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Purpose of review To provide pieces of evidence and an overview of the pathophysiology of ventilator-induced lung injury (VILI) on subjects with noninjured lungs, and the intraoperative mechanical ventilation strategies to prevent VILI. Recent findings Numerous evidence has indicated that intraoperative mechanical ventilation is associated with an increased risk of postoperative pulmonary complications (PPCs) in patients with noninjured lungs. This risk is blamed for volutrauma, barotrauma, atelectrauma, and biotrauma, which are the primary mechanisms of ventilator-induced lung injury (VILI) during mechanical ventilation. VILI was worsened by a nonprotective ventilator setting using a high tidal volume (>10–12 ml/kg), a low level of positive end-expiratory pressure (PEEP

Introduction Preterm infants often require assisted ventilation, however ventilation when applied to the immature lung can initiate ventilator-induced lung injury (VILI). The biotrauma which underscores VILI is largely undefined, and is likely to involve vascular injury responses, including hemostasis. We aimed to use a ventilated, preterm lamb model to: (1) characterize regional alterations in hemostatic mediators within the lung and (2) assess the functional impact of protein alterations on hemostasis by analyzing temporal thrombin generation. Materials and methods Preterm lambs delivered at 124 to 127 days gestation received 90 min of mechanical ventilation (positive end-expiratory pressure = 8 cm H2O, VT = 6–8 ml/kg) and were compared with unventilated control lambs. At study completion, lung tissue was taken from standardized nondependent and gravity-dependent regions, and Orbitrap-mass spectrometry and KEGG were used to identify and map regional alterations in hemostasis pathway members. Temporal alterations in plasma thrombin generation were assessed. Results Ventilation was distributed towards the nondependent lung. Significant changes in hemostatic protein abundance, were detected at a two-fold higher rate in the nondependent lung when compared with the gravity-dependent lung. Seven proteins were uniquely altered in non-dependent lung (SERPINA1, MYL12A, RAP1B, RHOA, ITGB1, A2M, GNAI2), compared with a single proteins in gravity-dependent lung (COL1A2). Four proteins were altered in both regions (VTN, FGG, FGA, and ACTB). Tissue protein alterations were mirrored by plasma hypocoagulability at 90-minutes of ventilation. Conclusions We observed regionally specific, hemostatic alterations within the preterm lung together with disturbed fibrinolysis following a short period of mechanical ventilation.

Ventilatory support, while life saving, can also cause or aggravate lung injury through several mechanisms which are encompassed within ventilator-associated lung injury (VALI). The important realizationin the acute respiratory distress syndrome that the “baby” lung resided in non-dependent areas led to the conceptualization of “lung rest” to reduce stress and strain to exposed alveolar units. We discuss concepts and mechanisms within VALI that ultimately induce maladaptive lung responses, as well as, current and future management strategies to detect and mitigate VALI at the bedside.

Background Cardiogenic pulmonary oedema (CPE) may contribute to ventilator-associated lung injury (VALI) in patients with cardiogenic shock. The appropriate ventilatory strategy remains unclear. We aimed to evaluate the impact of ultra-low tidal volume ventilation with tidal volume of 3 ml/kg predicted body weight (PBW) in patients with CPE and veno–arterial extracorporeal membrane oxygenation (V–A ECMO) on lung inflammation compared to conventional ventilation. Methods A single-centre randomized crossover trial was performed in the Cardiac Intensive Care Unit (ICU) at a tertiary university hospital. Seventeen adults requiring V–A ECMO and mechanical ventilation due to cardiogenic shock were included from February 2017 to December 2018. Patients were ventilated for two consecutive periods of 24 h with tidal volumes of 6 and 3 ml/kg of PBW, respectively, applied in random order. Primary outcome was the change in proinflammatory mediators in bronchoalveolar lavage fluid (BALF) between both ventilatory strategies. Results Ventilation with 3 ml/kg PBW yielded lower driving pressures and end-expiratory lung volumes. Overall, there were no differences in BALF cytokines. Post hoc analyses revealed that patients with high baseline levels of IL-6 showed statistically significant lower levels of IL-6 and IL-8 during ultra-low tidal volume ventilation. This reduction was significantly proportional to the decrease in driving pressure. In contrast, those with lower IL-6 baseline levels showed a significant increase in these biomarkers. Conclusions Ultra-low tidal volume ventilation in patients with CPE and V–A ECMO may attenuate inflammation in selected cases. VALI may be driven by an interaction between the individual proinflammatory profile and the mechanical load overimposed by the ventilator. Trial registration The trial was registered in ClinicalTrials.gov (identifier NCT03041428, Registration date: 2nd February 2017).

Mortality rates among patients suffering from acute respiratory failure remain perplexingly high despite maintenance of blood homeostasis. Thebiotraumahypothesis advances that mechanical forces from invasive ventilation trigger immunological factors that spread systemically. Yet, how these forces elicit an immune response remains unclear. Here we show that flow-induced stresses under mechanical ventilation can injure the bronchial epithelium of ventilatedin vitroupper airway models and directly modulate inflammatory cytokine secretion associated with pulmonary injury. We identify site-specific susceptibility to epithelial erosion in airways from jet-flow impaction and measure an increase in cell apoptosis and modulated secretions of cytokines IL-6, 8 and 10. We find that prophylactic pharmacological treatment with anti-inflammatory therapeutics reduces apoptosis and pro-inflammatory signaling during ventilation. Our 3Din vitroairway platform points to a previously overlooked origin of lung injury and showcases translational opportunities in preclinical pulmonary research towards protective therapies and improved protocols for patient care.

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 One important explanation for the detrimental effects of conventional mechanical ventilation is the biotrauma hypothesis that ventilation may trigger proinflammatory responses that subsequently cause lung injury. This hypothesis has frequently been studied in so-called one-hit models (overventilation of healthy lungs) that so far have failed to establish an unequivocal link between inflammation and hypoxemic lung failure. This study was designed to develop a one-hit biotrauma model. Methods Mice (six per group) were ventilated for up to 7 h (positive end-expiratory pressure 2 cm H2O) and received 300 μl/h fluid support. Series_1: initial plateau pressures of 10, 24, 27, or 30 cm H2O. Series_2: ventilation with pressure release at 34 cm H2O and initial plateau pressure of 10, 24, 27, or 30 cm H2O. To study the significance of inflammation, the latter groups were also pretreated with the steroid dexamethasone. Results Within 7 h, 20 of 24 mice ventilated with plateau pressure of 27 cm H2O or more died of a catastrophic lung failure characterized by strongly increased proinflammatory markers and a precipitous decrease in pulmonary compliance, blood pressure, and oxygenation. Pretreatment with dexamethasone reduced inflammation, but prolonged median survival time by 30 min. Conclusions Our findings demonstrate a sharp distinction between ventilation with 24 cm H2O that was well tolerated and ventilation with 27 cm H2O that was lethal for most animals due to catastrophic lung failure. In the former case, inflammation was benign and in the latter, a by-product that only accelerated lung failure. The authors suggest that biotrauma—when defined as a ventilation-induced and inflammation-dependent hypoxemia—is difficult to study in murine one-hit models of ventilation, at least not within 7 h. (Anesthesiology 2017; 126:909-22)

Patients undergoing mechanical ventilation in intensive care units (ICUs) may develop ventilator-induced lung injury (VILI). Beside the high tidal volume (Vt) and plateau pressure (Pplat), hyperoxia is supposed to precipitate lung injury. Oxygen toxicity is presumed to occur at levels of fraction of inspired oxygen (FiO2) exceeding 0.40. The exposure time to hyperoxia is certainly very important and patients who spend extended time on mechanical ventilation (MV) are probably more exposed to severe hyperoxic acute lung injury (HALI). Together, hyperoxia and biotrauma (release of cytokines) have a synergistic effect and can induce VILI. In the clinical practice, the reduction of FiO2 to safe levels through the appropriate use of the positive end expiratory pressure (PEEP) and the alignment of mean airway pressure is an appropriate goal. The strategy for lung protective ventilation must include setting up FiO2 to a safe level that is accomplished by using PaO2/FiO2 ratio with a lower limit of FiO2 to achieve acceptable levels of PaO2, which will be safe for the patient without local (lungs) or systemic inflammatory response. The protocol from the ARDS-net study is used for ventilator setup and adjustment. Cytokines (IL-1, IL-6, TNFα and MIP-2) that are involved in the inflammatory response are determined in order to help the therapeutic approach in counteracting HALI. Computed tomography findings reflect the pathological phases of the diffuse alveolar damage. At least preferably the lowest level of FiO2 should be used in order to provide full lung protection against the damage induced by MV.

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, ourin silicowall 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.

Invasive mechanical ventilation is essential for respiratory failure management, especially when patients are not able to provide good oxygenation and ventilation. The main uses are respiratory failure, apneas, neuromuscular disorders, cardiogenic shock, surgery and for airway protection (e.g., complicated trauma), and to diminish metabolic consumption (e.g., septic shock). Among the many variants for mechanical ventilation administration are controlled, assisted, and intermittent synchronized support. They are indicated according to patient’s needs. Mechanical ventilation has adverse effects related to lung injury (barotrauma, volotrauma, atelctrauma, and biotrauma) but also secondary to sedation and trauma to the airway.

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.

It is well established that mechanical ventilation can injure the lung, producing an entity known as ventilator-induced lung injury (VILI). There are various forms of VILI, including volutrauma (i.e., injury caused by overdistending the lung), atelectrauma (injury due to repeated opening/closing of lung units), and biotrauma (release of mediators that can induce lung injury or aggravate pre-existing injury, potentially leading to multiple organ failure). Experimental data in the pediatric context are in accord with the importance of VILI, and appear to show age-related susceptibility to VILI; although a conclusive link between use of large V-TS and mortality has not been demonstrated in this population. The relevance of VILI in the pediatric intensive care unit population is thus unclear. Given the physiological and biological differences in the respiratory systems of infants, children, and adults, it is difficult to directly extrapolate clinical practice from adults to children. This Critical Care Perspective analyzes the relevance of VILI to the pediatric population, and addresses why pediatric patients might be less susceptible than adults to VILI.

Mechanical ventilation (MV) is the main supportive treatment in respiratory failure due to different etiologies. However, MV might aggravate ventilator-associated lung injury (VALI). Four main mechanisms leading to VALI are: 1) increased stress and strain, induced by high tidal volume (VT); 2) increased shear stress, i.e. opening and closing, of previously atelectatic alveolar units; 3) distribution of perfusion and 4) biotrauma. In severe acute respiratory distress syndrome patients, low VT, higher levels of positive end expiratory pressure, long duration prone position and neuromuscular blockade within the first 48 hours are associated to a better outcome. VALI can also occur by using high VT in previously non injured lungs. We believe that prevention is the target to minimize injurious effects of MV. This review aims to describe pathophysiology of VALI, the possible prevention and treatment as well as monitoring MV to minimize VALI.

Objectives: Ventilator-induced lung injury has substantive impact on mortality of patients with acute respiratory distress syndrome. Although low tidal volume ventilation has been shown to reduce mortality, clinical benefits of open-lung strategy are controversial. In this study, we investigated the impact of two distinct forms of ventilator-induced lung injury, i.e., volutrauma and atelectrauma, on the progression of lung injury and inflammation, in particular alveolar and systemic cytokine production. Design: Ex vivo study. Setting: University research laboratory. Subjects: C57BL/6 mice. Interventions: Isolated, buffer-perfused lungs were allocated to one of three ventilatory protocols for 3 hours: control group received low tidal volume (7 mL/kg) with positive end-expiratory pressure (5 cm H2O) and regular sustained inflation; high-stretch group received high tidal volume (30–32 mL/kg) with positive end-expiratory pressure (3 cm H2O) and sustained inflation; and atelectasis group received the same tidal volume as control but neither positive end-expiratory pressure nor sustained inflation. Measurements and Main Results: Both injurious ventilatory protocols developed comparable levels of physiological injury and pulmonary edema, measured by respiratory system mechanics and lavage fluid protein. High-stretch induced marked increases in proinflammatory cytokines in perfusate and lung lavage fluid, compared to control. In contrast, atelectasis had no effect on perfusate cytokines compared to control but did induce some up-regulation of lavage cytokines. Depletion of monocytes marginated within the lung microvasculature, achieved by pretreating mice with IV liposome-encapsulated clodronate, significantly attenuated perfusate cytokine levels, especially tumor necrosis factor, in the high-stretch, but not atelectasis group. Conclusions: Volutrauma (high-stretch), but not atelectrauma (atelectasis), directly activates monocytes within the pulmonary vasculature, leading to cytokine release into systemic circulation. We postulate this as a potential explanation why open-lung strategy has limited mortality benefits in ventilated critically ill patients.

Mechanical ventilation of disease-affected lungs, as well as being an inadequate mode of ventilation for initially healthy lungs, can cause significant changes in their structure and function. In order to differentiate these processes, two terms are used: ventilator-associated lung injury (VALI) and ventilator-induced lung injury (VILI). In both cases, lung injury primarily results from differences in transpulmonary pressure - a consequence of an imbalance between lung stress and strain. This paper focuses on changes in lung structure and function due to this imbalance. Moreover, in this context, barotrauma, volutrauma and atelectrauma are interpreted, and the importance of signal transduction as a process inducing local and systemic inflammatory responses (biotrauma), is determined. None of the assessed methods of reducing VALI and VILI has been found to be entirely satisfactory, yet studies evaluating oscillatory ventilation, liquid ventilation, early ECMO, super-protective ventilation or noisy ventilation and administration of certain drugs are under way. Low tidal volume ventilation and adequately adjusted PEEP appear to be the best preventive measures of mechanical ventilation in any setting, including the operating theatre. Furthermore, this paper highlights the advances in VILI/VALI prevention resulting from better understanding of pathophysiological phenomena.

An acute lung injury represents a continuum of injury that may arise from a number of primary insults. When it is present, it may progress due to the trauma from mechanical ventilation, a finding that has led to an intense debate over the optimal ventilator management. Moreover, it has been demonstrated that mechanical ventilation per se, even in the absence of a preexisting lung injury, may lead to the development of ventilator-induced lung injury (VILI). The association between positive pressure mechanical ventilation and lung injury has fostered the concepts of barotrauma, volutrauma, atelectrauma, and biotrauma and led to the clinical development of “lung-protective ventilation,” which has led to a significant improvement in outcomes. Several theories have attempted to explain the mechanistic basis of VILI. The stretched-pore hypothesis suggested that vascular distention may open the endothelial intercellular junctions, thus increasing fluid and protein leak and leading to a compromised lung function. The stress failure hypothesis proposes that pressure-induced tensile failure of capillary endothelium and basement membrane may result in hemorrhage and fluid leak. The stretch-recoil hypothesis introduced the concept that active cellular components are involved in the development of VILI. In the current chapter, ventilator-induced lung injury is examined as it relates to the pathophysiological changes beyond direct airway trauma. The role of lung-related factors such as stress, strain, and lung inhomogeneity will be examined, as well as extra-parenchymal factors and factors more directly related to mechanical ventilation (such as tidal volume, driving pressure, respiratory rate, inspiratory-to-expiratory ratio and flow). The recently proposed, unifying theory of mechanical power will also be presented and discussed.

Prevention of ventilator-induced lung injury (VILI) can attenuate multiorgan failure and improve survival in at-risk patients. Clinically significant VILI occurs from volutrauma, barotrauma, atelectrauma, biotrauma, and shear strain. Differences in regional mechanics are important in VILI pathogenesis. Several interventions are available to protect against VILI. However, most patients at risk of lung injury do not develop VILI. VILI occurs most readily in patients with concomitant physiologic insults. VILI prevention strategies must balance risk of lung injury with untoward side effects from the preventive effort, and may be most effective when targeted to subsets of patients at increased risk.

Critical care physicians deal every day with patients suffering from acute lung injury and respiratory failure. Acute respiratory distress syndrome (ARDS) is the most severe form of acute lung injury. Mechanical ventilation remains the mainstay of supportive treatment for ARDS. There are patients with ARDS who are unable to achieve adequate gas exchange while receiving conventional mechanical ventilation. In this setting, high-frequency oscillatory ventilation (HFOV) arises as a nonconventional mode of mechanical ventilation with the potential not only of reversing severe hypoxemia, but also of minimizing ventilator-induced lung injury. HFOV is a unique mode of mechanical ventilation characterized by very low tidal volumes, lower than anatomic dead space (1 to 3 mL/kg), and a constant, high mean airway pressure. Ventilation at such low tidal volumes is possible using high respiratory cycle frequencies (3 to 20 Hz). Oxygenation and ventilation can be managed on high-frequency ventilation relatively uncoupled. Changes in oxygenation are addressed by changing mean airway pressure or the oxygen inspiratory fraction. CO2 elimination is dealt with by modifying oscillator pressure amplitude, frequency (inversely), inspiratory to expiratory ratio, and bias flow. High-grade evidence supporting the use of HFOV is scarce. This ventilation technique has proven to be at least as efficient and safe as conventional mechanical ventilation for patients with ARDS. Current literature suggests that it may be useful not only to rescue patients failing on mechanical ventilation, but also to minimize barotrauma, volutrauma, and biotrauma. Selection of candidates for high-frequency oscillation and utilization of the appropriate ventilatory strategies are key issues if benefits from this technique are to be maximized.

A cute respiratory distress syndrome (ARDS) is a major cause of mortality in critical care , but to d ate no specific treatment exists. There is growing concern about our failure to translate from bench to bedside within the acute lung injury research community, and t he crucial importance of better modelling in preclinical studies to identify targets with more predictive power is increasingly appreciated . Mechanical ventilation , while being a vital tool for support of ARDS patients , produces or worsens lung injury . This ‘ ventilator -­ induced lung injury ’ ( VILI ) has substantive negative impact on the outcom e of ARDS . I ncreasing tidal volumes are associated with enhanced release of local and systemic inflammatory mediators in patients , and a nimal model s d emonstrated that excessive tidal volumes induce lung inflammation, edema and physiological dysfunction. Such findings have lent support to the ‘biotrauma’ hypothesis, i.e. VILI promotes the release of inflammatory mediators , which play a critical role in the progression of injury of the lungs as well as other systemic organs [1]. In this issue of Anesthesiol ogy, Lex and Uhlig [ 2 ] investigate whether this biotrauma can be studied in so -­ called ‘one -­ hit’ models of VILI in mice . Their results provide useful information for physiologists to better design mouse VILI experiments, but more importantly, p rovoke a seri es of important questions that are essential for clinicians desiring to interpret animal VILI models for future clinical translation.

Neonatal tidal volume breathing is fundamental to gas exchange and ventilatory support after birth. In uniquely vulnerable preterm infants, excessive tidal volume, volutrauma, is a significant contributor to ventilator-induced lung injury (VILI). This biotrauma triggers a cascade of proinflammatory responses associated with an increased occurrence of bronchopulmonary dysplasia (BPD). Understanding of physiologic determinants of tidal volume allow for optimal tidal volume delivery by using minimal pressures to achieve desired carbon dioxide exchange without air-trapping. Tidal volumes (Vt) can be measured continuously by monitoring airflow signals of assisted ventilation. Currently, pneumotachography is the most commonly utilized bedside technology. Ideal techniques to measure continuous, bi-directional airflow proximal to the endotracheal tube require accuracy over a range of airflow, negligible contribution to dead space and resistive load, reliability, minimal need for operator intervention or calibration, adaptability to a warmed and humidified environment, and validated performance for long-term use. For all infants receiving assisted ventilation, clinicians require accurate technologies to continuously measure Vt until respiratory stability is reached to minimize the risk of VILI.

Term newborn infants with lung injury have varying degrees of pulmonary edema, increased airway resistance and uneven distribution of atelectasis contributing to decreased pulmonary compliance and functional residual capacity. Lung injury is often initiated by the inflammatory process associated with the primary etiology of respiratory failure and is further exacerbated by ventilator-induced lung injury. Volutrauma, atelectotrauma and, to a lesser extent, barotrauma and rheotrauma contribute to inducing biotrauma, which is lung injury that results from uncontrolled inflammation. Recognizing the mechanisms of lung injury and the pattern and limitations of measured changes in lung function and mechanics might also serve as indicators of lung injury and are important in the formulation of lung protective strategies. Maintaining adequate functional residual capacity (open lung strategy), assuring appropriate tidal volumes to avoid both atelectotrauma and volutrauma and avoiding excessive exposure to oxygen should help achieve this goal.

Ventilator Associated Lung Injury (VALI) is an iatrogenic phenomena that significantly impacts on the morbidity and mortality of critically ill patients. The hazards associated with mechanical ventilation are becoming increasingly understood courtesy of a large body of research. Barotrauma, volutrauma and biotrauma all play a role in VALI. Concomitant to this growth in understanding is the development of strategies to reduce the deleterious impact of mechanical ventilation. The majority of the research is based upon adult populations but with careful extrapolation this review will focus on paediatrics. This review article describes the physiological basis of VALI and discusses the various lung protective strategies that clinicians can employ to minimise its incidence and optimise outcomes for paediatric patients.

Summary Background High-pressure ventilation induces barotrauma and pulmonary inflammation, thus leading to ventilator-induced lung injury (VILI). By limiting the pulmonal inflammation cascade the anti-inflammatory cytokine interleukin (IL)-10 may have protective effects. Via inhalation, IL-10 reaches the pulmonary system directly and in high concentrations. Methods Thirty six male, anesthetized and mechanically ventilated Sprague–Dawley rats were randomly assigned to the following groups (n = 9, each): SHAM: pressure controlled ventilation with pmax = 20 cmH2O, PEEP = 4; VILI: ventilator settings were changed for 20 min to pmax = 45 cmH2O, PEEP = 0; IL-10high: inhalation of 10 μg/kg IL-10 prior to induction of VILI; and IL-10low: inhalation of 1 μg/kg IL-10 prior to induction of VILI. All groups were ventilated and observed for 4 h. Results High-pressure ventilation increased the concentrations of macrophage inflammatory protein (MIP)-2 and IL-1β in bronchoalveolar lavage fluid (BALF) and plasma. This effect was reduced by the inhalation of IL-10 (10 μg/kg). Additionally, IL-10 increased the animal survival time (78% vs. 22% 4-h mortality rate) and reduced NO-release from ex vivo cultured alveolar macrophages. Moreover, VILI-induced pulmonary heat shock protein-70 expression was reduced by IL-10 aerosol in a dose-dependent manner. Similarly, the activation of matrix metalloproteinase (MMP)-9 in BALF was reduced dose-dependently by IL-10. IL-10-treated animals showed a lower macroscopic lung injury score and less impairment of lung integrity and gas exchange. Conclusions Prophylactic inhalation of IL-10 improved survival and reduced lung injury in experimental VILI. Results indicate that this effect may be mediated by the inhibition of stress-induced inflammation and pulmonary biotrauma.

Ventilation-induced lung injury is often studied in animal models by using ventilation strategies with high-tidal volumes and high-oxygen concentration over a relatively short period of time. The injury induced by these ventilation strategies includes alterations to the surfactant system and up-regulation of inflammatory markers. Whether these responses to ventilation occur with more clinically relevant ventilation strategies is not known.To assess how healthy adult rats respond to 24 hrs of conventional mechanical ventilation with respect to lung physiology, markers of inflammation, and alterations to pulmonary surfactant, and how this is affected by the oxygen concentration.Adult rats were mechanically ventilated for 24 hrs with a tidal volume of 8 mL/kg, 5 cm H2O positive end-expiratory pressure, at 60 breaths/min with either 21% or 100% oxygen. Animals were monitored for blood oxygenation and other physiologic parameters. After ventilation, lungs were lavaged and analyzed for inflammatory markers and pulmonary surfactant. These outcomes were compared with measurements obtained from spontaneously breathing rats exposed to either 21% or 100% oxygen for 24 hrs.Twenty-four hours of ventilation did not result in significant changes in blood oxygenation. Inflammatory markers, such as interleukin-6 concentration and the number of neutrophils in the lavage, were increased in ventilated animals compared with the nonventilated controls, regardless of the level of inspired oxygen. The amount of active surfactant was increased after ventilation; however, the surface activity of this material was impaired as compared with controls.Prolonged mechanical ventilation of health lungs with a physiologically benign strategy can contribute to the inflammatory response and cause alterations to pulmonary surfactant.

Mechanical ventilation may lead to lung injury depending on the ventilatory settings (e.g. pressure amplitudes, endexpiratory pressures, frequency) and the length of mechanical ventilation. Particularly in the inhomogeneously injured lungs of ARDS patients, alveolar overextension results in volutrauma, cyclic opening and closure of alveolar units in atelectrauma. Particularly important appears to be the fact that these processes may also cause biotrauma, i.e. the ventilator-induced hyperactivation of inflammatory responses in the lung. These side effects are reduced, but not eliminated with the currently recommended ventilation strategy with a tidal volume of 6 ml/kg idealized body weight. It is our hope that in the future optimization of ventilator settings will be facilated by bedside monitoring of novel indices of respiratory mechanics such as the stress index or the Slice technique, and by innovative real-time imaging technologies such as electrical impedance tomography.

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

High frequency oscillatory ventilation (HFOV) has been the subject of extensive physiological research for 30 years and even more so of an intense debate on its potential usefulness in the treatment of acute respiratory distress syndrome (ARDS). This technique has been enthusiastically promoted by some teams until two high-quality randomized clinical trials in adults with ARDS showed that HFOV did not decrease and might have even increased mortality. As a consequence of these results, physiological concepts such as atelectrauma and biotrauma on which ARDS management with HFOV were based should be reexamined. In contrast, the concept of volutrauma, i.e., end-inspiratory overdistension, as the cause for ventilator-induced lung injury might help explain excess mortality during mechanical ventilation of ARDS when inspiratory volumes are too high. This is what might have happened during one of the recent studies on HFOV. Failure of this complex technique must be put in perspective with the dramatic improvement of ARDS prognosis with very simple interventions such as tidal volume reduction, early pharmacological paralysis, and prone positioning which all limited end-inspiratory volume.

BACKGROUND With the widespread use of ventilators in treating critically ill patients, the morbidity of ventilator-induced lung injury (VILI) is increasing accordingly. VILI is characterized by a considerable increase in microvascular leakiness and activation of inflammatory processes. In this study we investigated the effects of inflammatory mediators in VILI rat serum on endothelial cytoskeleton and monolayer cellular permeability, as well as the therapeutic effect of ulinastatin, to explore the pathogenesis and the relationship between biotrauma and lung oedema induced by VILI. METHODS Thirty healthy male Sprague-Dawley rats were randomly divided into three groups: group A (normal tidal volume ventilation), group B (high tidal volume ventilation) and group C (high tidal volume ventilation plus ulinastatin). The serum of each rat after ventilation was added to endothelial cell line ECV-304 medium for two hours to observe the effects of serum and/or ulinastatin on endothelial fibrous actin and permeability. RESULTS Compared to rats ventilated with normal tidal volume, serum of rats ventilated with high tidal volume caused a striking reorganization of actin cytoskeleton with a weakening of fluorescent intensity at the peripheral filament bands and formation of the long and thick stress fibres in the centre resulting in endothelial contraction and higher permeability. Prior treatment with ulinastatin lessened the above changes significantly. The changes of permeability coefficient of endothelial permeability after group A, B or C rats serum stimulation were (6.95 +/- 1.66)%, (27.50 +/- 7.77)% and (17.71 +/- 4.66)% respectively with statistically significant differences (P < 0.05) among the three groups. CONCLUSIONS The proinflammatory mediators in the serum of the rats given high tidal volume ventilation increases endothelial permeability by reorganizing actin cytoskeleton, and pretreatment with ulinastatin lessens the permeability by inhibiting of proinflammatory mediators.

▪ Abstract Patients with severe acute respiratory distress syndrome who die usually succumb to multiorgan failure as opposed to hypoxia. Despite appropriate resuscitation, some patients' symptoms persist on a downward spiral, apparently propagated by an uncontained systemic inflammatory response. This phenomenon is not well understood. However, a novel hypothesis to explain this observation proposes that it is related to the life-saving ventilatory support used to treat the respiratory failure. According to this hypothesis, mechanical ventilation per se, by alterating both the magnitude and the pattern of lung stretch, can cause changes in gene expression and/or cellular metabolism that ultimately can lead to the development of an overwhelming inflammatory response—even in the absence of overt structural damage. This mechanism of injury has been termed biotrauma. In this review we explore the biotrauma hypothesis, the causal relationship between biophysical injury and organ failure, and its implications for the future therapy and management of critically ill patients.

Septic acute lung injury (ALI) causes high morbidity and mortality in intensive care service as a result of biotrauma and dysfunction in the lungs and other organ systems. We hypothesized that surfactant and/or inhaled nitric oxide (iNO) may have different effects in modulation of inflammatory injury in septic ALI. Twenty-four healthy, 6–9 kg piglets were anesthetized, and intraperitoneally injected with Escherichia coli, followed by a low tidal volume ventilation until sepsis and ALI developed within 4–6 h. They were then randomly treated in groups (n=6 each) as: control (C), inhaled NO at 10 ppm (NO), surfactant at 100 mg/kg (Surf), or both surfactant and iNO (SNO). A normal control group (N) was sham-injected and similarly ventilated. Over the 24 h of treatment period, both Surf, and SNO groups had significantly improved PaO2/FiO2, dynamic compliance and resistance of respiratory system. At 24 h, the best alveolar aeration and least protein leakage, the lowest wet-to-dry lung weight ratio and lung injury score were found in SNO. Activity of nuclear factor kappa B (NF-κB) and myeloperoxidase, interleukin 8 mRNA expression and melondialdehyde were significantly increased, and IL-10 mRNA decreased, in lung tissue of the C group, but were significantly altered in the SNO group, and moderately altered in either NO or Surf group. We conclude that the effects of lung protection by surfactant and/or iNO in this model may be different in modulation of inflammatory cytokine mRNA expression and activity of NF-κB, and iNO did not have adverse effects.

To review how biotrauma leads to the development of multiple system organ failure (MSOF).Published articles on experimental and clinical studies and review articles in the English language were collected and analyzed.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.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.

En la era de las estrategias de ventilación protectoras para el pulmón, la ventilación de alta frecuencia oscilatoria (VAFO) ha logrado un interés renovado, y su uso ha aumentado de manera significativa en las unidades de cuidados intensivos neonatales y pediátricas. La VAFO es capaz de disminuir el daño pulmonar inducido por la ventilación, limitando la incidencia de volutrauma, atelectrauma, barotrauma y biotrauma. Durante la VAFO, se logra una oxigenación y una ventilación adecuadas, utilizando volúmenes corrientes bajos y pequeños cambios de presión, a frecuencias suprafisiológicas. Al contrario que otros modos de ventilación de alta frecuencia, la VAFO tiene una fase espiratoria activa. La VAFO constituye un modo de ventilación seguro y eficaz en el tratamiento de pacientes pediátricos con insuficiencia respiratoria refractaria a la ventilación mecánica convencional optimizada, con mejores resultados cuando se inicia precozmente. Por otro lado, el uso electivo de VAFO requiere más estudios que precisen sus beneficios sobre los modos convencionales de VM y que justifiquen su uso habitual como tratamiento de primera línea. El Grupo de Trabajo Respiratorio de la Sociedad Española de Cuidados Intensivos Pediátricos revisa en este trabajo los principales aspectos de la aplicación pediátrica de la VAFO. Además, establece un protocolo general práctico y estrategias específicas de tratamiento, monitorización, cuidados del paciente y otros aspectos peculiares, del uso de la VAFO en el contexto pediátrico. : In the era of lung-protective ventilation strategies, high frequency oscillatory ventilation (HFOV) has attracted renewed interest and its use has dramatically increased in neonatal and pediatric intensive care units. HFOV is able to reduce ventilator-induced lung injury by limiting the incidence of volutrauma, atelectrauma, barotrauma and biotrauma. During HFOV, adequate oxygenation and ventilation is achieved by using low tidal volumes and small pressure swings at supraphysiologic frequencies. Unlike other high-frequency ventilation modes, HFOV has an active expiration phase. HFOV constitutes a safe and successful ventilation mode for managing pediatric patients with respiratory insufficiency refractory to optimized conventional mechanical ventilation and provides better results when initiated early. However, the elective use of HFOV requires further studies to identify its benefits over conventional modes of mechanical ventilation and to support its routine use as a first line therapy. In the present article, the Respiratory Working Group of the Spanish Society of Pediatric Critical Care reviews the main issues in the pediatric application of HFOV. In addition, a general practical protocol and specific management strategies, as well as the monitoring, patient care and other special features of the use of HFOV in the pediatric setting, are discussed.

La VM puede originar múltiples complicaciones. Las complicaciones agudas más importantes son: problemas mecánicos (fallos de la fuente de gases o del respirador, problemas con las tubuladuras), error en la programación del respirador y sus alarmas, problemas en la vía aérea (desconexión, extubación, malposición del tubo endotraqueal, fuga, lesiones en el ala de la nariz, obstrucción del tubo endotraqueal por acodadura o secreciones, intubación bronquial selectiva, broncospasmo, estridor postextubación), complicaciones pulmonares (lesión inducida por la VM, con volutrauma, barotrauma y biotrauma), alteraciones hemodinámicas, infecciones (traqueobronquitis, neumonía, otitis, sinusitis), problemas de adaptación del paciente y el respirador y trastornos nutricionales. Las secuelas crónicas más importantes de la VM son la estenosis subglótica, la lesión pulmonar crónica y las alteraciones psicológicas. : Mechanical ventilation can produce multiple complications. The most important acute complications are mechanical problems (respirator failure, problems with the connections and circuit, incorrect parameters or alarms), problems in the airway (disconnection, extubation, malpositioning of the endotracheal tube, leaks, nose erosions, obstruction of the endotracheal tube due to secretions or kinking, mainstem bronchus intubation, bronchospasm, postextubation croup), pulmonary complications (ventilator-induced lung injury with barotrauma, volutrauma and biotrauma), hemodynamic complications, nosocomial infections (tracheobronchitis, pneumonia, otitis, sinusitis), failure of adjustment of the respirator to the patient, and nutritional complications. The most important chronic problems are subglottal stenosis, chronic pulmonary injury, and psychological alterations.

Purpose of review To discuss the mechanisms of ventilator-induced lung injury and the pro and cons of the different approaches proposed by literature to minimize its impact in patients with acute respiratory distress syndrome. Recent findings Mechanical ventilation is indispensable to manage respiratory failure. The evolution of knowledge of the physiological principles and of the clinical implementation of mechanical ventilation is characterized by the shift of interest from its capability to restore 'normal gas exchange' to its capability of causing further lung damage and multisystem organ failure. Summary If one of the essential teachings to young intensivists in the 1980s was to ensure mechanical ventilation restored being able to immediately drain a pneumothorax (barotrauma), nowadays priority we teach to young intensivists is to implement 'protective' ventilation to protect the lungs from the pulmonary and systemic effects of ventilator-induced lung injury (biotrauma). At the same time, priority of clinical research shifted from the search of optimal ventilator settings (best positive end-expiratory pressure) and to the evaluation of 'super-protective' ventilation that integrating partial or total extracorporeal support tries to minimize the use of mechanical ventilation.

The human acute respiratory distress syndrome (ARDS) is a severe pulmonary complication with high mortality rates. To support their vital functions, patients suffering from ARDS are mechanically ventilated. Recently it was shown that low tidal volume ventilation reduces mortality and pro-inflammatory mediator release in these patients, suggesting biotrauma as a side effect of mechanical ventilation. Because the application of exogenous surfactant has been proposed as a treatment for ARDS, we investigated the effect of surfactant on ventilation-induced release of tumor necrosis factor (TNF), interleukin-6 (IL-6) and 6-keto-PGF(1 alpha) (the stable metabolite of prostacyclin) in isolated perfused mouse lungs ventilated with high end-inspiratory pressures. Instillation of 100mg/kg surfactant into the lungs was well tolerated and improved tidal volume, pulmonary compliance and alveolar expansion. Exogenous surfactant increased the ventilation-induced liberation of TNF and IL-6 into the perfusate, but had no effect on the release of 6-keto-PGF(1 alpha). The surfactant preparation used reduced baseline TNF production by murine alveolar macrophages, indicating that the exaggeration of ventilation-induced TNF release cannot be explained by a direct effect of surfactant on these cells. We hypothesize that ventilation-induced mediator release is explained by stretching of lung cells, which is reinforced by surfactant. The findings that in this model of ventilation-induced lung injury exogenous surfactant at the same time improved lung functions and enhanced mediator release suggest that surfactant treatment may prevent barotrauma and augment biotrauma.

To investigate the kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury (ALI).Prospective observational cross-over study.Intensive care unit of a university hospital.Twelve mechanically ventilated patients with ALI.Mechanical ventilation was transiently changed from a lung protective setting with PEEP of 15 cmH(2)O and a V(T) of 5 ml/kg predicted body weight to a more conventional ventilatory setting with PEEP of 5 cmH(2)O and V(T) of 12 ml/kg predicted body weight for a period of 6 h.We examined the profile of interleukin (IL)-1beta, IL-1 receptor antagonist, IL-6, IL-10, and tumor necrosis factor in the plasma of all patients, and in the bronchoalveolar lavage (mini-BAL) fluid of six of these patients. Measurements were performed at baseline, 1 h, and 6 h after each change of the ventilatory setting. Switching to conventional mechanical ventilation was associated with a higher PaO(2) ( P0.05) and a marked increase ( P0.05) of measured plasma cytokines in patients with and without mini-BAL with a maximum after 1 h. Similarly, intraalveolar cytokine concentrations increased with conventional mechanical ventilation. While plasma cytokine levels returned to baseline values, intraalveolar cytokine concentrations further increased when lung protective mechanical ventilation was reestablished.In patients with ALI, initiation of low PEEP and high V(T) mechanical ventilation is associated with cytokine release into circulation which occurred within 1 h. It is independent from BAL procedures and can be reversed by reinstitution of lung protective mechanical ventilation.

Objectives: To determine the effect on compartmentalization of the tumor necrosis factor (TNF)-α response in the lung and systemically after ventilation with high peak inspiratory pressure with and without positive end-expiratory pressure (PEEP). Design and setting: Prospective, randomized, animal study in an experimental laboratory of a university. Subjects and interventions: 85 male Sprague-Dawley rats. Lipopolysaccharide was given intratracheally or intraperitoneally to stimulate TNF-α production; control animals received a similar amount of saline. Animals were subsequently ventilated for 20 min in a pressure control mode with peak inspiratory pressure/PEEP ratio of either 45/0 or 45/10 (frequency 30 bpm, I/E ratio 1:2, FIO2 = 1). Measurements and results: Blood gas tension and arterial pressures were recorded at 1, 10, and 20 min after start of mechanical ventilation. After killing of the animals pressure-volume curves were recorded, and bronchoalveolar lavage (BAL) was performed for assessment of protein content and the small/large surfactant aggregate ratio. TNF-α was determined in serum and BAL. TNF-α levels were significantly increased after lipopolysaccharide stimulation; furthermore ventilation without PEEP resulted in a significant shift of TNF-α to the nonstimulated compartment as opposed to ventilation with a PEEP level of 10 cmH2O. Conclusions: Ventilation strategies which are known to induce ventilation-induced lung injury (VILI) disturb the compartmentalization of the early cytokines response in the lung and systemically. Furthermore, the loss of compartmentalization is a two-way disturbance, with cytokines shifting from the vascular side to the alveolar side and vice versa. A ventilation strategy (PEEP level of 10 cmH2O) which prevents VILI significantly diminished this shift in cytokines.

To evaluate the role of tumor necrosis factor (TNF)-alpha in the pathogenesis of ventilator-induced lung injury, we 1) measured TNF-alpha production in the lung caused by conventional mechanical ventilation (CMV) and 2) evaluated the protective effect of anti-TNF-alpha antibody (Ab) in saline-lavaged rabbit lungs. After they received saline lung lavage, rabbits were intratracheally instilled with 1 mg/kg of polyclonal anti-TNF-alpha Ab in the high-dose group (n = 6), 0.2 mg/kg of anti-TNF-alpha Ab in the low-dose group (n = 6), serum IgG fraction in the Ab control group (n = 6), and saline in the saline control group (n = 7). Animals then underwent CMV for 4 h. Levels of TNF-alpha in lung lavage fluid were significantly higher after CMV than before in both control groups. Pretreatment with intratracheal instillation of high and low doses of anti-TNF-alpha Ab improved oxygenation and respiratory compliance, reduced the infiltration of leukocytes, and ameliorated pathological findings. CMV led to TNF-alpha production in the lungs, and intratracheal instillation of anti-TNF-alpha Ab attenuated CMV-induced lung injury in this model.

Mechanical ventilation is the most widely used therapy in intensive care units and the cornerstone treatment for patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) 1. Although essential for successful management of respiratory failure, mechanical ventilation can also exacerbate or even directly injure the lungs 2, 3. This damage, commonly referred to as ventilator-induced lung injury (VILI), is characterised by increased permeability of the alveolar epithelium to fluids and macromolecules 4. Mechanisms leading to such increase include direct mechanical damage caused by excessive stretch of the lungs (barotrauma and volutrauma) or by repetitive opening and closing of recruitable alveolar units (atelectrauma) 3. In addition, mechanical stretch alone can trigger mechanotransduction pathways that may lead to local 5 and systemic inflammatory responses (biotrauma) 6. To understand each of these mechanisms and their relative contribution to the pathogenesis of VILI, several in vitro strategies have been adopted. One of these strategies is to subject cells cultured on deformable substrates to stretch patterns mimicking those experienced by lung cells during mechanical ventilation 7–9. This approach has provided a wealth of knowledge regarding the biological consequences of overstretching lung cells. It is well known, for instance, that large stretches induce: apoptosis, the release of inflammatory cytokines, structural changes in tight junctions, and plasma membrane breaks 3, 8–10. A major drawback of in vitro stretch systems, however, is that the final readout is generally limited to biochemical markers. Stretch-induced synthesis, secretion and (de)phosphorylation of proteins as well as levels of mRNA production have become routinely available, but a quantitative analysis of microstructural changes in the epithelium and their influence on epithelial permeability has remained virtually inaccessible. To overcome this limitation, Cavanaugh et al. 11 recently developed a technique …

he acute respiratory distress syndrome (ARDS) mor-tality decreased dramatically in the last 35 years with-out any specific treatment or new drug. In this period, we learned that aggressive mechanical ventilation (MV) may induce lung injury (oxygen toxicity, volutrauma, atelectrauma, and biotrauma), worsening the prognosis and increasing the mortality rate. Experimental studies and robust researches enrolling adult patients have demonstrated that adopting a protective lung strategy based on low tidal volumes (

Despite over 40 years of research, there is no specific lung-directed therapy for the acute respiratory distress syndrome (ARDS). Although much has evolved in our understanding of its pathogenesis and factors affecting patient outcome, supportive care with mechanical ventilation remains the cornerstone of treatment. Perhaps the most important advance in ARDS research has been the recognition that mechanical ventilation, although necessary to preserve life, can itself aggravate or cause lung damage through a variety of mechanisms collectively referred to as ventilator-induced lung injury (VILI). This improved understanding of ARDS and VILI has been important in designing lung-protective ventilatory strategies aimed at attenuating VILI and improving outcomes. Considerable effort has been made to enhance our mechanistic understanding of VILI and to develop new ventilatory strategies and therapeutic interventions to prevent and ameliorate VILI with the goal of improving outcomes in patients with ARDS. In this review, we will review the pathophysiology of VILI, discuss a number of novel physiological approaches for minimizing VILI, therapies to counteract biotrauma, and highlight a number of experimental studies to support these concepts.

In a recent issue of the British Journal of Anaesthesia, Moloney and Griffiths reviewed clinically pertinent issues surrounding the management of the acute respiratory distress syndrome (ARDS) patient, particularly as it pertains to the treatment of ventilator induced/associated lung injury (VILI). In addition to highlighting the important observations that have contributed to further our understanding of the relationship between the mechanical ventilator and inflammatory lung injury, the authors also offer a concise reappraisal of the clinical strategies used to minimize VILI in ARDS. Special emphasis is placed on the theory of biotrauma, which attempts to explain how multi-organ failure may develop in patients who ultimately succumb to this syndrome.

The purpose of mechanical ventilation is to rest the respiratory muscles while providing adequate gas exchange. Ventilatory support proved to be indispensable during the 1952 polio epidemic in Copenhagen, decreasing mortality among patients with paralytic polio from more than 80% to approximately 40%.1 Despite the clear benefits of this therapy, many patients eventually die after the initiation of mechanical ventilation, even though their arterial blood gases may have normalized. This mortality has been ascribed to multiple factors, including complications of ventilation such as barotrauma (i.e., gross air leaks), oxygen toxicity, and hemodynamic compromise.2,3 During the polio epidemic, investigators noted that mechanical ventilation could cause structural damage to the lung.4 In 1967, the term “respirator lung” was coined to describe the diffuse alveolar infiltrates and hyaline membranes that were found on postmortem examination of patients who had undergone mechanical ventilation.5 More recently, there has been a renewed focus on the worsening injury that mechanical ventilation can cause in previously damaged lungs and the damage it can initiate in normal lungs. This damage is characterized pathologically by inflammatory-cell infiltrates, hyaline membranes, increased vascular permeability, and pulmonary edema. The constellation of pulmonary consequences of mechanical ventilation has been termed ventilator-induced lung injury. The concept of ventilator-induced lung injury is not new. In 1744, John Fothergill discussed a case of a patient who was “dead in appearance” after exposure to coal fumes and who was successfully treated by mouth-to-mouth resuscitation.6 Fothergill noted that mouth-to-mouth resuscitation was preferable to using bellows because “the lungs of one man may bear, without injury, as great a force as those of another man can exert; which by the bellows cannot always be determin'd.” Fothergill clearly understood the concept that mechanical forces generated by bellows (i.e., a ventilator) could lead to injury. However, it was not until early in this century that the clinical importance of ventilator-induced lung injury in adults was confirmed by a study showing that a ventilator strategy designed to minimize such injury decreased mortality among patients with the acute respiratory distress syndrome (ARDS).7 Given the clinical importance of ventilator-induced lung injury, this article will review mechanisms underlying the condition, its biologic and physiological consequences, and clinical strategies to prevent it and mitigate its effects.

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.

Ventilator-induced lung injury in children and adults is characterized by an initial inflammatory phase. To investigate whether the inflammatory cytokine, IL-1, plays a role in this process, a rabbit model of ventilator-induced injury was created. Animals maintained under pentobarbital anesthesia were primed for injury by undergoing lung lavage with 22 mL/kg of saline and then ventilated for 8 h with either FIO2 0.21 and normal pressures or FIO2 1.0 and high ventilator pressures. The animals exposed to hyperoxia/hyperventilation demonstrated a greater increase in lung lavage neutrophil counts and a higher histological injury score, as well as a faster decline in oxygenation compared to the control animals. A third group of rabbits received 800 micrograms of recombinant IL-1 receptor antagonist after lung lavage and prior to the exposure to FIO2 1.0 and high ventilator pressures. These animals had significantly lower concentrations of albumin and elastase and lower neutrophil counts in their lungs after the 8-h ventilatory period compared to hyperoxia/hyperventilation rabbits. IL-1 blockade had no effect on the decline in dynamic compliance and oxygenation seen in saline-treated hyperoxic/hyperventilated rabbits. IL-1 is a mediator of acute inflammation due to ventilator-induced lung injury.

Mechanical ventilation of the lungs, as an important therapeutic measure, cannot be avoided in critically ill patients. However, when machines take over some of vital functions there is always a risk of complications and accidents. Complications associated with mechanical ventilation can be divided into: 1) airway-associated complications; 2) complications in the response of patients to mechanical ventilation; and 3) complications related to the patient?s response to the device for mechanical ventilation. Complications of artificial airway may be related to intubation and extubation or the endotracheal tube. Complications of mechanical ventilation, which arise because of the patient?s response to mechanical ventilation, may primarily cause significant side effects to the lungs. During the last two decades it was concluded that mechanical ventilation can worsen or cause acute lung injury. Mechanical ventilation may increase the alveolar/capillary permeability by overdistension of the lungs (volutrauma), it can exacerbate lung damage due to the recruitment/derecruitment of collapsed alveoli (atelectrauma) and may cause subtle damages due to the activation of inflammatory processes (biotrauma). Complications caused by mechanical ventilation, beside those involving the lungs, can also have significant effects on other organs and organic systems, and can be a significant factor contributing to the increase of morbidity and mortality in critically ill of mechanically ventilated patients. Complications are fortunately rare and do not occur in every patient, but due to their seriousness and severity they require extensive knowledge, experience and responsibility by health-care workers.

Depending on the applied ventilation strategy, mechanical ventilation leads to alveolar epithelial and capillary endothelial damage. Protective ventilatory approaches try to minimize this biotrauma while still ensuring sufficient gas exchange. However, the optimization of ventilation strategies is hampered by the lack of insights into the cellular and molecular mechanisms underlying ventilator-induced lung injury, and by the lack of morphological and biomechanical information pertinent to the development of suitable computational and experimental models for ventilation-dependent biofluid mechanics [13, 15, 30].