Ventilator-induced Lung Injury Research Articles

Adherence to Lung Protective Ventilation in ARDS: A Mixed Methods Study Using Real-Time Continuously Monitored Ventilation Data.

Lung-protective ventilation is a standard intervention for mitigating ventilator-induced lung injury in patients with ARDS. Despite its efficacy, adherence to contemporary evidence-based guidelines remains suboptimal. We aimed to identify factors that affect the adherence of staff to applying lung-protective ventilation guidelines by analyzing real-time, continuously monitored ventilation data over a 5-year longitudinal period. We conducted retrospective cohort and qualitative studies. Subjects with billing code J80 who survived at least 48 h of continuous mandatory ventilation with volume control in critical care settings between January 1, 2018, and December 31, 2022, were eligible. Tidal volume was measured dynamically (1-min resolution) and averaged hourly. The lung-protective ventilation setting studied was ≤ 6 mL/kg predicted body weight. A subgroup analysis was conducted by considering COVID-19 status. Focus groups of critical-care providers were convened to investigate the possible reasons for the non-utilization of lung-protective ventilation. Among 1,055 subjects, 42.4% were on lung-protective ventilation settings at 48 h. Male sex was correlated with lung-protective ventilation (odds ratio [OR] 1.63, 95% CI 1.08-2.47), whereas age ≥ 60 y was associated with no lung-protective ventilation use (OR 0.61, 95% CI 0.39-0.94] in the subjects with non-COVID-19 etiologies. Improved staff adherence was observed in the subjects with COVID-19 early in the pandemic when COVID-19 (OR 1.48, 95% CI 1.07-2.04), male sex (OR 2.42, 95% CI 1.79-3.29), and neuromuscular blocking agent use within 48 h (OR 1.69, 95% CI 1.25-2.29) were correlated with staff placing subjects on lung-protective ventilation. However, lung-protective ventilation use occurred less frequently by staff managing subjects with cancer (OR 0.59, 95% CI 0.35-0.99) and hypertension (OR 0.62, 95% CI 0.45-0.85). Focus groups supported these findings and highlighted the need for an accurate height measurement on unit admission to determine the appropriate target tidal volume. Staff are not yet universally adherent to lung-protective ventilation best practices. Strategies, for example, continuous monitoring, with frequent feedback to clinical teams may help.

Does patient-ventilator asynchrony really matter?

Past observational studies have reported the association between patient-ventilator asynchronies and poor clinical outcomes, namely longer duration of mechanical ventilation and higher mortality. But causality has remained undetermined. During the era of lung and diaphragm protective ventilation, should we revolutionize our clinical practice to detect and treat dyssynchrony? Clinicians' ability to recognize asynchronies is typically low. Automatized softwares based on artificial intelligence have been trained to largely outperform human eyesight and are close to be implemented at the bedside. There is growing evidence that in susceptible patients, dyssynchrony may lead to ventilation-induced lung injury (or patient self-inflicted lung injury) and that clusters of such dyssynchronous events have the highest association with poor outcomes. Dyssynchrony may also be associated with harm indirectly when it reflects over-assistance or over-sedation. However, the occurrence of reverse triggering by means of low inspiratory efforts during passive ventilation may prevent diaphragm dysfunction and atrophy and be beneficial. Most recent evidence on the topic suggests that synchrony between the patient and the mechanical ventilator is a critical element for protecting lung and diaphragm during the time of invasive mechanical ventilation or may reflect inadequate settings or sedation. Therefore, it is a complex situation, and clinical trials are still needed to test the effectiveness of keeping patient-ventilator interaction synchronous on clinical outcomes.

Microglia ameliorate delirium-like phenotypes in a murine model of acute ventilator-induced lung injury

BackgroundDelirium affects 50–85% of patients on mechanical ventilation and is associated with increased mortality, prolonged hospitalization, and a three-fold higher risk of dementia. Microglia, the resident immune cells of the brain, exhibit both neuroprotective and neurotoxic functions; however, their effects in mechanical ventilation-induced acute lung injury (VILI) are unknown. We hypothesize that in a model of short-term VILI, microglia play a neuroprotective role to ameliorate delirium-like phenotypes.MethodsMicroglia depletion (n = 18) was accomplished using an orally administered colony stimulating factor 1 receptor inhibitor, while controls received a vehicle diet (n = 18). We then compared extent of neuronal injury in the frontal cortex and hippocampus using cleaved caspase-3 (CC3) and multiple delirium-like behaviors in microglia depleted and non-microglia depleted male mice (C57BL/6 J aged 4–9 months) following VILI. Delirium-like behaviors were evaluated using the Open Field, Elevated Plus Maze, and Y-maze assays. We subsequently evaluated whether repopulation of microglia (n = 14 repopulation, 14 vehicle) restored the phenotypes.ResultsFrontal/hippocampal neuronal CC3 levels were significantly higher in microglia depleted VILI mice compared to vehicle-treated VILI controls (p < 0.01, p < 0.01, respectively). These structural changes were accompanied by worse delirium-like behaviors in microglia depleted VILI mice compared to vehicle controls. Specifically, microglia depleted VILI mice demonstrated: (1) significantly increased time in the periphery of the Open Field (p = 0.01), (2) significantly increased coefficient of variation (p = 0.02), (3) trend towards reduced time in the open arms of the Elevated Plus Maze (p = 0.09), and (4) significantly decreased spontaneous alternations on Y-maze (p < 0.01). There was a significant inverse correlation between frontal CC3 and percent spontaneous alternations (R2 = 0.51, p < 0.01). Microglia repopulation showed a near-complete return to vehicle levels of delirium like-behaviors.ConclusionsThis study demonstrates that microglia depletion exacerbates structural and functional delirium-like phenotypes after VILI, while subsequent repopulation of microglia restores these phenotypes. These findings suggest a neuroprotective role for microglia in ameliorating neuronal and functional delirium-like phenotypes and call for consideration of interventions that leverage endogenous microglia physiology to mitigate delirium.

A self-regulated expiratory flow device for mechanical ventilation: a bench study

IntroductionUnregulated expiratory flow may contribute to ventilator-induced lung injury. The amount of energy dissipated into the lungs with tidal mechanical ventilation may be used to quantify potentially injurious ventilation. Previously reported devices for variable expiratory flow regulation (FLEX) require, either computer-controlled feedback, or an initial expiratory flow trigger. In this bench study we present a novel passive expiratory flow regulation device.MethodsThe device was tested using a commercially available mechanical ventilator with a range of settings (tidal volume 420 ml and 630 ml, max. inspiratory flow rate 30 L/min and 50 L/min, respiratory rate 10 min−1, positive end-expiratory pressure 5 cmH2O), and a test lung with six different combinations of compliance and resistance settings. The effectiveness of the device was evaluated for reduction in peak expiratory flow, expiratory time, mean airway pressure, and the reduction of tidal dissipated energy (measured as the area within the airway pressure–volume loop).ResultsMaximal and minimal reduction in peak expiratory flow was from 97.18 ± 0.41 L/min to 25.82 ± 0.07 L/min (p < 0.001), and from 44.11 ± 0.42 L/min to 26.30 ± 0.06 L/min, respectively. Maximal prolongation in expiratory time was recorded from 1.53 ± 0.06 s to 3.64 ± 0.21 s (p < 0.001). As a result of the extended expiration, the maximal decrease in I:E ratio was from 1:1.15 ± 0.03 to 1:2.45 ± 0.01 (p < 0.001). The greatest increase in mean airway pressure was from 10.04 ± 0.03 cmH2O to 17.33 ± 0.03 cmH2O. Dissipated energy was significantly reduced with the device under all test conditions (p < 0.001). The greatest reduction in dissipated energy was from 1.74 ± 0.00 J to 0.84 ± 0.00 J per breath. The least reduction in dissipated energy was from 0.30 ± 0.00 J to 0.16 ± 0.00 J per breath. The greatest and least percentage reduction in dissipated energy was 68% and 33%, respectively.ConclusionsThe device bench tested in this study demonstrated a significant reduction in peak expiratory flow rate and dissipated energy, compared to ventilation with unregulated expiratory flow. Application of the device warrants further experimental and clinical evaluation.

Impact of mechanical power on ICU mortality in ventilated critically ill patients: a retrospective study with continuous real-life data

BackgroundOver the past decade, numerous studies on potential factors contributing to ventilation-induced lung injury have been carried out. Mechanical power has been pointed out as the parameter that encloses all ventilation-induced lung injury-contributing factors. However, studies conducted to date provide data regarding mechanical power during the early hours of mechanical ventilation that may not accurately reflect the impact of power throughout the period of mechanical ventilatory support on intensive care unit mortality.MethodsRetrospective observational study conducted at a single center in Spain. Patients admitted to the intensive care unit, > o = 18 years of age, and ventilated for over 24 h were included. We extracted the mechanical power values throughout the entire mechanical ventilation in controlled modes period from the clinical information system every 2 min. First, we calculate the cutoff-point for mechanical power beyond which there was a greater change in the probability of death. After, the sum of time values above the safe cut-off point was calculated to obtain the value in hours. We analyzed if the number of hours the patient was under ventilation with a mechanical power above the safe threshold was associated with intensive care unit mortality, invasive mechanical ventilation days, and intensive care unit length of stay. We repeated the analysis in different subgroups based on the degree of hypoxemia and in patients with SARS CoV-2 pneumonia.ResultsThe cut-off point of mechanical power at with there is a higher increase in intensive care unit mortality was 18 J/min. The greater the number of hours patients were under mechanical power > 18 J/min the higher the intensive care unit mortality in all the study population, in patients with SARS CoV-2 pneumonia and in mild to moderate hypoxemic respiratory failure. The risk of death in the intensive care unit increases 0.1% for each hour with mechanical power exceeding 18 J/min. The number of hours with mechanical power > 18 J/min also affected the days of invasive mechanical ventilation and intensive care unit length of stay.ConclusionsThe number of hours with mechanical power > 18 J/min is associated with mortality in the intensive care unit in critically ill patients. Continuous monitoring of mechanical power in controlled modes using an automated clinical information system could alert the clinician to this risk.

A short duration of mechanical ventilation alters redox status in the diaphragm and aggravates inflammation in septic mice

BackgroundMechanical ventilation (MV) is a life support method used to treat patients with respiratory failure. High tidal volumes during MV can cause ventilator-induced lung injury (VILI), but also affect other organs, such as the diaphragm (Dia) causing ventilator-induced diaphragmatic dysfunction (VIDD). VIDD is often associated with a complicated course on MV. Sepsis can induce inflammation and oxidative stress, contributing to the impairment of the Dia and worsening of the prognosis. This study evaluated the additive or synergistic effects of a short course of mechanical ventilation on Dia in healthy and septic adult mice. Methods32 adult male C57BL/6 mice were randomly into four groups: Control (CG), non-ventilated animals instilled with saline solution (PBS1x); Lipopolysaccharide (LPS), non-ventilated animals instilled with PBS solution containing lipopolysaccharide; Mechanical Ventilation (MV) for 1 h, ventilated animals instilled with PBS solution; and Mechanical Ventilation and LPS (MV+LPS), ventilated animals instilled with PBS solution containing LPS. At the end of the experimental protocol, the animals were euthanized, then blood and diaphragm tissue samples were collected. ResultsEvaluation of leukocyte/blood parameters and diaphragm muscle showed that MV, LPS and the combination of both were able to increase neutrophil count, creatine kinase, inflammatory mediators and oxidative stress in all groups compared to the control. MV and sepsis combined had additive effects on inflammation and lipid peroxidation. ConclusionsA short course of Mechanical ventilation promotes inflammation and oxidative stress and, its combination with sepsis further increases local and systemic inflammation.

ACE2 Alleviates Endoplasmic Reticulum Stress and Protects against Pyroptosis by Regulating Ang1-7/Mas in Ventilator-Induced Lung Injury

Background: Ventilator-induced lung injury (VILI) is a consequence of inflammation and increased alveolar-capillary membrane permeability due to alveolar hyperdistention or elevated intrapulmonary pressure, but the precise mechanisms remain unclear. The aim of the study was to analyze the mechanism by which angiotensin converting enzyme 2 (ACE2) alleviates endoplasmic reticulum stress (ERS) and protects alveolar cells from pyroptosis in VILI by regulating angiotensin (Ang)1-7/Mas. Methods: VILI was induced in mice by mechanical ventilation by regulating the tidal volume. The alveolar cell line, A549, mimics VILI in vitro by cyclic stretch (CS). Ang (1-7) (100 nmol/L) was added to the medium. ERS was induced in cells by stimulating with tunicamycin (TM, 2 μg/mL). ERS was inhibited by tracheal instillation of 4-phenylbutyric acid (4-PBA) (1 mg/kg). ACE2's enzymatic function was activated or inhibited by subcutaneous injection of resorcinolnaphthalein (RES, 20 μg/kg) or MLN-4760 (20 μg/kg). pGLV-EF1a-GFP-ACE2 was instilled into the trachea to increase the protein expression of ACE2. The Ang (1-7) receptor, Mas, was antagonized by injecting A779 subcutaneously (80 μg/kg). Results: ACE2 protein levels decreased after modeling. Ang (1-7) level was decreased and Ang II was accumulated. ERS was significantly induced in VILI mice, and pyroptosis was observed in cells. When ERS was inhibited, pyroptosis under the VILI condition was significantly inhibited. Ang (1-7) alleviated ERS and pyroptosis under CS. When ERS was continuously activated, the function of Ang (1-7) in inhibiting pyroptosis was blocked. Resorcinolnaphthalein (RES) effectively promoted Ang II conversion, alleviated the Ang (1-7) level in VILI, ameliorated lung injury, and inhibited ERS and cell pyroptosis. Inhibiting ACE2's function in VILI hindered the production of Ang (1-7), promoted the accumulation of Ang II, and exacerbated ERS and pyroptosis, along with lung injury. The Mas antagonist significantly blocked the inhibitory effects of ACE2 on ERS and pyroptosis in VILI. Conclusions: Reduced ACE2 expression in VILI is involved in ERS and pyroptosis-related injury. ACE2 can alleviate ERS in alveolar cells by catalyzing the production of Ang (1-7), thus inhibiting pyroptosis in VILI.

The blockade of neddylation alleviates ventilator-induced lung injury by reducing stretch-induced damage to pulmonary epithelial cells

Ventilator-induced lung injury is a serious complication in mechanically ventilated patients. Neddylation, the post-translational modification of neural precursor cell-expressed developmentally down-regulated 8 (NEDD8) conjugation, regulates numerous biological functions. However, its involvement and therapeutic significance in ventilator-induced lung injury remains unknown. Therefore, this study aimed to examine the kinetics and contribution of activated neddylation and the impact of neddylation inhibition in mice subjected to high tidal volume (HTV) ventilation in vivo and human pulmonary alveolar epithelial cells stimulated through cyclic stretching (CS) in vitro. The neddylation and expression of ubiquitin conjugating enzyme 3 (UBA3), a NEDD8-activating enzyme (NAE) catalytic subunit, were time-dependently upregulated in HTV-ventilated mice. Additionally, the NAE inhibitor MLN4924 considerably attenuated acute lung injury induced by HTV ventilation, manifesting as reduced inflammation and oxidative stress. Furthermore, MLN4924 effectively reduced the secretion of inflammatory cytokines from Ly6Chigh monocytes and neutrophils, subsequently decreasing endothelial permeability. Moreover, our study revealed an upregulation of the neddylation pathway, oxidative stress, and apoptosis during CS of alveolar epithelial cells. However, blockade of neddylation via MLN4924 or through UBA3 knockdown suppressed this upregulation. Overall, the inhibition of neddylation may alleviate HTV-induced acute lung injury by preventing CS-induced damage to alveolar epithelial cells. This indicates that the neddylation pathway plays a critical role in the progression of ventilator-induced lung injury. These findings may provide a new therapeutic target for treating ventilator-induced lung injury.

The impact of PEEP on mechanical power and driving pressure in children with pediatric acute respiratory distress syndrome.

Positive end-expiratory pressure (PEEP) is widely used to improve oxygenation and avoid alveolar collapse in mechanically ventilated patients with pediatric acute respiratory distress syndrome (PARDS). However, its improper use can be harmful, impacting variables associated with ventilation-induced lung injury, such as mechanical power (MP) and driving pressure (∆P). Our main objective was to assess the impact of increasing PEEP on MP and ∆P in children with PARDS. Mechanically ventilated children on pressure-controlled volume-guaranteed mode were prospectively assessed for inclusion. PEEP was sequentially changed to 5, 12, 10, 8, and again to 5 cm H2O. After 10 min at each PEEP level, ventilatory data were collected and then variables of interest were determined. Respiratory system mechanics were measured using the least squares fitting method. Thirty-one patients were included, with median age and weight of 6 months and 6.3 kg. Most subjects were admitted for acute viral bronchiolitis (45%) or community-acquired pneumonia (32%) and were diagnosed with mild (45%) or moderate (42%) PARDS. There was a significant increase in MP and ∆P at PEEP levels of 10 and 12 cm H2O. When PEEP was increased from 5 to 12 cm H2O, there was a relative increase in MP of 60.7% (IQR 49.3-82.9) and in ΔP of 33.3% (IQR 17.8-65.8). A positive correlation was observed between MP and ΔP (ρ = 0.59). Children with mild or moderate PARDS may experience a significant increase in MP and ∆P with increased PEEP. Therefore, respiratory system mechanics and lung recruitability must be carefully evaluated during PEEP titration.

Capsaicin mitigates ventilator-induced lung injury by suppressing ferroptosis and maintaining mitochondrial redox homeostasis through SIRT3-dependent mechanisms

BackgroundVentilator-induced lung injury (VILI) is one of the severe complications in the clinic concerning mechanical ventilation (MV). Capsaicin (CAP) has anti-inflammatory and inhibitory effects on oxidative stress, which is a significant element causing cellular ferroptosis. Nevertheless, the specific role and potential mechanistic pathways through which CAP modulates ferroptosis in VILI remain elusive.MethodsVILI was established in vivo, and the pulmonary epithelial cell injury model induced by circulation stretching (CS) was established in vitro. Both mice and cells were pretreated with CAP. Transmission electron microscopy, ELISA, Western blot, immunofluorescence, RT-PCR, fluorescent probes, and other experimental methods were used to clarify the relationship between iron death and VILI in alveolar epithelial cells, and whether capsaicin alleviates VILI by inhibiting iron death and its specific mechanism.ResultsFerroptosis was involved in VILI by utilizing in vivo models. CAP inhibited ferroptosis and alleviated VILI's lung damage and inflammation, and this protective effect of CAP was dependent on maintaining mitochondrial redox system through SITR3 signaling. In the CS-caused lung epithelial cell injury models, CAP reduced pathological CS-caused ferroptosis and cell injury. Knockdown SIRT3 reversed the role of CAP on the maintaining mitochondria dysfunction under pathological CS and eliminated its subsequent advantageous impacts for ferroptosis against overstretching cells.ConclusionThe outcomes showed that CAP alleviated ferroptosis in VILI via improving the activity of SITR3 to suppressing mitochondrial oxidative damage and maintaining mitochondrial redox homeostasis, illustrating its possibility as a novel therapeutic goal for VILI.Graphical

Driving pressure: A useful tool for reducing postoperative pulmonary complications.

The operating room is a unique environment where surgery exposes patients to non-physiological changes that can compromise lung mechanics. Therefore, raising clinicians' awareness of the potential risk of ventilator-induced lung injury (VILI) is mandatory. Driving pressure is a useful tool for reducing lung complications in patients with acute respiratory distress syndrome and those undergoing elective surgery. Driving pressure has been most extensively studied in the context of single-lung ventilation during thoracic surgery. However, the awareness of association of VILI risk and patient positioning (prone, beach-chair, park-bench) and type of surgery must be raised.

Resolvin E1 and Inhibition of BLT2 Signaling Attenuate the Inflammatory Response and Improve One-Lung Ventilation-Induced Lung Injury.

One-lung ventilation (OLV) is a prevalently used technique to sustain intraoperative pulmonary function. Resolvin E1 (RvE1), a specialized pro-resolving lipid mediator, accelerates the resolution of inflammation in the lungs. However, its therapeutic effects on OLV-induced lung injury remain unclear. We initially developed an OLV rat model and treated it with RvE1. Subsequently, we assessed the wet/dry ratio of the lung tissue, performed hematoxylin and eosin staining, and calculated the ratio of polymorphonuclear cells to white blood cells in the bronchoalveolar lavage fluid. Additionally, we assessed apoptosis, inflammatory factor levels, and lung permeability in the rat lung tissues in the RvE1 treated and untreated groups and explored the molecular mechanisms mediated by RvE1. Our results indicated that RvE1 alleviated lung injury and inflammation and improved lung tissue apoptosis and permeability in OLV rats. Moreover, RvE1 suppressed the expression of the BLT1/2 signaling pathway and its ligands. The use of BLT2 and BLT1 inhibitors (LY255283 and U-75302, respectively) enhanced RvE1's anti-inflammatory effects and reduced lung injury. Furthermore, synergistic treatment with the BLT2 inhibitor and RvE1 provided grater benefits by more effectively inhibiting the NF-kB, p38 MAPK, and ERK pathways. RvE1 and the inhibition of BLT2 signalling reduce the inflammatory response and mitigate OLV-induced lung injury. These findings suggest a novel therapeutic pathway for managing OLV-related complications.

ROLE OF CASPASE-1/CASPASE-11-HMGB1-RAGE/TLR4 SIGNALING IN THE EXACERBATION OF EXTRAPULMONARY SEPSIS INDUCED LUNG INJURY BY MECHANICAL VENTILATION.

Mechanical ventilation (MV) is a clinically important measure for respiratory support in critically ill patients. Although moderate tidal volume MV does not cause lung injury, it can further exacerbate lung injury in pathological state such as sepsis. This pathological process is known as the 'two-hit' theory, whereby an initial lung injury (e.g., infection, trauma, or sepsis) triggers an inflammatory response that activates immune cells, presenting the lung tissue in a fragile state and rendering it more susceptible to subsequent injury. The second hit occurs when mechanical ventilation is applied to lung tissue in a fragile state, and it is noteworthy that this mechanical ventilation is harmless to healthy lung tissue, further aggravating pre-existing lung injury through unknown mechanisms. This interaction between initial injury and subsequent mechanical ventilation develops a malignant cycle significantly exacerbating lung injury and severely hampering patient prognosis. The two-hit theory is critical to understanding the complicated mechanisms of ventilator-associated lung injury and facilitates the subsequent development of targeted therapeutic strategies. CLP mice model was used to mimic clinical sepsis patients. After 12 hours the mice were mechanical ventilated for 2-6 hours. MV by itself didn't lead to HMGB1 release, but significantly strengthened HMGB1 in plasma and cytoplasm of lung tissue in septic mice. Plasma and lung tissue activation of cytokines and chemokines, MAPK signaling pathway, neutrophil recruitment, and ALI were progressively decreased in LysM HMGB1-/- (Hmgb1 deletion in myeloid cells) and iHMGB1-/- mice (inducible HMGB1-/- mouse strain where the Hmgb1 gene was globally deleted after tamoxifen treatment). Compared with C57BL/6 mice, although EC-HMGB1-/- (Hmgb1 deletion in endothelial cells) mice didn't have lower levels of inflammation, neutrophil recruitment and lung injury were reduced. Compared with LysM HMGB1-/- mice, EC-HMGB1-/- mice had higher levels of inflammation but significantly lower neutrophil recruitment and lung injury. Overall, iHMGB1-/- mice had the lowest levels of all the above indicators. The level of inflammation, neutrophil recruitment and the degree of lung injury were decreased in RAGE-/- mice, and even the above indices were further decreased in TLR4/RAGE-/- mice. Levels of inflammation and neutrophil recruitment were decreased in Caspase-11-/- and Caspase-1/11-/- mice, but no statistical difference between these two gene knockout mice. These data show for the first time that the Caspase-1/Caspase-11-HMGB1-TLR4/RAGE signaling pathway plays a key role in mice model of sepsis induced lung injury exacerbated by MV. Different species of HMGB1 knockout mice have different lung protective mechanisms in the 'two hits' model, and location is the key to function. Specifically, LysM HMGB1-/- mice due to the deletion of HMGB1 in myeloid cells resulted in a pulmonary protective mechanism that was associated with a downregulation of the inflammatory response. EC HMGB1-/- mice are deficient in HMGB1 owing to endothelial cells, resulting in a distinct pulmonary protective mechanism independent of the inflammatory response and more relevant to the improvement of alveolar-capillary permeability. iHMGB1-/- mice, which are systemically HMGB1-deficient, share both of these lung-protective mechanisms.

Regional distribution of mechanical strain and macrophage-associated lung inflammation after ventilator-induced lung injury: an experimental study

BackgroundAlveolar macrophages activation to the pro-inflammatory phenotype M1 is pivotal in the pathophysiology of Ventilator-Induced Lung Injury (VILI). Increased lung strain is a known determinant of VILI, but a direct correspondence between regional lung strain and macrophagic activation remains unestablished. [68Ga]Ga-DOTA-TATE is a Positron Emission Tomography (PET) radiopharmaceutical with a high affinity for somatostatin receptor subtype 2 (SSTR2), which is overexpressed by pro-inflammatory-activated macrophages. Aim of the study was to determine, in a porcine model of VILI, whether mechanical strain correlates topographically with distribution of activated macrophages detected by [68Ga]Ga-DOTA-TATE uptake.MethodsSeven anesthetized pigs underwent VILI, while three served as control. Lung CT scans were acquired at incremental tidal volumes, simultaneously recording lung mechanics. [68Ga]Ga-DOTA-TATE was administered, followed by dynamic PET scans. Custom MatLab scripts generated voxel-by-voxel gas volume and strain maps from CT slices at para-diaphragmatic (Para-D) and mid-thoracic (Mid-T) levels. Analysis of regional Voxel-associated Normal Strain (VoStrain) and [68Ga]Ga-DOTA-TATE uptake was performed and a measure of the statistical correlation between these two variables was quantified using the linear mutual information (LMI) method.ResultsCompared to controls, the VILI group exhibited statistically significant higher VoStrain and Standardized Uptake Value Ratios (SUVR) both at Para-D and Mid-T levels. Both VoStrain and SUVR increased along the gravitational axis with an increment described by statistically different regression lines between VILI and healthy controls and reaching the peak in the dependent regions of the lung (for strain in VILI vs. control was at Para-D: 760 ± 210 vs. 449 ± 106; at Mid-T level 497 ± 373 vs. 193 ± 160; for SUVR, in VILI vs. control was at Para-D: 2.2 ± 1.3 vs. 1.3 ± 0.1; at Mid-T level 1.3 ± 1.0 vs. 0.6 ± 0.03). LMI in both Para-D and Mid-T was statistically significantly higher in VILI than in controls.ConclusionsIn this porcine model of VILI, we found a topographical correlation between lung strain and [68Ga]Ga-DOTA-TATE uptake at voxel level, suggesting that mechanical alteration and specific activation of inflammatory cells are strongly linked in VILI. This study represents the first voxel-by-voxel examination of this relationship in a multi-modal imaging analysis.

Recombinant thrombomodulin and recombinant antithrombin attenuate pulmonary endothelial glycocalyx degradation and neutrophil extracellular trap formation in ventilator-induced lung injury in the context of endotoxemia

BackgroundVascular endothelial damage is involved in the development and exacerbation of ventilator-induced lung injury (VILI). Pulmonary endothelial glycocalyx and neutrophil extracellular traps (NETs) are endothelial protective and damaging factors, respectively; however, their dynamics in VILI and the effects of recombinant thrombomodulin and antithrombin on these dynamics remain unclear. We hypothesized that glycocalyx degradation and NETs are induced by VILI and suppressed by recombinant thrombomodulin, recombinant antithrombin, or their combination.MethodsVILI was induced in male C57BL/6J mice by intraperitoneal lipopolysaccharide injection (20 mg/kg) and high tidal volume ventilation (20 mL/kg). In the intervention groups, recombinant thrombomodulin, recombinant antithrombin, or their combination was administered at the start of mechanical ventilation. Glycocalyx degradation was quantified by measuring serum syndecan-1, fluorescence-labeled lectin intensity, and glycocalyx-occupied area in the pulmonary vascular lumen. Double-stranded DNA in the bronchoalveolar fluid and fluorescent areas of citrullinated histone H3 and myeloperoxidase were quantified as NET formation.ResultsSerum syndecan-1 increased, and lectin fluorescence intensity decreased in VILI. Electron microscopy revealed decreases in glycocalyx-occupied areas within pulmonary microvessels in VILI. Double-stranded DNA levels in the bronchoalveolar lavage fluid and the fluorescent area of citrullinated histone H3 and myeloperoxidase in lung tissues increased in VILI. Recombinant thrombomodulin, recombinant antithrombin, and their combination reduced glycocalyx injury and NET marker levels. There was little difference in glycocalyx injury and NET makers between the intervention groups.ConclusionVILI induced glycocalyx degradation and NET formation. Recombinant thrombomodulin and recombinant antithrombin attenuated glycocalyx degradation and NETs in our VILI model. The effect of their combination did not differ from that of either drug alone. Recombinant thrombomodulin and antithrombin have the potential to be therapeutic agents for biotrauma in VILI.

Acute respiratory distress syndrome: A review of ARDS across the life course.

Acute respiratory distress syndrome (ARDS) is a multifactorial, inflammatory lung disease with significant morbidity and mortality that predominantly requires supportive care in its management. Although initially described in adult patients, the diagnostic definitions for ARDS have evolved over time to accurately describe this disease process in pediatric and, more recently, neonatal patients. The management of ARDS in each age demographic has converged in the application of lung-protective ventilatory strategies to mitigate the primary disease process and prevent its exacerbation by limiting ventilator-induced lung injury. However, differences arise in the preferred ventilatory strategies or adjunctive pulmonary therapies used to mitigate each type of ARDS. In this review, we compare and contrast the epidemiology, common etiologies, pathophysiology, diagnostic criteria, and outcomes of ARDS across the lifespan. Additionally, we discuss in detail the different management strategies used for each subtype of ARDS and spotlight how these strategies were applied to mitigate poor outcomes during the COVID-19 pandemic. This review is geared toward both clinicians and clinician-scientists as it not only summarizes the latest information on disease pathogenesis and patient management in ARDS across the lifespan but also highlights knowledge gaps for further investigative efforts. We conclude by projecting how future studies can fill these gaps in research and what improvements may be envisioned in the management of NARDS and PARDS based on the current breadth of literature on adult ARDS treatment strategies.

Mechanical power in decelerating flow versus square flow ventilation in pediatric ARDS.

Mechanical power (MP) is a summary variable quantifying the risk of ventilator-induced lung injury (VILI). The original MP equation was developed using square flow ventilation. However, most children are ventilated using decelerating flow. It is unclear whether MP differs according to mode of flow delivery. We compared MP in children with acute respiratory distress syndrome (ARDS) who received both square and decelerating flow ventilation. This was a secondary analysis of a prospectively enrolled cohort of pediatric ARDS. Patients were ventilated on decelerating flow, and then placed in square flow and allowed to stabilize. Ventilator metrics from both modes were collected within 24 hours of ARDS onset. Paired t-tests were used to compare differences in MP between the modes. We enrolled 185 subjects with a median oxygenation index of 9.5 (IQR 7, 13) and median age 8.3 years (IQR 1.8, 14). MP was lower in square flow (mean 0.46 J・min-1·Kg-1, SD 0.25, 95% CI 0.42-0.50) than in decelerating flow modes (mean 0.49 J・min-1·Kg-1, SD 0.28, 95% CI 0.45-0.53) with a mean difference of 0.03 J・min-1·Kg-1 (SD 0.08, 95% CI 0.014-0.038) (p<0.001). This result remained statistically significant when stratified by age < 2 years in square flow compared to decelerating flow and also when stratified by age >/= 2 years in square flow compared to decelerating flow. The elastic contribution in square flow was 70% and the resistive contribution was 30%. MP was marginally lower in square flow than in decelerating flow, although the clinical significance of this is unclear. Upward of 30% of MP may go towards overcoming resistance, regardless of age. This is nearly three-fold greater resistance compared to what has been reported in adults.

Relationship between strain energy and alveolar overdistension in patients with acute respiratory distress syndrome: The research protocol

Background: Energy produced during mechanical ventilation has been es¬tablished as a contributor to mortality in acute respiratory distress syndrome (ARDS) patients, elucidated through ventilator-induced lung injury (VILI). How¬ever, the potential association between strain energy, an engineering-based concept, and the risk of VILI remains unexplored. Objectives: This study aims to investigate the correlation between strain en¬ergy and alveolar overdistension and the relationship between strain energy and single-breath mechanical power (MP) calculated by a simplified formula in patients with ARDS. Methods: A prospective observational study will be conducted on moderate to severe ARDS patients under sedation and paralysis. We will gradually reduce positive end-expiratory pressure (PEEP) by two cmH2O every two minutes from 20 to 8 cmH2O in pressure-controlled ventilation mode. During decremental PEEP titration, patients would be monitored simultaneously for esophageal pressure and electrical impedance tomography (EIT). Data gathered from the mechanical ventilator and EIT during the decrementing PEEP titration were fo¬cused on seven PEEP levels: 20, 18, 16, 14, 12, 10, and 8 cmH2O, providing a dataset of 7 events per patient for analysis. Strain energy and single-breath MP were calculated from ventilator parameters, while EIT provided data on alveolar overdistension. Hypothesis: We hypothesized that strain energy and single-breath mechanical MP correlate with alveolar overdistension in ARDS patients. Conclusions: This study aims to assess the correlation between strain energy and alveolar overdistension, as well as the correlation between strain energy and single-breath MP in ARDS patients. Ethics and dissemination: The study protocol has been approved by the fac¬ulty of medicine ethics committee, Ramathibodi Hospital, Mahidol University (COA MURA2023/718). Trial registration: TCTR20240320001

Pressure Control Ventilation Versus Volume Control Ventilation in Laparoscopic Surgery: A Narrative Review.

This review compares the safety and effectiveness of volume control ventilation (VCV) and pressure control ventilation (PCV) during laparoscopic surgery. Nine studies were chosen for in-depth examination following the application of stringent inclusion and exclusion criteria to the 184 publications that the literature search turned up. PCV is well-known for its capacity to preserve lower peak airway pressures during laparoscopic procedures, lowering the risk of volutrauma and barotrauma and enhancing oxygenation under these conditions of elevated intra-abdominal pressures. On the other hand, VCV guarantees a constant tidal volume and offers accurate ventilation management, both of which are essential for preserving stable carbon dioxide levels. VCV, however, may result in higher peak airway pressures, raising the risk of lung damage brought on by a ventilator. Research indicates that PCV provides better respiratory mechanics management during laparoscopic surgery, but VCV consistent tidal volume delivery is useful in some clinical situations. When choosing between PCV and VCV, the anesthesia team's experience, the demands of each patient, and the surgical circumstances should all be taken into consideration. Real-time monitoring tools and sophisticated ventilatory technology are essential for maximizing ventilation techniques. Further improving patient outcomes can be achieved by incorporating multimodal anesthesia approaches, such as the use of muscle relaxants and customized intraoperative fluid management. Muscle relaxants optimize conditions for mechanical ventilation by ensuring adequate muscle relaxation, reducing the risk of ventilator-associated lung injury, and enabling more precise control of ventilation parameters. Tailored intraoperative fluid management helps maintain optimal lung mechanics by avoiding fluid overload, which can lead to pulmonary edema and compromised gas exchange, necessitating adjustments in ventilation strategy. While both ventilation modalities can be utilized efficiently, the research suggests that PCV may be more advantageous in controlling oxygenation and airway pressures. In the dynamic and demanding world of laparoscopic surgery, ongoing research and clinical innovation are crucial to improving these tactics and guaranteeing the best possible treatment. In order to obtain the best possible patient outcomes during laparoscopic surgeries, this review emphasizes the significance of customized breathing techniques.

Mechanical ventilation guided by driving pressure optimizes local pulmonary biomechanics in an ovine model.

Mechanical ventilation exposes the lung to injurious stresses and strains that can negatively affect clinical outcomes in acute respiratory distress syndrome or cause pulmonary complications after general anesthesia. Excess global lung strain, estimated as increased respiratory system driving pressure, is associated with mortality related to mechanical ventilation. The role of small-dimension biomechanical factors underlying this association and their spatial heterogeneity within the lung are currently unknown. Using four-dimensional computed tomography with a voxel resolution of 2.4 cubic millimeters and a multiresolution convolutional neural network for whole-lung image segmentation, we dynamically measured voxel-wise lung inflation and tidal parenchymal strains. Healthy or injured ovine lungs were evaluated as the mechanical ventilation positive end-expiratory pressure (PEEP) was titrated from 20 to 2 centimeters of water. The PEEP of minimal driving pressure (PEEPDP) optimized local lung biomechanics. We observed a greater rate of change in nonaerated lung mass with respect to PEEP below PEEPDP compared with PEEP values above this threshold. PEEPDP similarly characterized a breaking point in the relationships between PEEP and SD of local tidal parenchymal strain, the 95th percentile of local strains, and the magnitude of tidal overdistension. These findings advance the understanding of lung collapse, tidal overdistension, and strain heterogeneity as local triggers of ventilator-induced lung injury in large-animal lungs similar to those of humans and could inform the clinical management of mechanical ventilation to improve local lung biomechanics.