Acute Respiratory Distress Research Articles

Broadening indications: A descriptive and comparative in-depth analysis of venovenous extracorporeal membrane oxygenation outcomes in trauma and nontrauma patients.

Venovenous extracorporeal membrane oxygenation (VV ECMO) has been used for medical etiologies of acute respiratory distress syndrome refractory to conventional management. More recently, VV ECMO has been used to stabilize trauma patients with acute lung injury. We hypothesize that patients with traumatic injuries requiring VV ECMO have similar survival outcomes and describe the characteristics between the two populations. This single-center, retrospective cohort study included all trauma and nontrauma patients in an 8-year period who were placed on VV ECMO. Cannulation decisions were made via multidisciplinary discussions between two intensivists and a trauma surgeon. Data were analyzed with descriptive statistics and regression analysis. After testing for normality, significance was defined as a p < 0.05. A total of 516 patients were identified (438 nontrauma and 78 trauma VV ECMO patients). The trauma patient, defined as undergoing cannulation during initial trauma admission, had a median age of 29 years with 81% of patients being male, while the nontrauma patient had a median age of 41 years with 64% being males. Trauma VV ECMO patients had shorter ECMO courses (216 hours vs. 372 hours, p < 0.001), earlier cannulation (8 hours vs. 120 hours, p < 0.001), higher lactic acid levels precannulation (4.2 mmol/L vs. 2.3 mmol/L, p < 0.001), higher Sequential Organ Failure Assessment scores (13 vs. 11, p = 0.001), and higher Simplified Acute Physiology Scores II (63 vs. 48, p < 0.001). There was no difference in bleeding complications. Survival to discharge rates were similar between trauma and nontrauma VV ECMO groups (69% vs. 71%, p = 0.81). This study demonstrates that trauma VV ECMO patients have higher markers of severe illness/injury when compared with their nontrauma VV ECMO counterparts yet have similar survival rates and shorter ECMO runs. Venovenous extracorporeal membrane oxygenation in trauma patients is a useful treatment modality for refractory hypoxemia, respiratory acidosis, and stabilization because of acute lung and thoracic injury. Therapeutic/Care Management; Level IV.

Discovery of Balasubramide Derivative with Tissue-Specific Anti-Inflammatory Activity Against Acute Lung Injury by Targeting VDAC1.

Macrophage-mediated inflammatory responses including pyroptosis are involved in the pathogenesis of sepsis and acute lung injury (ALI), for which there are currently no effective therapeutic treatments. The natural product (+)-Balasubramide is an eight-membered lactam compound extracted from the leaves of the Sri Lanka plant Clausena Indica and has shown anti-inflammatory activities, but its poor pharmacokinetic properties limit its further application for ALI. In this study, a compound (+)3C-20 is discovered with improved both pharmacokinetic properties and anti-inflammatory activity from a series of (+)-Balasubramide derivatives. The compound (+)3C-20 exhibits a markedly enhanced inhibitory effect against LPS-induced expressions of pro-inflammatory factors in mouse macrophages and human PBMCs from ALI patients and shows a preferable lung tissue distribution in mice. (+)3C-20 remarkably attenuates LPS-induced ALI through lung tissue-specific anti-inflammatory actions. Mechanistically, a chemical proteomics study shows that (+)3C-20 directly binds to mitochondrial VDAC1 and inhibits VDAC1 oligomerization to block mtDNA release, further preventing NLRP3 inflammasome activation. These findings identify (+)3C-20 as a novel VDAC1 inhibitor with promising therapeutic potential for ALI associated with inflammation.

Restoring brain connectivity by phrenic nerve stimulation in sedated and mechanically ventilated patients.

In critically ill patients, deep sedation and mechanical ventilation suppress the brain-diaphragm-lung axis and are associated with cognitive issues in survivors. This exploratory crossover design study investigates whether phrenic nerve stimulation can enhance brain activity and connectivity in six deeply sedated, mechanically ventilated patients with acute respiratory distress syndrome. Our findings indicate that adding phrenic stimulation on top of invasive mechanical ventilation in deeply sedated, critically ill, moderate acute respiratory distress syndrome patients increases cortical activity, connectivity, and synchronization in the frontal-temporal-parietal cortices. Adding phrenic stimulation on top of invasive mechanical ventilation in deeply sedated, critically ill, moderate acute respiratory distress syndrome patients increases cortical activity, connectivity, and synchronization. The observed changes resemble those during diaphragmatic breathing in awake humans. These results suggest that phrenic nerve stimulation has the potential to restore the brain-diaphragm-lung crosstalk when it has been shut down or impaired by mechanical ventilation and sedation. Further research should evaluate the clinical significance of these results.

Common Comorbidities and Complications in COVID-19 Deaths: An Analysis from Italian Data in Comparison with Influenza

Multiple cause data refer to all conditions reported on death certificates. Compared to the single underlying cause of death, these data provide additional information concerning the presence of comorbidities and complications leading to death. The objective of the study is to use a novel multiple cause approach for identifying comorbidities and complications of COVID-19. We analysed certificates referring to deaths that occurred in Italy in 2020–2021. With a double step chi squared test, we identified the conditions associated with COVID-19 and whether such conditions were reported as ‘cause of’ (comorbidities) or ‘due to’ (complications) COVID-19. For comparison, we adopted the same procedure for influenza deaths that occurred in Italy in 2016–2019. Pneumonia, respiratory failure and adult respiratory distress syndrome are the most frequent complications of COVID-19 and are also associated with it. These diseases have the same role for influenza, nevertheless this latter is strongly associated also with heart failure reported as a complication. Comorbidities are similar for COVID-19 and influenza: diabetes mellitus, chronic obstructive pulmonary disease (COPD) and obesity are the most frequent, with obesity much more frequent in COVID-19 cases. Hypertension is strongly associated with COVID-19 and is more frequent than in influenza cases. This approach is also suitable for other target diseases.

Comparison of ketoacidosis in type 1 and 2 diabetic patients with and without concurrent COVID-19 and determining the factors affecting their treatment and survival: a retrospective cohort study

Objective: To assess the incidence of diabetic ketoacidosis in coronavirus disease-2019 patients and their survival rate, and to compare their outcomes with diabetic ketoacidosis patients without coronavirus disease-2019. Method: The retrospective cohort study was conducted at Aga Khan University Hospital, Karachi, and comprised data March 1, 2020, to March 31, 2021, related to patients. who had diabetic ketoacidosis with coronavirus disease-2019 in group A, and those who had diabetic ketoacidosis without coronavirus disease-2019 in group B. Data included age, gender, duration and type of diabetes and the final outcome. Data was analysed using SPSS 25. Results: Of the 120 patients, 40(33.3%) were in group A; 21(52.5%) males and 19(47.5%) females, with 22(55%) aged 45-64 years. There were 80(66.6%) patients in group B; 42(52.5%) males and 38(47.5%) females, with 36(45%) aged &lt;45 years (p&gt;0.05). The mortality was higher in group A patients13(32.5%) compared to those in group B 10(12.5%) (p&lt;0.05). The data analysis was performed with the Statistical Package for Social Sciences (SPSS), V.25. Survival analysis showed that age, dyslipidaemia, history of cardiac revascularisation, acute respiratory distress syndrome, ventilator requirement, and severity of coronavirus disease-2019 were significantly associated with mortality (p&lt;0.05). Conclusion: Patients of diabetic ketoacidosis with coronavirus disease-2019had poor survival outcomes compared to diabetic ketoacidosis patients without coronavirus disease-2019. Key Words: Diabetes mellitus, Diabetic ketoacidosis, COVID-19, Mechanical ventilator, Acidosis.

Possible Link between Gut Microbiota, Diet, and COVID-19 Infection

Background: Coronavirus disease 2019 (COVID-19) is a concern for world health since it may impact both the upper (nose, throat, sinuses) and lower (trachea, lungs) respiratory tracts. Death (at a rate of 10%), respiratory failure, multi-organ failure, and acute respiratory distress syndrome (ARDS) are among the problems that might arise. Recent years have seen a global spread of zoonotic coronaviruses, which have caused human epidemics such as MERS and SARS. Various clinical symptoms may be seen in this sickness because to the numerous changes in intestinal homeostasis caused by SARS-CoV-2. Because of the beneficial impact that probiotics have on the host immune system, gastrointestinal disorders may now be effectively treated. This article discusses the close relationship between what we eat, the bacteria in our gut, and the risk of contracting the COV-19 virus. Conclusion: The relationship between gut microbiota, dietary factors, and COVID-19 severity indicates that the microbiome may influence immune regulation. Imbalances in microbial communities and reduced diversity can intensify inflammation, potentially worsening COVID-19 outcomes. Strategies such as probiotics, prebiotics, and dietary changes might provide therapeutic benefits by improving gut health and strengthening immune defenses. However, further research is required to clarify these mechanisms and establish effective interventions.

Humanin-G Ameliorates Hemorrhage-Induced Acute Lung Injury in Mice Through AMPKα1-Dependent and -Independent Mechanisms.

Background/Objectives: The severity of acute lung injury is significantly impacted by age and sex in patients with hemorrhagic shock. AMP-activated protein kinase (AMPK) is a crucial regulator of energy metabolism but its activity declines with aging. Humanin is a mitochondrial peptide that exerts cytoprotective effects in response to oxidative stressors and is associated with longevity. Using a mouse model of hemorrhagic shock that mimics the clinical condition of adult patients, we investigated whether treatment with a humanin analog, humanin-G, mitigates lung injury and whether its mechanisms of action are dependent on the catalytic AMPKα1 subunit activation. Methods: Male and female AMPKα1 wild-type (WT) and knock-out (KO) mice (8-13 months old) were subjected to hemorrhagic shock by blood withdrawal, followed by resuscitation with shed blood and lactated Ringer's solution. The mice were treated with PEGylated humanin-G or vehicle and euthanized 3 h post-resuscitation. Results: Sex- and genotype-related differences were observed after hemorrhagic shock as lung neutrophil infiltration was more pronounced in the male AMPKα1 WT mice than the female WT mice; also, the male AMPKα1 KO mice experienced a significant decline in mean arterial blood pressure when compared to the male WT mice after resuscitation. The scores of histological lung injury were similarly elevated in all the male and female AMPKα1 WT and KO mice when compared to the control mice. At molecular analysis, acute lung injury was associated with the downregulation of AMPKα1/α2 catalytic subunits in the WT mice, whereas an increased activation of the signal transducer and activator of transcription-3 (STAT3) was observed in all the vehicle-treated groups. The in vivo administration of humanin-G ameliorated histological lung damage in all the groups of animals and ameliorated mean arterial blood pressure in the male AMPKα1 KO mice. The in vivo administration of humanin-G lowered lung neutrophil infiltration in the male and female AMPKα1 WT mice only but not in the KO mice. The beneficial results of humanin-G correlated with the lung cytosolic and nuclear activation of AMPKα in the male and female AMPKα1 WT groups, whereas STAT3 activation was not modified. Conclusions: In adult age, hemorrhage-induced acute lung injury manifests with sex-dependent characteristics. Humanin-G has therapeutic potential and the AMPKα1subunit is an important requisite for its inhibitory effects on lung leucosequestration, but not for the amelioration of lung alveolar structure or the hemodynamic effects of the peptide.

Pharmacokinetics of Enteral Lormetazepam in Mechanically Ventilated ICU Patients with COVID-19: An Adjunct Sedative Study.

During the coronavirus disease 2019 (COVID-19) pandemic, sedative prescriptions surged, leading to shortages of midazolam. This study investigates lormetazepam as an adjunct sedative alternative to midazolam for mechanically ventilated patients with COVID-19. We aimed to determine the clinical pharmacokinetics (PK) of enterally administered lormetazepam and provide dosing recommendations. Critically ill patients with acute respiratory distress syndrome (ARDS) or COVID-19 requiring mechanical ventilation were enrolled in April 2020. Lormetazepam 2 mg every 12 h was administered enterally. Blood samples were collected to quantify lormetazepam and its glucuronide. PK analysis was conducted using a one-compartment model with the Edsim++ KinPop plugin. The primary PK parameters (means ± coefficient of variation [CV] %) for absorption constant (Ka), volume of distribution (Vd/F), and clearance (CL/F) were 6.4 h-1, 207 L/70 kg, and 14.5 L/h/kg0.75, respectively. Vd/F and CL/F median values were 2.64 L/kg and 2.53 mL/kg/min, respectively, with a half-life of 10.7 h. Lormetazepam's median ratio to its glucuronide was 11.5. Trough-guided dosing suggested alternatives of 0.92 mg three times daily, 1.62 mg twice daily, or 5.36 mg once daily. This is the first study to report a validated PK model for enterally administered lormetazepam as a sedative adjunct in critically ill adults on mechanical ventilation for ARDS and COVID-19. The model was internally validated using a bootstrap procedure. Adequate lormetazepam concentrations were achieved at prescribed doses, with no significant alterations in clearance or half-life. This population model may aid in dose optimization and sedation management for future intensive care unit (ICU) patients.

Use of Granulocyte Transfusions in the Management of Severe Infections Among Children with Neutropenia.

Background/Objectives: Infections remain the leading cause of mortality among neutropenic patients with haematologic malignancies, making effective infection management crucial. Achieving a sufficient neutrophil count is essential for the elimination of pathogens. Granulocyte concentrate (GC) can be a treatment option for neutropenic patients with severe infections. This study aimed to evaluate the efficacy, safety, and impact on survival of GC transfusions in neutropenic children with severe infections treated over the past 13 years in a single centre. Methods: The retrospective study analysed clinical data from 60 children (median age 9.5 years) who received GC transfusions at our centre. Granulocytes were collected by apheresis from donors stimulated with granulocyte colony-stimulating factor. The majority of the patients (70%) were diagnosed with acute leukaemia. The main indications for GC were severe pneumonia (45%) and bacterial sepsis (38.33%). Results: The patients received 1 to 29 GC transfusions for 1 to 70 days, with a median time of administration of 3 days. Neutrophil counts increased to >1000/µL within a median of 5 days. GCs were well tolerated by most patients. One patient presented symptoms of anaphylaxis, the other acute lung injury related to transfusions, and alloimmunisation was reported in one patient. Of the patients analysed, 78.33% survived the infection that justified GC administration. We did not observe significant differences in survival depending on the aetiology of the infection. Conclusions: Based on our research, GC appears to be a beneficiary for neutropenic children with severe infections and reduces infection mortality rates. However, further well-designed randomised trials are needed to define its role in this setting.

Fibroblast growth factor 10 alleviates LPS-induced acute lung injury by promoting recruited macrophage M2 polarization.

Acute lung injury (ALI) is characterized by damage to the alveoli and an overabundance of inflammation. Representing a serious inflammatory condition, ALI lacks a precise treatment approach. Despite the recognized benefit impacts of Fibroblast growth factor-10 (FGF10) on ALI, the underlying mechanisms remain unelucidated. To study the role of FGF10 in ALI, C57BL/6J mice were intratracheally injected with 5mg/kg Lipopolysaccharide (LPS) with FGF10 (5mg/kg) or an equal volume of PBS. Inflammatory factors were quantified in bronchoalveolar lavage fluid (BALF) and plasma using ELISA. RNA sequencing of F4/80+Ly6G- macrophages in BALF explored changes in macrophage phenotype and potential mechanisms. Macrophage polarization in BALF was assessed using qRT-PCR, flow cytometry, and Western blot analysis. In vitro, a Transwell co-culture of mouse lung epithelial cells (MLE12) and bone marrow macrophages (BMDM) validated the role of FGF10 in modulating LPS-induced macrophage phenotypic changes. FGF10 ameliorated LPS-induced ALI by diminishing pro-inflammatory factors (IL-1β, TNF-α, and IL-6) and the neutrophil accumulation in BALF. FGF10 also increased the levels of anti-inflammatory factor IL-10. The FGF10 intervention group exhibited enhanced gene expression of macrophage arginine biosynthesis marker (ARG1), and expression of M2-type marker CD206 in monocytes and macrophages. In addition, phosphorylated STAT3 expression increased in isolated monocyte-derived macrophages. Experiments in vitro confirmed that FGF10 could elevate macrophage M2 marker ARG1 expression through the JAK2/STAT3 pathway. FGF10 ameliorates acute LPS-induced lung injury by modulating the polarization of monocyte-derived macrophages recruited in the alveolar space to the M2 type.

Effects of acetaminophen use on mortality of patients with acute respiratory distress syndrome: secondary data mining based on the MIMIC-IV database

BackgroundAcetaminophen is a commonly used analgesic after surgery, and its impact on prognosis in patients with acute respiratory distress syndrome (ARDS) has not been studied. This study explores the association between the use of acetaminophen and the risk of mortality in patients with ARDS.MethodsIn this retrospective cohort study, 3,227 patients with ARDS who had or had not received acetaminophen were obtained from the Medical Information Mart for Intensive Care IV, patients were divided into acetaminophen and non- acetaminophen groups. In-hospital mortality of ARDS patients was considered as primary end point. We used univariate and multivariate Cox regression analyses to assess the relationship of acetaminophen use and in-hospital mortality in patients with ARDS. Subgroup analysis was performed according to age, gender, and severity of ARDS.ResultsOf the total patients, 2,438 individuals were identified as acetaminophen users. The median duration of follow-up was 10.54 (5.57, 18.82) days. The results showed that the acetaminophen use was associated with a decreased risk of in-hospital mortality [hazard ratio (HR) = 0.67, 95% confidence interval (CI): 0.57–0.78]. Across various subgroups of patients with ARDS based on age, gender, and severity, acetaminophen use exhibited an association with reduced risk of in-hospital mortality.ConclusionAcetaminophen use was associated with in-hospital mortality of patients with ARDS. Acetaminophen therapy may represent a promising therapeutic option for ARDS patients and warrants further investigation.

Taraxerone inhibits M1 polarization and alleviates sepsis-induced acute lung injury by activating SIRT1

BackgroundAcute lung injury (ALI) is the most lethal disease associated with sepsis, and there is a lack of effective drug treatment. As the major cells of sepsis-induced ALI, macrophages polarize toward the proinflammatory M1 phenotype and secrete multiple inflammatory cytokines to accelerate the disease process through nuclear factor kappa-B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling pathways. Taraxerone, the main component of the Chinese medicinal Sedum, possesses numerous biological activities. However, uncertainty remains regarding the potential of taraxerone to protect against sepsis-induced ALI. This study aimed to investigate the effects and mechanisms of taraxerone against ALI.MethodsAn animal model for ALI was established by cecal ligation and puncture and treated with taraxerone via intraperitoneal administration. The protective effect of taraxerone on the lungs was analyzed using H&E staining, dihydroethidium staining, ELISA kits, cell counting, myeloperoxidase kit, malondialdehyde kit, glutathione kit, superoxide dismutase kit and flow cytometry. Western blotting, RT-PCR, flow cytometry, co-immunoprecipitation, and immunofluorescence were used to investigate the regulatory of taraxerone on SIRT1.ResultsOur study demonstrates for the first time that taraxerone can activate SIRT1 in macrophages, promoting SIRT1 activity. This activation inhibited the NF-κB signaling pathway primarily through the dephosphorylation and deacetylation of p65. Simultaneously, taraxerone disrupted the NLRP3 inflammasome signaling pathway, thereby alleviating M1 polarization of macrophages and mitigating sepsis-induced pulmonary inflammation and oxidative stress. In vivo, EX527 was used to validate the anti-inflammatory and anti-oxidative stress effects of taraxerone mediated by SIRT1.ConclusionSIRT1-mediated anti-inflammatory and anti-oxidative stress effects may be important targets for taraxerone in treating ALI.

Early Postoperative Complications Following Extensive Lung Surgery

Background: Extensive surgical procedures play a key role in treatment of various lung diseases. Nevertheless, these complex procedures are associated with a high risk of early postoperative complications.Objective: To evaluate outcomes of the early postoperative period in patients with various lung diseases and determine risk factors for postoperative complications.Material and methods: We analyzed postoperative complications in 377 patients who underwent extensive lung surgery. The mean age was 45.7 ± 5.2 years. The majority of patients (56.0%) had malignant or benign lung tumors. Lobectomy was the most common type of surgery. Pneumonectomy accounted for 26.5%.Results: The overall rate of cardiovascular complications was 8.2%. The highest number of complications was observed after right-sided pneumonectomy (21.7%). Respiratory complications after right-sided pneumonectomy accounted for 34.8%. Lobectomy and bilobectomy had lower rates of complications (4.4% and 6.3%, respectively). The highest number of systemic complications was also recorded after right-sided pneumonectomy (23.9%), whereas lobectomy had a lower risk (4.4%). Patients with primary lung tumors had significantly more complications (32.2%) compared with patients without cancer (10.8%). The main risk factors were male gender (odds ratio [OR], 1.6; 95% CI, 1.1-2.2; P = .032), age ≥60 years (OR, 1.9; 95% CI, 1.5-2.6; P = .001), smoking (OR, 1.7; 95% CI, 1.2-2.5; P = .019), C-reactive protein level &gt;3 mg/dL (OR, 1.8; 95% CI, 1.1-2.7; P = .015) and forced expiratory volume in the first second of expiration (FEV1) &lt;60% (OR, 1.5; 95% CI, 1.1-2.2; P = .042), surgery duration ≥180 minutes (OR, 1.8; 95% CI, 1.3-2.3; P = .002), and anesthesia without additional epidural analgesia (OR, 1.5; 95% CI, 1.2-2.1; P = .007).Conclusions: The complication rate after extensive lung surgery was 22.8%, with the highest rate after right-sided pneumonectomy (4.8%). Respiratory complications predominated (14.1%): hydrothorax/pneumothorax (5.0%), acute respiratory distress syndrome (4.2%), pneumonia (2.9%), and ventilator-associated tracheobronchitis (2.1%). The main risk factors were male gender, age ≥60 years, smoking, FEV1 &lt;60%, long surgery, no epidural analgesia, and high crystalloid infusion rate.

Mortality in the Burn Intensive Care Unit (2017-2023) at Mohammed VI University Hospital, Department of Reconstructive and Aesthetic Surgery, Marrakech

This internal audit aims to evaluate the management of burn patients in the intensive care unit (ICU) of Mohammed VI University Hospital in Marrakech, a specialized burn treatment center in Morocco. The retrospective study spans from 2017 to 2023, analyzing the deaths of 27 patients admitted to the ICU, with an average age of 62. The primary causes of death identified were septic shock (54%) and acute respiratory distress syndrome (18%). Key challenges emerged, including nursing staff shortages, inadequate stock management of dressing materials, and the absence of care assistants, all of which impacted the quality of care provided. The study also underscores the importance of improved care organization, drawing from international best practices. The report proposes several solutions, such as increasing nursing staff, optimizing workflows, and improving sanitary infrastructure to minimize infection risks. A crucial recommendation involves reassessing admission criteria to ensure that critically ill patients are redirected to appropriate units, particularly by strengthening the presence of full-time intensivists in the burn ICU. Furthermore, the report highlights the need for continuous training of medical personnel and interdisciplinary collaboration to enhance the quality of care. The introduction of assistive technologies and companion programs for isolated patients would also improve their nutritional and psychological support. These initiatives could alleviate the burden on medical staff and improve patient outcomes. By implementing these recommendations, the burn ICU could be transformed into a model of excellence, providing optimal, safe, and respectful care tailored to the individual needs of burn patients. This audit serves as a foundation for ongoing improvement, emphasizing patient safety and well-being as the core priorities in burn patient management.

The use of a heated helium-oxygen mixture in patients with severe COVID-19 and ARDS against the background of standard therapy and noninvasive ventilation

Introduction. One of the insufficiently studied methods of Acute Respiratory Distress Syndrome (ARDS) therapy is therapy with a heated helium-oxygen mixture. Due to physico-chemical properties, helium demonstrates high efficiency in the treatment of various diseases of the pulmonological profile.Aim. To study the effect of a heated helium-oxygen mixture on the course of a severe form of COVID-19 occurring with the development of ARDS.Materials and methods. The study involved 58 patients with severe and extremely severe coronavirus infection and ARDS, divided into the NVL + t-He/O2 group (n = 30) and the NVL+O2 control group (n = 28). In addition to standard treatment, patients of the NVL + t-He/O2 group received noninvasive ventilation (NVL) and therapy with a heated helium-oxygen mixture, according to clinical recommendations. In the main group, inhalations took place daily for 60 minutes per day for 5 days.Results. Against the background of therapy with a heated helium-oxygen mixture, a more intense increase in the level of lymphocytes was observed: 1.39 (1.09–1.66) × 109/l in the NVL + t-He/O2 group versus 1.02 (0.78–1.40) × 109/l (p = 0.02). Also, as a result of treatment, there was a significant decrease in RR, D-dimer and CRP in the study group: the level of RR (21 (20–22)/minute versus 22.5 (21–24)/minute, p = 0.003), D-dimer (0.44 (0.29–0.60) FEU ng/ml versus 0.79 (0.42–1.34) FEU ng/ml, p = 0.02) and CRP (1.1 (0.7–3.1)mg/l versus 16.6 (8.5–29.5) mg/l, p = 0.03), respectively. Similarly to the NVL + t-He/O2 group, an increase in the level of PaO2 and the oxygenation index was noted. In addition, there were significantly fewer patients with grade III and IV lung damage in the NVL + t-He/O2 group compared with the control (p = 0.05).Conclusion. The use of a heated helium-oxygen mixture in patients with severe COVID-19, occurring with the development of ARDS, against the background of standard therapy and NIV has shown its safety and effectiveness: there was a decrease in the intensity of inflammation, improved oxygenation and a reduction in the need for respiratory support.

Systemic Coagulation Derangement as an Early Sign of Oxygenator Failure in Veno-Venous Extracorporeal Membrane Oxygenation (VV ECMO) Without Anticoagulation

Background and Clinical Significance: Veno-venous extracorporeal membrane oxygenation (VV ECMO) has become a widely accepted supportive treatment for severe acute respiratory distress syndrome (ARDS) in intensive care units (ICUs). Although it has gained popularity, some of its aspects, including optimal anticoagulation management and the best means of monitoring hemostasis, remain unresolved. Thrombosis and bleeding are still important complications of ECMO. Case Presentation: A 44-year-old male patient, with no underlying conditions, was diagnosed with severe acute respiratory distress syndrome (ARDS) due to AH1N1 influenza. He presented severe hypoxemia despite the use of mechanical ventilation, neuromuscular blocking agent infusion and prone position. VV ECMO was used, and coagulation was stopped on ECLS day 6 due to severe pulmonary hemorrhage. The systemic hemostatic disorders found in this patient were difficult to differentiate from disseminated intravascular coagulation (DIC) or sepsis-induced coagulopathy (SIC), improved transiently after circuit exchange, and resolved only after discontinuation of ECMO. The patient was discharged fully conscious and cooperative, with no apparent neurological deficit. Conclusions: Systemic hemostatic abnormalities may precede oxygenator failure and mimic DIC or SIC. Timely oxygenator exchange may therefore be considered. However, it is a high-risk procedure, especially in fully ECLS-dependent patients.

Increased Circulating Extracellular Superoxide Dismutase Attenuates Platelet-Neutrophil Interactions.

Acute respiratory distress syndrome (ARDS) is a serious illness accounting for 10% of ICU admissions and high mortality of 31-45% with a paucity of pharmacologic treatment options. Dysregulated inflammation and oxidative stress are hallmark features of ARDS. We previously showed that transgenic mice expressing a naturally occurring polymorphism of the antioxidant enzyme extracellular superoxide dismutase (EC-SOD), are protected against Staphylococcus aureus (S. aureus) pneumonia, acute lung injury, and pulmonary neutrophilia. In this mouse strain, an R213G amino acid substitution leads to lower tissue binding affinity and elevated alveolar and plasma EC-SOD levels, though the redox-regulated mechanisms responsible for protection against S. aureus are not yet elucidated. Neutrophils are recruited to the areas of injury and inflammation, in part by activated platelets, which contain multiple redox-sensitive targets. Thus, we hypothesize that increased circulating EC-SOD due to the EC-SOD R213G variant protects against S. aureus pneumonia by reducing platelet activation and subsequent neutrophil recruitment to the lung. We demonstrate that, compared to WT mice with S. aureus pneumonia, platelet activation, formation of platelet-neutrophil aggregates (PNAs), and influx of neutrophils and PNAs into the lung are decreased in the infected R213G mice. Furthermore, pre-treatment with a MnTE-2-PyP SOD mimetic protects against S. aureus-induced platelet activation, pulmonary neutrophilia, and acute lung injury. Our data highlight the redox regulation of platelet activation as a driver of S. aureus-induced acute lung injury.

Abstract 4135700: Effects of Mitochondrial Dysfunction on Extracellular Vesicle Release and Subsequent Disruption of the Lung Vascular Endothelial Barrier

Background: Lung endothelial cell (EC) barrier disruption is a hallmark of acute lung injury (ALI), which is commonly caused by bacterial pneumonia. Alveolar epithelial cells (AEC) are the first line of defence against invading respiratory pathogens in the lungs and can mediate inflammatory signaling to the adjacent EC contributing to barrier disruption. We have previously demonstrated that pneumolysin (PLY), a major Streptococcus pneumoniae virulence factor, induces both mitochondrial dysfunction in lung AEC and release of large extracellular vesicles (EVs). These EVs, which are enriched with mitochondrial cargo, contribute to increased permeability of the lung EC barrier. Here, we investigate strategies to inhibit mitochondrial dysfunction in AEC and examine how these interventions impact EC barrier function. Methods: Human alveolar epithelial cells (A549) or immortalized AEC (Cell Biologics) were pre-treated with mitoTEMPO (mtROS scavenger), P110 (excessive fission inhibitor), or ensifentrine [dual phosphodiesterase (PDE) 3/4 inhibitor] prior to PLY treatment (100-300 ng/ml, 4 hrs). Mitochondrial function was assessed by the JC-1 assay. EVs were isolated from cell media and analyzed for their mitochondrial content (Tom20 and Tim23 expression). To assess their functional role, EVs were added to TNF-α treated human lung microvascular EC, and barrier function was then determined using the ECIS assay to measure transendothelial electrical resistance (TER). Results: PLY-induced mitochondrial dysfunction was reduced in the presence of mitoTempo or P110. EVs from PLY-treated AEC (EV PLY ; enriched mitochondrial content) exacerbated TNF-α-induced EC barrier permeability as indicated by the significant decrease in TER. EV PLY derived from MitoTEMPO or P110-pretreated AEC contained less mitochondrial cargo and resulted in less EC permeability after TNF-α. Compared to mitoTEMPO and P110, ensifentrine exhibited superior protection against mitochondrial dysfunction after PLY exposure. In addition, in the presence of ensifentrine, the quantity of EV release and their extracelllular mitochondrial content were both dramatically reduced. In contrast to control EV PLY , EV PLY from ensifentrine-pretreated AEC demonstrated no barrier disruptive properties. Conclusions: Mitochondrial dysfunction in AEC contributes to vascular endothelial injury in ALI through mechanisms involving the release of barrier-disruptive EVs, which can be effectively targeted by inhibiting PDE3/4.

Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which can result in severe disease, often characterised by a 'cytokine storm' and the associated acute respiratory distress syndrome. However, many infections with SARS-CoV-2 are mild or asymptomatic throughout the course of infection. Although blood biomarkers of severe disease are well studied, less well understood are the inflammatory signatures in lung tissues associated with mild disease or silent infections, wherein infection and inflammation are rapidly resolved leading to sequelae-free recovery. Herein we described RNA-Seq and histological analyses of lungs over time in an omicron BA.1/K18-hACE2 mouse infection model, which displays these latter features. Although robust infection was evident at 2 days post infection (dpi), viral RNA was largely cleared by 10 dpi. Acute inflammatory signatures showed a slightly different pattern of cytokine signatures compared with severe infection models, and where much diminished 30 dpi and absent by 66 dpi. Cellular deconvolution identified significantly increased abundance scores for a number of anti-inflammatory pro-resolution cell types at 5/10 dpi. These included type II innate lymphoid cells, T regulatory cells, and interstitial macrophages. Genes whose expression trended downwards over 2-66 dpi included biomarkers of severe disease and were associated with 'cytokine storm' pathways. Genes whose expression trended upward during this period were associated with recovery of ciliated cells, AT2 to AT1 transition, reticular fibroblasts and innate lymphoid cells, indicating a return to homeostasis. Very few differentially expressed host genes were identified at 66 dpi, suggesting near complete recovery. The parallels between mild or subclinical infections in humans and those observed in this BA.1/K18-hACE2 mouse model are discussed with reference to the concept of "protective inflammation".

Evolution of the oxyhemoglobin dissociation curve in COVID-19 related ARDS patients.

Severe hypoxemia is the leading cause of admission in intensive care (ICU) in patients with COVID-19 related acute respiratory distress syndrome (ARDS). In these patients, several studies reported a left shift of the oxyhemoglobin dissociation curve associated with a lower mortality. However, these results are conflicting, as these studies include few patients and often no control groups. Moreover, the calculation of P50, representing the PaO2 value at which 50% of hemoglobin is saturated, is not corrected for factors known to influence it (pH, PaCO2 or temperature). For all of these reasons, we compared the corrected P50 between ICU patients with severe COVID-19 related ARDS on mechanical ventilation or not, and ARDS from other causes. We investigated the evolution of the corrected P50 during the first 3 days of ICU and its relationship with ICU mortality. We retrospectively calculated the corrected P50 in three groups of patients: intubated and mechanically ventilated COVID-19 related ARDS, non-intubated COVID-19 related ARDS and intubated patients with ARDS due to other infectious causes. The corrected P50 was calculated, on the worst blood gas analysis on days 1 and 3 of ICU admission, by the formula of Hill but modified by Dash et al., controlled for pH, PaCO2 and temperature. We collected ICU mortality. 463 blood gas analysis at days 1 and 3 from 214 ICU COVID-19 related ARDS patients (114 with intubation and 100 without) and 35 ICU patients with ARDS from other causes were analyzed. All patients were severely hypoxemic: PaO2/FiO2 of 76 [58-108] mmHg for intubated COVID-19, 79 [60-108] mmHg for non-intubated COVID-19 and 142 [78-197] mmHg for the third group (p < 0.001). The mortality rate was higher in intubated COVID-19 related ARDS patients (44.7 versus 14 versus 37% in ARDS from other causes; p < 0.001). The corrected P50 was significantly lower in COVID-19 patients, especially in non- intubated patients (21.2 [18.8-25.2] mmHg vs. 25.5 [19.2-30.3] mmHg in intubated patients; compared to ARDS from other causes: 27.2 [23.3-35.4] mmHg; p < 0.001. The corrected P50 does not change over the first 3 days, except for the non intubated COVID-19 related ARDS and is not correlated with ICU mortality (odds ratio = 0.98 [0.95-1.03]; p = 0.51), in contrast of PaO2/FiO2 and ICU gravity scores. The oxyhemoglobin dissociation curve at ICU admission was left shifting in severe COVID-19 related ARDS patients regardless of the type of ventilation. This deviation increases the third day only in non-intubated COVID-19 related ARDS and was not related to the outcome.