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 non-cardiac surgery: a prospective cohort study.

BACKGROUND: Postoperative pulmonary complications (PPCs) can increase hospital length of stay, postoperative morbidity and mortality. Despite many factors can increase the risk of PPCs, it is not known whether intraoperative ventilation/perfusion (V/Q) mismatch can be associated with an increased risk of PPCs after major non-cardiac surgery. METHODS: We enrolled patients undergoing general anesthesia for non-cardiac surgery and evaluated intraoperative V/Q distribution using the Automatic Lung Parameter Estimator technique. The assessment was done after anesthesia induction (T1), after 1 hour from surgery start (T2) and at the end of surgery (T3). We collected demographic and procedural information and measured intraoperative ventilatory and hemodynamic parameters at each time-point. Patients were followed up for 7 days after surgery and assessed daily for PPCs occurrence. RESULTS: We enrolled 101 patients with a median age of 71 [62-77] years, a BMI of 25 [22.4-27.9] kg/m 2 and a preoperative ARISCAT score of 41 [34-47]. Of them, 29 (29%) developed PPCs, mainly acute respiratory failure (23%) and pleural effusion (11%). Patients with and without PPCs did not differ in levels of shunt at T1 (PPCs:22.4[10.4-35.9] % vs No PPCs:19.3[9.4-24.1] %, p=0.18) or during the protocol, while significantly different levels of high V/Q were found during surgery (PPCs:13[11-15] mmHg vs No PPCs:10[8-13.5] mmHg, p=0.007) and before extubation (PPCs:13[11-14]mmHg vs No PPCs:10[8-12] mmHg, p=0.006). After adjusting for age, ARISCAT, BMI, smoking, fluid balance, anesthesia type, laparoscopic procedure and surgery duration, high V/Q before extubation was independently associated with the development of PPCs (OR 1.147, CI 95% [1.021-1.289], p=0.02). The sensitivity analysis showed an E-value of 1.35 (CI=1.11). CONCLUSIONS: In patients with intermediate/high risk of PPCs undergoing major non-cardiac surgery, intraoperative V/Q mismatch is associated with the development of PPCs. Increased high V/Q before extubation is independently associated with the occurrence of PPCs in the first 7 days after surgery.

Serum from COVID-19 patients promotes endothelial cell dysfunction through protease-activated receptor 2.

BACKGROUND: Endothelial dysfunction plays a central role in the pathophysiology of COVID-19 and is closely linked to the severity and mortality of the disease. The inflammatory response to SARS-CoV-2 infection can alter the capacity of the endothelium to regulate vascular tone, immune responses, and the balance between anti-thrombotic and pro-thrombotic properties. However, the specific endothelial pathways altered during COVID-19 still need to be fully understood. OBJECTIVE: In this study, we sought to identify molecular changes in endothelial cells induced by circulating factors characteristic of COVID-19. METHODS AND RESULTS: To this aim, we cultured endothelial cells with sera from patients with COVID-19 or non-COVID-19 pneumonia. Through transcriptomic analysis, we were able to identify a distinctive endothelial phenotype that is induced by sera from COVID-19 patients. We confirmed and expanded this observation in vitro by showing that COVID-19 serum alters functional properties of endothelial cells leading to increased apoptosis, loss of barrier integrity, and hypercoagulability. Furthermore, we demonstrated that these endothelial dysfunctions are mediated by protease-activated receptor 2 (PAR-2), as predicted by transcriptome network analysis validated by in vitro functional assays. CONCLUSION: Our findings provide the rationale for further studies to evaluate whether targeting PAR-2 may be a clinically effective strategy to counteract endothelial dysfunction in COVID-19.

Pathological findings associated with the updated European Society of Cardiology 2022 guidelines for preoperative cardiac testing: an observational cohort modelling study.

BACKGROUND: In 2022, the European Society of Cardiology updated guidelines for preoperative evaluation. The aims of this study were to quantify: (1) the impact of the updated recommendations on the yield of pathological findings compared with the previous guidelines published in 2014; (2) the impact of preoperative B-type natriuretic peptide (NT-proBNP) use for risk estimation on the yield of pathological findings; and (3) the association between 2022 guideline adherence and outcomes. METHODS: This was a secondary analysis of MET-REPAIR, an international, prospective observational cohort study (NCT03016936). Primary endpoints were reduced ejection fraction (EF<40%), stress-induced ischaemia, and major adverse cardiovascular events (MACE). The explanatory variables were class of recommendations for transthoracic echocardiography (TTE), stress imaging, and guideline adherence. We conducted second-order Monte Carlo simulations and multivariable regression. RESULTS: In total, 15,529 patients (39% female, median age 72 [inter-quartile range: 67-78] yr) were included. The 2022 update changed the recommendation for preoperative TTE in 39.7% patients, and for preoperative stress imaging in 12.9% patients. The update resulted in missing 1 EF <40% every 3 fewer conducted TTE, and in 4 additional stress imaging per 1 additionally detected ischaemia events. For cardiac stress testing, four more investigations were performed for every 1 additionally detected ischaemia episodes. Use of NT-proBNP did not improve the yield of pathological findings. Multivariable regression analysis failed to find an association between adherence to the updated guidelines and MACE. CONCLUSIONS: The 2022 update for preoperative cardiac testing resulted in a relevant increase in tests receiving a stronger recommendation. The updated recommendations for TTE did not improve the yield of pathological cardiac testing.

Lung Recruitment Assessed by Electrical Impedance Tomography (RECRUIT): A Multicenter Study of COVID-19 Acute Respiratory Distress Syndrome.

Rationale: Defining lung recruitability is needed for safe positive end-expiratory pressure (PEEP) selection in mechanically ventilated patients. However, there is no simple bedside method including both assessment of recruitability and risks of overdistension as well as personalized PEEP titration. Objectives: To describe the range of recruitability using electrical impedance tomography (EIT), effects of PEEP on recruitability, respiratory mechanics and gas exchange, and a method to select optimal EIT-based PEEP. Methods: This is the analysis of patients with coronavirus disease (COVID-19) from an ongoing multicenter prospective physiological study including patients with moderate-severe acute respiratory distress syndrome of different causes. EIT, ventilator data, hemodynamics, and arterial blood gases were obtained during PEEP titration maneuvers. EIT-based optimal PEEP was defined as the crossing point of the overdistension and collapse curves during a decremental PEEP trial. Recruitability was defined as the amount of modifiable collapse when increasing PEEP from 6 to 24 cm H2O (ΔCollapse24-6). Patients were classified as low, medium, or high recruiters on the basis of tertiles of ΔCollapse24-6. Measurements and Main Results: In 108 patients with COVID-19, recruitability varied from 0.3% to 66.9% and was unrelated to acute respiratory distress syndrome severity. Median EIT-based PEEP differed between groups: 10 versus 13.5 versus 15.5 cm H2O for low versus medium versus high recruitability (P < 0.05). This approach assigned a different PEEP level from the highest compliance approach in 81% of patients. The protocol was well tolerated; in four patients, the PEEP level did not reach 24 cm H2O because of hemodynamic instability. Conclusions: Recruitability varies widely among patients with COVID-19. EIT allows personalizing PEEP setting as a compromise between recruitability and overdistension. Clinical trial registered with www.clinicaltrials.gov (NCT04460859).

Factors affecting adherence to recommendations on pre-operative cardiac testing: A cohort study.

BACKGROUND: Cardiac risk evaluation prior to noncardiac surgery is fundamental to tailor peri-operative management to patient's estimated risk. Data on the degree of adherence to guidelines in patients at cardiovascular risk in Europe and factors influencing adherence are underexplored. OBJECTIVES: The aim of this analysis was to describe the degree of adherence to [2014 European Society of Cardiology (ESC)/European Society of Anaesthesiology (ESA) guidelines] recommendations on rest echocardiography [transthoracic echocardiography (TTE)] and to stress imaging prior to noncardiac surgery in a large European sample and to assess factors potentially affecting adherence. DESIGN: Secondary analysis of a multicentre, international, prospective cohort study (MET-REPAIR). SETTING: Twenty-five European centres of all levels of care that enrolled patients between 2017 and 2020. PATIENTS: With elevated cardiovascular risk undergoing in-hospital elective, noncardiac surgery. MAIN OUTCOME MEASURES: (Non)adherence to each pre-operative TTE and stress imaging recommendations classified as guideline-adherent, overuse and underuse. We performed descriptive analysis. To explore the impact of patients' sex, age, geographical region, and hospital teaching status, we conducted multivariate multinominal regression analysis. RESULTS: Out of 15 983 patients, 15 529 were analysed (61% men, mean age 72 ±â€Š8 years). Overuse (conduction in spite of class III) and underuse (nonconduction in spite of class I recommendation) for pre-operative TTE amounted to 16.6% (2542/15 344) and 6.6% (1015/15 344), respectively. Stress imaging overuse and underuse amounted to 1.7% (241/14 202) and 0.4% (52/14 202) respectively. Male sex, some age categories and some geographical regions were significantly associated with TTE overuse. Male sex and some regions were also associated with TTE underuse. Age and regions were associated with overuse of stress imaging. Male sex, age, and some regions were associated with stress imaging underuse. CONCLUSION: Adherence to pre-operative stress imaging recommendation was high. In contrast, adherence to TTE recommendations was moderate. Both patients' and geographical factors affected adherence to joint ESC/ESA guidelines. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03016936.

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.

Diaphragmatic morphological post-mortem findings in critically ill COVID-19 patients: an observational study.

Our study investigates the post-mortem findings of the diaphragm's muscular structural changes in mechanically ventilated COVID-19 patients. Diaphragm samples of the right side from 42 COVID-19 critically ill patients were analyzed and correlated with the type and length of mechanical ventilation (MV), ventilatory parameters, prone positioning, and use of sedative drugs. The mean number of fibers was 550±626. The cross-sectional area was 4120±3280 µm2, while the muscular fraction was 0.607±0.126. The overall population was clustered into two distinct populations (clusters 1 and 2). Cluster 1 showed a lower percentage of slow myosin fiber and higher fast fiber content than cluster 2, 68% versus 82%, p<0.00001, and 29.8% versus 18.8%, p=0.00045 respectively. The median duration of MV was 180 (41-346) hours. In cluster 1, a relationship between assisted ventilation and fast myosin fiber percentage (R2=-0.355, p=0.014) was found. In cluster 2, fast fiber content increased with increasing the length of the controlled MV (R2=0.446, p=0.006). A high grade of fibrosis was reported. Cluster 1 was characterized by fibers' atrophy and cluster 2 by hypertrophy, supposing different effects of ventilation on the diaphragm but without excluding a possible direct viral effect on diaphragmatic fibers.

Advanced Point-of-care Bedside Monitoring for Acute Respiratory Failure.

Advanced respiratory monitoring involves several mini- or noninvasive tools, applicable at bedside, focused on assessing lung aeration and morphology, lung recruitment and overdistention, ventilation-perfusion distribution, inspiratory effort, respiratory drive, respiratory muscle contraction, and patient-ventilator asynchrony, in dealing with acute respiratory failure. Compared to a conventional approach, advanced respiratory monitoring has the potential to provide more insights into the pathologic modifications of lung aeration induced by the underlying disease, follow the response to therapies, and support clinicians in setting up a respiratory support strategy aimed at protecting the lung and respiratory muscles. Thus, in the clinical management of the acute respiratory failure, advanced respiratory monitoring could play a key role when a therapeutic strategy, relying on individualization of the treatments, is adopted.

Risk assessment for major adverse cardiovascular events after noncardiac surgery using self-reported functional capacity: international prospective cohort study.

BACKGROUND: Guidelines endorse self-reported functional capacity for preoperative cardiovascular assessment, although evidence for its predictive value is inconsistent. We hypothesised that self-reported effort tolerance improves prediction of major adverse cardiovascular events (MACEs) after noncardiac surgery. METHODS: This is an international prospective cohort study (June 2017 to April 2020) in patients undergoing elective noncardiac surgery at elevated cardiovascular risk. Exposures were (i) questionnaire-estimated effort tolerance in metabolic equivalents (METs), (ii) number of floors climbed without resting, (iii) self-perceived cardiopulmonary fitness compared with peers, and (iv) level of regularly performed physical activity. The primary endpoint was in-hospital MACE consisting of cardiovascular mortality, non-fatal cardiac arrest, acute myocardial infarction, stroke, and congestive heart failure requiring transfer to a higher unit of care or resulting in a prolongation of stay on ICU/intermediate care (≥24 h). Mixed-effects logistic regression models were calculated. RESULTS: In this study, 274 (1.8%) of 15 406 patients experienced MACE. Loss of follow-up was 2%. All self-reported functional capacity measures were independently associated with MACE but did not improve discrimination (area under the curve of receiver operating characteristic [ROC AUC]) over an internal clinical risk model (ROC AUCbaseline 0.74 [0.71-0.77], ROC AUCbaseline+4METs 0.74 [0.71-0.77], ROC AUCbaseline+floors climbed 0.75 [0.71-0.78], AUCbaseline+fitnessvspeers 0.74 [0.71-0.77], and AUCbaseline+physical activity 0.75 [0.72-0.78]). CONCLUSIONS: Assessment of self-reported functional capacity expressed in METs or using the other measures assessed here did not improve prognostic accuracy compared with clinical risk factors. Caution is needed in the use of self-reported functional capacity to guide clinical decisions resulting from risk assessment in patients undergoing noncardiac surgery. CLINICAL TRIAL REGISTRATION: NCT03016936.

Diaphragm ultrasound evaluation during weaning from mechanical ventilation in COVID-19 patients: a pragmatic, cross-section, multicenter study.

BACKGROUND: Diaphragmatic dysfunction is a major factor responsible for weaning failure in patients that underwent prolonged invasive mechanical ventilation for acute severe respiratory failure from COVID-19. This study hypothesizes that ultrasound measured diaphragmatic thickening fraction (DTF) could provide corroborating information for weaning COVID-19 patients from mechanical ventilation. METHODS: This was an observational, pragmatic, cross-section, multicenter study in 6 Italian intensive care units. DTF was assessed in COVID-19 patients undergoing weaning from mechanical ventilation from 1st March 2020 to 30th June 2021. Primary aim was to evaluate whether DTF is a predictive factor for weaning failure. RESULTS: Fifty-seven patients were enrolled, 25 patients failed spontaneous breathing trial (44%). Median length of invasive ventilation was 14 days (IQR 7-22). Median DTF within 24 h since the start of weaning was 28% (IQR 22-39%), RASS score (- 2 vs - 2; p = 0.031); Kelly-Matthay score (2 vs 1; p = 0.002); inspiratory oxygen fraction (0.45 vs 0.40; p = 0.033). PaO2/FiO2 ratio was lower (176 vs 241; p = 0.032) and length of intensive care stay was longer (27 vs 16.5 days; p = 0.025) in patients who failed weaning. The generalized linear regression model did not select any variables that could predict weaning failure. DTF was correlated with pH (RR 1.56 × 1027; p = 0.002); Kelly-Matthay score (RR 353; p < 0.001); RASS (RR 2.11; p = 0.003); PaO2/FiO2 ratio (RR 1.03; p = 0.05); SAPS2 (RR 0.71; p = 0.005); hospital and ICU length of stay (RR 1.22 and 0.79, respectively; p < 0.001 and p = 0.004). CONCLUSIONS: DTF in COVID-19 patients was not predictive of weaning failure from mechanical ventilation, and larger studies are needed to evaluate it in clinical practice further. Registered: ClinicalTrial.gov (NCT05019313, 24 August 2021).

Integrating electrical impedance tomography and transpulmonary pressure monitoring to personalize PEEP in hypoxemic patients undergoing pressure support ventilation.

Monitoring with electrical impedance tomography (EIT) during a decremental PEEP trial has been used to identify the PEEP that yields the optimal balance of pulmonary overdistension and collapse. This method is based on pixel-level changes in respiratory system compliance and depends on fixed or measured airway driving pressure. We developed a novel approach to quantify overdistension and collapse during pressure support ventilation (PSV) by integrating transpulmonary pressure and EIT monitoring and performed pilot tests in three hypoxemic patients. We report that our experimental approach is feasible and capable of identifying a PEEP that balances overdistension and collapse in intubated hypoxemic patients undergoing PSV.

Effects of PEEP on regional ventilation-perfusion mismatch in the acute respiratory distress syndrome.

PURPOSE: In the acute respiratory distress syndrome (ARDS), decreasing Ventilation-Perfusion [Formula: see text] mismatch might enhance lung protection. We investigated the regional effects of higher Positive End Expiratory Pressure (PEEP) on [Formula: see text] mismatch and their correlation with recruitability. We aimed to verify whether PEEP improves regional [Formula: see text] mismatch, and to study the underlying mechanisms. METHODS: In fifteen patients with moderate and severe ARDS, two PEEP levels (5 and 15 cmH2O) were applied in random order. [Formula: see text] mismatch was assessed by Electrical Impedance Tomography at each PEEP. Percentage of ventilation and perfusion reaching different ranges of [Formula: see text] ratios were analyzed in 3 gravitational lung regions, leading to precise assessment of their distribution throughout different [Formula: see text] mismatch compartments. Recruitability between the two PEEP levels was measured by the recruitment-to-inflation ratio method. RESULTS: In the non-dependent region, at higher PEEP, ventilation reaching the normal [Formula: see text] compartment (p = 0.018) increased, while it decreased in the high [Formula: see text] one (p = 0.023). In the middle region, at PEEP 15 cmH2O, ventilation and perfusion to the low [Formula: see text] compartment decreased (p = 0.006 and p = 0.011) and perfusion to normal [Formula: see text] increased (p = 0.003). In the dependent lung, the percentage of blood flowing through the non-ventilated compartment decreased (p = 0.041). Regional [Formula: see text] mismatch improvement was correlated to lung recruitability and changes in regional tidal volume. CONCLUSIONS: In patients with ARDS, higher PEEP optimizes the distribution of both ventilation (in the non-dependent areas) and perfusion (in the middle and dependent lung). Bedside measure of recruitability is associated with improved [Formula: see text] mismatch.

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.

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.

Role of Sedation and Analgesia during Noninvasive Ventilation: Systematic Review of Recent Evidence and Recommendations.

Aim: This systematic review aimed to investigate the drugs used and their potential effect on noninvasive ventilation (NIV). Background: NIV is used increasingly in acute respiratory failure (ARF). Sedation and analgesia are potentially beneficial in NIV, but they can have a deleterious impact. Proper guidelines to specifically address this issue and the recommendations for or against it are scarce in the literature. In the most recent guidelines published in 2017 by the European Respiratory Society/American Thoracic Society (ERS/ATS) relating to NIV use in patients having ARF, the well-defined recommendation on the selective use of sedation and analgesia is missing. Nevertheless, some national guidelines suggested using sedation for agitation. Methods: Electronic databases (PubMed/Medline, Google Scholar, and Cochrane library) from January 1999 to December 2019 were searched systematically for research articles related to sedation and analgosedation in NIV. A brief review of the existing literature related to sedation and analgesia was also done. Review results: Sixteen articles (five randomized trials) were analyzed. Other trials, guidelines, and reviews published over the last two decades were also discussed. The present review analysis suggests dexmedetomidine as the emerging sedative agent of choice based on the most recent trials because of better efficacy with an improved and predictable cardiorespiratory profile. Conclusion: Current evidence suggests that sedation has a potentially beneficial role in patients at risk of NIV failure due to interface intolerance, anxiety, and pain. However, more randomized controlled trials are needed to comment on this issue and formulate strong evidence-based recommendations. How to cite this article: Karim HMR, Sarc I, Calandra C, Spadaro S, Mina B, Ciobanu LD, et al. Role of Sedation and Analgesia during Noninvasive Ventilation: Systematic Review of Recent Evidence and Recommendations. Indian J Crit Care Med 2022;26(8):938-948.