Search

Abstract Background Vascular 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. Methods VILI 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. Results Serum 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. Conclusion VILI 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.

Background: Vascular 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. Methods: VILI 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. Results: Serum 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. Conclusion: VILI 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. [ABSTRACT FROM AUTHOR]

Abstract Mechanical ventilation is a life-saving therapy in several clinical situations, promoting gas exchange and providing rest to the respiratory muscles. However, mechanical ventilation may cause hemodynamic instability and pulmonary structural damage, which is known as ventilator-induced lung injury (VILI). The four main injury mechanisms associated with VILI are as follows: barotrauma/volutrauma caused by overstretching the lung tissues; atelectrauma, caused by repeated opening and closing of the alveoli resulting in shear stress; and biotrauma, the resulting biological response to tissue damage, which leads to lung and multi-organ failure. This narrative review elucidates the mechanisms underlying the pathogenesis, progression, and resolution of VILI and discusses the strategies that can mitigate VILI. Different static variables (peak, plateau, and driving pressures, positive end-expiratory pressure, and tidal volume) and dynamic variables (respiratory rate, airflow amplitude, and inspiratory time fraction) can contribute to VILI. Moreover, the potential for lung injury depends on tissue vulnerability, mechanical power (energy applied per unit of time), and the duration of that exposure. According to the current evidence based on models of acute respiratory distress syndrome and VILI, the following strategies are proposed to provide lung protection: keep the lungs partially collapsed (SaO2 > 88%), avoid opening and closing of collapsed alveoli, and gently ventilate aerated regions while keeping collapsed and consolidated areas at rest. Additional mechanisms, such as subject-ventilator asynchrony, cumulative power, and intensity, as well as the damaging threshold (stress–strain level at which tidal damage is initiated), are under experimental investigation and may enhance the understanding of VILI.

Mechanical ventilation is a life-saving therapy in several clinical situations, promoting gas exchange and providing rest to the respiratory muscles. However, mechanical ventilation may cause hemodynamic instability and pulmonary structural damage, which is known as ventilator-induced lung injury (VILI). The four main injury mechanisms associated with VILI are as follows: barotrauma/volutrauma caused by overstretching the lung tissues; atelectrauma, caused by repeated opening and closing of the alveoli resulting in shear stress; and biotrauma, the resulting biological response to tissue damage, which leads to lung and multi-organ failure. This narrative review elucidates the mechanisms underlying the pathogenesis, progression, and resolution of VILI and discusses the strategies that can mitigate VILI. Different static variables (peak, plateau, and driving pressures, positive end-expiratory pressure, and tidal volume) and dynamic variables (respiratory rate, airflow amplitude, and inspiratory time fraction) can contribute to VILI. Moreover, the potential for lung injury depends on tissue vulnerability, mechanical power (energy applied per unit of time), and the duration of that exposure. According to the current evidence based on models of acute respiratory distress syndrome and VILI, the following strategies are proposed to provide lung protection: keep the lungs partially collapsed (SaO2 > 88%), avoid opening and closing of collapsed alveoli, and gently ventilate aerated regions while keeping collapsed and consolidated areas at rest. Additional mechanisms, such as subject-ventilator asynchrony, cumulative power, and intensity, as well as the damaging threshold (stress–strain level at which tidal damage is initiated), are under experimental investigation and may enhance the understanding of VILI. [ABSTRACT FROM AUTHOR]

Considering the increasing prevalence of obesity among the critically ill patient, mechanical ventilation of this type of patients has almost become a daily practice. However, no consensus regarding mechanical ventilation for obese patients has recently been published. Considering the particular pathophysiological features of respiratory system in obese patients, the risk of ventilator induced lung injury (VILI) is highly elevated. This narrative review aims to present the constrains related to mechanical ventilation in obese patients, as well as the features that predispose them to VILI. Moreover, the effects every determinant incriminated in VILI were described with application on the pathophysiological features of obese patients. Increased emphasis was placed on the newly concept of ergotrauma as one of the main determinants of VILI. This is one of the first reviews dedicated to the effects of mechanical power and ergotrauma on mechanically ventilated patients with obesity. Moreover, increased attention was given to the impact of biotrauma related to VILI, considering that the new concept of "pre-conditioning cloud" related to obesity has recently emerged. [ABSTRACT FROM AUTHOR]

Abstract Background Ultra-lung-protective ventilation may be useful during veno-venous extracorporeal membrane oxygenation (vv-ECMO) for severe acute respiratory distress syndrome (ARDS) to minimize ventilator-induced lung injury and to facilitate lung recovery. The objective was to compare pulmonary and systemic biotrauma evaluated by numerous biomarkers of inflammation, epithelial, endothelial injuries, and lung repair according to two ventilator strategies on vv-ECMO. Methods This is a prospective randomized controlled study. Patients were randomized to receive during 48 h either ultra-lung-protective ventilation combining very low tidal volume (1–2 mL/kg of predicted body weight), low respiratory rate (5–10 cycles per minute), positive expiratory transpulmonary pressure, and 16 h of prone position or lung-protective-ventilation which followed the ECMO arm of the EOLIA trial (control group). Results The primary outcome was the alveolar concentrations of interleukin-1-beta, interleukin-6, interleukin-8, surfactant protein D, and blood concentrations of serum advanced glycation end products and angiopoietin-2 48 h after randomization. Enrollment was stopped for futility after the inclusion of 39 patients. Tidal volume, respiratory rate, minute ventilation, plateau pressure, and mechanical power were significantly lower in the ultra-lung-protective group. None of the concentrations of the pre-specified biomarkers differed between the two groups 48 h after randomization. However, a trend to higher 60-day mortality was observed in the ultra-lung-protective group compared to the control group (45 vs 17%, p = 0.06). Conclusions Despite a significant reduction in the mechanical power, ultra-lung-protective ventilation during 48 h did not reduce biotrauma in patients with vv-ECMO-supported ARDS. The impact of this ventilation strategy on clinical outcomes warrants further investigation. Trial registration Clinical trial registered with www.clinicaltrials.gov ( NCT03918603 ). Registered 17 April 2019.

Background: Ultra-lung-protective ventilation may be useful during veno-venous extracorporeal membrane oxygenation (vv-ECMO) for severe acute respiratory distress syndrome (ARDS) to minimize ventilator-induced lung injury and to facilitate lung recovery. The objective was to compare pulmonary and systemic biotrauma evaluated by numerous biomarkers of inflammation, epithelial, endothelial injuries, and lung repair according to two ventilator strategies on vv-ECMO. Methods: This is a prospective randomized controlled study. Patients were randomized to receive during 48 h either ultra-lung-protective ventilation combining very low tidal volume (1–2 mL/kg of predicted body weight), low respiratory rate (5–10 cycles per minute), positive expiratory transpulmonary pressure, and 16 h of prone position or lung-protective-ventilation which followed the ECMO arm of the EOLIA trial (control group). Results: The primary outcome was the alveolar concentrations of interleukin-1-beta, interleukin-6, interleukin-8, surfactant protein D, and blood concentrations of serum advanced glycation end products and angiopoietin-2 48 h after randomization. Enrollment was stopped for futility after the inclusion of 39 patients. Tidal volume, respiratory rate, minute ventilation, plateau pressure, and mechanical power were significantly lower in the ultra-lung-protective group. None of the concentrations of the pre-specified biomarkers differed between the two groups 48 h after randomization. However, a trend to higher 60-day mortality was observed in the ultra-lung-protective group compared to the control group (45 vs 17%, p = 0.06). Conclusions: Despite a significant reduction in the mechanical power, ultra-lung-protective ventilation during 48 h did not reduce biotrauma in patients with vv-ECMO-supported ARDS. The impact of this ventilation strategy on clinical outcomes warrants further investigation. Trial registration Clinical trial registered with www.clinicaltrials.gov (NCT03918603). Registered 17 April 2019. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a major concern in critical care medicine with a high mortality of over 30%. Injury to the lungs is caused not only by underlying pathological conditions such as pneumonia, sepsis, or trauma, but also by ventilator-induced lung injury (VILI) resulting from high positive pressure levels and a high inspiratory oxygen fraction. Apart from mechanical factors that stress the lungs with a specific physical power and cause volutrauma and barotrauma, it is increasingly recognized that lung injury is further aggravated by biological mediators. The COVID-19 pandemic has led to increased interest in the role of the renin-angiotensin system (RAS) in the context of ARDS, as the RAS enzyme angiotensin-converting enzyme 2 serves as the primary cell entry receptor for severe acute respiratory syndrome (SARS) coronavirus (CoV)-2. Even before this pandemic, studies have documented the involvement of the RAS in VILI and its dysregulation in clinical ARDS. In recent years, analytical tools for RAS investigation have made major advances based on the optimized precision and detail of mass spectrometry. Given that many clinical trials with pharmacological interventions in ARDS were negative, RAS-modifying drugs may represent an interesting starting point for novel therapeutic approaches. Results from animal models have highlighted the potential of RAS-modifying drugs to prevent VILI or treat ARDS. While these drugs have beneficial pulmonary effects, the best targets and application forms for intervention still have to be determined to avoid negative effects on the circulation in clinical settings. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a major concern in critical care medicine with a high mortality of over 30%. Injury to the lungs is caused not only by underlying pathological conditions such as pneumonia, sepsis, or trauma, but also by ventilator-induced lung injury (VILI) resulting from high positive pressure levels and a high inspiratory oxygen fraction. Apart from mechanical factors that stress the lungs with a specific physical power and cause volutrauma and barotrauma, it is increasingly recognized that lung injury is further aggravated by biological mediators. The COVID-19 pandemic has led to increased interest in the role of the renin-angiotensin system (RAS) in the context of ARDS, as the RAS enzyme angiotensin-converting enzyme 2 serves as the primary cell entry receptor for severe acute respiratory syndrome (SARS) coronavirus (CoV)-2. Even before this pandemic, studies have documented the involvement of the RAS in VILI and its dysregulation in clinical ARDS. In recent years, analytical tools for RAS investigation have made major advances based on the optimized precision and detail of mass spectrometry. Given that many clinical trials with pharmacological interventions in ARDS were negative, RAS-modifying drugs may represent an interesting starting point for novel therapeutic approaches. Results from animal models have highlighted the potential of RAS-modifying drugs to prevent VILI or treat ARDS. While these drugs have beneficial pulmonary effects, the best targets and application forms for intervention still have to be determined to avoid negative effects on the circulation in clinical settings.

• We review the latest findings with regard to the effects of DAMP/PRRs and their blockade in the context of VILI. • Blocking proinflammatory signaling pathways diminished the progression of VILI on animal models. • Clinically relevant experimental models are needed to confirm the treatment of immunomodulatory drugs. Mechanical ventilation (MV) is a relatively common medical intervention in ICU patients. The main side effect of MV is the so-called "ventilator-induced lung injury" (VILI). The pathogenesis of VILI is not completely understood; however, it has been reported that MV might be associated with up-regulation of various inflammatory mediators within the lung tissue and that these mediators might act as pathogenic factors in lung tissue injury. One potential mechanism for the generation of inflammatory mediators is through the release of endogenous molecules known as damage associated molecular patterns (DAMPs). These molecules are released from injured tissues and can bind to pattern recognition receptors (PRRs). PRR activation generally leads to the production and release of inflammation-related molecules including innate immune cytokines and chemokines. It has been suggested that blocking DAMP/PRR signaling pathways might diminish the progression of VILI. Herein, we review the latest findings with regard to the effects of DAMP/PRRs and their blockade, as well as the potential therapeutic targets and future research directions in VILI. Results of studies performed on human samples, animal models of disease, as well as relevant in vitro systems will be discussed. [ABSTRACT FROM AUTHOR]

Background and Aims: Ventilation can induce increase in inflammatory mediators that may contribute to systemic organ dysfunction. Ventilation-induced organ dysfunction is likely to be accentuated if there is a pre-existing systemic inflammatory response. Material and Methods: Adult patients suffering from intestinal perforation peritonitis-induced systemic inflammatory response syndrome and scheduled for emergency laparotomy were randomized to receive intraoperative ventilation with 10 ml.kg-1 tidal volume (Group H) versus lower tidal volume of 6 ml.kg-1 along with positive end-expiratory pressure (PEEP) of 10 cmH2O (Group L), (n = 45 each). The primary outcome was postoperative organ dysfunction evaluated using the aggregate Sepsis-related Organ Failure Assessment (SOFA) score. The secondary outcomes were, inflammatory mediators viz. interleukin-6, tumor necrosis factor-α, procalcitonin, and C-reactive protein, assessed prior to (basal) and 1 h after initiation of mechanical ventilation, and 18 h postoperatively. Results: The aggregate SOFA score (3[1–3] vs. 1[1–3]); and that on the first postoperative day (2[1–3] vs. 1[0–3]) were higher for group L as compared to group H (P < 0.05). All inflammatory mediators were statistically similar between both groups at all time intervals (P > 0.05). Conclusions: Mechanical ventilation with low tidal volume of 6 ml/kg-1 along with PEEP of 10 cmH2O is associated with significantly worse postoperative organ functions as compared to high tidal volume of 10 ml.kg-1 in patients of perforation peritonitis-induced systemic inflammation undergoing emergency laparotomy.

Objective: Mechanical ventilation (MV) has long been used as a life-sustaining approach for several decades. However, researchers realized that MV not only brings benefits to patients but also cause lung injury if used improperly, which is termed as ventilator-induced lung injury (VILI). This review aimed to discuss the pathogenesis of VILI and the underlying molecular mechanisms. Data Sources: This review was based on articles in the PubMed database up to December 2017 using the following keywords: “ventilator-induced lung injury”, “pathogenesis”, “mechanism”, and “biotrauma”. Study Selection: Original articles and reviews pertaining to mechanisms of VILI were included and reviewed. Results: The pathogenesis of VILI was defined gradually, from traditional pathological mechanisms (barotrauma, volutrauma, and atelectrauma) to biotrauma. High airway pressure and transpulmonary pressure or cyclic opening and collapse of alveoli were thought to be the mechanisms of barotraumas, volutrauma, and atelectrauma. In the past two decades, accumulating evidence have addressed the importance of biotrauma during VILI, the molecular mechanism underlying biotrauma included but not limited to proinflammatory cytokines release, reactive oxygen species production, complement activation as well as mechanotransduction. Conclusions: Barotrauma, volutrauma, atelectrauma, and biotrauma contribute to VILI, and the molecular mechanisms are being clarified gradually. More studies are warranted to figure out how to minimize lung injury induced by MV.

Background and Aims: Ventilation can induce increase in inflammatory mediators that may contribute to systemic organ dysfunction. Ventilation-induced organ dysfunction is likely to be accentuated if there is a pre-existing systemic inflammatory response. Material and Methods: Adult patients suffering from intestinal perforation peritonitis-induced systemic inflammatory response syndrome and scheduled for emergency laparotomy were randomized to receive intraoperative ventilation with 10 ml.kg-1 tidal volume (Group H) versus lower tidal volume of 6 ml.kg-1 along with positive end-expiratory pressure (PEEP) of 10 cmH2O (Group L), (n = 45 each). The primary outcome was postoperative organ dysfunction evaluated using the aggregate Sepsis-related Organ Failure Assessment (SOFA) score. The secondary outcomes were, inflammatory mediators viz. interleukin-6, tumor necrosis factor-α, procalcitonin, and C-reactive protein, assessed prior to (basal) and 1 h after initiation of mechanical ventilation, and 18 h postoperatively. Results: The aggregate SOFA score (3[1–3] vs. 1[1–3]); and that on the first postoperative day (2[1–3] vs. 1[0–3]) were higher for group L as compared to group H (P < 0.05). All inflammatory mediators were statistically similar between both groups at all time intervals (P > 0.05). Conclusions: Mechanical ventilation with low tidal volume of 6 ml/kg-1 along with PEEP of 10 cmH2O is associated with significantly worse postoperative organ functions as compared to high tidal volume of 10 ml.kg-1 in patients of perforation peritonitis-induced systemic inflammation undergoing emergency laparotomy. [ABSTRACT FROM AUTHOR]

The pathophysiological mechanisms by which mechanical ventilation can contribute to lung injury, termed "ventilator-induced lung injury" (VILI), is increasingly well understood. "Biotrauma" describes the release of mediators by injurious ventilatory strategies, which can lead to lung and distal organ injury. Insights from preclinical models demonstrating that traditional high tidal volumes drove the inflammatory response helped lead to clinical trials demonstrating lower mortality in patients who underwent ventilation with a lower-tidal-volume strategy. Other approaches that minimize VILI, such as higher positive end-expiratory pressure, prone positioning, and neuromuscular blockade have each been demonstrated to decrease indices of activation of the inflammatory response. This review examines the evolution of our understanding of the mechanisms underlying VILI, particularly regarding biotrauma. We will assess evidence that ventilatory and other "adjunctive" strategies that decrease biotrauma offer great potential to minimize the adverse consequences of VILI and to improve the outcomes of patients with respiratory failure. [ABSTRACT FROM AUTHOR]

Abstract The acute respiratory distress syndrome (ARDS) is an inflammatory disease of the lungs characterized clinically by bilateral pulmonary infiltrates, decreased pulmonary compliance and hypoxemia. Although supportive care for ARDS seems to have improved over the past few decades, few studies have shown that any treatment can decrease mortality for this deadly syndrome. In the 4 May 2000 issue of New England Journal of Medicine, the results of an NIH-sponsored trial were presented; they demonstrated that the use of a ventilatory strategy that minimizes ventilator-induced lung injury leads to a 22% decrease in mortality. The implications of this study with respect to clinical practice, further ARDS studies and clinical research in the critical care setting are discussed.

Background: Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI) and may thereby contribute to fatal multiple organ failure. We tested the hypothesis that injurious MV of lipopolysaccharide (LPS) pre-injured lungs induces myocardial inflammation and further dysfunction ex vivo, through calcium (Ca2+)-dependent mechanism. Materials and methods: N = 35 male anesthetized and paralyzed male Wistar rats were randomized to intratracheal instillation of 2 mg/kg LPS or nothing and subsequent MV with lung-protective settings (low tidal volume (Vt) of 6 mL/kg and 5 cmH2O positive end-expiratory pressure (PEEP)) or injurious ventilation (high Vt of 19 mL/kg and 1 cmH2O PEEP) for 4 hours. Myocardial function ex vivo was evaluated in a Langendorff setup and Ca2+ exposure. Key mediators were determined in lung and heart at the mRNA level. Results: Instillation of LPS and high Vt MV impaired gas exchange and, particularly when combined, increased pulmonary wet/dry ratio; heat shock protein (HSP)70 mRNA expression also increased by the interaction between LPS and high Vt MV. For the heart, C-X-C motif ligand (CXCL)1 and Toll-like receptor (TLR)2 mRNA expression increased, and ventricular (LV) systolic pressure, LV developed pressure, LV +dP/dtmax and contractile responses to increasing Ca2+ exposure ex vivo decreased by LPS. High Vt ventilation aggravated the effects of LPS on myocardial inflammation and dysfunction but not on Ca2+ responses. Conclusions: Injurious MV by high Vt aggravates the effects of intratracheal instillation of LPS on myocardial dysfunction, possibly through enhancing myocardial inflammation via pulmonary release of HSP70 stimulating cardiac TLR2, not involving Ca2+ handling and sensitivity. [ABSTRACT FROM AUTHOR]

Abstract: Histone deacetylase (HDAC) isoenzymes have been suggested as possible drug targets in pulmonary cancer and in inflammatory lung diseases such as asthma and COPD. Whether HDAC inhibition is pro- or anti-inflammatory is under debate. To further examine this clinically relevant paradigm, we analyzed 8 genes that are upregulated by two pro-inflammatory stimuli, i.e. endotoxin and mechanical stress (overventilation), in isolated rat and mouse lungs, respectively. We studied the effect of the HDAC inhibitor trichostatin A (TSA) under control conditions, in response to endotoxin and overventilation, and on the effects of the steroid dexamethasone. TSA affected gene expression largely independent of the stimulus (endotoxin, overventilation) and the species (rat, mouse) leading to upregulation of some genes (Tnf, Cxcl2) and downregulation of others (Cxcl10, Timp1, Selp, Il6). At the protein level, TSA reduced the stimulated release of TNF, MIP-2α and IL-6, indicating that TSA may affect protein translation independent from gene transcription. In general, the anti-inflammatory effects of TSA on gene expression and protein release were additive to that of dexamethasone, suggesting that both drugs employ different mechanisms. We conclude that pro-inflammatory stimuli induce distinct sets of genes that are regulated by HDAC in a diverse, but consistent manner across two rodent species. The present findings together with previous in vivo studies suggest that the effect of HDAC inhibition in the intact lung is in part anti-inflammatory. [Copyright &y& Elsevier]

The article reports on results of a study of the effects of long-term conventional mechanical ventilation on the lungs of adult rats. A description of the experimental set-up and measurement methods is provided. The study concluded that prolonged mechanical ventilation of healthy lungs with a physiologically benign strategy can contribute to the inflammatory response and cause alterations to pulmonary surfactant.

Acute lung injury (ALI) in combination with acute kidney injury carriesa mortality approaching 80% in the intensive care unit. Recently, attention has focused on the interaction of the lung and kidney in the setting of ALI and mechanical ventilation (MV). Small animal models of ALI and MV have demonstrated changes in inflammatory mediators, water channels, apoptosis, and function in the kidney early in the course of injury. The purpose of this investigation was to test the hypothesis that ALI and injurious MV cause early, measurable changes in kidney structure and function in a canine HCl aspiration model of ALI when hemodynamics and arterial blood gas tensions are carefully controlled. Intratracheal HCl induced profound ALI as demonstrated by increased shunt fraction and airway pressures compared with sham injury. Sham-injured animals had similar mean arterial pressure and arterial Pco2 and HCO3 levels compared with injured animals. Measurements of renal function including renal blood flow, urine flow, serum creatinine, glomerular filtration rate, urine albumin-to-creatinine ratio, and kidney histology scores were not different between groups. With maintenance of hemodynamic parameters and alveolar ventilation, ALI and injurious MV do not alter kidney structure and function early in the course of injury in this acid aspiration canine model. Kidney injury in large animal models may be more similar to humans and may differ from results seen in small animal models. [ABSTRACT FROM AUTHOR]

Background: Different levels of positive end-expiratory pressure (PEEP) with and without a recruitment maneuver (RM) may have a significant impact on ventilator-induced lung injury but this issue has not been well addressed. Methods: Anesthetized rats received hydrochloric acid (HCl, pH 1.5) aspiration, followed by mechanical ventilation with a tidal volume of 6 ml/kg. The animals were randomized into four groups of 10 each: (1) high PEEP at 6 cm H2O with an RM by applying peak airway pressure at 30 cm H2O for 10 s every 15 min; (2) low PEEP at 2 cm H2O with RM; (3) high PEEP alone; and (4) low PEEP alone. Results: The mean arterial pressure and the amounts of fluid infused were similar in the four groups. Application of the higher PEEP improved oxygenation compared with the lower PEEP groups ( P<0.05). The lung compliance was better reserved, and the systemic cytokine responses and lung wet to dry ratio were lower in the high PEEP than in the low PEEP group for a given RM ( P<0.05). Conclusions: The use of a combination of periodic RM and the higher PEEP had an additive effect in improving oxygenation and pulmonary mechanics and attenuation of inflammation. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the effects of mechanical ventilation with a moderately high tidal volume (VT) on acute lung injury (ALI) induced by wood smoke inhalation in anesthetized mice. Animals received challenges of air, 30 breaths of smoke (30SM) or 60 breaths of smoke (60SM) and were then ventilated with a VT of 10ml/kg (10VT) or 16ml/kg (16VT). After 4-h mechanical ventilation, the bronchoalveolar-capillary permeability, pulmonary infiltration of inflammatory cells, total lung injury score and pulmonary expressions of interleukin-1β and macrophage inflammatory protein-2 mRNA and proteins in the 30SM+16VT and 60SM+16VT groups were greater than those in the 30SM+10VT and 60SM+10VT groups, respectively. Additionally, the wet/dry weight ratio of lung tissues and lung epithelial cell apoptosis in the 60SM+16VT group were greater than those in the 60SM+10VT group. These differences between the 16VT and 10VT groups were not seen in animals with air challenge. Thus, mechanical ventilation with a moderately high VT in mice exacerbates ALI induced by wood smoke inhalation. [Copyright &y& Elsevier]

OBJECTIVE. Using the 125-day baboon model of bronchopulmonary dysplasia treated with prenatal steroid and exogenous surfactant, we hypothesized that a delay of extubation from low tidal volume positive pressure ventilation to nasal continuous positive airway pressure at 5 days (delayed nasal continuous positive airway pressure group) would not induce more lung injury when compared with baboons aggressively weaned to nasal continuous positive airway pressure at 24 hours (early nasal continuous positive airway pressure group), because both received positive pressure ventilation. METHODS AND RESULTS. After delivery by cesarean section at 125 days (term: 185 days), infants received 2 doses of Curosurf (Chiesi Farmaceutica S.p.A., Parma, Italy) and daily caffeine citrate. The delay in extubation to 5 days resulted in baboons in the delayed nasal continuous positive airway pressure group having a lower arterial to alveolar oxygen ratio, high Paco2, and worse respiratory function. The animals in the delayed nasal continuous positive airway pressure group exhibited a poor respiratory drive that contributed to more reintubations and time on mechanical ventilation. A few animals in both groups developed necrotizing enterocolitis and/or sepsis, but infectious pneumonias were not documented. Cellular bronchiolitis and peribronchiolar alveolar wall thickening were more frequently seen in the delayed nasal continuous positive airway pressure group. Bronchoalveolar lavage levels of interleukin-6, interleukin-8, monocyte chemotactic protein-1, macrophage inflammatory protein-1 α, and growth-regulated oncogene-α were significantly increased in the delayed nasal continuous positive airway pressure group. Standard and digital morphometric analyses showed no significant differences in internal surface area and nodal measurements between the groups. Platelet endothelial cell adhesion molecule vascular staining was not significantly different between the 2 nasal continuous positive airway pressure groups. CONCLUSlONS. Volutrauma and/or low-grade colonization of airways secondary to increased reintubations and ventilation times are speculated to play causative roles in the delayed nasal continuous positive airway pressure group findings. [ABSTRACT FROM AUTHOR]

Objective: To review how biotrauma leads to the development of multiple system organ failure (MSOF).Design and Setting: Published articles on experimental and clinical studies and review articles in the English language were collected and analyzed.Results: The concept that ventilation strategies using "large" tidal volumes and zero PEEP of injured lungs can enhance injury by the release of inflammatory mediators into the lungs and circulation, a mechanism that has been called biotrauma, is supported by evidence from experimental models ranging from mechanically stressed cell systems, to isolated lungs, intact animals, and humans. Biotrauma may lead to MSOF via spillover of lung-borne inflammatory mediators into the systemic circulation. However, spillover of other agents such as bacteria and soluble proapoptotic factors may also contribute to the onset of MSOF. Other less well studied mechanisms such as peripheral immunosuppression and translocation of bacteria and/or products from the gut may play an important role. Finally, genetic variability is a crucial factor.Conclusions: The development of MSOF is a multifactorial process. Our proposed mechanisms linking mechanical ventilation and MSOF suggest several novel therapeutic approaches. However, it will first be necessary to study the mechanisms described above to delineate more precisely the contribution of each proposed factor, their interrelationships, and their time course. We suggest that scientific advances in immunology may offer novel approaches for prevention of MSOF secondary to ventilator-induced lung injury. [ABSTRACT FROM AUTHOR]

The acute respiratory distress syndrome (ARDS) is an inflammatory disease of the lungs characterized clinically by bilateral pulmonary infiltrates, decreased pulmonary compliance and hypoxemia. Although supportive care for ARDS seems to have improved over the past few decades, few studies have shown that any treatment can decrease mortality for this deadly syndrome. In the 4 May 2000 issue of New England Journal of Medicine, the results of an NIH-sponsored trial were presented; they demonstrated that the use of a ventilatory strategy that minimizes ventilator-induced lung injury leads to a 22% decrease in mortality. The implications of this study with respect to clinical practice, further ARDS studies and clinical research in the critical care setting are discussed. [ABSTRACT FROM AUTHOR]

Supportive care with mechanical ventilation continues to be an essential strategy for managing severe neonatal respiratory failure; however, it is well known to cause and accentuate neonatal lung injury. The pathogenesis of ventilator-induced lung injury (VILI) is multifactorial and complex, resulting predominantly from interactions between ventilator-related factors and patient-related factors. Importantly, VILI is a significant risk factor for developing bronchopulmonary dysplasia (BPD), the most common chronic respiratory morbidity of preterm infants that lacks specific therapies, causes life-long morbidities, and imposes psychosocial and economic burdens. Studies of older children and adults suggest that understanding how and why VILI occurs is essential to developing strategies for mitigating VILI and its consequences. This article reviews the preclinical and clinical evidence on the pathogenesis and pathophysiology of VILI in neonates. We also highlight the evidence behind various lung-protective strategies to guide clinicians in preventing and attenuating VILI and, by extension, BPD in neonates. Further, we provide a snapshot of future directions that may help minimize neonatal VILI. [ABSTRACT FROM AUTHOR]

Ventilator-induced diaphragm dysfunction (VIDD) is the loss of diaphragmatic muscle strength'related to of mechanical ventilation, noticed during the first day or 48hours after initiating controlled mechanical ventilation. This alteration has been related to disruption on the insulin growth factor/phosphoinositol 3-kinase/kinase B protein pathway (IGF/PI3K/AKT), in addition to an overexpression of FOXO, expression of NF-kB signaling, increase function of muscular ubiquitin ligase and activation of caspasa-3. VIDD has a negative impact on quality of life, duration of mechanical ventilation, and hospitalization stance and cost. More studies are necessary to understated the process and impact of VIDD. This is a narrative review of non-systematic literature, aiming to explain the molecular pathways involved in VIDD., (Copyright © 2019 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.)

• ARDS presents with hypoxemia, pulmonary edema, lung inflammation and an increased expression of cytokines. • RM improves oxygenation and pulmonary edema in ARDS patients. • RM leads to the increased expression of pro-inflammatory cytokines. Acute respiratory distress syndrome (ARDS) is a disease with high morbidity and mortality rates. The recruitment maneuver (RM) is one of the interventions used for ARDS patients suffering from severe hypoxemia. RM works by opening the atelectatic lungs using high transpulmonary pressure. RM has therefore been widely used for many years in patients with ARDS. However, because of the high transpulmonary pressure used in this intervention, there are concerns about both biotrauma and hemodynamic instability. To assess the effects of RM in ARDS, we conducted a study using three groups of pigs (n = 6 in each group): group I (control), group II (ARDS), and group III (ARDS with RM). After measuring the baseline values, ARDS was induced by deactivating the surfactant with 5% Tweens lavage. For pigs of group III, the RM protocol used was positive end-expiratory pressure (PEEP) of 25 cmH 2 O and peak pressure of 45 cmH 2 O. Gas exchange, hemodynamics, the expression of cytokines in serum, bronchoalveolar lavage fluid (BALF), and exhaled breath condensates (EBCs) were measured. The baseline measurements taken were similar across the three groups, and no significant difference was noted. After the induction of ARDS, PaO 2 substantially decreased, while PaCO 2 , alveolar-arterial O 2 gradient, pulmonary arterial pressure, lung water, level of cytokines in serum, EBCs, and BALF all increased. After RM, gas exchange and lung water level improved, but the level of cytokines in EBCs and BALF increased. Although RM led to an improvement in gas exchange, it may cause release of inflammatory cytokines in the EBCs and BALF. [ABSTRACT FROM AUTHOR]

We investigate respiratory flow phenomena in a reconstructed upper airway model of an intubated neonate undergoing invasive mechanical ventilation, spanning conventional to high-frequency ventilation (HFV) modes. Using high-speed tomographic particle image velocimetry, we resolve transient, three-dimensional flow fields and observe a persistent jet flow exiting the endotracheal tube whose strength is directly modulated according to the ventilation protocol. We identify this synthetic jet as the dominating signature of convective flow under intubated ventilation. Concurrently, our in silico wall shear stress analysis reveals a hitherto overlooked source of ventilator-induced lung injury as a result of jet impingement on the tracheal carina, suggesting damage to the bronchial epithelium; this type of injury is known as biotrauma. We find HFV advantageous in mitigating the intensity of such impingement, which may contribute to its role as a lung protective method. Our findings may encourage the adoption of less invasive ventilation procedures currently used in neonatal intensive care units.

The author expresses his views on the concept of slow recruitment maneuver (RM) in acute respiratory distress syndrome and acute lung injury (ALI), in relation to a study published in a 2011 issue of the journal "Critical Care Medicine." The study focused on the effect of pressure profile and duration of RM on biochemical and morphofunctional variables in experimental lung injury. He talks about the impact of time-dependent airway pressure increase on the improvement of gas exchange and the reduction of ventilator-induced lung injury.