Into the Dark Serum Proteome: Personalized Features of IgG1 and IgA1 Repertoires in Severe COVID-19 Patients.

Serum proteomics has matured and is now able to monitor hundreds of proteins quantitatively in large cohorts of patients. However, the fine characteristics of some of the most dominant proteins in serum, the immunoglobulins, are in these studies often ignored, due to their vast, and highly personalized, diversity in sequences. Here, we focus exclusively on these personalized features in the serum proteome and distinctively chose to study individual samples from a low diversity population: elderly donors infected by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). By using mass spectrometry-based methods, immunoglobulin IgG1 and IgA1 clonal repertoires were monitored quantitatively and longitudinally in more than 50 individual serum samples obtained from 17 Corona virus disease 2019 patients admitted to intensive care units. These clonal profiles were used to examine how each patient reacted to a severe SARS-CoV-2 infection. All 17 donors revealed unique polyclonal repertoires and substantial changes over time, with several new clones appearing following the infection, in a few cases leading to a few, very high, abundant clones dominating their repertoire. Several of these clones were de novo sequenced through combinations of top-down, middle-down, and bottom-up proteomics approaches. This revealed sequence features in line with sequences deposited in the SARS-CoV-specific antibody database. In other patients, the serological Ig profiles revealed the treatment with tocilizumab, that subsequently dominated their serological IgG1 repertoire. Tocilizumab clearance could be monitored, and a half-life of approximately 6 days was established. Overall, our longitudinal monitoring of IgG1 and IgA1 repertoires of individual donors reveals that antibody responses are highly personalized traits of each patient, affected by the disease and the chosen clinical treatment. The impact of these observations argues for a more personalized and longitudinal approach in patients' diagnostics, both in serum proteomics as well as in monitoring immune responses.

Intraoperative Ventilation/Perfusion Mismatch and Postoperative Pulmonary Complications after Major Noncardiac Surgery: A Prospective Cohort Study.

BACKGROUND: Postoperative pulmonary complications can increase hospital length of stay, postoperative morbidity, and mortality. Although many factors can increase the risk of postoperative pulmonary complications, it is not known whether intraoperative ventilation/perfusion (V/Q) mismatch can be associated with an increased risk of postoperative pulmonary complications after major noncardiac surgery. METHODS: This study enrolled patients undergoing general anesthesia for noncardiac surgery and evaluated intraoperative V/Q distribution using the automatic lung parameter estimator technique. The assessment was done after anesthesia induction, after 1 h from surgery start, and at the end of surgery. Demographic and procedural information were collected, and intraoperative ventilatory and hemodynamic parameters were measured at each timepoint. Patients were followed up for 7 days after surgery and assessed daily for postoperative pulmonary complication occurrence. RESULTS: The study enrolled 101 patients with a median age of 71 [62 to 77] years, a body mass index of 25 [22.4 to 27.9] kg/m2, and a preoperative Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) score of 41 [34 to 47]. Of these patients, 29 (29%) developed postoperative pulmonary complications, mainly acute respiratory failure (23%) and pleural effusion (11%). Patients with and without postoperative pulmonary complications did not differ in levels of shunt at T1 (postoperative pulmonary complications: 22.4% [10.4 to 35.9%] vs. no postoperative pulmonary complications:19.3% [9.4 to 24.1%]; P = 0.18) or during the protocol, whereas significantly different levels of high V/Q ratio were found during surgery (postoperative pulmonary complications: 13 [11 to 15] mmHg vs. no postoperative pulmonary complications: 10 [8 to 13.5] mmHg; P = 0.007) and before extubation (postoperative pulmonary complications: 13 [11 to 14] mmHg vs. no postoperative pulmonary complications: 10 [8 to 12] mmHg; P = 0.006). After adjusting for age, ARISCAT, body mass index, smoking, fluid balance, anesthesia type, laparoscopic procedure and surgery duration, high V/Q ratio before extubation was independently associated with the development of postoperative pulmonary complications (odds ratio, 1.147; 95% CI, 1.021 to 1.289; P = 0.02). The sensitivity analysis showed an E-value of 1.35 (CI, 1.11). CONCLUSIONS: In patients with intermediate or high risk of postoperative pulmonary complications undergoing major noncardiac surgery, intraoperative V/Q mismatch is associated with the development of postoperative pulmonary complications. Increased high V/Q ratio before extubation is independently associated with the occurrence of postoperative pulmonary complications in the first 7 days after surgery.

Impact of positive end-expiratory pressure on renal resistive index in mechanical ventilated patients.

PURPOSE: Growing evidence shows the complex interaction between lung and kidney in critically ill patients. The renal resistive index (RRI) is a bedside measurement of the resistance of the renal blood flow and it is correlated with kidney injury. The positive end-expiratory pressure (PEEP) level could affect the resistance of renal blood flow, so we assumed that RRI could help to monitoring the changes in renal hemodynamics at different PEEP levels. Our hypothesis was that the RRI at ICU admission could predict the risk of acute kidney injury in mechanical ventilated critically ill patients. METHODS: We performed a prospective study including 92 patients requiring mechanical ventilation for ≥ 48 h. A RRI ≥ 0.70, was deemed as pathological. RRI was measured within 24 h from ICU admission while applying 5,10 and 15 cmH2O of PEEP in random order (PEEP trial). RESULTS: Overall, RRI increased from 0.62 ± 0.09 at PEEP 5 to 0.66 ± 0.09 at PEEP 15 (p < 0.001). The mean RRI value during the PEEP trial was able to predict the occurrence of AKI with AUROC = 0.834 [95%CI 0.742-0.927]. Patients exhibiting a RRI ≥ 0.70 were 17/92(18%) at PEEP 5, 28/92(30%) at PEEP 10, 38/92(41%) at PEEP 15, respectively. Thirty-eight patients (41%) exhibited RRI ≥ 0.70 at least once during the PEEP trial. In these patients, AKI occurred in 55% of the cases, versus 13% remaining patients, p < 0.001. CONCLUSIONS: RRI seems able to predict the risk of AKI in mechanical ventilated patients; further, RRI values are influenced by the PEEP level applied. TRIAL REGISTRATION: Clinical gov NCT03969914 Registered 31 May 2019.

Estimation of the transpulmonary pressure from the central venous pressure in mechanically ventilated patients.

Transpulmonary pressure (PL) calculation requires esophageal pressure (PES) as a surrogate of pleural pressure (Ppl), but its calibration is a cumbersome technique. Central venous pressure (CVP) swings may reflect tidal variations in Ppl and could be used instead of PES, but the interpretation of CVP waveforms could be difficult due to superposition of heartbeat-induced pressure changes. Thus, we developed a digital filter able to remove the cardiac noise to obtain a filtered CVP (f-CVP). The aim of the study was to evaluate the accuracy of CVP and filtered CVP swings (ΔCVP and Δf-CVP, respectively) in estimating esophageal respiratory swings (ΔPES) and compare PL calculated with CVP, f-CVP and PES; then we tested the diagnostic accuracy of the f-CVP method to identify unsafe high PL levels, defined as PL>10 cmH2O. Twenty patients with acute respiratory failure (defined as PaO2/FiO2 ratio below 200 mmHg) treated with invasive mechanical ventilation and monitored with an esophageal balloon and central venous catheter were enrolled prospectively. For each patient a recording session at baseline was performed, repeated if a modification in ventilatory settings occurred. PES, CVP and airway pressure during an end-inspiratory and -expiratory pause were simultaneously recorded; CVP, f-CVP and PES waveforms were analyzed off-line and used to calculate transpulmonary pressure (PLCVP, PLf-CVP, PLPES, respectively). Δf-CVP correlated better than ΔCVP with ΔPES (r = 0.8, p = 0.001 vs. r = 0.08, p = 0.73), with a lower bias in Bland Altman analysis in favor of PLf-CVP (mean bias - 0.16, Limits of Agreement (LoA) -1.31, 0.98 cmH2O vs. mean bias - 0.79, LoA - 3.14, 1.55 cmH2O). Both PLf-CVP and PLCVP correlated well with PLPES (r = 0.98, p < 0.001 vs. r = 0.94, p < 0.001), again with a lower bias in Bland Altman analysis in favor of PLf-CVP (0.15, LoA - 0.95, 1.26 cmH2O vs. 0.80, LoA - 1.51, 3.12, cmH2O). PLf-CVP discriminated high PL value with an area under the receiver operating characteristic curve 0.99 (standard deviation, SD, 0.02) (AUC difference = 0.01 [-0.024; 0.05], p = 0.48). In mechanically ventilated patients with acute respiratory failure, the digital filtered CVP estimated ΔPES and PL obtained from digital filtered CVP represented a reliable value of standard PL measured with the esophageal method and could identify patients with non-protective ventilation settings.

Clinical risk factors for increased respiratory drive in intubated hypoxemic patients.

BACKGROUND: There is very limited evidence identifying factors that increase respiratory drive in hypoxemic intubated patients. Most physiological determinants of respiratory drive cannot be directly assessed at the bedside (e.g., neural inputs from chemo- or mechano-receptors), but clinical risk factors commonly measured in intubated patients could be correlated with increased drive. We aimed to identify clinical risk factors independently associated with increased respiratory drive in intubated hypoxemic patients. METHODS: We analyzed the physiological dataset from a multicenter trial on intubated hypoxemic patients on pressure support (PS). Patients with simultaneous assessment of the inspiratory drop in airway pressure at 0.1-s during an occlusion (P0.1) and risk factors for increased respiratory drive on day 1 were included. We evaluated the independent correlation of the following clinical risk factors for increased drive with P0.1: severity of lung injury (unilateral vs. bilateral pulmonary infiltrates, PaO2/FiO2, ventilatory ratio); arterial blood gases (PaO2, PaCO2 and pHa); sedation (RASS score and drug type); SOFA score; arterial lactate; ventilation settings (PEEP, level of PS, addition of sigh breaths). RESULTS: Two-hundred seventeen patients were included. Clinical risk factors independently correlated with higher P0.1 were bilateral infiltrates (increase ratio [IR] 1.233, 95%CI 1.047-1.451, p = 0.012); lower PaO2/FiO2 (IR 0.998, 95%CI 0.997-0.999, p = 0.004); higher ventilatory ratio (IR 1.538, 95%CI 1.267-1.867, p < 0.001); lower pHa (IR 0.104, 95%CI 0.024-0.464, p = 0.003). Higher PEEP was correlated with lower P0.1 (IR 0.951, 95%CI 0.921-0.982, p = 0.002), while sedation depth and drugs were not associated with P0.1. CONCLUSIONS: Independent clinical risk factors for higher respiratory drive in intubated hypoxemic patients include the extent of lung edema and of ventilation-perfusion mismatch, lower pHa, and lower PEEP, while sedation strategy does not affect drive. These data underline the multifactorial nature of increased respiratory drive.

Transparent decision support for mechanical ventilation using visualization of clinical preferences.

BACKGROUND: Systems aiding in selecting the correct settings for mechanical ventilation should visualize patient information at an appropriate level of complexity, so as to reduce information overload and to make reasoning behind advice transparent. Metaphor graphics have been applied to this effect, but these have largely been used to display diagnostic and physiologic information, rather than the clinical decision at hand. This paper describes how the conflicting goals of mechanical ventilation can be visualized and applied in making decisions. Data from previous studies are analyzed to assess whether visual patterns exist which may be of use to the clinical decision maker. MATERIALS AND METHODS: The structure and screen visualizations of a commercial clinical decision support system (CDSS) are described, including the visualization of the conflicting goals of mechanical ventilation represented as a hexagon. Retrospective analysis is performed on 95 patients from 2 previous clinical studies applying the CDSS, to identify repeated patterns of hexagon symbols. RESULTS: Visual patterns were identified describing optimal ventilation, over and under ventilation and pressure support, and over oxygenation, with these patterns identified for both control and support modes of mechanical ventilation. Numerous clinical examples are presented for these patterns illustrating their potential interpretation at the bedside. CONCLUSIONS: Visual patterns can be identified which describe the trade-offs required in mechanical ventilation. These may have potential to reduce information overload and help in simple and rapid identification of sub-optimal settings.

Long-term dyspnea, regional ventilation distribution and peripheral lung function in COVID-19 survivors: a 1 year follow up study.

BACKGROUND: Dyspnea is common after COVID-19 pneumonia and can be characterized by a defective CO2 diffusion (DLCO) despite normal pulmonary function tests (PFT). Nevertheless, DLCO impairment tends to normalize at 1 year, with no dyspnea regression. The altered regional distribution of ventilation and a dysfunction of the peripheral lung may characterize dyspnea at 1 year after COVID-19 pneumonia. We aimed at assessing the pattern of airway resistance and inflammation and the regional ventilation inhomogeneity in COVID-19 pneumonia survivors at 12-months after hospital discharge. METHODS: We followed up at 1-year patients previously admitted to the respiratory units (intensive care or sub-intensive care unit) for COVID-19 acute respiratory failure at 1-year after hospital discharge. PFT (spirometry, DLCO), impulse oscillometry (IOS), measurements of the exhaled nitric oxide (FENO) and Electrical Impedance Tomography (EIT) were used to evaluate lung volumes, CO2 diffusion capacity, peripheral lung inflammation/resistances and the regional inhomogeneity of ventilation distribution. A full medical examination was conducted, and symptoms of new onset (not present before COVID-19) were recorded. Patients were therefore divided into two groups based on the presence/absence of dyspnea (defined as mMRC ≥1) compared to evaluate differences in the respiratory function derived parameters. RESULTS: Sixty-seven patients were admitted between October and December 2020. Of them, 42/67 (63%) patients were discharged alive and 33 were evaluated during the follow up. Their mean age was 64 ± 11 years and 24/33 (73%) were males. Their maximum respiratory support was in 7/33 (21%) oxygen, in 4/33 (12%) HFNC, in 14/33 (42%) NIV/CPAP and in 8/33 (24%) invasive mechanical ventilation. During the clinical examination, 15/33 (45%) reported dyspnea. When comparing the two groups, no significant differences were found in PFT, in the peripheral airway inflammation (FENO) or mechanical properties (IOS). However, EIT showed a significantly higher regional inhomogeneity in patients with dyspnea both during resting breathing (0.98[0.96-1] vs 1.1[1-1.1], p = 0.012) and during forced expiration (0.96[0.94-1] vs 1 [0.98-1.1], p = 0.045). CONCLUSIONS: New onset dyspnea characterizes 45% of patients 1 year after COVID-19 pneumonia. In these patients, despite pulmonary function test may be normal, EIT shows a higher regional inhomogeneity both during quiet and forced breathing which may contribute to dyspnea. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT04343053, registration date 13/04/2020.

Associations Between Expiratory Flow Limitation and Postoperative Pulmonary Complications in Patients Undergoing Cardiac Surgery.

OBJECTIVES: To determine whether driving pressure and expiratory flow limitation are associated with the development of postoperative pulmonary complications (PPCs) in cardiac surgery patients. DESIGN: Prospective cohort study. SETTING: University Hospital San Raffaele, Milan, Italy. PARTICIPANTS: Patients undergoing elective cardiac surgery. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the occurrence of a predefined composite of PPCs. The authors determined the association among PPCs and intraoperative ventilation parameters, mechanical power and energy load, and occurrence of expiratory flow limitation (EFL) assessed with the positive end-expiratory pressure test. Two hundred patients were enrolled, of whom 78 (39%) developed one or more PPCs. Patients with PPCs, compared with those without PPCs, had similar driving pressure (mean difference [MD] -0.1 [95% confidence interval (CI), -1.0 to 0.7] cmH2O, p = 0.561), mechanical power (MD 0.5 [95% CI, -0.3 to 1.1] J/m, p = 0.364), and total energy load (MD 95 [95% CI, -78 to 263] J, p = 0.293), but they had a higher incidence of EFL (51% v 38%, p = 0.005). Only EFL was associated independently with the development of PPCs (odds ratio 2.46 [95% CI, 1.28-4.80], p = 0.007). CONCLUSIONS: PPCs occurred frequently in this patient population undergoing cardiac surgery. PPCs were associated independently with the presence of EFL but not with driving pressure, total energy load, or mechanical power.

Point-of-care ultrasound training for residents in anaesthesia and critical care: results of a national survey comparing residents and training program directors' perspectives.

BACKGROUND: Point-of-care ultrasound (POCUS) has become an essential tool for anaesthesia and critical care physicians and dedicated training is mandatory. This survey describes the current state of Italian residency training programs through the comparison of residents' and directors' perspective. METHODS: Observational prospective cross-sectional study: 12-question national e-survey sent to Italian directors of anaesthesia and critical care residency programs (N = 40) and residents (N = 3000). Questions focused on POCUS teaching (vascular access, transthoracic echocardiography, focused assessment for trauma, transcranial Doppler, regional anaesthesia, lung and diaphragm ultrasound), organization (dedicated hours, teaching tools, mentors), perceived adequacy/importance of the training and limiting factors. RESULTS: Five hundred seventy-one residents and 22 directors completed the survey. Bedside teaching (59.4-93.2%) and classroom lessons (29.7-54.4%) were the most frequent teaching tools. Directors reported higher participation in research projects (p < 0.05 for all techniques but focused assessment for trauma) and simulation (p < 0.05 for all techniques but transthoracic echocardiography). Use of online teaching was limited (< 10%); however, 87.4% of residents used additional web-based tools. Consultants were the most frequent mentors, with different perspectives between residents (72.0%) and directors (95.5%; p = 0.013). Residents reported self-training more frequently (48.5 vs. 9.1%; p < 0.001). Evaluation was mainly performed at the bedside; a certification was not available in most cases (< 10%). Most residents perceived POCUS techniques as extremely important. Residents underestimated the relevance given by directors to ultrasound skills in their evaluation and the minimal number of exams required to achieve basic competency. Overall, the training was considered adequate for vascular access only (62.2%). Directors mainly agreed on the need of ultrasound teaching improvement in all fields. Main limitations were the absence of a standardized curriculum for residents and limited mentors' time/expertise for directors. CONCLUSION: POCUS education is present in Italian anaesthesia and critical care residency programs, although with potential for improvement. Significant discrepancies between residents' and directors' perspectives were identified.

Clinical implications of microvascular CT scan signs in COVID-19 patients requiring invasive mechanical ventilation.

PURPOSE: COVID-19-related acute respiratory distress syndrome (ARDS) is characterized by the presence of signs of microvascular involvement at the CT scan, such as the vascular tree in bud (TIB) and the vascular enlargement pattern (VEP). Recent evidence suggests that TIB could be associated with an increased duration of invasive mechanical ventilation (IMV) and intensive care unit (ICU) stay. The primary objective of this study was to evaluate whether microvascular involvement signs could have a prognostic significance concerning liberation from IMV. MATERIAL AND METHODS: All the COVID-19 patients requiring IMV admitted to 16 Italian ICUs and having a lung CT scan recorded within 3 days from intubation were enrolled in this secondary analysis. Radiologic, clinical and biochemical data were collected. RESULTS: A total of 139 patients affected by COVID-19 related ARDS were enrolled. After grouping based on TIB or VEP detection, we found no differences in terms of duration of IMV and mortality. Extension of VEP and TIB was significantly correlated with ground-glass opacities (GGOs) and crazy paving pattern extension. A parenchymal extent over 50% of GGO and crazy paving pattern was more frequently observed among non-survivors, while a VEP and TIB extent involving 3 or more lobes was significantly more frequent in non-responders to prone positioning. CONCLUSIONS: The presence of early CT scan signs of microvascular involvement in COVID-19 patients does not appear to be associated with differences in duration of IMV and mortality. However, patients with a high extension of VEP and TIB may have a reduced oxygenation response to prone positioning. TRIAL REGISTRATION: NCT04411459.

Focus on renal blood flow in mechanically ventilated patients with SARS-CoV-2: a prospective pilot study.

Mechanically ventilated patients with ARDS due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) seem particularly susceptible to AKI. Our hypothesis was that the renal blood flow could be more compromised in SARS-CoV-2 patients than in patients with "classical" ARDS. We compared the renal resistivity index (RRI) and the renal venous flow (RVF) in ARDS patients with SARS-CoV-2 and in ARDS patients due to other etiologies. Prospective, observational pilot study performed on 30 mechanically ventilated patients (15 with SARS-COV-2 ARDS and 15 with ARDS). Mechanical ventilation settings included constant-flow controlled ventilation, a tidal volume of 6 ml/kg of ideal body weight and the PEEP level titrated to the lowest driving pressure. Ultrasound Doppler measurements of RRI and RVF pattern were performed in each patient. Patients with SARS-COV-2 ARDS had higher RRI than patients with ARDS (0.71[0.67-0.78] vs 0.64[0.60-0.74], p = 0.04). RVF was not-continuous in 9/15 patients (71%) in the SARS-COV-2 ARDS group and in and 5/15 (33%) in the ARDS group (p = 0.27). A linear correlation was found between PEEP and RRI in patients with SARS-COV-2 ARDS (r2 = 0.31; p = 0.03) but not in patients with ARDS. Occurrence of AKI was 53% in patients with SARS-COV-2 ARDS and 33% in patients with ARDS (p = 0.46). We found a more pronounced impairment in renal blood flow in mechanically ventilated patients with SARS-COV-2 ARDS, compared with patients with "classical" ARDS.

Respiratory Drive in Patients with Sepsis and Septic Shock: Modulation by High-flow Nasal Cannula.

BACKGROUND: Experimental and pilot clinical data suggest that spontaneously breathing patients with sepsis and septic shock may present increased respiratory drive and effort, even in the absence of pulmonary infection. The study hypothesis was that respiratory drive and effort may be increased in septic patients and correlated with extrapulmonary determinant and that high-flow nasal cannula may modulate drive and effort. METHODS: Twenty-five nonintubated patients with extrapulmonary sepsis or septic shock were enrolled. Each patient underwent three consecutive steps: low-flow oxygen at baseline, high-flow nasal cannula, and then low-flow oxygen again. Arterial blood gases, esophageal pressure, and electrical impedance tomography data were recorded toward the end of each step. Respiratory effort was measured as the negative swing of esophageal pressure (ΔPes); drive was quantified as the change in esophageal pressure during the first 500 ms from start of inspiration (P0.5). Dynamic lung compliance was calculated as the tidal volume measured by electrical impedance tomography, divided by ΔPes. The results are presented as medians [25th to 75th percentile]. RESULTS: Thirteen patients (52%) were in septic shock. The Sequential Organ Failure Assessment score was 5 [4 to 9]. During low-flow oxygen at baseline, respiratory drive and effort were elevated and significantly correlated with arterial lactate (r = 0.46, P = 0.034) and inversely with dynamic lung compliance (r = -0.735, P < 0.001). Noninvasive support by high-flow nasal cannula induced a significant decrease of respiratory drive (P0.5: 6.0 [4.4 to 9.0] vs. 4.3 [3.5 to 6.6] vs. 6.6 [4.9 to 10.7] cm H2O, P < 0.001) and effort (ΔPes: 8.0 [6.0 to 11.5] vs. 5.5 [4.5 to 8.0] vs. 7.5 [6.0 to 12.6] cm H2O, P < 0.001). Oxygenation and arterial carbon dioxide levels remained stable during all study phases. CONCLUSIONS: Patients with sepsis and septic shock of extrapulmonary origin present elevated respiratory drive and effort, which can be effectively reduced by high-flow nasal cannula.

Markers of endothelial and epithelial pulmonary injury in mechanically ventilated COVID-19 ICU patients.

BACKGROUND: Biomarkers can be used to detect the presence of endothelial and/or alveolar epithelial injuries in case of ARDS. Angiopoietin-2 (Ang-2), soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), P-selectin and E-selectin are biomarkers of endothelial injury, whereas the receptor for advanced glycation end-products (RAGE) reflects alveolar epithelial injury. The aims of this study were to evaluate whether the plasma concentration of the above-mentioned biomarkers was different 1) in survivors and non-survivors of COVID-19-related ARDS and 2) in COVID-19-related and classical ARDS. METHODS: This prospective study was performed in two COVID-19-dedicated Intensive Care Units (ICU) and one non-COVID-19 ICU at Ferrara University Hospital. A cohort of 31 mechanically ventilated patients with COVID-19 ARDS and a cohort of 11 patients with classical ARDS were enrolled. Ang-2, ICAM-1, VCAM-1, P-selectin, E-selectin and RAGE were determined with a bead-based multiplex immunoassay at three time points: inclusion in the study (T1), after 7 ± 2 days (T2) and 14 ± 2 days (T3). The primary outcome was to evaluate the plasma trend of the biomarker levels in survivors and non-survivors. The secondary outcome was to evaluate the differences in respiratory mechanics variables and gas exchanges between survivors and non-survivors. Furthermore, we compared the plasma levels of the biomarkers at T1 in patients with COVID-19-related ARDS and classical ARDS. RESULTS: In COVID-19-related ARDS, the plasma levels of Ang-2 and ICAM-1 at T1 were statistically higher in non-survivors than survivors, (p = 0.04 and p = 0.03, respectively), whereas those of P-selectin, E-selectin and RAGE did not differ. Ang-2 and ICAM-1 at T1 were predictors of mortality (AUROC 0.650 and 0.717, respectively). At T1, RAGE and P-selectin levels were higher in classical ARDS than in COVID-19-related ARDS. Ang-2, ICAM-1 and E-selectin were lower in classical ARDS than in COVID-19-related ARDS (all p < 0.001). CONCLUSIONS: COVID-19 ARDS is characterized by an early pulmonary endothelial injury, as detected by Ang-2 and ICAM-1. COVID-19 ARDS and classical ARDS exhibited a different expression of biomarkers, suggesting different pathological pathways. Trial registration NCT04343053 , Date of registration: April 13, 2020.

Quality of life of COVID-19 critically ill survivors after ICU discharge: 90 days follow-up.

PURPOSE: The onset of the coronavirus disease 19 (COVID-19) pandemic in Italy induced a dramatic increase in the need for intensive care unit (ICU) beds for a large proportion of patients affected by COVID-19-related acute respiratory distress syndrome (ARDS). The aim of the present study was to describe the health-related quality of life (HRQoL) at 90 days after ICU discharge in a cohort of COVID-19 patients undergoing invasive mechanical ventilation and to compare it with an age and sex-matched sample from the general Italian and Finnish populations. Moreover, the possible associations between clinical, demographic, social factors, and HRQoL were investigated. METHODS: COVID-19 ARDS survivors from 16 participating ICUs were followed up until 90 days after ICU discharge and the HRQoL was evaluated with the 15D instrument. A parallel cohort of age and sex-matched Italian population from the same geographic areas was interviewed and a third group of matched Finnish population was extracted from the Finnish 2011 National Health survey. A linear regression analysis was performed to evaluate potential associations between the evaluated factors and HRQoL. RESULTS: 205 patients answered to the questionnaire. HRQoL of the COVID-19 ARDS patients was significantly lower than the matched populations in both physical and mental dimensions. Age, sex, number of comorbidities, ARDS class, duration of invasive mechanical ventilation, and occupational status were found to be significant determinants of the 90 days HRQoL. Clinical severity at ICU admission was poorly correlated to HRQoL. CONCLUSION: COVID-19-related ARDS survivors at 90 days after ICU discharge present a significant reduction both on physical and psychological dimensions of HRQoL measured with the 15D instrument. TRIAL REGISTRATION: NCT04411459.

Over time relationship between platelet reactivity, myocardial injury and mortality in patients with SARS-CoV-2-associated respiratory failure.

The aim of this study (NCT04343053) is to investigate the relationship between platelet activation, myocardial injury, and mortality in patients affected by Coronavirus disease 2019 (COVID-19). Fifty-four patients with respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were enrolled as cases. Eleven patients with the same clinical presentation, but negative for SARS-CoV-2 infection, were included as controls. Blood samples were collected at three different time points (inclusion [T1], after 7 ± 2 days [T2] and 14 ± 2 days [T3]). Platelet aggregation by light transmittance aggregometry and the circulating levels of soluble CD40 ligand (sCD40L) and P-selectin were measured. Platelet biomarkers did not differ between cases and controls, except for sCD40L which was higher in COVID-19 patients (p = .003). In COVID-19 patients, P-selectin and sCD40L levels decreased from T1 to T3 and were higher in cases requiring admission to intensive care unit (p = .004 and p = .008, respectively). Patients with myocardial injury (37%), as well as those who died (30%), had higher values of all biomarkers of platelet activation (p < .05 for all). Myocardial injury was an independent predictor of mortality. In COVID-19 patients admitted to hospital for respiratory failure, heightened platelet activation is associated with severity of illness, myocardial injury, and mortality.ClinicalTrials.gov number: NCT04343053.

Effect of Helmet Noninvasive Ventilation vs High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients With COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure: The HENIVOT Randomized Clinical Trial.

Importance: High-flow nasal oxygen is recommended as initial treatment for acute hypoxemic respiratory failure and is widely applied in patients with COVID-19. Objective: To assess whether helmet noninvasive ventilation can increase the days free of respiratory support in patients with COVID-19 compared with high-flow nasal oxygen alone. Design, Setting, and Participants: Multicenter randomized clinical trial in 4 intensive care units (ICUs) in Italy between October and December 2020, end of follow-up February 11, 2021, including 109 patients with COVID-19 and moderate to severe hypoxemic respiratory failure (ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ≤200). Interventions: Participants were randomly assigned to receive continuous treatment with helmet noninvasive ventilation (positive end-expiratory pressure, 10-12 cm H2O; pressure support, 10-12 cm H2O) for at least 48 hours eventually followed by high-flow nasal oxygen (n = 54) or high-flow oxygen alone (60 L/min) (n = 55). Main Outcomes and Measures: The primary outcome was the number of days free of respiratory support within 28 days after enrollment. Secondary outcomes included the proportion of patients who required endotracheal intubation within 28 days from study enrollment, the number of days free of invasive mechanical ventilation at day 28, the number of days free of invasive mechanical ventilation at day 60, in-ICU mortality, in-hospital mortality, 28-day mortality, 60-day mortality, ICU length of stay, and hospital length of stay. Results: Among 110 patients who were randomized, 109 (99%) completed the trial (median age, 65 years [interquartile range {IQR}, 55-70]; 21 women [19%]). The median days free of respiratory support within 28 days after randomization were 20 (IQR, 0-25) in the helmet group and 18 (IQR, 0-22) in the high-flow nasal oxygen group, a difference that was not statistically significant (mean difference, 2 days [95% CI, -2 to 6]; P = .26). Of 9 prespecified secondary outcomes reported, 7 showed no significant difference. The rate of endotracheal intubation was significantly lower in the helmet group than in the high-flow nasal oxygen group (30% vs 51%; difference, -21% [95% CI, -38% to -3%]; P = .03). The median number of days free of invasive mechanical ventilation within 28 days was significantly higher in the helmet group than in the high-flow nasal oxygen group (28 [IQR, 13-28] vs 25 [IQR 4-28]; mean difference, 3 days [95% CI, 0-7]; P = .04). The rate of in-hospital mortality was 24% in the helmet group and 25% in the high-flow nasal oxygen group (absolute difference, -1% [95% CI, -17% to 15%]; P > .99). Conclusions and Relevance: Among patients with COVID-19 and moderate to severe hypoxemia, treatment with helmet noninvasive ventilation, compared with high-flow nasal oxygen, resulted in no significant difference in the number of days free of respiratory support within 28 days. Further research is warranted to determine effects on other outcomes, including the need for endotracheal intubation. Trial Registration: ClinicalTrials.gov Identifier: NCT04502576.

Physiological effects of two driving pressure-based methods to set positive end-expiratory pressure during one lung ventilation.

During one-lung ventilation (OLV), titrating the positive end-expiratory pressure (PEEP) to target a low driving pressure (∆P) could reduce postoperative pulmonary complications. However, it is unclear how to conduct PEEP titration: by stepwise increase starting from zero PEEP (PEEPINCREMENTAL) or by stepwise decrease after a lung recruiting manoeuvre (PEEPDECREMENTAL). In this randomized trial, we compared the physiological effects of these two PEEP titration strategies on respiratory mechanics, ventilation/perfusion mismatch and gas exchange. Patients undergoing video-assisted thoracoscopic surgery in OLV were randomly assigned to a PEEPINCREMENTAL or PEEPDECREMENTAL strategy to match the lowest ∆P. In the PEEPINCREMENTAL group, PEEP was stepwise titrated from ZEEP up to 16 cm H2O, whereas in the PEEPDECREMENTAL group PEEP was decrementally titrated, starting from 16 cm H2O, immediately after a lung recruiting manoeuvre. Respiratory mechanics, ventilation/perfusion mismatch and blood gas analyses were recorded at baseline, after PEEP titration and at the end of surgery. Sixty patients were included in the study. After PEEP titration, shunt decreased similarly in both groups, from 50 [39-55]% to 35 [28-42]% in the PEEPINCREMENTAL and from 45 [37-58]% to 33 [25-45]% in the PEEPDECREMENTAL group (both p < 0.001 vs baseline). The resulting ∆P, however, was lower in the PEEPDECREMENTAL than in the PEEPINCREMENTAL group (8 [7-11] vs 10 [9-11] cm H2O; p = 0.03). In the PEEPDECREMENTAL group the PaO2/ FIO2 ratio increased significantly after intervention (from 140 [99-176] to 186 [152-243], p < 0.001). Both the PEEPINCREMENTAL and the PEEPDECREMENTAL strategies were able to decrease intraoperative shunt, but only PEEPDECREMENTAL improved oxygenation and lowered intraoperative ΔP.Clinical trial number NCT03635281; August 2018; "retrospectively registered".

Personalized Positive End-Expiratory Pressure in Acute Respiratory Distress Syndrome: Comparison Between Optimal Distribution of Regional Ventilation and Positive Transpulmonary Pressure.

OBJECTIVES: Different techniques exist to select personalized positive end-expiratory pressure in patients affected by the acute respiratory distress syndrome. The positive end-expiratory transpulmonary pressure strategy aims to counteract dorsal lung collapse, whereas electrical impedance tomography could guide positive end-expiratory pressure selection based on optimal homogeneity of ventilation distribution. We compared the physiologic effects of positive end-expiratory pressure guided by electrical impedance tomography versus transpulmonary pressure in patients affected by acute respiratory distress syndrome. DESIGN: Cross-over prospective physiologic study. SETTING: Two academic ICUs. PATIENTS: Twenty ICU patients affected by acute respiratory distress syndrome undergoing mechanical ventilation. INTERVENTION: Patients monitored by an esophageal catheter and a 32-electrode electrical impedance tomography monitor underwent two positive end-expiratory pressure titration trials by randomized cross-over design to find the level of positive end-expiratory pressure associated with: 1) positive end-expiratory transpulmonary pressure (PEEPPL) and 2) proportion of poorly or nonventilated lung units (Silent Spaces) less than or equal to 15% (PEEPEIT). Each positive end-expiratory pressure level was maintained for 20 minutes, and afterward, lung mechanics, gas exchange, and electrical impedance tomography data were collected. MEASUREMENTS AND MAIN RESULTS: PEEPEIT and PEEPPL differed in all patients, and there was no correlation between the levels identified by the two methods (Rs = 0.25; p = 0.29). PEEPEIT determined a more homogeneous distribution of ventilation with a lower percentage of dependent Silent Spaces (p = 0.02), whereas PEEPPL was characterized by lower airway-but not transpulmonary-driving pressure (p = 0.04). PEEPEIT was significantly higher than PEEPPL in subjects with extrapulmonary acute respiratory distress syndrome (p = 0.006), whereas the opposite was true for pulmonary acute respiratory distress syndrome (p = 0.03). CONCLUSIONS: Personalized positive end-expiratory pressure levels selected by electrical impedance tomography- and transpulmonary pressure-based methods are not correlated at the individual patient level. PEEPPL is associated with lower dynamic stress, whereas PEEPEIT may help to optimize lung recruitment and homogeneity of ventilation. The underlying etiology of acute respiratory distress syndrome could deeply influence results from each method.

Electrocardiographic features of 431 consecutive, critically ill COVID-19 patients: an insight into the mechanisms of cardiac involvement.

AIMS: Our aim was to describe the electrocardiographic features of critical COVID-19 patients. METHODS AND RESULTS: We carried out a multicentric, cross-sectional, retrospective analysis of 431 consecutive COVID-19 patients hospitalized between 10 March and 14 April 2020 who died or were treated with invasive mechanical ventilation. This project is registered on ClinicalTrials.gov (identifier: NCT04367129). Standard ECG was recorded at hospital admission. ECG was abnormal in 93% of the patients. Atrial fibrillation/flutter was detected in 22% of the patients. ECG signs suggesting acute right ventricular pressure overload (RVPO) were detected in 30% of the patients. In particular, 43 (10%) patients had the S1Q3T3 pattern, 38 (9%) had incomplete right bundle branch block (RBBB), and 49 (11%) had complete RBBB. ECG signs of acute RVPO were not statistically different between patients with (n = 104) or without (n=327) invasive mechanical ventilation during ECG recording (36% vs. 28%, P = 0.10). Non-specific repolarization abnormalities and low QRS voltage in peripheral leads were present in 176 (41%) and 23 (5%), respectively. In four patients showing ST-segment elevation, acute myocardial infarction was confirmed with coronary angiography. No ST-T abnormalities suggestive of acute myocarditis were detected. In the subgroup of 110 patients where high-sensitivity troponin I was available, ECG features were not statistically different when stratified for above or below the 5 times upper reference limit value. CONCLUSIONS: The ECG is abnormal in almost all critically ill COVID-19 patients and shows a large spectrum of abnormalities, with signs of acute RVPO in 30% of the patients. Rapid and simple identification of these cases with ECG at hospital admission can facilitate classification of the patients and provide pathophysiological insights.

Continuous assessment of neuro-ventilatory drive during 12 h of pressure support ventilation in critically ill patients.

INTRODUCTION: Pressure support ventilation (PSV) should allow spontaneous breathing with a "normal" neuro-ventilatory drive. Low neuro-ventilatory drive puts the patient at risk of diaphragmatic atrophy while high neuro-ventilatory drive may causes dyspnea and patient self-inflicted lung injury. We continuously assessed for 12 h the electrical activity of the diaphragm (EAdi), a close surrogate of neuro-ventilatory drive, during PSV. Our aim was to document the EAdi trend and the occurrence of periods of "Low" and/or "High" neuro-ventilatory drive during clinical application of PSV. METHOD: In 16 critically ill patients ventilated in the PSV mode for clinical reasons, inspiratory peak EAdi peak (EAdiPEAK), pressure time product of the trans-diaphragmatic pressure per breath and per minute (PTPDI/b and PTPDI/min, respectively), breathing pattern and major asynchronies were continuously monitored for 12 h (from 8 a.m. to 8 p.m.). We identified breaths with "Normal" (EAdiPEAK 5-15 µV), "Low" (EAdiPEAK < 5 µV) and "High" (EAdiPEAK > 15 µV) neuro-ventilatory drive. RESULTS: Within all the analyzed breaths (177.117), the neuro-ventilatory drive, as expressed by the EAdiPEAK, was "Low" in 50.116 breath (28%), "Normal" in 88.419 breaths (50%) and "High" in 38.582 breaths (22%). The average times spent in "Low", "Normal" and "High" class were 1.37, 3.67 and 0.55 h, respectively (p < 0.0001), with wide variations among patients. Eleven patients remained in the "Low" neuro-ventilatory drive class for more than 1 h, median 6.1 [3.9-8.5] h and 6 in the "High" neuro-ventilatory drive class, median 3.4 [2.2-7.8] h. The asynchrony index was significantly higher in the "Low" neuro-ventilatory class, mainly because of a higher number of missed efforts. CONCLUSIONS: We observed wide variations in EAdi amplitude and unevenly distributed "Low" and "High" neuro ventilatory drive periods during 12 h of PSV in critically ill patients. Further studies are needed to assess the possible clinical implications of our physiological findings.