We examined the effect of ventilation strategy on lung inflammatory mediators in the presence and absence of a preexisting inflammatory stimulus. 55 Sprague-Dawley rats were randomized to either intravenous saline or lipopolysaccharide (LPS). After 50 min of spontaneous respiration, the lungs were excised and randomized to 2 h of ventilation with one of four strategies: (a) control (C), tidal volume (Vt) = 7 cc/kg, positive end expiratory pressure (PEEP) = 3 cm H2O; (b) moderate volume, high PEEP (MVHP), Vt = 15 cc/kg; PEEP = 10 cm H2O; (c) moderate volume, zero PEEP (MVZP), Vt = 15 cc/kg, PEEP = 0; or (d) high volume, zero PEEP (HVZP), Vt = 40 cc/kg, PEEP = 0. Ventilation with zero PEEP (MVZP, HVZP) resulted in significant reductions in lung compliance. Lung lavage levels of TNFalpha, IL-1beta, IL-6, IL-10, MIP-2, and IFNgamma were measured by ELISA. Zero PEEP in combination with high volume ventilation (HVZP) had a synergistic effect on cytokine levels (e.g., 56-fold increase of TNFalpha versus controls). Identical end inspiratory lung distention with PEEP (MVHP) resulted in only a three-fold increase in TNFalpha, whereas MVZP produced a six-fold increase in lavage TNFalpha. Northern blot analysis revealed a similar pattern (C, MVHP < MVZP < HVZP) for induction of c-fos mRNA. These data support the concept that mechanical ventilation can have a significant influence on the inflammatory/anti-inflammatory milieu of the lung, and thus may play a role in initiating or propagating a local, and possibly systemic inflammatory response.

Rationale: Lung injury caused by a ventilator results from nonphysiologic lung stress (transpulmonary pressure) and strain (inflated volume to functional residual capacity ratio). Objectives: To determine whether plateau pressure and tidal volume are adequate surrogates for stress and strain, and to quantify the stress to strain relationship in patients and control subjects. Methods: Nineteen postsurgical healthy patients (group 1), 11 patients with medical diseases (group 2), 26 patients with acute lung injury (group 3), and 24 patients with acute respiratory distress syndrome (group 4) underwent a positive end-expiratory pressure (PEEP) trial (5 and 15 cm H2O) with 6, 8, 10, and 12 ml/kg tidal volume. Measurements and Main Results: Plateau airway pressure, lung and chest wall elastances, and lung stress and strain significantly increased from groups 1 to 4 and with increasing PEEP and tidal volume. Within each group, a given applied airway pressure produced largely variable stress due to the variability of the lung elastance to respiratory system elastance ratio (range, 0.33–0.95). Analogously, for the same applied tidal volume, the strain variability within subgroups was remarkable, due to the functional residual capacity variability. Therefore, low or high tidal volume, such as 6 and 12 ml/kg, respectively, could produce similar stress and strain in a remarkable fraction of patients in each subgroup. In contrast, the stress to strain ratio—that is, specific lung elastance—was similar throughout the subgroups (13.4 ± 3.4, 12.6 ± 3.0, 14.4 ± 3.6, and 13.5 ± 4.1 cm H2O for groups 1 through 4, respectively; P = 0.58) and did not change with PEEP and tidal volume. Conclusions: Plateau pressure and tidal volume are inadequate surrogates for lung stress and strain. Clinical trial registered with www.clinicaltrials.gov (NCT 00143468).

This report summarizes current physiological and technical knowledge on esophageal pressure (Pes) measurements in patients receiving mechanical ventilation. The respiratory changes in Pes are representative of changes in pleural pressure. The difference between airway pressure (Paw) and Pes is a valid estimate of transpulmonary pressure. Pes helps determine what fraction of Paw is applied to overcome lung and chest wall elastance. Pes is usually measured via a catheter with an air-filled thin-walled latex balloon inserted nasally or orally. To validate Pes measurement, a dynamic occlusion test measures the ratio of change in Pes to change in Paw during inspiratory efforts against a closed airway. A ratio close to unity indicates that the system provides a valid measurement. Provided transpulmonary pressure is the lung-distending pressure, and that chest wall elastance may vary among individuals, a physiologically based ventilator strategy should take the transpulmonary pressure into account. For monitoring purposes, clinicians rely mostly on Paw and flow waveforms. However, these measurements may mask profound patient–ventilator asynchrony and do not allow respiratory muscle effort assessment. Pes also permits the measurement of transmural vascular pressures during both passive and active breathing. Pes measurements have enhanced our understanding of the pathophysiology of acute lung injury, patient–ventilator interaction, and weaning failure. The use of Pes for positive end-expiratory pressure titration may help improve oxygenation and compliance. Pes measurements make it feasible to individualize the level of muscle effort during mechanical ventilation and weaning. The time is now right to apply the knowledge obtained with Pes to improve the management of critically ill and ventilator-dependent patients.

The distribution of tidal volume (VT) and recruitment was investigated by chest computed tomography (CT) in eight sedated-paralyzed patients with the adult respiratory distress syndrome (ARDS). A CT section was obtained in the supine position at 0, 5, 10, 15, and 20 cm H2O positive end-expiratory pressure (PEEP) and at the corresponding inspiratory plateau pressure (21 +/- 1.8, 26 +/- 1.4, 31 +/- 1.8, 38 +/- 2.1, and 46 +/- 3.2 cm H2O [mean +/- SE]), keeping VT constant. Each CT section was divided along its ventral-dorsal height into 10 equally spaced intervals (levels). Vi(insp) and Vi(exp) were defined as the gas volume for level i (i = 1 to 10) at end-inspiration and at end-expiration, respectively. The following variables were computed at each lung level: (1) distribution of CT section tidal volume (VTct), i.e., the fraction of VT that inflates a given lung level; (2) the plateau-induced and PEEP-induced recruitment, i.e., the amount of lung tissue previously collapsed that inflates at plateau pressure and at PEEP, respectively; (3) the reopening-collapsing tissue, i.e., the amount of lung tissue that regains inflation at plateau pressure and collapses at PEEP. With increasing PEEP from 0 to 20 cm H2O, the VTct distribution decreased significantly (p < 0.01) in the upper levels, did not change in the middle levels, and increased significantly (p < 0.01) in the lower levels.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied 16 patients with acute lung injury receiving volume-controlled ventilation to assess the relationships between gas exchange and respiratory mechanics before, during, and after 2 h in the prone position. We measured the end-expiratory lung volume (EELV, helium dilution), the total respiratory system (Cst,rs), the lung (Cst,L) and the thoracoabdominal cage (Cst,w) compliances (end- inspiratory occlusion technique and esophageal balloon), the hemodynamics, and gas exchange. In the prone position, PaO2 increased from 103.2 ± 23.8 to 129.3 ± 32.9 mm Hg (p < 0.05) without significant changes of Cst,rs and EELV. However, Cst,w decreased from 204.8 ± 97.4 to 135.9 ± 52.5 ml/ cm H2O (p < 0.01) and the decrease was correlated with the oxygenation increase (r = 0.62, p < 0.05). Furthermore, the greater the baseline supine Cst,w, the greater its decrease in the prone position (r = 0.82, p < 0.01). Consequently, the oxygenation changes in the prone position were predictable from baseline supine Cst,w (r = 0.80, p < 0.01). Returning to the supine position, Cst,rs increased compared with baseline (42.3 ± 14.4 versus 38.4 ± 13.7 ml/cm H2O; p < 0.01), mainly because of the lung component (57.5 ± 25.1 versus 52.4 ± 23.3 ml/cm H2O; p < 0.01). Thus, (1) baseline Cst,w and its changes may play a role in determining the oxygenation response in the prone position; (2) the prone position improves Cst,rs and Cst,L when the supine position is resumed.

Ventilator-induced lung injury is a side-effect of mechanical ventilation. Its prevention or attenuation implies knowledge of the sequence of events that lead from mechanical stress to lung inflammation and stress at rupture.A literature review was undertaken which focused on the link between the mechanical forces in the diseased lung and the resulting inflammation/rupture.The distending force of the lung is the transpulmonary pressure. This applied force, in a homogeneous lung, is shared equally by each fibre of the lung's fibrous skeleton. In a nonhomogeneous lung, the collapsed or consolidated regions do not strain, whereas the neighbouring fibres experience excessive strain. Indeed, if the global applied force is excessive, or the fibres near the diseased regions experience excessive stress/strain, biological activation and/or mechanical rupture are observed. Excessive strain activates macrophages and epithelial cells to produce interleukin‐8. This cytokine recruits neutrophils, with consequent full-blown inflammation.In order to prevent initiation of ventilator-induced lung injury, transpulmonary pressure must be kept within the physiological range. The prone position may attenuate ventilator-induced lung injury by increasing the homogeneity of transpulmonary pressure distribution. Positive end-expiratory pressure may prevent ventilator-induced lung injury by keeping open the lung, thus reducing the regional stress/strain maldistribution. If the transpulmonary pressure rather than the tidal volume per kilogram of body weight is taken into account, the contradictory results of the randomised trials dealing with different strategies of mechanical ventilation may be better understood.