict preload responsiveness in patients treated with nasal high flow: a physiological study.

J Appl Physiol (1985) 2021 Apr 15. Epub 2021 Apr 15.

Intensive Care Medicine Department, Hospital Universitari Vall d'Hebron, Spain.

The purpose of this study was to determine whether the plethysmographic variability index (PVi) can predict preload responsiveness in nasal high flow (NHF) patients (≥30 L/min) with any sign of hypoperfusion. Preload responsiveness was defined as a ≥10% increase in stroke volume (SV), measured by transthoracic echocardiography, after passive leg raising. SV and PVi were reassessed in preload responders after receiving a 250-mL fluid challenge. Twenty patients were included, and 12 patients (60%) were preload responders. Responders showed higher baseline mean PVi (24% vs. 13%; p=0.001) and higher mean PVi variation (∆PVi) after passive leg raising (6.8% vs. -1.7%; p<0.001). No differences between mean ∆PVi after passive leg raising and mean ∆PVi after fluid challenge were observed (6.8 % vs. 7.4%; p=0.24), and both values were strongly correlated (r=0.84; p<0.001). Baseline PVi and ∆PVi after passive leg raising showed excellent diagnostic accuracy identifying preload responders (AUROC 0.92 and 1.00, respectively). Baseline PVi ≥16% had a sensitivity of 91.7% and a specificity of 87.5% for detecting preload responders. Similarly, ∆PVi after passive leg raising ≥2%, had a 100% of both sensitivity and specificity. Thus, PVi might predict preload responsiveness in patients treated with NHF, suggesting that it may guide fluid administration in these patients.
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http://dx.doi.org/10.1152/japplphysiol.00614.2020DOI Listing
April 2021

Bridging animal and clinical research during SARS-CoV-2 pandemic: A new-old challenge.

EBioMedicine 2021 Apr 1;66:103291. Epub 2021 Apr 1.

Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the AUVA Research Center, Donaueschingenstrasse 13, 1200, Vienna, Austria. Electronic address:

Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.
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http://dx.doi.org/10.1016/j.ebiom.2021.103291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016444PMC
April 2021

PULMONARY FUNCTION AND RADIOLOGICAL FEATURES IN SURVIVORS OF CRITICAL COVID-19: A 3-MONTH PROSPECTIVE COHORT.

Chest 2021 Mar 4. Epub 2021 Mar 4.

Pulmonary Department, Hospital Universitari Arnau de Vilanova and Santa Maria, Lleida, Spain; Translational Research in Respiratory Medicine Group (TRRM), Lleida, Spain; Lleida Biomedical Research Institute (IRBLleida), Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain. Electronic address:

Background: More than 20% of hospitalized patients with coronavirus disease 2019 (COVID-19) develop acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) admission. The long-term respiratory sequelae in ICU survivors remain unclear.

Research Question: what are the major long-term pulmonary sequelae in critical COVID-19 survivors?

Study Design And Methods: Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated 3 months after hospitalization discharge. The follow-up comprised symptom and quality of life, anxiety and depression questionnaires, pulmonary function tests, exercise test (6-minute walking test (6MWT)) and chest computed tomography (CT).

Results: 125 ICU patients with ARDS secondary to COVID-19 were recruited between March and June 2020. At the 3-month follow-up, 62 patients were available for pulmonary evaluation. The most frequent symptoms were dyspnea (46.7%), and cough (34.4%). Eighty-two percent of patients showed a lung diffusing capacity of less than 80%. The median (IQR) distance in the 6MWT was 400 (362;440) meters. CT scans were abnormal in 70.2% of patients, showing reticular lesions in 49.1% and fibrotic patterns in 21.1%. Patients with more severe alterations on chest CT had worse pulmonary function and presented more degrees of desaturation in the 6MWT. Factors associated with the severity of lung damage on chest CT were age and length of invasive mechanical ventilation during the ICU stay.

Interpretation: Pulmonary structural abnormalities and functional impairment are highly prevalent in surviving ICU patients with ARDS secondary to COVID-19 3 months after hospital discharge. Pulmonary evaluation should be considered for all critical COVID-19 survivors 3 months post discharge.
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http://dx.doi.org/10.1016/j.chest.2021.02.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930807PMC
March 2021

Hemodynamic support in septic shock.

Curr Opin Anaesthesiol 2021 Apr;34(2):99-106

Intensive Care Department, Hospital Universitari Vall d'Hebron, Barcelona.

Purpose Of Review: The current article reviews recent findings on the monitoring and hemodynamic support of septic shock patients.

Recent Findings: The ultimate goal of hemodynamic resuscitation is to restore tissue oxygenation. A multimodal approach combining global and regional markers of tissue hypoxia seems appropriate to guide resuscitation. Several multicenter clinical trials have provided evidence against an aggressive fluid resuscitation strategy. Fluid administration should be personalized and based on the evidence of fluid responsiveness. Dynamic indices have proven to be highly predictive of responsiveness. Recent data suggest that balanced crystalloids may be associated with less renal failure. When fluid therapy is insufficient, a multimode approach with different types of vasopressors has been suggested as an initial approach. Dobutamine remains the firs inotropic option in patients with persistent hypotension and decrease ventricular systolic function. Calcium sensitizer and phosphodiesterase inhibitors may be considered, but evidence is still limited. Veno-arterial extracorporeal membrane oxygenation may be considered in selected unresponsive patients, particularly with myocardial depression, and in a highly experienced center.

Summary: Resuscitation should be personalized and based on global and regional markers of tissue hypoxia as well as the fluid responsiveness indices. The beneficial effect of multimode approach with different types of vasopressors, remains to be determined.
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http://dx.doi.org/10.1097/ACO.0000000000000959DOI Listing
April 2021

The Surviving Sepsis Campaign: Research Priorities for Coronavirus Disease 2019 in Critical Illness.

Crit Care Med 2021 04;49(4):598-622

Chirec Hospitals, Université Libre de Bruxelles, Brussels, Belgium.

Objectives: To identify research priorities in the management, pathophysiology, and host response of coronavirus disease 2019 in critically ill patients.

Design: The Surviving Sepsis Research Committee, a multiprofessional group of 17 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine, was virtually convened during the coronavirus disease 2019 pandemic. The committee iteratively developed the recommendations and subsequent document.

Methods: Each committee member submitted a list of what they believed were the most important priorities for coronavirus disease 2019 research. The entire committee voted on 58 submitted questions to determine top priorities for coronavirus disease 2019 research.

Results: The Surviving Sepsis Research Committee provides 13 priorities for coronavirus disease 2019. Of these, the top six priorities were identified and include the following questions: 1) Should the approach to ventilator management differ from the standard approach in patients with acute hypoxic respiratory failure?, 2) Can the host response be modulated for therapeutic benefit?, 3) What specific cells are directly targeted by severe acute respiratory syndrome coronavirus 2, and how do these cells respond?, 4) Can early data be used to predict outcomes of coronavirus disease 2019 and, by extension, to guide therapies?, 5) What is the role of prone positioning and noninvasive ventilation in nonventilated patients with coronavirus disease?, and 6) Which interventions are best to use for viral load modulation and when should they be given?

Conclusions: Although knowledge of both biology and treatment has increased exponentially in the first year of the coronavirus disease 2019 pandemic, significant knowledge gaps remain. The research priorities identified represent a roadmap for investigation in coronavirus disease 2019.
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http://dx.doi.org/10.1097/CCM.0000000000004895DOI Listing
April 2021

Deploying unsupervised clustering analysis to derive clinical phenotypes and risk factors associated with mortality risk in 2022 critically ill patients with COVID-19 in Spain.

Crit Care 2021 02 15;25(1):63. Epub 2021 Feb 15.

ICU Hospital Universitario Vall d'Hebron, Barcelona, Spain.

Background: The identification of factors associated with Intensive Care Unit (ICU) mortality and derived clinical phenotypes in COVID-19 patients could help for a more tailored approach to clinical decision-making that improves prognostic outcomes.

Methods: Prospective, multicenter, observational study of critically ill patients with confirmed COVID-19 disease and acute respiratory failure admitted from 63 ICUs in Spain. The objective was to utilize an unsupervised clustering analysis to derive clinical COVID-19 phenotypes and to analyze patient's factors associated with mortality risk. Patient features including demographics and clinical data at ICU admission were analyzed. Generalized linear models were used to determine ICU morality risk factors. The prognostic models were validated and their performance was measured using accuracy test, sensitivity, specificity and ROC curves.

Results: The database included a total of 2022 patients (mean age 64 [IQR 5-71] years, 1423 (70.4%) male, median APACHE II score (13 [IQR 10-17]) and SOFA score (5 [IQR 3-7]) points. The ICU mortality rate was 32.6%. Of the 3 derived phenotypes, the A (mild) phenotype (537; 26.7%) included older age (< 65 years), fewer abnormal laboratory values and less development of complications, B (moderate) phenotype (623, 30.8%) had similar characteristics of A phenotype but were more likely to present shock. The C (severe) phenotype was the most common (857; 42.5%) and was characterized by the interplay of older age (> 65 years), high severity of illness and a higher likelihood of development shock. Crude ICU mortality was 20.3%, 25% and 45.4% for A, B and C phenotype respectively. The ICU mortality risk factors and model performance differed between whole population and phenotype classifications.

Conclusion: The presented machine learning model identified three clinical phenotypes that significantly correlated with host-response patterns and ICU mortality. Different risk factors across the whole population and clinical phenotypes were observed which may limit the application of a "one-size-fits-all" model in practice.
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http://dx.doi.org/10.1186/s13054-021-03487-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883885PMC
February 2021

COVID-19 Infection in Critically Ill Patients Carries a High Risk of Venous Thrombo-embolism.

Eur J Vasc Endovasc Surg 2021 Apr 23;61(4):628-634. Epub 2020 Dec 23.

Angiology and Vascular Surgery Department, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.

Objective: The coronavirus disease of 2019 (COVID-19) due to SARS-CoV-2 infection has been found to cause an increased risk of venous thrombo-embolism (VTE). The aims of the study were to determine the frequency of VTE in critically ill patients with COVID-19 and its correlation with D dimer levels and pharmacological prophylaxis.

Methods: This was a cohort study of critically ill patients due to COVID-19. All patients admitted to the intensive care unit on the same day of April 2020 were selected, regardless of length of stay, and a single bilateral venous duplex ultrasound in the lower extremities was performed up to 72 hours later. Pulmonary embolism (PE) was diagnosed by computed tomography angiography. Asymptomatic and symptomatic VTE were registered, including pre-screening in hospital VTE. Characteristics of patients, blood test results, doses of thromboprophylaxis received, VTE events, and mortality after seven day follow up were recorded.

Results: A total of 230 critically ill patients were studied. The median intensive care unit stay of these patients was 12 days (interquartile range [IQR] 5 - 19 days). After seven days follow up, the frequency of patients with VTE, both symptomatic and asymptomatic, was 26.5% (95% confidence interval [CI] 21% - 32%) (69 events in 61 patients): 45 with DVT and 16 with PE (eight of them with concomitant DVT). The cumulative frequency of symptomatic VTE was 8.3% (95% CI 4.7% - 11.8%). D dimer values ≥ 1 500 ng/mL were diagnostic of VTE, with a sensitivity of 80% and a specificity of 42%. During follow up after screening, six patients developed new VTE. Three of them developed a recurrence after a DVT diagnosed at screening, despite receiving therapeutic doses of heparin. Mortality rates at seven day follow up were the same for those with (6.6%) and without (5.3%) VTE.

Conclusion: Patients with severe COVID-19 infection are at high risk of VTE, and further new symptomatic VTE events and recurrence can occur despite anticoagulation. The prophylactic anticoagulant dose may need to be increased in patients with a low risk of bleeding.
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http://dx.doi.org/10.1016/j.ejvs.2020.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757344PMC
April 2021

Comparison of real-time and droplet digital PCR to detect and quantify SARS-CoV-2 RNA in plasma.

Eur J Clin Invest 2021 Jan 29:e13501. Epub 2021 Jan 29.

Centro de Investigación Biomédica en Red en Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Av. de Monforte de Lemos, Madrid, Spain.

Background: The presence of SARS-CoV-2 RNA in plasma has been linked to disease severity and mortality. We compared RT-qPCR to droplet digital PCR (ddPCR) to detect SARS-CoV-2 RNA in plasma from COVID-19 patients (mild, moderate, and critical disease).

Methods: The presence/concentration of SARS-CoV-2 RNA in plasma was compared in three groups of COVID-19 patients (30 outpatients, 30 ward patients and 30 ICU patients) using both RT-qPCR and ddPCR. Plasma was obtained in the first 24h following admission, and RNA was extracted using eMAG. ddPCR was performed using Bio-Rad SARS-CoV-2 detection kit, and RT-qPCR was performed using GeneFinder™ COVID-19 Plus RealAmp Kit. Statistical analysis was performed using Statistical Package for the Social Science.

Results: SARS-CoV-2 RNA was detected, using ddPCR and RT-qPCR, in 91% and 87% of ICU patients, 27% and 23% of ward patients and 3% and 3% of outpatients. The concordance of the results obtained by both methods was excellent (Cohen's kappa index = 0.953). RT-qPCR was able to detect 34/36 (94.4%) patients positive for viral RNA in plasma by ddPCR. Viral RNA load was higher in ICU patients compared with the other groups (P < .001), by both ddPCR and RT-qPCR. AUC analysis revealed Ct values (RT-qPCR) and viral RNA load values (ddPCR) can similarly differentiate between patients admitted to wards and to the ICU (AUC of 0.90 and 0.89, respectively).

Conclusion: Both methods yielded similar prevalence of RNAemia between groups, with ICU patients showing the highest (>85%). RT-qPCR was as useful as ddPCR to detect and quantify SARS-CoV-2 RNAemia in plasma.
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http://dx.doi.org/10.1111/eci.13501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995030PMC
January 2021

CIBERESUCICOVID: A strategic project for a better understanding and clinical management of COVID-19 in critical patients.

Arch Bronconeumol 2020 Nov 11. Epub 2020 Nov 11.

Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Madrid, España; Group of Translational Research in Respiratory Medicine, Hospital Universitari Arnau de Vilanova y Santa Maria, IRB Lleida, Lleida, España.

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http://dx.doi.org/10.1016/j.arbres.2020.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657609PMC
November 2020

Polymyxin B hemoperfusion in coronavirus disease 2019 patients with endotoxic shock: Case series from EUPHAS2 registry.

Artif Organs 2020 Dec 30. Epub 2020 Dec 30.

International Renal Research Institute of Vicenza and Department of Nephrology, Dialysis and Transplantation and International Renal Research Institute of Vicenza, San Bortolo Hospital, Vicenza, Italy.

The coronavirus disease 2019 (COVID-19) has been shown to involve the gastrointestinal tract, which implies bacterial translocation and endotoxemia. The aim of this study was to evaluate the role of extracorporeal endotoxin removal by Polymyxin B hemoperfusion (PMX-HP), in the treatment of patients with COVID-19 and secondary bacterial infection. We conducted a subgroup analysis of a multicenter, multinational, prospective, and observational web-based database (EUPHAS2 registry). We included 12 patients with severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time reverse transcriptase-polymerase chain reaction from nasal/oral swab, admitted to the intensive care unit between February and May 2020, who were affected by septic shock and received PMX-HP as per clinical indication of the attending physician. Septic shock was diagnosed in nine patients (75%), with a median time between symptoms onset and PMX-HP treatment of 16 (14-22) days. We identified Gram-negative bacteria in most of the microbiological cultures (N = 17, 65%), followed by Gram-positive bacteria in (N = 4, 15%), fungi (N = 3, 12%) and no growth (N = 2, 8%). Sequential Organ Failure Assessment (SOFA) score progressively improved over the next 120 hours following PMX-HP and it was associated with median endotoxin activity assay (EAA) decrease from 0.78 [0.70-0.92] at T0 to 0.60 [0.44-0.72] at T120 (P = .245). A direct correlation was observed between SOFA score and EAA. Lung Injury Score decreased and was associated with hemodynamic improvement over the same period. No statistically significant difference was observed for RIFLE score at each time point. Nine out of 12 patients (75%) required continuous renal replacement therapy because of acute kidney injury. In a series of consecutive COVID-19 patients with endotoxic shock, PMX-HP was associated with organ function recovery, hemodynamic improvement, and contemporary EAA level reduction. No PMX-HP-related complications were observed.
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http://dx.doi.org/10.1111/aor.13900DOI Listing
December 2020

Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19.

Crit Care 2020 12 14;24(1):691. Epub 2020 Dec 14.

Department of Microbiology and Immunology, Faculty of Medicine, Canadian Center for Vaccinology CCfV, Dalhousie University, Halifax, NS, B3H 4R2, Canada.

Background: COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response.

Methods: A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients.

Results: The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%], p): RNAemia (3.92 [1.183-12.968], 0.025), viral RNA load (N1) (1.962 [1.244-3.096], 0.004); viral RNA load (N2) (2.229 [1.382-3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia).

Conclusions: SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease.
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http://dx.doi.org/10.1186/s13054-020-03398-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734467PMC
December 2020

Procalcitonin Is Useful for Antibiotic Deescalation in Sepsis.

Crit Care Med 2021 Apr;49(4):693-696

Shock, Organ Dysfunction, and Resuscitation (SODIR) Research Group, Vall d'Hebron Research Institute, Vall d´Hebron Barcelona Hospital Campus, Barcelona, Spain.

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http://dx.doi.org/10.1097/CCM.0000000000004776DOI Listing
April 2021

Plasmapheresis for the Treatment of Acute Pancreatitis due to Severe Hypertriglyceridemia.

Blood Purif 2020 Nov 24:1-3. Epub 2020 Nov 24.

Intensive Care Department, Vall d'Hebron University Hospital, Barcelona, Spain.

Severe hypertriglyceridemia (HTG) is associated with acute pancreatitis (AP). Treatment options include total plasma exchange (TPE). We report a case of AP due to severe HTG treated with TPE.
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http://dx.doi.org/10.1159/000510647DOI Listing
November 2020

Fever management in COVID-19 patients.

Minerva Anestesiol 2021 01 24;87(1):1-3. Epub 2020 Nov 24.

Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium.

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http://dx.doi.org/10.23736/S0375-9393.20.15195-2DOI Listing
January 2021

Extracorporeal Membrane Oxygenation Retrieval in Coronavirus Disease 2019: A Case-Series of 19 Patients Supported at a High-Volume Extracorporeal Membrane Oxygenation Center.

Crit Care Explor 2020 Oct 28;2(10):e0228. Epub 2020 Sep 28.

Department of Critical Care, Vall d'Hebron University Hospital, Barcelona, Spain.

Objective: To evaluate the performance of the extracorporeal membrane oxygenation retrieval team at a high-volume extracorporeal membrane oxygenation center during the coronavirus disease 2019 pandemic.

Design: Observational study including all adult patients with confirmed infection due to severe acute respiratory syndrome coronavirus-2 cannulated at other centers and transported on extracorporeal membrane oxygenation to the ICU of the Vall d'Hebron University Hospital between 15 March and 10 June 2020.

Setting: The ICU (capacity expanded to 200 during the pandemic) of the Vall d'Hebron University Hospital (a 1,100-bed public university hospital in Barcelona), the referral center for extracorporeal respiratory support in Catalonia (7.5 million inhabitants).

Patients: Extracorporeal membrane oxygenation was considered if the Pao/Fio ratio less than 80 mm Hg (refractory to prone position) and/or Paco greater than 80 mm Hg and pH less than 7.25 for more than 6 hours, and no contraindications for extracorporeal support were present.

Interventions: Venovenous extracorporeal membrane oxygenation was initiated in the primary center. Then, patients were transferred to the ICU of the Vall d'Hebron University Hospital where they received support until respiratory improvement. After decannulation, patients were discharged for rehabilitation at the primary center.

Measurements And Main Results: Nineteen patients with severe acute respiratory syndrome coronavirus-2 infection and with a mean Pao/Fio ratio of 71 mm Hg (57-118 mm Hg) despite prone positioning and a mean Paco of 70 mm Hg (47-110 mm Hg) were transferred to our center from their primary hospital after cannulation and received venovenous extracorporeal membrane oxygenation support. Prior to cannulation, six patients (31.5%) presented vascular thrombosis, and nine (47.4%) were already receiving anticoagulant therapy. Eighteen transfers were carried out with no significant complications. While on extracorporeal membrane oxygenation, thrombotic events were recorded in nine patients (47.4%) and hemorrhagic events in 13 (68.4%). Thirteen patients (68.4%) were successfully weaned, and 12 (63.1%) were discharged home.

Conclusions: Extracorporeal membrane oxygenation retrieval can rescue young, previously healthy patients with severe coronavirus disease 2019 in whom all the conventional respiratory measures have failed. Thrombotic and hemorrhagic complications are frequent in this cohort.
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http://dx.doi.org/10.1097/CCE.0000000000000228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523810PMC
October 2020

Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial.

Lancet Infect Dis 2021 02 12;21(2):226-240. Epub 2020 Oct 12.

Shionogi, Osaka, Japan. Electronic address:

Background: New antibiotics are needed for the treatment of patients with life-threatening carbapenem-resistant Gram-negative infections. We assessed the efficacy and safety of cefiderocol versus best available therapy in adults with serious carbapenem-resistant Gram-negative infections.

Methods: We did a randomised, open-label, multicentre, parallel-group, pathogen-focused, descriptive, phase 3 study in 95 hospitals in 16 countries in North America, South America, Europe, and Asia. We enrolled patients aged 18 years or older admitted to hospital with nosocomial pneumonia, bloodstream infections or sepsis, or complicated urinary tract infections (UTI), and evidence of a carbapenem-resistant Gram-negative pathogen. Participants were randomly assigned (2:1 by interactive web or voice response system) to receive either a 3-h intravenous infusion of cefiderocol 2 g every 8 h or best available therapy (pre-specified by the investigator before randomisation and comprised of a maximum of three drugs) for 7-14 days. For patients with pneumonia or bloodstream infection or sepsis, cefiderocol treatment could be combined with one adjunctive antibiotic (excluding polymyxins, cephalosporins, and carbapenems). The primary endpoint for patients with nosocomial pneumonia or bloodstream infection or sepsis was clinical cure at test of cure (7 days [plus or minus 2] after the end of treatment) in the carbapenem-resistant microbiological intention-to-treat population (ITT; ie, patients with a confirmed carbapenem-resistant Gram-negative pathogen receiving at least one dose of study drug). For patients with complicated UTI, the primary endpoint was microbiological eradication at test of cure in the carbapenem-resistant microbiological ITT population. Safety was evaluated in the safety population, consisting of all patients who received at least one dose of study drug. Mortality was reported through to the end of study visit (28 days [plus or minus 3] after the end of treatment). Summary statistics, including within-arm 95% CIs calculated using the Clopper-Pearson method, were collected for the primary and safety endpoints. This trial is registered with ClinicalTrials.gov (NCT02714595) and EudraCT (2015-004703-23).

Findings: Between Sept 7, 2016, and April 22, 2019, we randomly assigned 152 patients to treatment, 101 to cefiderocol, 51 to best available therapy. 150 patients received treatment: 101 cefiderocol (85 [85%] received monotherapy) and 49 best available therapy (30 [61%] received combination therapy). In 118 patients in the carbapenem-resistant microbiological ITT population, the most frequent carbapenem-resistant pathogens were Acinetobacter baumannii (in 54 patients [46%]), Klebsiella pneumoniae (in 39 patients [33%]), and Pseudomonas aeruginosa (in 22 patients [19%]). In the same population, for patients with nosocomial pneumonia, clinical cure was achieved by 20 (50%, 95% CI 33·8-66·2) of 40 patients in the cefiderocol group and ten (53%, 28·9-75·6) of 19 patients in the best available therapy group; for patients with bloodstream infection or sepsis, clinical cure was achieved by ten (43%, 23·2-65·5) of 23 patients in the cefiderocol group and six (43%, 17·7-71·1) of 14 patients in the best available therapy group. For patients with complicated UTIs, microbiological eradication was achieved by nine (53%, 27·8-77·0) of 17 patients in the cefiderocol group and one (20%, 0·5-71·6) of five patients in the best available therapy group. In the safety population, treatment-emergent adverse events were noted for 91% (92 patients of 101) of the cefiderocol group and 96% (47 patients of 49) of the best available therapy group. 34 (34%) of 101 patients receiving cefiderocol and nine (18%) of 49 patients receiving best available therapy died by the end of the study; one of these deaths (in the best available therapy group) was considered to be related to the study drug.

Interpretation: Cefiderocol had similar clinical and microbiological efficacy to best available therapy in this heterogeneous patient population with infections caused by carbapenem-resistant Gram-negative bacteria. Numerically more deaths occurred in the cefiderocol group, primarily in the patient subset with Acinetobacter spp infections. Collectively, the findings from this study support cefiderocol as an option for the treatment of carbapenem-resistant infections in patients with limited treatment options.

Funding: Shionogi.
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http://dx.doi.org/10.1016/S1473-3099(20)30796-9DOI Listing
February 2021

Biomarkers in the ICU: less is more? No.

Intensive Care Med 2021 Jan 15;47(1):97-100. Epub 2020 Oct 15.

Intensive Care Department, Vall D'Hebron University Hospital, Barcelona, Spain.

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http://dx.doi.org/10.1007/s00134-020-06271-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558550PMC
January 2021

Planning for the assistance of critically ill patients in a Pandemic Situation: The experience of Vall d'Hebron University Hospital.

Enferm Infecc Microbiol Clin 2020 Sep 8. Epub 2020 Sep 8.

Servicio de Medicina Intensiva. Hospital Universitario Vall d'Hebron. Sepsis Organ Dysfunction and Resuscitation (SODIR) Research group. Vall d'Hebron Institut de Recerca (VHIR). Universidad Autónoma de Barcelona (UAB), Barcelona, España.

Introduction: In the context of community transmission of the virus, the impact of the pandemic on health-care systems, mainly on intensive care units (ICU), was expected to be devastating. Vall d́Hebron University Hospital (HUVH) implemented an unprecedented critical patient-care planning and management of resources.

Methods: We describe a cohort of critically ill patients during the first two months of the pandemic (from March 3, 2020, to May 2, 2020) in HUVH, Barcelona. In this manuscript, we report our previsions, strategies implemented, and the outcomes obtained.

Results: Three-thousand and thirty-three patients were admitted to the HUVH Critical Care Units. Throughout the study period, the proportion of patients on IMV or IMV and ECMO remained above 78%. Most patients were men (65%); the most common age group was 60-70 years. Twenty-three patients received ECMO, and eighteen were cannulated at another center and transferred to HUVH. At the end of the study, fourteen patients were successfully decannulated, three patients died, and the rest of the patients were still on ECMO. Eight pregnant women have been treated in the ICU, with a survival rate of 100%. The ICU mortality of patients younger than 60 years was 3.2%. The mean ICU stay of both survivors and nonsurvivors was 14 days.

Conclusion: The adequate preparation for resource expansion for critically ill patients care, main challenges, and overall positive results can serve as a precedent for similar future scenarios.
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http://dx.doi.org/10.1016/j.eimc.2020.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834691PMC
September 2020

Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome.

Crit Care 2020 08 26;24(1):522. Epub 2020 Aug 26.

Intensive Care Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, Barcelona, 08035, Spain.

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http://dx.doi.org/10.1186/s13054-020-03249-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447967PMC
August 2020

Symptoms of burnout in intensive care unit specialists facing the COVID-19 outbreak.

Ann Intensive Care 2020 Aug 8;10(1):110. Epub 2020 Aug 8.

Humanitas Clinical and Research Center, Humanitas University, Milan, Italy.

Background: The COVID-19 pandemic has resulted in an unprecedented healthcare crisis with a high prevalence of psychological distress in healthcare providers. We sought to document the prevalence of burnout syndrome amongst intensivists facing the COVID-19 outbreak.

Methods: Cross-sectional survey among intensivists part of the European Society of Intensive Care Medicine. Symptoms of severe burnout, anxiety and depression were collected. Factors independently associated with severe burnout were assessed using Cox model.

Results: Response rate was 20% (1001 completed questionnaires were returned, 45 years [39-53], 34% women, from 85 countries, 12 regions, 50% university-affiliated hospitals). The prevalence of symptoms of anxiety and depression or severe burnout was 46.5%, 30.2%, and 51%, respectively, and varied significantly across regions. Rating of the relationship between intensivists and other ICU stakeholders differed significantly according to the presence of anxiety, depression, or burnout. Similar figures were reported for their rating of the ethical climate or the quality of the decision-making. Factors independently associated with anxiety were female gender (HR 1.85 [1.33-2.55]), working in a university-affiliated hospital (HR 0.58 [0.42-0.80]), living in a city of > 1 million inhabitants (HR 1.40 [1.01-1.94]), and clinician's rating of the ethical climate (HR 0.83 [0.77-0.90]). Independent determinants of depression included female gender (HR 1.63 [1.15-2.31]) and clinician's rating of the ethical climate (HR 0.84 [0.78-0.92]). Factors independently associated with symptoms of severe burnout included age (HR 0.98/year [0.97-0.99]) and clinician's rating of the ethical climate (HR 0.76 [0.69-0.82]).

Conclusions: The COVID-19 pandemic has had an overwhelming psychological impact on intensivists. Follow-up, and management are warranted to assess long-term psychological outcomes and alleviate the psychological burden of the pandemic on frontline personnel.
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http://dx.doi.org/10.1186/s13613-020-00722-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414284PMC
August 2020

International variation in the management of severe COVID-19 patients.

Crit Care 2020 08 5;24(1):486. Epub 2020 Aug 5.

Humanitas Clinical and Research Center, Humanitas University, Milan, Italy.

Background: There is little evidence to support the management of severe COVID-19 patients.

Methods: To document this variation in practices, we performed an online survey (April 30-May 25, 2020) on behalf of the European Society of Intensive Care Medicine (ESICM). A case vignette was sent to ESICM members. Questions investigated practices for a previously healthy 39-year-old patient presenting with severe hypoxemia from COVID-19 infection.

Results: A total of 1132 ICU specialists (response rate 20%) from 85 countries (12 regions) responded to the survey. The survey provides information on the heterogeneity in patient's management, more particularly regarding the timing of ICU admission, the first line oxygenation strategy, optimization of management, and ventilatory settings in case of refractory hypoxemia. Practices related to antibacterial, antiviral, and anti-inflammatory therapies are also investigated.

Conclusions: There are important practice variations in the management of severe COVID-19 patients, including differences at regional and individual levels. Large outcome studies based on multinational registries are warranted.
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http://dx.doi.org/10.1186/s13054-020-03194-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403819PMC
August 2020

Naturally occurring SARS-CoV-2 gene deletions close to the spike S1/S2 cleavage site in the viral quasispecies of COVID19 patients.

Emerg Microbes Infect 2020 Dec;9(1):1900-1911

Liver Unit, Liver Diseases - Viral Hepatitis, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain.

The SARS-CoV-2 spike (S) protein, the viral mediator for binding and entry into the host cell, has sparked great interest as a target for vaccine development and treatments with neutralizing antibodies. Initial data suggest that the virus has low mutation rates, but its large genome could facilitate recombination, insertions, and deletions, as has been described in other coronaviruses. Here, we deep-sequenced the complete SARS-CoV-2 gene from 18 patients (10 with mild and 8 with severe COVID-19), and found that the virus accumulates deletions upstream and very close to the S1/S2 cleavage site (PRRAR/S), generating a frameshift with appearance of a stop codon. These deletions were found in a small percentage of the viral quasispecies (2.2%) in samples from all the mild and only half the severe COVID-19 patients. Our results suggest that the virus may generate free S1 protein released to the circulation. We suggest that natural selection has favoured a "Don't burn down the house" strategy, in which free S1 protein may compete with viral particles for the ACE2 receptor, thus reducing the severity of the infection and tissue damage without losing transmission capability.
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http://dx.doi.org/10.1080/22221751.2020.1806735DOI Listing
December 2020

Cardiac tamponade as a cause of cardiac arrest in severe COVID-19 pneumonia.

Resuscitation 2020 10 21;155:1-2. Epub 2020 Jul 21.

Intensive Care Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain; Shock, Organ Dysfunction and Resuscitation Research Group. Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.

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http://dx.doi.org/10.1016/j.resuscitation.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371590PMC
October 2020

Antibiotic treatment in patients with sepsis: a narrative review.

Hosp Pract (1995) 2020 Jul 20:1-11. Epub 2020 Jul 20.

Centro Hospitalar de Lisboa Ocidental - Polyvalent Intensive Care Unit, Hospital de S.Francisco Xavier , Lisboa, Portugal.

Sepsis is a medical emergency and life-threatening condition due to a dysregulated host response to infection, with unacceptably high morbidity and mortality. Similar to acute myocardial infarction or cerebral vascular accident, sepsis is a severe and continuous time-dependent condition. Thus, in the case of sepsis, early and adequate administration of antimicrobials must be a priority, ideally within the first hour of diagnosis, simultaneously with organ support. As a consequence of the emergence of multidrug-resistant pathogens, the choice of antimicrobials should be performed according to the local pathogen patterns of resistance. Individual antimicrobial optimization is essential to achieve adequate concentrations of antimicrobials, to reduce adverse effects, and to ensure successful outcomes, as well as preventing the emergence of multidrug-resistant pathogens. The loading dose is the administration of an initial higher dose of antimicrobials, regardless of the presence of organ dysfunction. Further doses should be implemented according to pharmacokinetics/pharmacodynamics of antimicrobials and should be adjusted according to the presence of renal or liver dysfunction. Extended or continuous infusion of beta-lactams and therapeutic drug monitoring can help to achieve therapeutic levels of antimicrobials. Duration and adequacy of treatment must be reviewed at regular intervals to allow effective de-escalation and administration of short courses of antimicrobials for most patients. Antimicrobial stewardship frameworks, leadership, focus on the optimal duration of treatments, de-escalation, and novel diagnostic stewardship approaches will help us to improve patients the process of care and overall quality of care.
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http://dx.doi.org/10.1080/21548331.2020.1791541DOI Listing
July 2020

Update of the treatment of nosocomial pneumonia in the ICU.

Crit Care 2020 06 29;24(1):383. Epub 2020 Jun 29.

ICU, Trinity Centre for Health Science HRB-Wellcome Trust, St James's Hospital, Dublin, Ireland.

In accordance with the recommendations of, amongst others, the Surviving Sepsis Campaign and the recently published European treatment guidelines for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), in the event of a patient with such infections, empirical antibiotic treatment must be appropriate and administered as early as possible. The aim of this manuscript is to update treatment protocols by reviewing recently published studies on the treatment of nosocomial pneumonia in the critically ill patients that require invasive respiratory support and patients with HAP from hospital wards that require invasive mechanical ventilation. An interdisciplinary group of experts, comprising specialists in anaesthesia and resuscitation and in intensive care medicine, updated the epidemiology and antimicrobial resistance and established clinical management priorities based on patients' risk factors. Implementation of rapid diagnostic microbiological techniques available and the new antibiotics recently added to the therapeutic arsenal has been reviewed and updated. After analysis of the categories outlined, some recommendations were suggested, and an algorithm to update empirical and targeted treatment in critically ill patients has also been designed. These aspects are key to improve VAP outcomes because of the severity of patients and possible acquisition of multidrug-resistant organisms (MDROs).
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http://dx.doi.org/10.1186/s13054-020-03091-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322703PMC
June 2020

Genomewide Association Study of Severe Covid-19 with Respiratory Failure.

Authors:
David Ellinghaus Frauke Degenhardt Luis Bujanda Maria Buti Agustín Albillos Pietro Invernizzi Javier Fernández Daniele Prati Guido Baselli Rosanna Asselta Marit M Grimsrud Chiara Milani Fátima Aziz Jan Kässens Sandra May Mareike Wendorff Lars Wienbrandt Florian Uellendahl-Werth Tenghao Zheng Xiaoli Yi Raúl de Pablo Adolfo G Chercoles Adriana Palom Alba-Estela Garcia-Fernandez Francisco Rodriguez-Frias Alberto Zanella Alessandra Bandera Alessandro Protti Alessio Aghemo Ana Lleo Andrea Biondi Andrea Caballero-Garralda Andrea Gori Anja Tanck Anna Carreras Nolla Anna Latiano Anna Ludovica Fracanzani Anna Peschuck Antonio Julià Antonio Pesenti Antonio Voza David Jiménez Beatriz Mateos Beatriz Nafria Jimenez Carmen Quereda Cinzia Paccapelo Christoph Gassner Claudio Angelini Cristina Cea Aurora Solier David Pestaña Eduardo Muñiz-Diaz Elena Sandoval Elvezia M Paraboschi Enrique Navas Félix García Sánchez Ferruccio Ceriotti Filippo Martinelli-Boneschi Flora Peyvandi Francesco Blasi Luis Téllez Albert Blanco-Grau Georg Hemmrich-Stanisak Giacomo Grasselli Giorgio Costantino Giulia Cardamone Giuseppe Foti Serena Aneli Hayato Kurihara Hesham ElAbd Ilaria My Iván Galván-Femenia Javier Martín Jeanette Erdmann Jose Ferrusquía-Acosta Koldo Garcia-Etxebarria Laura Izquierdo-Sanchez Laura R Bettini Lauro Sumoy Leonardo Terranova Leticia Moreira Luigi Santoro Luigia Scudeller Francisco Mesonero Luisa Roade Malte C Rühlemann Marco Schaefer Maria Carrabba Mar Riveiro-Barciela Maria E Figuera Basso Maria G Valsecchi María Hernandez-Tejero Marialbert Acosta-Herrera Mariella D'Angiò Marina Baldini Marina Cazzaniga Martin Schulzky Maurizio Cecconi Michael Wittig Michele Ciccarelli Miguel Rodríguez-Gandía Monica Bocciolone Monica Miozzo Nicola Montano Nicole Braun Nicoletta Sacchi Nilda Martínez Onur Özer Orazio Palmieri Paola Faverio Paoletta Preatoni Paolo Bonfanti Paolo Omodei Paolo Tentorio Pedro Castro Pedro M Rodrigues Aaron Blandino Ortiz Rafael de Cid Ricard Ferrer Roberta Gualtierotti Rosa Nieto Siegfried Goerg Salvatore Badalamenti Sara Marsal Giuseppe Matullo Serena Pelusi Simonas Juzenas Stefano Aliberti Valter Monzani Victor Moreno Tanja Wesse Tobias L Lenz Tomas Pumarola Valeria Rimoldi Silvano Bosari Wolfgang Albrecht Wolfgang Peter Manuel Romero-Gómez Mauro D'Amato Stefano Duga Jesus M Banales Johannes R Hov Trine Folseraas Luca Valenti Andre Franke Tom H Karlsen

N Engl J Med 2020 10 17;383(16):1522-1534. Epub 2020 Jun 17.

From the Institute of Clinical Molecular Biology, Christian-Albrechts-University (D.E., F.D., J.K., S. May, M. Wendorff, L.W., F.U.-W., X.Y., A.T., A. Peschuck, C.G., G.H.-S., H.E.A., M.C.R., M.E.F.B., M. Schulzky, M. Wittig, N.B., S.J., T.W., W.A., M. D'Amato, A.F.), and University Hospital Schleswig-Holstein, Campus Kiel (N.B., A.F.), Kiel, the Institute for Cardiogenetics, University of Lübeck, Lübeck (J.E.), the German Research Center for Cardiovascular Research, partner site Hamburg-Lübeck-Kiel (J.E.), the University Heart Center Lübeck (J.E.), and the Institute of Transfusion Medicine, University Hospital Schleswig-Holstein (S.G.), Lübeck, Stefan-Morsch-Stiftung, Birkenfeld (M. Schaefer, W.P.), and the Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plön (O.O., T.L.L.) - all in Germany; Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen (D.E.); the Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital-University of the Basque Country (L.B., K.G.-E., L.I.-S., P.M.R., J.M.B.), Osakidetza Basque Health Service, Donostialdea Integrated Health Organization, Clinical Biochemistry Department (A.G.C., B.N.J.), and the Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute (M. D'Amato), San Sebastian, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III (L.B., M. Buti, A. Albillos, A. Palom, F.R.-F., B.M., L. Téllez, K.G.-E., L.I.-S., F.M., L.R., M.R.-B., M. Rodríguez-Gandía, P.M.R., M. Romero-Gómez, J.M.B.), the Departments of Gastroenterology (A. Albillos, B.M., L. Téllez, F.M., M. Rodríguez-Gandía), Intensive Care (R.P., A.B.O.), Respiratory Diseases (D.J., A.S., R.N.), Infectious Diseases (C.Q., E.N.), and Anesthesiology (D. Pestaña, N. Martínez), Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, University of Alcalá, and Histocompatibilidad y Biologia Molecular, Centro de Transfusion de Madrid (F.G.S.), Madrid, the Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus (M. Buti, A. Palom, L.R., M.R.-B.), Hospital Clinic, University of Barcelona, and the August Pi i Sunyer Biomedical Research Institute (J.F., F.A., E.S., J.F.-A., L.M., M.H.-T., P.C.), the European Foundation for the Study of Chronic Liver Failure (J.F.), Vall d'Hebron Institut de Recerca (A. Palom, F.R.-F., A.J., S. Marsal), and the Departments of Biochemistry (A.-E.G.-F., F.R.-F., A.C.-G., C.C., A.B.-G.), Intensive Care (R.F.), and Microbiology (T.P.), University Hospital Vall d'Hebron, the Immunohematology Department, Banc de Sang i Teixits, Autonomous University of Barcelona (E.M.-D.), Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Consortium for Biomedical Research in Epidemiology and Public Health and University of Barcelona, l'Hospitalet (V. Moreno), and Autonoma University of Barcelona (T.P.), Barcelona, Universitat Autònoma de Barcelona, Bellatera (M. Buti, F.R.-F., M.R.-B.), GenomesForLife-GCAT Lab Group, Germans Trias i Pujol Research Institute (A.C.N., I.G.-F., R.C.), and High Content Genomics and Bioinformatics Unit, Germans Trias i Pujol Research Institute (L. Sumoy), Badalona, Institute of Parasitology and Biomedicine Lopez-Neyra, Granada (J.M., M.A.-H.), the Digestive Diseases Unit, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville, University of Seville, Seville (M. Romero-Gómez), and Ikerbasque, Basque Foundation for Science, Bilbao (M. D'Amato, J.M.B.) - all in Spain; the Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca (P.I., C.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (D. Prati, G.B., A.Z., A. Bandera, A.G., A.L.F., A. Pesenti, C.P., F.C., F.M.-B., F.P., F.B., G.G., G. Costantino, L. Terranova, L. Santoro, L. Scudeller, M. Carrabba, M. Baldini, M.M., N. Montano, R.G., S.P., S. Aliberti, V. Monzani, S. Bosari, L.V.), the Department of Biomedical Sciences, Humanitas University (R.A., A. Protti, A. Aghemo, A. Lleo, E.M.P., G. Cardamone, M. Cecconi, V.R., S.D.), Humanitas Clinical and Research Center, IRCCS (R.A., A. Protti, A. Aghemo, A. Lleo, A.V., C.A., E.M.P., H.K., I.M., M. Cecconi, M. Ciccarelli, M. Bocciolone, P.P., P.O., P.T., S. Badalamenti, S.D.), University of Milan (A.Z., A. Bandera, A.G., A.L.F., A. Pesenti, F.M.-B., F.P., F.B., G.G., G. Costantino, M.M., N. Montano, R.G., S.P., S. Aliberti, S. Bosari, L.V.), and the Center of Bioinformatics, Biostatistics, and Bioimaging (M.G.V.) and the Phase 1 Research Center (M. Cazzaniga), School of Medicine and Surgery, and the Departments of Emergency, Anesthesia, and Intensive Care (G.F.), Pneumologia (P.F.), and Infectious Diseases (P.B.); University of Milano-Bicocca, Milan, the European Reference Network on Hepatological Diseases (P.I., C.M.) and the Infectious Diseases Unit (P.B.), San Gerardo Hospital, Monza, the Pediatric Departement and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo (A. Biondi, L.R.B., M. D'Angiò), the Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (A. Latiano, O.P.), the Department of Medical Sciences, Università degli Studi di Torino, Turin (S. Aneli, G.M.), and the Italian Bone Marrow Donor Registry, E.O. Ospedali Galliera, Genoa (N.S.) - all in Italy; the Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases, and Transplantation, and the Research Institute for Internal Medicine, Division of Surgery, Inflammatory Diseases, and Transplantation, Oslo University Hospital Rikshospitalet and University of Oslo (M.M.G., J.R.H., T.F., T.H.K.), and the Section for Gastroenterology, Department of Transplantation Medicine, Division for Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital Rikshospitalet (J.R.H., T.F., T.H.K.), Oslo; the School of Biological Sciences, Monash University, Clayton, VIC, Australia (T.Z., M. D'Amato); Private University in the Principality of Liechtenstein (C.G.); the Institute of Biotechnology, Vilnius University, Vilnius, Lithuania (S.J.); and the Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm (M. D'Amato).

Background: There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.

Methods: We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels.

Results: We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10, respectively). At locus 3p21.31, the association signal spanned the genes , , , , and . The association signal at locus 9q34.2 coincided with the blood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10).

Conclusions: We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.).
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http://dx.doi.org/10.1056/NEJMoa2020283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315890PMC
October 2020

Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial.

Intensive Care Med 2020 Jul 28;46(7):1425-1437. Epub 2020 May 28.

Department of Critical Care Medicine, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium.

Purpose: Nangibotide is a specific TREM-1 inhibitor that tempered deleterious host-pathogens interactions, restored vascular function, and improved survival, in animal septic shock models. This study evaluated the safety and pharmacokinetics of nangibotide and its effects on clinical and pharmacodynamic parameters in septic shock patients.

Methods: This was a multicenter randomized, double-blind, two-stage study. Patients received either continuous infusion of nangibotide (0.3, 1.0, or 3.0 mg/kg/h) or placebo. Treatment began < 24 h after shock onset and continued for up to 5 days. Safety primary outcomes were adverse events (AEs), whether serious or not, and death. Exploratory endpoints evaluated nangibotide effects on pharmacodynamics, organ function, and mortality, and were analyzed according to baseline sTREM-1 concentrations.

Results: Forty-nine patients were randomized. All treatment emergent AEs (TEAEs) were collected until Day 28. No significant differences were observed in TEAEs between treatment groups. No drug withdrawal linked to TEAE nor appearance of anti-drug antibodies were reported. Nangibotide pharmacokinetics appeared to be dose-proportional and clearance was dose-independent. Nangibotide did not significantly affect pharmacodynamic markers. Decrease in SOFA score LS mean change (± SE) from baseline to Day 5 in pooled nangibotide groups versus placebo was - 0.7 (± 0.85) in the randomized population and - 1.5 (± 1.12) in patients with high baseline plasma sTREM-1 concentrations (non-significant). This pattern was similar to organ support end points.

Conclusion: No significant increases in TEAEs were detected in nangibotide-treated patients versus placebo. These results encourage further evaluation of nangibotide and further exploration of plasma sTREM-1 concentrations as a predictive efficacy biomarker.
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http://dx.doi.org/10.1007/s00134-020-06109-zDOI Listing
July 2020

Full neurological recovery 6 h after cardiac arrest due to accidental hypothermia.

Lancet 2020 05;395(10236):e89

Department of Critical Care, Vall d'Hebron University Hospital and Vall d'Hebron Research Institute, Barcelona, Spain.

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http://dx.doi.org/10.1016/S0140-6736(20)30751-0DOI Listing
May 2020