Beyond volutrauma in ARDS: the critical role of lung tissue deformation

Ventilator-induced lung injury (VILI) consists of tissue damage and a biological response resulting from the application of inappropriate mechanical forces to the lung parenchyma. The current paradigm attributes VILI to overstretching due to very high-volume ventilation (volutrauma) and cyclic changes in aeration due to very low-volume ventilation (atelectrauma); however, this model cannot explain some research findings. In the present review, we discuss the relevance of cyclic deformation of lung tissue as the main determinant of VILI. Parenchymal stability resulting from the interplay of respiratory parameters such as tidal volume, positive end-expiratory pressure or respiratory rate can explain the results of different clinical trials and experimental studies that do not fit with the classic volutrauma/atelectrauma model. Focusing on tissue deformation could lead to new bedside monitoring and ventilatory strategies

Comparative study of four sigmoid models of pressure-volume curve in acute lung injury

BACKGROUND: The pressure-volume curve of the respiratory system is a tool to monitor and set mechanical ventilation in acute lung injury. Mathematical models of the static pressure-volume curve of the respiratory system have been proposed to overcome the inter- and intra-observer variability derived from eye-fitting. However, different models have not been compared. METHODS: The goodness-of-fit and the values of derived parameters (upper asymptote, maximum compliance and points of maximum curvature) in four sigmoid models were compared, using pressure-volume data from 30 mechanically ventilated patients during the early phase of acute lung injury. RESULTS: All models showed an excellent goodness-of-fit (R(2 )always above 0.92). There were significant differences between the models in the parameters derived from the inspiratory limb, but not in those derived from the expiratory limb of the curve. The within-case standard deviations of the pressures at the points of maximum curvature ranged from 2.33 to 6.08 cmH(2)O. CONCLUSION: There are substantial variabilities in relevant parameters obtained from the four different models of the static pressure-volume curve of the respiratory system

A Simple Procedure to Measure the Tidal Volume Delivered by Mechanical Ventilators: A Tool for Bedside Verification and Quality Control

Mechanical ventilation is the most extensively employed life support intervention among patients with severe respiratory fail ure of different etiologies. In this context, consistent delivery of the most suitable tidal volume (VT) to the patientis criticalto achieving personalized mechanical ventilation. Indeed, in addition to its con tribution to minute volume for optimization of blood gas exchange,appropriate VT strategies are critical to avoid ventilator-induced lung injury in the general context of lung-protective ventilation and when specifically applying ultra-low tidal volume ventilation. Additionally, VT is required to compute respiratory system com pliance or ventilatory ratio, useful indices in the classification of patient phenotype and estimation of prognosis

Ventilatory support in critically ill hematology patients with respiratory failure

Introduction: Hematology patients admitted to the ICU frequently experience respiratory failure and require mechanical ventilation. Noninvasive mechanical ventilation (NIMV) may decrease the risk of intubation, but NIMV failure poses its own risks. Methods: To establish the impact of ventilatory management and NIMV failure on outcome, data from a prospective, multicenter, observational study were analyzed. All hematology patients admitted to one of the 34 participating ICUs in a 17-month period were followed up. Data on demographics, diagnosis, severity, organ failure, and supportive therapies were recorded. A logistic regression analysis was done to evaluate the risk factors associated with death and NIVM failure. Results: Of 450 patients, 300 required ventilatory support. A diagnosis of congestive heart failure and the initial use of NIMV significantly improved survival, whereas APACHE II score, allogeneic transplantation, and NIMV failure increased the risk of death. The risk factors associated with NIMV success were age, congestive heart failure, and bacteremia. Patients with NIMV failure experienced a more severe respiratory impairment than did those electively intubated. Conclusions: NIMV improves the outcome of hematology patients with respiratory insufficiency, but NIMV failure may have the opposite effect. A careful selection of patients with rapidly reversible causes of respiratory failure may increase NIMV success

Resistance to Bleomycin-Induced Lung Fibrosis in MMP-8 Deficient Mice Is Mediated by Interleukin-10

BACKGROUND: Matrix metalloproteinases (MMPs) may have pro and antifibrotic roles within the lungs, due to its ability to modulate collagen turnover and immune mediators. MMP-8 is a collagenase that also cleaves a number of cytokines and chemokines. METHODOLOGY AND PRINCIPAL FINDINGS: To evaluate its relevance in lung fibrosis, wildtype and Mmp8(-/-) mice were treated with either intratracheal bleomycin or saline, and lungs were harvested at different time points. Fibrosis, collagen, collagenases, gelatinases, TGFβ and IL-10 were measured in lung tissue. Mmp8(-/-) mice developed less fibrosis than their wildtype counterparts. This was related to an increase in lung inflammatory cells, MMP-9 and IL-10 levels in these mutant animals. In vitro experiments showed that MMP-8 cleaves murine and human IL-10, and tissue from knockout animals showed decreased IL-10 processing. Additionally, lung fibroblasts from these mice were cultured in the presence of bleomycin and collagen, IL-10 and STAT3 activation (downstream signal in response to IL-10) measured by western blotting. In cell cultures, bleomycin increased collagen synthesis only in wildtype mice. Fibroblasts from knockout mice did not show increased collagen synthesis, but increased levels of unprocessed IL-10 and STAT3 phosphorylation. Blockade of IL-10 reverted this phenotype, increasing collagen in cultures. CONCLUSIONS: According to these results, we conclude that the absence of MMP-8 has an antifibrotic effect by increasing IL-10 and propose that this metalloprotease could be a relevant modulator of IL-10 metabolism in vivo

Activation of p21 limits acute lung injury and induces early senescence after acid aspiration and mechanical ventilation

The p53/p21 pathway is activated in response to cell stress. However, its role in acute lung injury has not been elucidated. Acute lung injury is associated with disruption of the alveolo-capillary barrier leading to acute respiratory distress syndrome (ARDS). Mechanical ventilation may be necessary to support gas exchange in patients with ARDS, however, high positive airway pressures can cause regional overdistension of alveolar units and aggravate lung injury. Here, we report that acute lung injury and alveolar overstretching activate the p53/p21 pathway to maintain homeostasis and avoid massive cell apoptosis. A systematic pooling of transcriptomic data from animal models of lung injury demonstrates the enrichment of specific p53- and p21-dependent gene signatures and a validated senescence profile. In a clinically relevant, murine model of acid aspiration and mechanical ventilation, we observed changes in the nuclear envelope and the underlying chromatin, DNA damage and activation of the Tp53/p21 pathway. Absence of Cdkn1a decreased the senescent response, but worsened lung injury due to increased cell apoptosis. Conversely, treatment with lopinavir/ritonavir led to Cdkn1a overexpression and ameliorated cell apoptosis and lung injury. The activation of these mechanisms was associated with early markers of senescence, including expression of senescence-related genes and increases in senescence-associated heterochromatin foci in alveolar cells. Autopsy samples from lungs of patients with ARDS revealed increased senescence-associated heterochromatin foci. Collectively, these results suggest that acute lung injury activates p53/p21 as an anti-apoptotic mechanism to ameliorate damage, but with the side effect of induction of senescence