Tidal Volume Mechanical Ventilation Research Articles

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.

Alveolar macrophage-derived gVPLA2 promotes ventilator-induced lung injury via the cPLA2/PGE2 pathway

BackgroundVentilator-induced lung injury (VILI) is a clinical complication of mechanical ventilation observed in patients with acute respiratory distress syndrome. It is characterized by inflammation mediated by inflammatory cells and their secreted mediators.MethodsTo investigate the mechanisms underlying VILI, a C57BL/6J mouse model was induced using high tidal volume (HTV) mechanical ventilation. Mice were pretreated with Clodronate liposomes to deplete alveolar macrophages or administered normal bone marrow-derived macrophages or Group V phospholipase A2 (gVPLA2) intratracheally to inhibit bone marrow-derived macrophages. Lung tissue and bronchoalveolar lavage fluid (BALF) were collected to assess lung injury and measure Ca2 + concentration, gVPLA2, downstream phosphorylated cytoplasmic phospholipase A2 (p-cPLA2), prostaglandin E2 (PGE2), protein expression related to mitochondrial dynamics and mitochondrial damage. Cellular experiments were performed to complement the animal studies.ResultsDepletion of alveolar macrophages attenuated HTV-induced lung injury and reduced gVPLA2 levels in alveolar lavage fluid. Similarly, inhibition of alveolar macrophage-derived gVPLA2 had a similar effect. Activation of the cPLA2/PGE2/Ca2 + pathway in alveolar epithelial cells by gVPLA2 derived from alveolar macrophages led to disturbances in mitochondrial dynamics and mitochondrial dysfunction. The findings from cellular experiments were consistent with those of animal experiments.ConclusionsHTV mechanical ventilation induces the secretion of gVPLA2 by alveolar macrophages, which activates the cPLA2/PGE2/Ca2 + pathway, resulting in mitochondrial dysfunction. These findings provide insights into the pathogenesis of VILI and may contribute to the development of therapeutic strategies for preventing or treating VILI.

Low Tidal Volume Ventilation Is Poorly Implemented for Patients in North American and United Kingdom ICUs Using Electronic Health Records

Low tidal volume ventilation (LTVV;< 8mL/kg predicted body weight [PBW]) is a well-established standard of care associated with improved outcomes. This study used data collated in multicenter electronic health record ICU databases from the United Kingdom and the United States to analyze the use of LTVV in routine clinical practice. What factors are associated with adherence to LTVV in the United Kingdom and North America? This was a retrospective, multicenter study across the United Kingdom and United States of patients who were mechanically ventilated. Factors associated with adherence to LTVV were assessed in all patients in both databases who were mechanically ventilated for > 48 h. We observed trends over time and investigated whether LTVV was associated with patient outcomes (30-day mortality and duration of ventilation) and identified strategies to improve adherence to LTVV. A total of 5,466 (Critical Care Health Informatics Collaborative [CCHIC]) and 7,384 electronic ICU collaborative research database [eICU-CRD] patients were ventilated for > 48h and had data of suitable quality for analysis. The median tidal volume (VT) values were 7.48mL/kg PBW (CCHIC) and 7.91mL/kg PBW (eICU-CRD). The patients at highest risk of not receiving LTVV were shorter than 160cm (CCHIC) and 165cm (eICU-CRD). Those with BMI > 30kg/m2 (CCHIC OR, 1.9 [95%CI, 1.7-2.13]; eICU-CRD OR, 1.61 [95%CI, 1.49-1.75]) and female patients (CCHIC OR, 2.39 [95%CI, 2.16-2.65]; eICU-CRD OR, 2.29 [95%CI, 2.26-2.31]) were at increased risk of having median VT > 8mL/kg PBW. Patients with median VT< 8mL/kg PBW had decreased 30-day mortality in the CCHIC database (CCHIC cause-specific hazard ratio, 0.86 [95%CI, 0.76-0.97]; eICU-CRD cause-specific hazard ratio, 0.9 [95%CI, 0.86-1.00]). There was a significant reduction in VT over time in the CCHIC database. There has been limited implementation of LTVV in routine clinical practice in the United Kingdom and the United States. VT > 8mL/kg PBW was associated with worse patient outcomes.

Systemic cytokines inhibition with Imp7 siRNA nanoparticle ameliorates gut injury in a mouse model of ventilator-induced lung injury

Mechanical ventilation (MV) may negatively affect the lungs and cause the release of inflammatory mediators, resulting in extra-pulmonary organ dysfunction. Studies have revealed systemically elevated levels of proinflammatory cytokines in animal models of ventilator-induced lung injury (VILI); however, whether these cytokines have an effect on gut injury and the mechanisms involved remain unknown. In this study, VILI was generated in mice with high tidal volume mechanical ventilation (20 ml/kg). Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 concentrations in serum and gut measured by ELISA showed significant elevation in the VILI mice. Significant increases in gut injury and PANoptosis were observed in the VILI mice, which were positively correlated with the serum levels of TNF-α, IL-1β, and IL-6. The VILI mice displayed intestinal barrier defects, decreased expressions of occludin and zonula occludin-1 (ZO-1), and increased expression of claudin-2 and the activation of myosin light chain (MLC). Importantly, intratracheal administration of Imp7 siRNA nanoparticle effectively inhibited cytokines production and protected mice from VILI-induced gut injury. These data provide evidence of systemic cytokines contributing to gut injury following VILI and highlight the possibility of targeting cytokines inhibition via Imp7 siRNA nanoparticle as a potential therapeutic intervention for alleviating gut injury following VILI.

Effect of ventilator-induced lung injury on blood-brain barrier permeability in rats

To observe the effect of ventilator-induced lung injury (VILI) on blood-brain barrier permeability in rats. Forty-eight healthy clean male Sprague-Dawley (SD) rats were randomly divided into sham operation (Sham) group, low tidal volume (LVT) mechanical ventilation group (LVT group), normal tidal volume (NVT) mechanical ventilation group (NVT group) and high tidal volume (HVT) mechanical ventilation group (HVT group) with 12 rats in each group. After anesthesia, rats in the Sham group were intubated and kept spontaneous breathing. The rats in different tidal volume (VT) groups were mechanically ventilated by endotracheal intubation with VT of 6 mL/kg (LVT group), 10 mL/kg (NVT group), and 20 mL/kg (HVT group), respectively. The inspiration-expiration ratio of the three groups was 1:1, the ventilation frequency was 40 times/min, and the ventilation time was 3 hours. At the end of the experiment, the bronchoalveolar lavage fluid (BALF) of rats was collected, and the levels of pro-inflammatory factors [tumor necrosis factor-α (TNF-α), interleukins (IL-1β and IL-6)] in BALF were detected by enzyme-linked immunosorbent assay (ELISA). The lung tissues of rats were collected, and the lung wet/dry weight (W/D) ratio was calculated. The pathological changes of lung tissues were observed under light microscopy after hematoxylin-eosin (HE) staining, and lung injury scores were performed. The brain tissue of rats was taken to measure the brain water content, and the Evans blue (EB) content of brain tissue was measured to reflect the permeability of the blood-brain barrier. The tight junction proteins in the brain tissues were detected by Western blotting. After 3 hours of mechanical ventilation, with the increase of VT, the degree of lung injury in VILI rats gradually increased. When VT reached 20 mL/kg, lung tissue structure was significantly injured, alveolar wall edema, alveolar congestion, lung interstitial thickening, a large number of inflammatory cells infiltrated, and the lung injury score, lung W/D ratio, and the levels of TNF-α, IL-1β and IL-6 in BALF were significantly higher than those in the Sham group [lung injury score: 10.6±1.1 vs. 1.4±1.0, lung W/D ratio: 6.6±0.8 vs. 3.7±0.6, TNF-α (ng/L): 832.9±97.9 vs. 103.8±23.3, IL-1β (ng/L): 68.9±14.1 vs. 15.7±2.6, IL-6 (ng/L): 70.8±16.4 vs. 20.3±5.4, all P < 0.05]. Lung injury in rats was accompanied by aggravating brain injury. When VT reached 20 mL/kg, brain water content and EB content in brain tissue were significantly higher than those in the Sham group [brain water content: (85.4±3.6)% vs. (68.7±2.7)%, EB content in brain tissue (μg/g): 887±78 vs. 97±14, both P < 0.05], and the protein expressions of claudin-5, occluding and zonula occluden-1 (ZO-1) in the brain tissue were significantly lower than those in the Sham group [claudin-5 protein (claudin-5/β-actin): 0.67±0.12 vs. 1.45±0.19, occludin protein (occludin/β-actin): 0.48±0.11 vs. 0.99±0.21, ZO-1 protein (ZO-1/β-actin): 0.13±0.03 vs. 0.63±0.12, all P < 0.05]. VILI can induce brain edema and increase blood-brain barrier permeability in rats, which may be related to the down-regulation of tight junction protein expression in the brain tissue.

Prone positioning reduces frontal and hippocampal neuronal dysfunction in a murine model of ventilator-induced lung injury.

Prone positioning is an established treatment for severe acute lung injury conditions. Neuronal dysfunction frequently occurs with mechanical ventilation-induced acute lung injury (VILI) and clinically manifests as delirium. We previously reported a pathological role for systemic interleukin 6 (IL-6) in mediating neuronal injury. However, currently no studies have investigated the relationship between prone or supine positioning and IL-6 mediated neuronal dysfunction. Here, we hypothesize that prone positioning mitigates neuronal injury, via decreased IL-6, in a model of VILI. VILI was induced by subjecting C57BL/6J mice to high tidal volume (35 cc/kg) mechanical ventilation. Neuronal injury markers [cleaved caspase-3 (CC3), c-fos, heat shock protein 90 (Hsp90)] and inflammatory cytokines (IL-6, IL-1β, TNF-α) were measured in the frontal cortex and hippocampus. We found statistically significantly less neuronal injury (CC3, c-Fos, Hsp90) and inflammatory cytokines (IL-6, IL-1β, TNF-α) in the frontal cortex and hippocampus with prone compared to supine positioning (p < 0.001) despite no significant group differences in oxygen saturation or inflammatory infiltrates in the bronchoalveolar fluid (p > 0.05). Although there were no group differences in plasma IL-6 concentrations, there was significantly less cortical and hippocampal IL-6 in the prone position (p < 0.0001), indicating supine positioning may enhance brain susceptibility to systemic IL-6 during VILI via the IL-6 trans-signaling pathway. These findings call for future clinical studies to assess the relationship between prone positioning and delirium and for investigations into novel diagnostic or therapeutic paradigms to mitigate delirium by reducing expression of systemic and cerebral IL-6.

ARDS IN THE SETTING OF SEROTONIN SYNDROME

ARDS IN THE SETTING OF SEROTONIN SYNDROME

Protective ventilation in a pig model of acute lung injury: timing is as important as pressure.

Ventilator-induced lung injury (VILI) is a significant risk for patients with acute respiratory distress syndrome (ARDS). Management of the patient with ARDS is currently dominated by the use of low tidal volume mechanical ventilation, the presumption being that this mitigates overdistension (OD) injury to the remaining normal lung tissue. Evidence exists, however, that it may be more important to avoid cyclic recruitment and derecruitment (RD) of lung units, although the relative roles of OD and RD in VILI remain unclear. Forty pigs had a heterogeneous lung injury induced by Tween instillation and were randomized into four groups (n = 10 each) with higher (↑) or lower (↓) levels of OD and/or RD imposed using airway pressure release ventilation (APRV). OD was increased by setting inspiratory airway pressure to 40 cmH2O and lessened with 28 cmH2O. RD was attenuated using a short duration of expiration (∼0.45 s) and increased with a longer duration (∼1.0 s). All groups developed mild ARDS following injury. RD ↑ OD↑ caused the greatest degree of lung injury as determined by [Formula: see text]/[Formula: see text] ratio (226.1 ± 41.4 mmHg). RD ↑ OD↓ ([Formula: see text]/[Formula: see text]= 333.9 ± 33.1 mmHg) and RD ↓ OD↑ ([Formula: see text]/[Formula: see text] = 377.4 ± 43.2 mmHg) were both moderately injurious, whereas RD ↓ OD↓ ([Formula: see text]/[Formula: see text] = 472.3 ± 22.2 mmHg; P < 0.05) was least injurious. Both tidal volume and driving pressure were essentially identical in the RD ↑ OD↓ and RD ↓ OD↑ groups. We, therefore, conclude that considerations of expiratory time may be at least as important as pressure for safely ventilating the injured lung.NEW & NOTEWORTHY In a large animal model of ARDS, recruitment/derecruitment caused greater VILI than overdistension, whereas both mechanisms together caused severe lung damage. These findings suggest that eliminating cyclic recruitment and derecruitment during mechanical ventilation should be a preeminent management goal for the patient with ARDS. The airway pressure release ventilation (APRV) mode of mechanical ventilation can achieve this if delivered with an expiratory duration (TLow) that is brief enough to prevent derecruitment at end expiration.

Systemic interleukin-6 inhibition ameliorates acute neuropsychiatric phenotypes in a murine model of acute lung injury

Acute neuropsychiatric impairments occur in over 70% of patients with acute lung injury. Mechanical ventilation is a well-known precipitant of acute lung injury and is strongly associated with the development of acute delirium and anxiety phenotypes. In prior studies, we demonstrated that IL-6 mediates neuropathological changes in the frontal cortex and hippocampus of animals with mechanical ventilation-induced brain injury; however, the effect of systemic IL-6 inhibition on structural and functional acute neuropsychiatric phenotypes is not known. We hypothesized that a murine model of mechanical ventilation-induced acute lung injury (VILI) would induce neural injury to the amygdala and hippocampus, brain regions that are implicated in diverse neuropsychiatric conditions, and corresponding delirium- and anxiety-like functional impairments. Furthermore, we hypothesized that these structural and functional changes would reverse with systemic IL-6 inhibition. VILI was induced using high tidal volume (35 cc/kg) mechanical ventilation. Cleaved caspase-3 (CC3) expression was quantified as a neural injury marker and found to be significantly increased in the VILI group compared to spontaneously breathing or anesthetized and mechanically ventilated mice with 10 cc/kg tidal volume. VILI mice treated with systemic IL-6 inhibition had significantly reduced amygdalar and hippocampal CC3 expression compared to saline-treated animals and demonstrated amelioration in acute neuropsychiatric behaviors in open field, elevated plus maze, and Y-maze tests. Overall, these data provide evidence of a pathogenic role of systemic IL-6 in mediating structural and functional acute neuropsychiatric symptoms in VILI and provide preclinical justification to assess IL-6 inhibition as a potential intervention to ameliorate acute neuropsychiatric phenotypes following VILI.

Abstract P2102: EB3 Inhibitor VT-109 Activated FOXM1 Pathways To Promote Resolution Of Acute Lung Injury

Acute respiratory distress syndrome (ARDS) is the acute onset of non-cardiogenic pulmonary edema, hypoxemia, and respiratory failure, conditions associated with a high mortality rate. ARDS is frequently caused by lung infections including SARS-CoV-2. In light of the COVID-19 pandemic, development of therapeutic approaches to combat ARDS have become an urgent unmet medical need. As increased vascular leakage is a culprit of alveolar damage and lung inflammation, we hypothesize that an effective therapy against vascular leakage should improve the clinical outcome of ARDS patients. We have identified a drug candidate Vascular Therapeutics (VT)-109, an allosteric inhibitor of End Binding protein 3, which contributes to vascular leakage by amplifying pathological calcium signaling in endothelial cells. Treatment of mice with VT-109 reduced the leakage of proteinous fluids in lungs to 55.4% (n=7, p&lt;0.05) after endotoxin challenge, 77.7% (n=6, p&lt;0.01) after exposure to high volume mechanical ventilation, and 42.5% (n=7, p&lt;0.05) in the two-hit model, a combination of polymicrobial sepsis with normal tidal volume mechanical ventilation. VT-109 reduced the mortality of both septic (n=10, p&lt;0.01) and endotoxin-challenged (n=10, p&lt;0.05) mice. Furthermore, treatment with VT-109 in mice expressing human ACE2 receptor blocked diffuse alveolar damage (n=5, p&lt;0.0001) caused by SARS-CoV-2 infection. In this COVID-19 model, the therapeutic benefits of VT-109 were observed when treatment was initiated at either day 1 or day 3 post-viral infection. Transcriptome analysis of lung endothelial cells in mice challenged with endotoxin showed that VT-109 upregulated 23 FOXM1 target genes (&gt;2-fold) suggesting that it promotes endothelial cell regeneration by activating the FOXM1 pathway. Our data demonstrate that VT-109 successfully treats vascular leakage and is a promising drug candidate for future clinical studies. Funding for this work is provided by the Congressionally Directed Medical Research Programs through the Peer Reviewed Medical Research Program (PRMRP) under award No. W81XWH-21-1-0639. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Mechanosensitive cation channel Piezo1 contributes to ventilator-induced lung injury by activating RhoA/ROCK1 in rats

BackgroundMechanical ventilation can induce or aggravate lung injury, which is termed ventilator-induced lung injury (VILI). Piezo1 is a key element of the mechanotransduction process and can transduce mechanical signals into biological signals by mediating Ca2+ influx, which in turn regulates cytoskeletal remodeling and stress alterations. We hypothesized that it plays an important role in the occurrence of VILI, and investigated the underlying mechanisms.MethodsHigh tidal volume mechanical ventilation and high magnitude cyclic stretch were performed on Sprague–Dawley rats, and A549 and human pulmonary microvascular endothelial cells, respectively, to establish VILI models. Immunohistochemical staining, flow cytometry, histological examination, enzyme-linked immunosorbent assay, western blotting, quantitative real-time polymerase chain reaction and survival curves were used to assess the effect of Piezo1 on induction of lung injury, as well as the signaling pathways involved.ResultsWe observed that Piezo1 expression increased in the lungs after high tidal volume mechanical ventilation and in cyclic stretch-treated cells. Mechanistically, we observed the enhanced expression of RhoA/ROCK1 in both cyclic stretch and Yoda1-treated cells, while the deficiency or inhibition of Piezo1 dramatically antagonized RhoA/ROCK1 expression. Furthermore, blockade of RhoA/ROCK1 signaling using an inhibitor did not affect Piezo1 expression. GSMTx4 was used to inhibit Piezo1, which alleviated VILI-induced pathologic changes, water content and protein leakage in the lungs, and the induction of systemic inflammatory mediators, and improved the 7-day mortality rate in the model rats.ConclusionsThese findings indicate that Piezo1 affects the development and progression of VILI through promotion of RhoA/ROCK1 signaling.

Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure

In patients who require mechanical ventilation for acute hypoxemic respiratory failure, further reduction in tidal volumes, compared with conventional low tidal volume ventilation, may improve outcomes. To determine whether lower tidal volume mechanical ventilation using extracorporeal carbon dioxide removal improves outcomes in patients with acute hypoxemic respiratory failure. This multicenter, randomized, allocation-concealed, open-label, pragmatic clinical trial enrolled 412 adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, of a planned sample size of 1120, between May 2016 and December 2019 from 51 intensive care units in the UK. Follow-up ended on March 11, 2020. Participants were randomized to receive lower tidal volume ventilation facilitated by extracorporeal carbon dioxide removal for at least 48 hours (n = 202) or standard care with conventional low tidal volume ventilation (n = 210). The primary outcome was all-cause mortality 90 days after randomization. Prespecified secondary outcomes included ventilator-free days at day 28 and adverse event rates. Among 412 patients who were randomized (mean age, 59 years; 143 [35%] women), 405 (98%) completed the trial. The trial was stopped early because of futility and feasibility following recommendations from the data monitoring and ethics committee. The 90-day mortality rate was 41.5% in the lower tidal volume ventilation with extracorporeal carbon dioxide removal group vs 39.5% in the standard care group (risk ratio, 1.05 [95% CI, 0.83-1.33]; difference, 2.0% [95% CI, -7.6% to 11.5%]; P = .68). There were significantly fewer mean ventilator-free days in the extracorporeal carbon dioxide removal group compared with the standard care group (7.1 [95% CI, 5.9-8.3] vs 9.2 [95% CI, 7.9-10.4] days; mean difference, -2.1 [95% CI, -3.8 to -0.3]; P = .02). Serious adverse events were reported for 62 patients (31%) in the extracorporeal carbon dioxide removal group and 18 (9%) in the standard care group, including intracranial hemorrhage in 9 patients (4.5%) vs 0 (0%) and bleeding at other sites in 6 (3.0%) vs 1 (0.5%) in the extracorporeal carbon dioxide removal group vs the control group. Overall, 21 patients experienced 22 serious adverse events related to the study device. Among patients with acute hypoxemic respiratory failure, the use of extracorporeal carbon dioxide removal to facilitate lower tidal volume mechanical ventilation, compared with conventional low tidal volume mechanical ventilation, did not significantly reduce 90-day mortality. However, due to early termination, the study may have been underpowered to detect a clinically important difference. ClinicalTrials.gov Identifier: NCT02654327.

Effects of the Prone Position on Regional Neutrophilic Lung Inflammation According to 18F-FDG Pet in an Experimental Ventilator-Induced Lung Injury Model.

Ventilator-induced lung injury (VILI) can be life-threatening and it is important to prevent the development of VILI. It remains unclear whether the prone position affects neutrophilic inflammation in the lung regions in vivo, which plays a crucial role in the pathogenesis of VILI. This study aimed to assess the relationship between the use of the prone position and the development of VILI-associated regional neutrophilic lung inflammation. Regional neutrophilic lung inflammation and lung aeration during low tidal volume mechanical ventilation were assessed using in vivo 2-deoxy-2-[(18)F] fluoro-D-glucose (18F-FDG) positron emission tomography and computed tomography in acutely experimentally injured rabbit lungs (lung injury induced by lung lavage and excessive ventilation). Direct comparisons were made among three groups: control, supine, and prone positions. After approximately 7 h, tissue-normalized 18F-FDG uptake differed significantly between the supine and prone positions (SUP: 0.038 ± 0.014 vs. PP: 0.029 ± 0.008, P = 0.038), especially in the ventral region (SUP: 0.052 ± 0.013 vs. PP: 0.026 ± 0.007, P = 0.003). The use of the prone position reduced lung inhomogeneities, which was demonstrated by the correction of the disproportionate rate of voxel gas over the given lung region. The progression of neutrophilic inflammation was affected by the interaction between the total strain (for aeration) and the inhomogeneity. The prone position is effective in slowing down the progression of VILI-associated neutrophilic inflammation. Under low-tidal-volume ventilation, the main drivers of its effect may be homogenization of lung tissue and that of mechanical forces.

IL-6 Inhibition Reduces Neuronal Injury in a Murine Model of Ventilator-induced Lung Injury.

Mechanical ventilation is a known risk factor for delirium, a cognitive impairment characterized by dysfunction of the frontal cortex and hippocampus. Although IL-6 is upregulated in mechanical ventilation-induced lung injury (VILI) and may contribute to delirium, it is not known whether the inhibition of systemic IL-6 mitigates delirium-relevant neuropathology. To histologically define neuropathological effects of IL-6 inhibition in an experimental VILI model, VILI was simulated in anesthetized adult mice using a 35 cc/kg tidal volume mechanical ventilation model. There were two control groups, as follow: 1) spontaneously breathing or 2) anesthetized and mechanically ventilated with 10 cc/kg tidal volume to distinguish effects of anesthesia from VILI. Two hours before inducing VILI, mice were treated with either anti-IL-6 antibody, anti-IL-6 receptor antibody, or saline. Neuronal injury, stress, and inflammation were assessed using immunohistochemistry. CC3 (cleaved caspase-3), a neuronal apoptosis marker, was significantly increased in the frontal (P < 0.001) and hippocampal (P < 0.0001) brain regions and accompanied by significant increases in c-Fos and heat shock protein-90 in the frontal cortices of VILI mice compared with control mice (P < 0.001). These findings were not related to cerebral hypoxia, and there was no evidence of irreversible neuronal death. Frontal and hippocampal neuronal CC3 were significantly reduced with anti-IL-6 antibody (P < 0.01 and P < 0.0001, respectively) and anti-IL-6 receptor antibody (P < 0.05 and P < 0.0001, respectively) compared with saline VILI mice. In summary, VILI induces potentially reversible neuronal injury and inflammation in the frontal cortex and hippocampus, which is mitigated with systemic IL-6 inhibition. These data suggest a potentially novel neuroprotective role of systemic IL-6 inhibition that justifies further investigation.

Multivariate Meta-Analysis of the Mortality Effect of Prone Positioning in the Acute Respiratory Distress Syndrome.

The efficacy of prone positioning (PP) as therapy of the acute respiratory distress syndrome (ARDS) has varied in recent meta-analyses. The efficacy question was reviewed using a cohesive multivariate meta-analysis model incorporating all available common time-point data. Data from a core group of 8 randomized controlled trials (2001-2013) utilized in 8 current meta-analyses (2014-2017) was extracted for common time points. Multivariate meta-analysis and meta-regression models for prone-hours per day, mechanical ventilation tidal-volume and baseline patient PaO2/FiO2, considered as continuous and categorical predictors, determined the pooled relative risk (RR) of mortality for prone versus supine positioning. Mortality RR at 28-30 days, 2-3 months and 6-months was not significant overall (P > 0.05). Meta-regression of categorical predictors indicated significant mortality reduction (P ≤ 0.001) for ≥ 12 prone-hours (versus < 12), lung protective ventilation (versus none) and moderate-severe ARDS (versus all ARDS). Meta-regressions of continuous predictors were also significant (P ≤ 0.021) and yielded treatment inflection points of efficacious therapy for ≥ 12 prone-hours per day, ≤ 8.5 mL/kg tidal volume and ≤ PaO2/FiO2 ratio of 130. The mortality treatment effect of PP in ARDS, was not demonstrated in the unadjusted meta-analysis model. Moderator effects indicated consistent significant benefit of prone positioning. In the absence of individual patient data, multivariate models provide more decisive conclusions than individual time point analyses.

Comprehensive lung protection during circulatory arrest in aortic arch surgery

Aim. The aim of the study was to analyze the effectiveness of comprehensive lung protection in patients who underwent thoracic aortic surgery using circulatory arrest. Material and Methods. A total of 57 patients undergoing operations for aneurysms and thoracic aortic dissection were enrolled in the prospective study. The patients were divided into two groups. The experimental group of patients ( n = 27) underwent comprehensive lung protection with pulmonary artery perfusion and mechanical ventilation. Patients in the control group ( n = 30) did not undergo comprehensive lung protection measures. Results. The median duration of mechanical ventilation in the postoperative period was 14 hours in the experimental group and 23 hours in the control group of patients ( p < 0.001). The incidence of analyzed pulmonary complications did not significantly differ between the groups during the early postoperative period. The number of pneumonia cases was 8 (14%) including 4 (15%) cases in the experimental group and 4 (13%) episodes in the control group ( p = 0.87). Conclusion. Selective pulmonary artery perfusion in combination with low tidal volume mechanical ventilation during operations on the thoracic aorta using circulatory arrest significantly reduced the duration of postoperative mechanical ventilation.

A role for bronchial epithelial autotaxin in ventilator-induced lung injury

BackgroundThe pathophysiology of acute respiratory distress syndrome (ARDS) may eventually result in heterogeneous lung collapse and edema-flooded airways, predisposing the lung to progressive tissue damage known as ventilator-induced lung injury (VILI). Autotaxin (ATX; ENPP2), the enzyme largely responsible for extracellular lysophosphatidic acid (LPA) production, has been suggested to play a pathogenic role in, among others, pulmonary inflammation and fibrosis.MethodsC57BL/6 mice were subjected to low and high tidal volume mechanical ventilation using a small animal ventilator: respiratory mechanics were evaluated, and plasma and bronchoalveolar lavage fluid (BALF) samples were obtained. Total protein concentration was determined, and lung histopathology was further performedResultsInjurious ventilation resulted in increased BALF levels of ATX. Genetic deletion of ATX from bronchial epithelial cells attenuated VILI-induced pulmonary edema.ConclusionATX participates in VILI pathogenesis.

A Study of Inflammatory Response and Lung Injury Induced by Variable Tidal Volumes in Mechanically Ventilated Children

Background We aimed to compare the effects of high tidal volume (Vt) versus low Vt mechanical ventilation (MV) on systemic interleukin-8 (IL-8), and tumor necrosis factor alpha (TNF- α) cytokines production and induction of lung injury in mechanically ventilated children. Materials and Methods: Thisprospectiveobservational study was performed on 60 critically ill mechanically ventilated children from 2018 to 2019, at PICU of South Valley University and Minia University hospitals, Qena and Minia cities, Egypt. After application of the inclusion and exclusion criteria, we compared MV with high Vt of 9-11 ml (group I) versus low Vt of 5-7ml (group II) per kilogram of predicted body weight in critically ill children. Plasma levels of IL8 and TNF- α cytokines were estimated at the onset of MV and after 24 hours in both groups. Lung injury development was evidenced by change in oxygenation parameters. Results: Sixty patients on MV (30 with high Vt versus 30 with lower Vt) were enrolled in the study. Plasma levels of interleukin-8 and TNF- α were increased in both groups 24 hours after initiation of MV, but this rise was significantly higher in high Vt group (p <0.05). There were significant positive correlations between tidal volume and oxygenation index (p-value <0.05, r=0.32), and with plasma IL-8 (r=0.34, p= 0.01), while negative correlation between tidal volume and change in PaO2/fiO2 ratio after 24 hours MV (r= -0.34, p <0.05). Conclusion Mechanical ventilation with high Vt was associated with increased IL-8, and TNF- α cytokines production, and will induce lung injury as evidenced by acute hypoxemia and deterioration in oxygenation parameters (PaO2/FiO2 ratio less than 300 mmHg).

Preliminary experimental study on the influence of different tidal volume and frequency of normal minute ventilation on the dynamic changes of carotid blood oxygen in living goats

Objective: On the basis of preliminarily verifying the use of ultra-fast reaction polymer matrix optical fiber oxygen sensor and its measuring system to record the continuous and dynamic changes of carotid artery oxygen partial pressure (PaO2), in order to analyze and discuss the influence of lung ventilation on the continuous and dynamic changes of PaO2, we designed a whole animal experimental study in vivo. Methods: Four hybrid goats were selected, and the skin was cut and exposed directly under general anesthesia and tracheal intubation. The oxygen sensor, connected with the measuring system, was inserted directly into the left carotid artery to continuously record the dynamic changes of PaO2. With normal minute ventilation,mechanical ventilation is implemented through three tidal volumes: normal tidal volume (VT=15 ml/kg, Rf=20 bpm), half tidal volume (halved VT, doubled Rf) and double tidal volume (doubled VT, halved Rf). Each tidal volume was stable for 10~15 min respectively. We analyzed and calculated the average values of PaO2, the fluctuation magnitudes of PaO2 changes between breaths of last 180 s and the delay times of lung-carotid artery were. We analyzed the effects of different tidal volumes. Results: The heart rate and blood pressure of living goats were maintained stable during the mechanical ventilation experiment with normal ventilation volume Lung-carotid artery delay time is 1.4~1.8 s (about 3 heartbeats at this time). Under normal tidal volume of mechanical ventilation, the average value of PaO2 was (102.94±2.40, 99.38~106.16) mmHg, and the fluctuation range was (21.43±1.65, 19.21~23.59) mmHg, accounting for (20.80± 1.34, 18.65~22.22)% of the average value. Under the condition of halving tidal volume, the average value of PaO2 was maintained at (101.01±4.25, 94.09~105.66) mmHg, which was slightly decreased but not significant (P>0.05 compared with normal mechanical ventilation), but the fluctuation range of PaO2 was significantly reduced to (18.14±1.43, 16.46~20.05) mmHg, accounting for 17.5% of the average value. Under double tidal volume mechanical ventilation, although the average value of PaO2 increased slightly remained at (106.42±4.74, 101.19~114.08) mmHg (P>0.05 compared with normal mechanical ventilation and P<0.05 compared with half tidal volume mechanical ventilation), the fluctuation magnitude of PaO2 increased significantly to (26.58±1.88, 23.46~28.46)mmHg. Conclusion: Inspiration and expiration of normal lung ventilation are the initial factors for the increase and decrease of PaO2 in carotid artery. Under normal ventilation, halving tidal volume and doubling tidal volume significantly changed the fluctuation magnitude of PaO2, but the average value of PaO2 changed only slightly, while the lung-carotid delay time was similar.