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Background: The effects of obesity on pulmonary gas and blood distribution in patients with acute respiratory failure remain unknown. Dual-energy computed tomography (DECT) is a X-ray-based method used to study regional distribution of gas and blood within the lung. We hypothesized that 1) regional gas/blood mismatch can be quantified by DECT; 2) obesity influences the global and regional distribution of pulmonary gas and blood; 3) regardless of ventilation modality (invasive vs. non-invasive ventilation), patients' body mass index (BMI) has an impact on pulmonary gas/blood mismatch. Methods: This single-centre prospective observational study enrolled 118 hypoxic COVID-19 patients (92 male) in need of respiratory support and intensive care who underwent DECT. The cohort was divided into three groups according to BMI: 1. BMI<25 kg/m2 (non-obese), 2. BMI = 25-40 kg/m2 (overweight to obese), and 3. BMI>40 kg/m2 (morbidly obese). Gravitational analysis of Hounsfield unit distribution of gas and blood was derived from DECT and used to calculate regional gas/blood mismatch. A sensitivity analysis was performed to investigate the influence of the chosen ventilatory modality and BMI on gas/blood mismatch and adjust for other possible confounders (i.e., age and sex). Results: 1) Regional pulmonary distribution of gas and blood and their mismatch were quantified using DECT imaging. 2) The BMI>40 kg/m2 group had less hyperinflation in the non-dependent regions and more lung collapse in the dependent regions compared to the other BMI groups. In morbidly obese patients, gas and blood were more evenly distributed; therefore, the mismatch was lower than in other patients (30% vs. 36%, p < 0.05). 3) An increase in BMI of 5 kg/m2 was associated with a decrease in mismatch of 3.3% (CI: 3.67% to -2.93%, p < 0.05). Neither the ventilatory modality nor age and sex affected the gas/blood mismatch (p > 0.05). Conclusion: 1) In a hypoxic COVID-19 population needing intensive care, pulmonary gas/blood mismatch can be quantified at a global and regional level using DECT. 2) Obesity influences the global and regional distribution of gas and blood within the lung, and BMI>40 kg/m2 improves pulmonary gas/blood mismatch. 3) This is true regardless of the ventilatory mode and other possible confounders, i.e., age and sex. [ABSTRACT FROM AUTHOR]

Background: The effects of awake prone positioning (APP) on respiratory mechanics in patients with COVID-19 are not well characterized. The aim of this study was to investigate changes of global and regional lung volumes during APP compared with the supine position using electrical lung impedance tomography (EIT) in patients with hypoxemic respiratory failure due to COVID-19. Materials and methods: This exploratory non-randomized cross-over study was conducted at two university hospitals in Sweden between January and May 2021. Patients admitted to the intensive care unit with confirmed COVID-19, an arterial cannula in place, a PaO2/FiO2 ratio <26.6 kPa (<200 mmHg) and high-flow nasal oxygen or non-invasive ventilation were eligible for inclusion. EIT-data were recorded at supine baseline, at 30 and 60 minutes after APP-initiation, and 30 minutes after supine repositioning. The primary outcomes were changes in global and regional tidal impedance variation (TIV), center of ventilation (CoV), global and regional delta end-expiratory lung-impedance (dEELI) and global inhomogeneity (GI) index at the end of APP compared with supine baseline. Data were reported as median (IQR). Results: All patients (n = 10) were male and age was 64 (47–73) years. There were no changes in global or regional TIV, CoV or GI-index during the intervention. dEELI increased from supine reference value 0 to 1.51 (0.32–3.62) 60 minutes after APP (median difference 1.51 (95% CI 0.19–5.16), p = 0.04) and returned to near baseline values after supine repositioning. Seven patients (70%) showed an increase >0.20 in dEELI during APP. The other EIT-variables did not change during APP compared with baseline. Conclusion: Awake prone positioning was associated with a transient lung recruiting effect without changes in ventilation distribution measured with EIT in patients with hypoxemic respiratory failure due to COVID-19. [ABSTRACT FROM AUTHOR]

Background: Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods: This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results: Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions: Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021). [ABSTRACT FROM AUTHOR]

Background: Potentially harmful lung overstretch can follow intraparenchymal gas redistribution during mechanical ventilation. We hypothesized that inspiratory efforts characterizing spontaneous breathing, positive end-expiratory pressure (PEEP), and high inspiratory resistances influence inspiratory intraparenchymal gas redistribution. Methods: This was an experimental study conducted on a swine model of mild acute respiratory distress syndrome. Dynamic computed tomography and respiratory mechanics were simultaneously acquired at different PEEP levels and external resistances, during both spontaneous breathing and controlled mechanical ventilation. Images were collected at two cranial–caudal levels. Delta-volume images (ΔVOLs) were obtained subtracting pairs of consecutive inspiratory images. The first three ΔVOLs, acquired for each analyzed breath, were used for the analysis of inspiratory pendelluft defined as intraparenchymal gas redistribution before the start of inspiratory flow at the airway opening. The following ΔVOLs were used for the analysis of gas redistribution during ongoing inspiratory flow at the airway opening. Results: During the first flow-independent phase of inspiration, the pendelluft of gas was observed only during spontaneous breathing and along the cranial-to-caudal and nondependent-to-dependent directions. The pendelluft was reduced by high PEEP (p < 0.04 comparing PEEP 15 and PEEP 0 cm H2O) and low external resistances (p < 0.04 comparing high and low external resistance). During the flow-dependent phase of inspiration, two patterns were identified: (1) gas displacing characterized by large gas redistribution areas; (2) gas scattering characterized by small, numerous areas of gas redistribution. Gas displacing was observed at low PEEP, high external resistances, and it characterized controlled mechanical ventilation (p < 0.01, comparing high and low PEEP during controlled mechanical ventilation). Conclusions: Low PEEP and high external resistances favored inspiratory pendelluft. During the flow-dependent phase of the inspiration, controlled mechanical ventilation and low PEEP and high external resistances favored larger phenomena of intraparenchymal gas redistribution (gas displacing) endangering lung stability. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is a new disease with different phases that can be catastrophic for subpopulations of patients with cardiovascular and pulmonary disease states at baseline. Appreciation for these different phases and treatment modalities, including manipulation of ventilatory settings and therapeutics, has made it a less lethal disease than when it emerged earlier this year. Different aspects of the disease are still largely unknown. However, laboratory investigation and clinical course of the COVID-19 show that this new disease is not a typical acute respiratory distress syndrome process, especially during the first phase. For this reason, the best strategy to be applied is to treat differently the single phases and to support the single functions of the failing organs as they appear. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Rationale: Tidal expiratory flow limitation (tidal-EFL) is not completely avoidable by applying positive end-expiratory pressure and may cause respiratory and hemodynamic complications in ventilated patients with lungs prone to collapse. During spontaneous breathing, expiratory diaphragmatic contraction counteracts tidal-EFL. We hypothesized that during both spontaneous breathing and controlled mechanical ventilation, external expiratory resistances reduce tidal-EFL.Objectives: To assess whether external expiratory resistances 1) affect expiratory diaphragmatic contraction during spontaneous breathing, 2) reduce expiratory flow and make lung compartments more homogeneous with more similar expiratory time constants, and 3) reduce tidal atelectasis, preventing hyperinflation.Methods: Three positive end-expiratory pressure levels and four external expiratory resistances were tested in 10 pigs after lung lavage. We analyzed expiratory diaphragmatic electric activity and respiratory mechanics. On the basis of computed tomography scans, four lung compartments-not inflated (atelectasis), poorly inflated, normally inflated, and hyperinflated-were defined.Measurements and Main Results: Consequently to additional external expiratory resistances, and mainly in lungs prone to collapse (at low positive end-expiratory pressure), 1) the expiratory transdiaphragmatic pressure decreased during spontaneous breathing by >10%, 2) expiratory flow was reduced and the expiratory time constants became more homogeneous, and 3) the amount of atelectasis at end-expiration decreased from 24% to 16% during spontaneous breathing and from 32% to 18% during controlled mechanical ventilation, without increasing hyperinflation.Conclusions: The expiratory modulation induced by external expiratory resistances preserves the positive effects of the expiratory brake while minimizing expiratory diaphragmatic contraction. External expiratory resistances optimize lung mechanics and limit tidal-EFL and tidal atelectasis, without increasing hyperinflation. [ABSTRACT FROM AUTHOR]

Rationale: The diaphragm is the major inspiratory muscle and is assumed to relax during expiration. However, electrical postinspiratory activity has been observed. Whether there is an expiratory diaphragmatic contraction that preserves lung patency has yet to be explored.Objectives: We hypothesized the occurrence of an expiratory diaphragmatic contraction directed at stabilizing peripheral airways and preventing or reducing cyclic expiratory lung collapse.Methods: Mild acute respiratory distress syndrome was induced in 10 anesthetized, spontaneously breathing pigs. Lung volume was decreased by lowering end-expiratory airway pressure in a stepwise manner. We recorded the diaphragmatic electric activity during expiration, dynamic computed tomographic scans, and respiratory mechanics. In five pigs, the same protocol was repeated during mechanical ventilation after muscle paralysis.Measurements and Main Results: Diaphragmatic electric activity during expiration increased by decreasing end-expiratory lung volume during spontaneous breathing. This enhanced the diaphragm muscle force, to a greater extent with lower lung volume, indicating a diaphragmatic electromechanical coupling during spontaneous expiration. In turn, the resulting diaphragmatic contraction delayed and reduced the expiratory collapse and increased lung aeration compared with mechanical ventilation with muscle paralysis and absence of diaphragmatic activity.Conclusions: The diaphragm is an important regulator of expiration. Its expiratory activity seems to preserve lung volume and to protect against lung collapse. The loss of diaphragmatic expiratory contraction during mechanical ventilation and muscle paralysis may be a contributing factor to unsuccessful respiratory support. [ABSTRACT FROM AUTHOR]

Computed tomography (CT), together with image analysis technologies, enable the construction of regional volume (V REG ) and local transpulmonary pressure (P TP,REG ) maps of the lung. Purpose of this study is to assess the distribution of V REG vs P TP,REG along the gravitational axis in healthy (HL) and experimental acute lung injury conditions (eALI) at various positive end-expiratory pressures (PEEPs) and inflation volumes. Mechanically ventilated pigs underwent inspiratory hold maneuvers at increasing volumes simultaneously with lung CT scans. eALI was induced via the iv administration of oleic acid. We computed voxel-level V REG vs P TP,REG curves into eleven isogravitational planes by applying polynomial regressions. Via F-test, we determined that V REG vs P TP,REG curves derived from different anatomical planes (p-values < 1.4E-3), exposed to different PEEPs (p-values < 1.5E-5) or subtending different lung status (p-values < 3E-3) were statistically different (except for two cases of adjacent planes). Lung parenchyma exhibits different elastic behaviors based on its position and the density of superimposed tissue which can increase during lung injury. [ABSTRACT FROM AUTHOR]

Little is known about the small airways dysfunction in acute respiratory distress syndrome (ARDS). By computed tomography (CT) imaging in a porcine experimental model of early ARDS, we aimed at studying the location and magnitude of peripheral airway closure and alveolar collapse under high and low distending pressures and high and low inspiratory oxygen fraction (FIO2). Six piglets were mechanically ventilated under anesthesia and muscle relaxation. Four animals underwent saline-washout lung injury, and two served as healthy controls. Beyond the site of assumed airway closure, gas was expected to be trapped in the injured lungs, promoting alveolar collapse. This was tested by ventilation with an FIO2 of 0.25 and 1 in sequence during low and high distending pressures. In the most dependent regions, the gas/tissue ratio of end-expiratory CT, after previous ventilation with FIO2 0.25 low-driving pressure, was significantly higher than after ventilation with FIO2 1; with high-driving pressure, this difference disappeared. Also, significant reduction in poorly aerated tissue and a correlated increase in nonaerated tissue in endexpiratory CT with FIO2 1 low-driving pressure were seen. When high-driving pressure was applied or after previous ventilation with FIO2 0.25 and low-driving pressure, this pattern disappeared. The findings suggest that low distending pressures produce widespread dependent airway closure and with high FIO2, subsequent absorption atelectasis. Low FIO2 prevented alveolar collapse during the study period because of slow absorption of gas behind closed airways. [ABSTRACT FROM AUTHOR]

ERN-EuroBloodNet, the European Reference Center in Rare Hematological Diseases (RHD) involves more than 450 RHD encompassing oncological and non oncological rare hematological diseases: rare anemias, rare coagulation disorders, polycythemia, myeloid and lymphoid tumors and rare hereditary hemochromatosis. (1) Availability of next generation sequencing for rare anemia disorders across the EU; (2) European Network of Sickle Cell Disease Patients' Organizations; (3) Training sessions for sickle cell disease patients; (4) Cross-Border collaborations agreements for bone marrow transplantation as a model for cross-border referral system; (5) Preceptorships for health professional cases based in EuroBloodNet healthcare providers and coordinated by Euro BloodNet sickle cell disease experts. In addition, RADeep, the Rare Anemia Disorders European Epidemiological Platform, is a joint venture conceived in the core of ERN-EuroBloodNet aiming at engaging clinical and basic research on Rare anemia disorders by facilitating the identification of patients' cohorts across Europe. [Extracted from the article]

Modern ventilatory strategies are based on the assumption that lung terminal airspaces act as isotropic balloons that progressively accommodate gas. Phase contrast synchrotron radiation computed tomography (PCSRCT) has recently challenged this concept, showing that in healthy lungs, deflation mechanisms are based on the sequential de-recruitment of airspaces. Using PCSRCT scans in an animal model of acute respiratory distress syndrome (ARDS), this study examined whether the numerosity (ASnum) and dimension (ASdim) of lung airspaces change during a deflation maneuver at decreasing levels of positive end-expiratory pressure (PEEP) at 12, 9, 6, 3, and 0 cmH2O. Deflation was associated with significant reduction of ASdim both in the whole lung section (passing from from 13.1 ± 2.0 at PEEP 12 to 7.6 ± 4.2 voxels at PEEP 0) and in single concentric regions of interest (ROIs). However, the regression between applied PEEP and ASnum was significant in the whole slice (ranging from 188 ± 52 at PEEP 12 to 146.4 ± 96.7 at PEEP 0) but not in the single ROIs. This mechanism of deflation in which reduction of ASdim is predominant, differs from the one observed in healthy conditions, suggesting that the peculiar alveolar micromechanics of ARDS might play a role in the deflation process. [ABSTRACT FROM AUTHOR]

Computed tomography (CT) can yield quantitative information about volume distribution in the lung. By combining information provided by CT and respiratory mechanics, this study aims at quantifying regional lung compliance (CL) and its distribution and homogeneity in mechanically ventilated pigs. The animals underwent inspiratory hold maneuvers at 12 lung volumes with simultaneous CT exposure at two end-expiratory pressure levels and before and after acute lung injury (ALI) by oleic acid administration. CL and the sum of positive voxel compliances from CT were linearly correlated; negative compliance areas were found. A remarkably heterogeneous distribution of voxel compliance was found in the injured lungs. As the lung inflation increased, the homogeneity increased in healthy lungs but decreased in injured lungs. Image analysis brought novel findings regarding spatial homogeneity of compliance, which increases in ALI but not in healthy lungs by applying PEEP after a recruitment maneuver. [ABSTRACT FROM AUTHOR]

Background: During the COVID-19 pandemic, intensive care units (ICU) introduced restrictions to in-person family visiting to safeguard patients, healthcare personnel, and visitors., Methods: We conducted a web-based survey (March-July 2021) investigating ICU visiting practices before the pandemic, at peak COVID-19 ICU admissions, and at the time of survey response. We sought data on visiting policies and communication modes including use of virtual visiting (videoconferencing)., Results: We obtained 667 valid responses representing ICUs in all continents. Before the pandemic, 20% (106/525) had unrestricted visiting hours; 6% (30/525) did not allow in-person visiting. At peak, 84% (558/667) did not allow in-person visiting for patients with COVID-19; 66% for patients without COVID-19. This proportion had decreased to 55% (369/667) at time of survey reporting. A government mandate to restrict hospital visiting was reported by 53% (354/646). Most ICUs (55%, 353/615) used regular telephone updates; 50% (306/667) used telephone for formal meetings and discussions regarding prognosis or end-of-life. Virtual visiting was available in 63% (418/667) at time of survey., Conclusions: Highly restrictive visiting policies were introduced at the initial pandemic peaks, were subsequently liberalized, but without returning to pre-pandemic practices. Telephone became the primary communication mode in most ICUs, supplemented with virtual visits., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Since developments are global in the healthcare arena, more should be done to align EU and other big markets' regulatory practices for rare disease patients. Notwithstanding efforts and cooperation between the US and EU aimed to harmonize their strategic plans in the field of orphan drugs, regulatory criteria and procedures to gain the designation, terms and classifications should be still harmonised. Aligning the criteria of prevalence and support to orphan medicines in the various jurisdictions internationally, would facilitate patient recruitment eventually at global level, so as to gain the data and the biological insights required to identify biomarkers and appropriate endpoints needed for progressing clinical development. A conducive regulatory environment can further support the development of medicines to treat rare diseases. Overall there is a need for joined-up regulatory process coordination. Better integration of regulatory pathways and better integration of regulatory systems, such as scientific tools and methods to generate evidence, would be helpful. There is a need to revise and agree the current frameworks to be improved which will take into account the considerations and challenges to diagnose and treat different rare diseases and improve quality of life. Deliberative processes with multi-stakeholders' involvement for reimbursement should be considered. This paper explores the successes and limitation of both the regulation and its implementation mechanisms in the current regulatory context, and suggests some improvements that could maximise its benefits and boost rare disease research even further., Competing Interests: All authors declare that they have no competing interests. Ivana Cattaneo is a Novartis employee and has stock options in Novartis., (Copyright © 2020 by S. Karger AG, Basel.)