Detailed stratified GWAS analysis for severe COVID-19 in four European populations.

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.

Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort.

BACKGROUND: Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster. METHODS: Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3. RESULTS: Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3. CONCLUSIONS: During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis.

Cerebro-spinal fluid glucose and lactate concentrations changes in response to therapies in patIents with primary brain injury: the START-TRIP study.

INTRODUCTION: Altered levels of cerebrospinal fluid (CSF) glucose and lactate concentrations are associated with poor outcomes in acute brain injury patients. However, no data on changes in such metabolites consequently to therapeutic interventions are available. The aim of the study was to assess CSF glucose-to-lactate ratio (CGLR) changes related to therapies aimed at reducing intracranial pressure (ICP). METHODS: A multicentric prospective cohort study was conducted in 12 intensive care units (ICUs) from September 2017 to March 2022. Adult (> 18 years) patients admitted after an acute brain injury were included if an external ventricular drain (EVD) for intracranial pressure (ICP) monitoring was inserted within 24 h of admission. During the first 48-72 h from admission, CGLR was measured before and 2 h after any intervention aiming to reduce ICP ("intervention"). Patients with normal ICP were also sampled at the same time points and served as the "control" group. RESULTS: A total of 219 patients were included. In the intervention group (n = 115, 53%), ICP significantly decreased and CPP increased. After 2 h from the intervention, CGLR rose in both the intervention and control groups, although the magnitude was higher in the intervention than in the control group (20.2% vs 1.6%; p = 0.001). In a linear regression model adjusted for several confounders, therapies to manage ICP were independently associated with changes in CGLR. There was a weak inverse correlation between changes in ICP and CGRL in the intervention group. CONCLUSIONS: In this study, CGLR significantly changed over time, regardless of the study group. However, these effects were more significant in those patients receiving interventions to reduce ICP.

Neurological Pupil Index and Delayed Cerebral Ischemia after Subarachnoid Hemorrhage: A Retrospective Multicentric Study.

BACKGROUND: Delayed cerebral ischemia (DCI) occurs in around 30% of patients suffering from nontraumatic subarachnoid hemorrhage (SAH) and is associated with poor neurological outcome. Whether the Neurological Pupil index (NPi) derived from the automated pupillometry could help to diagnose the occurrence of DCI remains unknown. The aim of this study was to investigate the association of NPi with the occurrence of DCI in patients with SAH. METHODS: This was a multicenter, retrospective cohort study of consecutive patients with SAH admitted to the intensive care units of five hospitals between January 2018 and December 2020 who underwent daily NPi recordings (every 8 h) during the first 10 days of admission. DCI was diagnosed according to standard definitions (in awake patients) or based on neuroimaging and neuromonitoring (in sedated or unconscious patients). An NPi < 3 was defined as abnormal. The primary outcome of the study was to assess the time course of daily NPi between patients with DCI and patients without DCI. Secondary outcome included the number of patients who had an NPi < 3 before DCI. RESULTS: A total of 210 patients were eligible for the final analysis; DCI occurred in 85 (41%) patients. Patients who developed DCI had similar values of mean and worst daily NPi over time when compared with patients without DCI. Patients with DCI had a higher proportion of at least one NPi < 3 at any moment before DCI when compared with others (39/85, 46% vs. 35/125, 38%, p = 0.009). Similarly, the worst NPi before DCI diagnosis was lower in the DCI group when compared with others (3.1 [2.5-3.8] vs. 3.7 [2.7-4.1], p = 0.05). In the multivariable logistic regression analysis, the presence of NPi < 3 was not independently associated with the development of DCI (odds ratio 1.52 [95% confidence interval 0.80-2.88]). CONCLUSIONS: In this study, NPi measured three times a day and derived from the automated pupillometry had a limited value for the diagnosis of DCI in patients with SAH.

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients.

BACKGROUND: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. METHODS: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. RESULTS: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). CONCLUSIONS: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation.

Cerebral Near-Infrared Spectroscopy in Adult Patients Undergoing Veno-Arterial Extracorporeal Membrane Oxygenation.

BACKGROUND: Acute cerebral complications (ACC) of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) are associated with poor long-term neurologic outcome. We described the role of rSO2 monitoring in detecting ACC and desaturations and their relationship with poor outcome when employing VA-ECMO. METHODS: Retrospective analysis of patients monitored by cerebral frontal near-infrared spectroscopy (NIRS) (CAS Medical Systems Inc., Branford, CT, USA) during VA-ECMO (November 2008-December 2015). ACC was defined as the presence of stroke and/or brain death, while cerebral desaturation as cortical oxygen tissue saturation (rSO2) < 60%. RESULTS: Fifty-six of 159 VA-ECMO patients (age 55 [36-60] years) were included; 18 (32%) developed ACC and 36 died (64%). Cerebral desaturation occurred in 43 (74%) patients, who had a higher mortality than those without cerebral desaturation (74 vs. 31%). A high sequential organ failure assessment (SOFA) score on the first day of ECMO (OR 1.40 [95% CIs 1.06-1.84]) and the minimum ECMO blood flow during the first 4 days of therapy (OR 3.05 [1.01-9.17]) were independently associated with the occurrence of cerebral desaturation. Cerebral desaturation occurred more frequently in patients with ACC than others (94 vs. 68%); patients with ACC also had a lower minimal rSO2 over time (49 vs. 54%) and more frequently had high right-left rSO2 differences (33 vs. 8%), which were both independent predictors of ACC. The occurrence of cerebral desaturation (OR 7.93 [1.62-38.74]) and high lactate concentrations during the first 4 days of ECMO support (OR 1.22 [1.03-1.46]) was independently associated with hospital mortality. CONCLUSIONS: Monitoring of rSO2 could be considered as an interesting tool to monitor the brain of patients on VA-ECMO.

Right ventricular dysfunction in the critically ill. Echocardiographic evaluation.

Right ventricular dysfunction is common in critically ill patients, and is associated with increased mortality. Its diagnosis moreover remains challenging. In this review, we aim to outline the potential mechanisms underlying abnormal biomechanics of the right ventricle and the different injury phenotypes. A comprehensive understanding of the pathophysiology and natural history of right ventricular injury can be informative for the intensivist in the diagnosis and management of this condition, and may serve to guide individualized treatment strategies. We describe the main recommended parameters for assessing right ventricular systolic and diastolic function. We also define how to evaluate cardiac output and pulmonary circulation pressures with echocardiography, with a focus on the diagnosis of acute cor pulmonale and relevant applications in critical disorders such as distress, septic shock, and right ventricular infarction.