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Background Previous studies linked a high intensity of ventilation, measured as mechanical power, to mortality in patients suffering from “classic” ARDS. By contrast, mechanically ventilated patients with a diagnosis of COVID-19 may present with intact pulmonary mechanics while undergoing mechanical ventilation for longer periods of time. We investigated whether an association between higher mechanical power and mortality is modified by a diagnosis of COVID-19. Methods This retrospective study included critically ill, adult patients who were mechanically ventilated for at least 24 h between March 2020 and December 2021 at a tertiary healthcare facility in Boston, Massachusetts. The primary exposure was median mechanical power during the first 24 h of mechanical ventilation, calculated using a previously validated formula. The primary outcome was 30-day mortality. As co-primary analysis, we investigated whether a diagnosis of COVID-19 modified the primary association. We further investigated the association between mechanical power and days being alive and ventilator free and effect modification of this by a diagnosis of COVID-19. Multivariable logistic regression, effect modification and negative binomial regression analyses adjusted for baseline patient characteristics, severity of disease and in-hospital factors, were applied. Results 1,737 mechanically ventilated patients were included, 411 (23.7%) suffered from COVID-19. 509 (29.3%) died within 30 days. The median mechanical power during the first 24 h of ventilation was 19.3 [14.6–24.0] J/min in patients with and 13.2 [10.2–18.0] J/min in patients without COVID-19. A higher mechanical power was associated with 30-day mortality (OR adj 1.26 per 1-SD, 7.1J/min increase; 95% CI 1.09–1.46; p  = 0.002). Effect modification and interaction analysis did not support that this association was modified by a diagnosis of COVID-19 (95% CI, 0.81–1.38; p -for-interaction = 0.68). A higher mechanical power was associated with a lower number of days alive and ventilator free until day 28 (IRR adj 0.83 per 7.1 J/min increase; 95% CI 0.75–0.91; p  < 0.001, adjusted risk difference − 2.7 days per 7.1J/min increase; 95% CI − 4.1 to − 1.3). Conclusion A higher mechanical power is associated with elevated 30-day mortality. While patients with COVID-19 received mechanical ventilation with higher mechanical power, this association was independent of a concomitant diagnosis of COVID-19.

In contrast to mammals, adult zebrafish achieve complete heart regeneration via proliferation of cardiomyocytes. Surprisingly, we found that regenerating cardiomyocytes experience DNA replication stress, which represents one reason for declining tissue regeneration during aging in mammals. Pharmacological inhibition of ATM and ATR kinases revealed that DNA damage response signaling is essential for zebrafish heart regeneration. Manipulation of Bone Morphogenetic Protein (BMP)-Smad signaling using transgenics and mutants showed that BMP signaling alleviates cardiomyocyte replication stress. BMP signaling also rescues neonatal mouse cardiomyocytes, human fibroblasts and human hematopoietic stem and progenitor cells (HSPCs) from replication stress. DNA fiber spreading assays indicate that BMP signaling facilitates re-start of replication forks after replication stress-induced stalling. Our results identify the ability to overcome replication stress as key factor for the elevated zebrafish heart regeneration capacity and reveal a conserved role for BMP signaling in promotion of stress-free DNA replication. Zebrafish show robust heart regeneration after injury. Here they show that zebrafish cardiomyocytes experience replication stress, which BMP signaling alleviates via a conserved mechanism of replication fork restart, suggesting a potential for anti-aging and regenerative therapies.

The noble gas argon (Ar) is a \"biologically\" active element and has been extensively studied preclinically for its organ protection properties. This work reviews all preclinical studies employing Ar and describes the clinical uses reported in literature, analyzing 55 pertinent articles found by means of a search on PubMed and Embase. Ventilation with Ar has been tested in different models of acute disease at concentrations ranging from 20% to 80% and for durations between a few minutes up to days. Overall, lesser cell death, smaller infarct size, and better functional recovery after ischemia have been repeatedly observed. Modulation of the molecular pathways involved in cell survival, with resulting anti-apoptotic and pro-survival effects, appeared as the determinant mechanism by which Ar fulfills its protective role. These beneficial effects have been reported regardless of onset and duration of Ar exposure, especially after cardiac arrest. In addition, ventilation with Ar was safe both in animals and humans. Thus, preclinical and clinical data support future clinical studies on the role of inhalatory Ar as an organ protector.

Veno-venous extracorporeal membrane oxygenation (V-V ECMO) in acute respiratory distress syndrome (ARDS) improves gas exchange and allows lung rest, thus minimizing ventilation-induced lung injury. In the last forty years, a major technological and clinical improvement allowed to dramatically improve the outcome of patients treated with V-V ECMO. However, many aspects of the care of patients on V-V ECMO remain debated. In this review, we will focus on main issues and controversies on caring of ARDS patients on V-V ECMO support. Particularly, the indications to V-V ECMO and the feasibility of a less invasive extracorporeal carbon dioxide removal will be discussed. Moreover, the controversies on management of mechanical ventilation, prone position and sedation will be explored. In conclusion, we will discuss evidences on transfusions and management of anticoagulation, also focusing on patients who undergo simultaneous treatment with ECMO and renal replacement therapy. This review aims to discuss all these clinical aspects with an eye on future directions and perspectives.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition, characterized by diffuse inflammatory lung injury. Since the coronavirus disease 2019 (COVID-19) pandemic spread worldwide, the most common cause of ARDS has been the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Both the COVID-19-associated ARDS and the ARDS related to other causes—also defined as classical ARDS—are burdened by high mortality and morbidity. For these reasons, effective therapeutic interventions are urgently needed. Among them, inhaled nitric oxide (iNO) has been studied in patients with ARDS since 1993 and it is currently under investigation. In this review, we aim at describing the biological and pharmacological rationale of iNO treatment in ARDS by elucidating similarities and differences between classical and COVID-19 ARDS. Thereafter, we present the available evidence on the use of iNO in clinical practice in both types of respiratory failure. Overall, iNO seems a promising agent as it could improve the ventilation/perfusion mismatch, gas exchange impairment, and right ventricular failure, which are reported in ARDS. In addition, iNO may act as a viricidal agent and prevent lung hyperinflammation and thrombosis of the pulmonary vasculature in the specific setting of COVID-19 ARDS. However, the current evidence on the effects of iNO on outcomes is limited and clinical studies are yet to demonstrate any survival benefit by administering iNO in ARDS.

PurposeLatent class analysis (LCA) has identified hyper- and non-hyper-inflammatory subphenotypes in patients with acute respiratory distress syndrome (ARDS). It is unknown how early inflammatory subphenotypes can be identified in patients at risk of ARDS. We aimed to test for inflammatory subphenotypes upon presentation to the emergency department.MethodsLIPS-A was a trial of aspirin to prevent ARDS in at-risk patients presenting to the emergency department. In this secondary analysis, we performed LCA using clinical, blood test, and biomarker variables.ResultsAmong 376 (96.4%) patients from the LIPS-A trial, two classes were identified upon presentation to the emergency department (day 0): 72 (19.1%) patients demonstrated characteristics of a hyper-inflammatory and 304 (80.9%) of a non-hyper-inflammatory subphenotype. 15.3% of patients in the hyper- and 8.2% in the non-hyper-inflammatory class developed ARDS (p = 0.07). Patients in the hyper-inflammatory class had fewer ventilator-free days (median [interquartile range, IQR] 28[23–28] versus 28[27–28]; p = 0.010), longer intensive care unit (3[2–6] versus 0[0–3] days; p < 0.001) and hospital (9[6–18] versus 5[3–9] days; p < 0.001) length of stay, and higher 1-year mortality (34.7% versus 20%; p = 0.008). Subphenotypes were identified on day 1 and 4 in a subgroup with available data (n = 244). 77.9% of patients remained in their baseline class throughout day 4. Patients with a hyper-inflammatory subphenotype throughout the study period (n = 22) were at higher risk of ARDS (36.4% versus 10.4%; p = 0.003).ConclusionHyper- and non-hyper-inflammatory subphenotypes may precede ARDS development, remain identifiable over time, and can be identified upon presentation to the emergency department. A hyper-inflammatory subphenotype predicts worse outcomes.

Previous studies proposed comorbidity-based prediction tools to facilitate patient-level assessment of mortality risk, which are essential for confounder adjustment in epidemiologic studies. We compared established comorbidity indices using real-world administrative data of a broad surgical population. Adult patients undergoing surgical or interventional procedures between January 2005 and June 2020 at a tertiary academic medical center in Massachusetts, USA, were included. The Elixhauser Comorbidity Index (van Walraven modification), Combined Comorbidity Score, and Charlson Comorbidity Index were compared regarding the prediction of 30-day mortality. Age and sex were included in all models. Discriminative ability was quantified by the area under the receiver operating characteristic curve (AUROC), and calibration was assessed using the Brier score and reliability plots. A total of 514,282 patients were included, of which 5849 (1.1%) died within 30 days. A model including age and sex alone had an AUROC of 0.73 (95% CI 0.72-0.74). The Elixhauser Comorbidity Index–based model showed the best discriminative ability with an AUROC of 0.86 (95% CI 0.86-0.87) compared to models, including the Combined Comorbidity Score (AUROC, 0.85 [95% CI 0.84-0.85]) and the Charlson Comorbidity Index (AUROC, 0.82 [95% CI 0.81-0.83], P < .001, respectively). The Brier score was 0.011 for all scores. Overall, score performances were similar or improved after the implementation of the 10th Revision International Classification of Diseases (Clinical Modification) coding system. The primary findings were confirmed for in-hospital, 7-day, 90-day, 180-day, and 1-year mortality and when including score comorbidities as separate indicator variables (P < .001, respectively). Patient and procedural characteristics were predictive of mortality (AUROC, 0.91 [95% CI 0.91-0.91]), with confirmatory findings and slightly improved performances when adding comorbidity scores (AUROC, 0.93 [95% CI 0.93-0.93] for the Elixhauser Comorbidity Index; AUROC, 0.93 [95% CI 0.93-0.93] for the Combined Comorbidity Score; AUROC, 0.92 [95% CI 0.92-0.93] for the Charlson Comorbidity Index, P < .001, respectively). All 3 comorbidity indices predicted mortality with excellent discrimination; however, they showed only slightly improved performance when incorporated into a model including patient and procedural characteristics. When surgical data are unavailable and in surgical setting–specific subgroups, the Elixhauser Comorbidity Index consistently performed best. [Display omitted] •Comorbidity-based prediction tools enable patient-level assessment of mortality risk.•We compared established prediction tools using electronic health records.•Among 514,282 surgical patients, the Elixhauser Comorbidity Index performed best.•The Elixhauser Comorbidity Index may be used preferably for mortality prediction in broad surgical populations.

Background Acute respiratory distress syndrome (ARDS) is a heterogeneous condition with varying response to prone positioning. We aimed to identify subphenotypes of ARDS patients undergoing prone positioning using machine learning and assess their association with mortality and response to prone positioning. Methods In this retrospective observational study, we enrolled 353 mechanically ventilated ARDS patients who underwent at least one prone positioning cycle. Unsupervised machine learning was used to identify subphenotypes based on respiratory mechanics, oxygenation parameters, and demographic variables collected in supine position. The primary outcome was 28-day mortality. Secondary outcomes included response to prone positioning in terms of respiratory system compliance, driving pressure, PaO 2 /FiO 2 ratio, ventilatory ratio, and mechanical power. Results Three distinct subphenotypes were identified. Cluster 1 (22.9% of whole cohort) had a higher PaO 2 /FiO 2 ratio and lower Positive End-Expiratory Pressure (PEEP). Cluster 2 (51.3%) had a higher proportion of COVID-19 patients, lower driving pressure, higher PEEP, and higher respiratory system compliance. Cluster 3 (25.8%) had a lower pH, higher PaCO 2 , and higher ventilatory ratio. Mortality differed significantly across clusters (p = 0.03), with Cluster 3 having the highest mortality (56%). There were no significant differences in the proportions of responders to prone positioning for any of the studied parameters. Transpulmonary pressure measurements in a subcohort did not improve subphenotype characterization. Conclusions Distinct ARDS subphenotypes with varying mortality were identified in patients undergoing prone positioning; however, predicting which patients benefited from this intervention based on available data was not possible. These findings underscore the need for continued efforts in phenotyping ARDS through multimodal data to better understand the heterogeneity of this population.

Hypoxemic respiratory failure was defined as a ratio of partial arterial pressure of oxygen to fraction of inspired oxygen (P/F) ≤ 300 at the first available blood gas analysis. The decrease in the utilization of LPV after the onset of the COVID-19 pandemic potentially reflects a systemic disruption of resource allocation after March 2020, including protective equipment supplies, ventilators, and hospital staff. [...]the COVID-19 pandemic may have influenced the existing trend in the implementation of LPV strategies in critically ill patients.

A 65-year-old man in cardiogenic shock with copious pulmonary edema could not be ventilated despite paralysis and was placed on venoarterial-extracorporeal membrane oxygenation. Initial ventilator settings were pressure control ventilation 10 cm H2O, positive end-expiratory pressure 20 cm H2O, and respiratory rate 15 breaths per minute. Both VT and VE were negligible.