Background: Mechanical ventilation with a tidal volume (V_T) of 6 mL/kg/predicted body weight (PBW), to maintain plateau pressure (P_plat) lower than 30 cmH₂O, does not completely avoid the risk of ventilator induced lung injury (VILI). The aim of this study was to evaluate safety and feasibility of a ventilation strategy consisting of very low V_T combined with extracorporeal carbon dioxide removal (ECCO₂R). Methods: In fifteen patients with moderate ARDS, V_T was reduced from baseline to 4 mL/kg PBW while PEEP was increased to target a plateau pressure – (P_plat) between 23 and 25 cmH₂O. Low-flow ECCO₂R was initiated when respiratory acidosis developed (pH < 7.25, PaCO₂ > 60 mmHg). Ventilation parameters (V_T, respiratory rate, PEEP), respiratory compliance (C_RS), driving pressure (DeltaP = V_T/C_RS), arterial blood gases, and ECCO₂R system operational characteristics were collected during the period of ultra-protective ventilation. Patients were weaned from ECCO₂R when PaO₂/FiO₂ was higher than 200 and could tolerate conventional ventilation settings. Complications, mortality at day 28, need for prone positioning and extracorporeal membrane oxygenation, and data on weaning from both MV and ECCO₂R were also collected. Results: During the 2 h run in phase, V_T reduction from baseline (6.2 mL/kg PBW) to approximately 4 mL/kg PBW caused respiratory acidosis (pH < 7.25) in all fifteen patients. At steady state, ECCO₂R with an average blood flow of 435 mL/min and sweep gas flow of 10 L/min was effective at correcting pH and PaCO₂ to within 10 % of baseline values. PEEP values tended to increase at V_T of 4 mL/kg from 12.2 to 14.5 cmH₂O, but this change was not statistically significant. Driving pressure was significantly reduced during the first two days compared to baseline (from 13.9 to 11.6 cmH₂O; p < 0.05) and there were no significant differences in the values of respiratory system compliance. Rescue therapies for life threatening hypoxemia such as prone position and ECMO were necessary in four and two patients, respectively. Only two study-related adverse events were observed (intravascular hemolysis and femoral catheter kinking). Conclusions: The low-flow ECCO₂R system safely facilitates a low volume, low pressure ultra-protective mechanical ventilation strategy in patients with moderate ARDS.

Percutaneous stellate ganglion block (PSGB) through single-bolus injection and thoracic epidural anaesthesia (TEA) have been proposed for the acute management of refractory ventricular arrhythmias (VAs). However, data on continuous PSGB (C-PSGB) are scant. The aim of this study is to report our dual-centre experience with C-PSGB and to perform a systematic review on C-PSGB and TEA. Consecutive patients receiving C-PSGB at two centres were enrolled. The systematic literature review follows the latest Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Our case series (26 patients, 88% male, 60 ± 16 years, all with advanced structural heart disease, left ventricular ejection fraction 23 ± 11%, 32 C-PSGBs performed, with a median duration of 3 days) shows that C-PSGB is feasible and safe and leads to complete VAs suppression in 59% and to overall clinical benefit in 94% of cases. Overall, 61 patients received 68 C-PSGBs and 22 TEA, with complete VA suppression in 63% of C-PSGBs (61% of patients). Most TEA procedures (55%) were performed on intubated patients, as opposed to 28% of C-PSGBs (P = 0.02); 63% of cases were on full anticoagulation at C-PSGB, none at TEA (P < 0.001). Ropivacaine and lidocaine were the most used drugs for C-PSGB, and the available data support a starting dose of 12 and 100 mg/h, respectively. No major complications occurred, yet TEA discontinuation rate due to side effects was higher than C-PSGB (18 vs. 1%, P = 0.01). Continuous PSGB seems feasible, safe, and effective for the acute management of refractory VAs. The antiarrhythmic effect may be accomplished with less concerns for concomitant anticoagulation compared with TEA and with a lower side-effect related discontinuation rate.

Objectives: Lung ischemia-reperfusion injury is the main cause of primary graft dysfunction after lung transplantation and results in increased morbidity and mortality. Fas-mediated apoptosis is one of the pathologic mechanisms involved in the development of ischemia-reperfusion injury. We hypothesized that the inhibition of Fas gene expression in lungs by intratracheal administration of small interfering RNA could reduce lung ischemia-reperfusion injury in an ex vivo model reproducing the procedural sequence of lung transplantation. Design: Prospective, randomized, controlled experimental study. Setting: University research laboratory. Subjects: C57/BL6 mice weighing 28–30 g. Interventions: Ischemia-reperfusion injury was induced in lungs isolated from mice, 48 hours after treatment with intratracheal small interfering RNA targeting Fas, control small interfering RNA, or vehicle. Isolated lungs were exposed to 6 hours of cold ischemia (4°C), followed by 2 hours of warm (37°C) reperfusion with a solution containing 10% of fresh whole blood and mechanical ventilation with constant low driving pressure. Measurements and Main Results: Fas gene expression was significantly silenced at the level of messenger RNA and protein after ischemia-reperfusion in lungs treated with small interfering RNA targeting Fas compared with lungs treated with control small interfering RNA or vehicle. Silencing of Fas gene expression resulted in reduced edema formation (bronchoalveolar lavage protein concentration and lung histology) and improvement in lung compliance. These effects were associated with a significant reduction of pulmonary cell apoptosis of lungs treated with small interfering RNA targeting Fas, which did not affect cytokine release and neutrophil infiltration. Conclusions: Fas expression silencing in the lung by small interfering RNA is effective against ischemia-reperfusion injury. This approach represents a potential innovative strategy of organ preservation before lung transplantation.

Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.

Cyclic adenosine 3′,5′-monophosphate (cAMP)–elevating agents, such as β ₂ -adrenergic receptor (β ₂ -AR) agonists and phosphodiesterase (PDE) inhibitors, remain a mainstay in the treatment of obstructive respiratory diseases, conditions characterized by airway constriction, inflammation, and mucus hypersecretion. However, their clinical use is limited by unwanted side effects because of unrestricted cAMP elevation in the airways and in distant organs. Here, we identified the A-kinase anchoring protein phosphoinositide 3-kinase γ (PI3Kγ) as a critical regulator of a discrete cAMP signaling microdomain activated by β ₂ -ARs in airway structural and inflammatory cells. Displacement of the PI3Kγ-anchored pool of protein kinase A (PKA) by an inhaled, cell-permeable, PI3Kγ mimetic peptide (PI3Kγ MP) inhibited a pool of subcortical PDE4B and PDE4D and safely increased cAMP in the lungs, leading to airway smooth muscle relaxation and reduced neutrophil infiltration in a murine model of asthma. In human bronchial epithelial cells, PI3Kγ MP induced unexpected cAMP and PKA elevations restricted to the vicinity of the cystic fibrosis transmembrane conductance regulator (CFTR), the ion channel controlling mucus hydration that is mutated in cystic fibrosis (CF). PI3Kγ MP promoted the phosphorylation of wild-type CFTR on serine-737, triggering channel gating, and rescued the function of F508del-CFTR, the most prevalent CF mutant, by enhancing the effects of existing CFTR modulators. These results unveil PI3Kγ as the regulator of a β ₂ -AR/cAMP microdomain central to smooth muscle contraction, immune cell activation, and epithelial fluid secretion in the airways, suggesting the use of a PI3Kγ MP for compartment-restricted, therapeutic cAMP elevation in chronic obstructive respiratory diseases.