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RATIONALE: Conventional positive-pressure ventilation delivers pressure to the airways; in contrast, negative pressure is delivered globally to the chest and abdomen. OBJECTIVES: To test the hypothesis that ventilation with negative pressure results in better oxygenation and less injury than with positive pressure. METHODS: Anesthetized, surfactant-depleted rabbits were ventilated for 2.5 hours in pairs (positive or negative). Tidal volume was 12 ml . kg(-1), normocapnia was maintained by adjusting respiratory rate, and Fi(O(2)) was 1.0. MEASUREMENTS AND MAIN RESULTS: Lung injury was assessed with histologic scoring, perfusion using thermodilution (global perfusion), and injected intravascular microspheres (regional perfusion); and dynamic computed tomography was used to determine inflation patterns. Negative pressure was associated with a higher Pa(O(2)), a lower Pa-Pet(CO(2)) gradient (despite identical minute ventilation), and less lung injury. Lung perfusion (global and regional) was similar with positive and negative pressure. Positive end-expiratory pressure applied to the airway was more efficiently transmitted to the pleural space than comparable levels of negative end-expiratory pressure applied to the chest wall; however, the oxygenation associated with any level of end-expiratory lung volume was greater when achieved by negative versus positive pressure. Dynamic computed tomography suggested that lung distension achieved with negative pressure is characterized by greater proportions of normally aerated lung (with less atelectasis) during inspiration and at end-expiration. CONCLUSIONS: Negative-pressure ventilation results in superior oxygenation that is unrelated to lung perfusion and may be explained by more effective inflation of lung volume during both inspiration and expiration. [ABSTRACT FROM AUTHOR]

Rationale: Many authors have suggested that the mechanism by which atelectasis contributes to injury is through the repetitive opening and closing of distal airways in lung regions that are atelectatic. However, neither the topographic nor mechanistic relationships between atelectasis and distribution of lung injury are known. Objectives: To investigate how atelectasis contributes to ventilator-induced lung injury. Methods: Surfactant depletion was performed in anesthetized rats that were then allocated to noninjurious or injurious ventilation for 90 min. Measurements: Lung injury was quantified by gas exchange, compliance, histology, wet-to-dry weight, and cytokine expression, and its distribution by histology, stereology, cytokine mRNA expression, in situ hybridization, and immunohistochemistry. Functional residual capacity, percent atelectasis, and injury-induced lung water accumulation were measured using gravimetric and volumetric techniques. Main Results: Atelectasis occurred in the dependent lung regions. Injurious ventilation was associated with alveolar and distal airway injury, while noninjurious ventilation was not. With injurious ventilation, alveolar injury (i.e., histology, myeloperoxidase protein expression, quantification, and localization of cytokine mRNA expression) was maximal in nondependent regions, whereas distal airway injury was equivalent in atelectatic and nonatelectatic regions. Conclusions: These data support the notion that lung injury associated with atelectasis involves trauma to the distal airways. We provide topographic and biochemical evidence that such distal airway injury is not localized solely to atelectatic areas, but is instead generalized in both atelectatic and nonatelectatic lung regions. In contrast, alveolar injury associated with atelectasis does not occur in those areas that are atelectatic but occurs instead in remote nonatelectatic alveoli. [ABSTRACT FROM AUTHOR]

Rationale: Ventilator-induced lung injury has been predominantly studied in adults., Objectives: To explore the effects of age and lung development on susceptibility to such injury., Methods: Ex vivo isolated nonperfused rat lungs (infant, juvenile, and adult) were mechanically ventilated where VT was based on milliliters per kilogram of body weight or as a percentage of the measured total lung capacity (TLC). In vivo anesthetized rats (infant, adult) were mechanically ventilated with pressure-limited VTs. Allocation to ventilation strategy was randomized., Measurements: Ex vivo injury was assessed by pressure-volume analysis, reduction in TLC, and histology, and in vivo injury by lung compliance, cytokine production, and wet- to dry-weight ratio., Main Results: Ex vivo ventilation (VT 30 ml.kg(-1)) resulted in a significant reduction (36.0 +/- 10.1%, p < 0.05) in TLC in adult but not in infant lungs. Ex vivo ventilation (VT 50% TLC) resulted in a significant reduction in TLC in both adult (27.8 +/- 2.8%) and infant (10.6 +/- 7.0%) lungs, but more so in the adult lungs (p < 0.05); these changes were paralleled by histology and pressure-volume characteristics. After high stretch in vivo ventilation, adult but not infant rats developed lung injury (total lung compliance, wet/dry ratio, tumor necrosis factor alpha). Surface video microscopy demonstrated greater heterogeneity of alveolar distension in ex vivo adult versus infant lungs., Conclusion: These data provide ex vivo and in vivo evidence that comparable ventilator settings are significantly more injurious in the adult than infant rat lung, probably reflecting differences in intrinsic susceptibility or inflation pattern.

We investigated the effect of high VT ventilation on adult and newborn rats by examining pulmonary injury and cytokine messenger RNA (mRNA). On the basis of compliance, edema formation, and histology, ventilation with 25 ml.kg(-1) was more injurious to adult rats than newborns. Ventilation with 40 ml kg(-1) minimally affected compliance in newborns but caused death in adults. Ventilation of adults for 30 minutes at 25 ml kg(-1) upregulated the mRNA expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2), and IL-10, whereas in newborns such ventilation only increased mRNA expression of MIP-2 and IL-10. When VT was raised to 40 ml kg(-1) in newborns, IL-1beta mRNA levels were additionally increased at 30 minutes, whereas ventilation for 3 hours additionally increased IL-6 and TNF-alpha mRNA. In newborns, the addition of 100% oxygen (O2) to 30 minutes of ventilation blunted the high VT induction of IL-1beta, IL-10, and MIP-2 mRNA expressions, whereas at 3 hours, 100% O2 concentration synergistically increased the mRNAs for TNF-alpha and IL-6. Overall, adult rats are more susceptible to high VT-induced lung injury compared with newborns. In newborns, the inflammatory response is dependent on VT, duration, and supplemental O2. Thus, recommendations for VT limitation based on adult data may be inappropriate for newborns.

Hypercapnic acidosis protects against direct lung injury in in vivo and ex vivo models, however, lung injury/acute respiratory distress syndrome commonly occurs after a nonpulmonary etiology. We investigated whether therapeutic hypercapnia (TH)-deliberate elevation of carbon dioxide (CO2) tension-would protect against lung injury after splanchnic ischemia-reperfusion injury in an in vivo model. TH was associated with preservation of lung mechanics, attenuation of protein leakage, and improved oxygenation compared with control conditions. Lung protection was therapeutic as well as prophylactic. Protection was dose-dependent, but inspired CO2 concentrations above 5.0% were associated with little additional lung protection. Before lung injury, increasing FICO2 resulted in a dose-dependent increase in PaO2. Lung protection with hypercapnia occurred despite pulmonary artery pressures that were greater than observed with normocapnia. Reperfusion increased lipid peroxidation (tissue 8-isoprostane concentration) in the bowel, liver, and lung, and caused histologically apparent bowel injury; however, none of these effects was altered by TH. Therefore, TH-induced by adding CO2 to inspired gas-provides consistent protection against lung injury in terms of lung permeability, oxygenation, and lung mechanics after mesenteric ischemia-reperfusion. These data further support the emerging evidence for ongoing physiologic study of TH at the bedside.

The purpose of this study was to use gene expression profiling to understand how adult rat lung responds to high tidal volume (HV) ventilation in vivo. HV ventilation for 30 minutes did not cause discernable lung injury (in terms of altered mechanics or histology) but caused obvious injury when continued for 90 minutes. However, at 30-minute ventilation, HV caused significant upregulation of 10 genes and suppression of 12 genes. Among the upregulated genes were transcription factors, stress proteins, and inflammatory mediators; the downregulated genes were exemplified by metabolic regulatory genes. On the basis of cluster analysis, we studied Egr-1, c-Jun, heat shock protein 70, and interleukin (IL)-1beta in further detail. Temporal studies demonstrated that Egr-1 and c-Jun were increased early and before heat shock protein 70 and IL-1beta. Spatial studies using in situ hybridization and laser capture microscopy revealed that all four genes were upregulated primarily in the bronchiolar airway epithelium. Furthermore, at 90 minutes of HV ventilation, a significant increase in intracellular IL-1beta protein was observed. Although there are limitations to gene array methodology, the current data suggest a global hypothesis that (1). the effects of HV are cumulative; (2). specific patterns of gene activation and suppression precede lung injury; and (3). alteration of gene expression after mechanical stretch is pathogenic.