Inflammatory Activity in Atelectatic and Normally Aerated Regions During Early Acute Lung Injury.

RATIONALE AND OBJECTIVES: Pulmonary atelectasis presumably promotes and facilitates lung injury. However, data are limited on its direct and remote relation to inflammation. We aimed to assess regional 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) kinetics representative of inflammation in atelectatic and normally aerated regions in models of early lung injury. MATERIALS AND METHODS: We studied supine sheep in four groups: Permissive Atelectasis (n = 6)-16 hours protective tidal volume (VT) and zero positive end-expiratory pressure; Mild (n = 5) and Moderate Endotoxemia (n = 6)- 20-24 hours protective ventilation and intravenous lipopolysaccharide (Mild = 2.5 and Moderate = 10.0 ng/kg/min), and Surfactant Depletion (n = 6)-saline lung lavage and 4 hours high VT. Measurements performed immediately after anesthesia induction served as controls (n = 8). Atelectasis was defined as regions of gas fraction <0.1 in transmission or computed tomography scans. 18F-FDG kinetics measured with positron emission tomography were analyzed with a three-compartment model. RESULTS: 18F-FDG net uptake rate in atelectatic tissue was larger during Moderate Endotoxemia (0.0092 ± 0.0019/min) than controls (0.0051 ± 0.0014/min, p = 0.01). 18F-FDG phosphorylation rate in atelectatic tissue was larger in both endotoxemia groups (0.0287 ± 0.0075/min) than controls (0.0198 ± 0.0039/min, p = 0.05) while the 18F-FDG volume of distribution was not significantly different among groups. Additionally, normally aerated regions showed larger 18F-FDG uptake during Permissive Atelectasis (0.0031 ± 0.0005/min, p < 0.01), Mild (0.0028 ± 0.0006/min, p = 0.04), and Moderate Endotoxemia (0.0039 ± 0.0005/min, p < 0.01) than controls (0.0020 ± 0.0003/min). CONCLUSION: Atelectatic regions present increased metabolic activation during moderate endotoxemia mostly due to increased 18F-FDG phosphorylation, indicative of increased cellular metabolic activation. Increased 18F-FDG uptake in normally aerated regions during permissive atelectasis suggests an injurious remote effect of atelectasis even with protective tidal volumes.

Regional Lung Recruitability During Pneumoperitoneum Depends on Chest Wall Elastance - A Mechanical and Computed Tomography Analysis in Rats.

Background: Laparoscopic surgery with pneumoperitoneum increases respiratory system elastance due to the augmented intra-abdominal pressure. We aim to evaluate to which extent positive end-expiratory pressure (PEEP) is able to counteract abdominal hypertension preventing progressive lung collapse and how rib cage elastance influences PEEP effect. Methods: Forty-four Wistar rats were mechanically ventilated and randomly assigned into three groups: control (CTRL), pneumoperitoneum (PPT) and pneumoperitoneum with restricted rib cage (PPT-RC). A pressure-volume (PV) curve followed by a recruitment maneuver and a decremental PEEP trial were performed in all groups. Thereafter, animals were ventilated using PEEP of 3 and 8 cmH2O divided into two subgroups used to evaluate respiratory mechanics or computed tomography (CT) images. In 26 rats, we compared respiratory system elastance (Ers) at the two PEEP levels. In 18 animals, CT images were acquired to calculate total lung volume (TLV), total volume and air volume in six anatomically delimited regions of interest (three along the cephalo-caudal and three along the ventro-dorsal axes). Results: PEEP of minimal Ers was similar in CTRL and PPT groups (3.8 ± 0.45 and 3.5 ± 3.89 cmH2O, respectively) and differed from PPT-RC group (9.8 ± 0.63 cmH2O). Chest restriction determined a right- and downward shift of the PV curve, increased Ers and diminished TLV and lung aeration. Increasing PEEP augmented TLV in CTRL group (11.8 ± 1.3 to 13.6 ± 2 ml, p < 0.05), and relative air content in the apex of PPT group (3.5 ± 1.4 to 4.6 ± 1.4% TLV, p < 0.03) and in the middle zones in PPT-RC group (21.4 ± 1.9 to 25.3 ± 2.1% TLV cephalo-caudally and 18.1 ± 4.3 to 22.0 ± 3.3% TLV ventro-dorsally, p < 0.005). Conclusion: Regional lung recruitment potential during pneumoperitoneum depends on rib cage elastance, reinforcing the concept of PEEP individualization according to the patient's condition.

Lower follicular fluid vitamin D concentration is related to a higher number of large ovarian follicles.

Vitamin D receptor-knockout mice fail to produce mature oocytes, indicating vitamin D is crucial for folliculogenesis in mice. However, the actions of vitamin D during folliculogenesis remain unknown. This prospective study aimed to assess whether follicular fluid (FF) vitamin D (25OHD3) concentrations are related to specific responses to ovarian stimulation. Women undergoing ovarian stimulation for IVF participated in the study. FF 25OHD3 concentrations were assessed in the first follicle aspirate on oocyte retrieval day. Oestradiol and progesterone concentrations were assessed on the trigger day. K-means grouping analysis showed that 25OHD3 FF concentrations clustered into a higher and lower group (mean ± SEM 17.4 ± 6.61 ng/ml and 35.5 ± 7.17 ng/ml, respectively, P < 0.001). The clusters were analysed according to the oestradiol and progesterone concentrations, follicle number and size and resulting oocyte number and maturity. The FF 25OHD3 concentrations were no different among the infertility diagnoses. The lower 25OHD3 group had more follicles (≥16.0 mm, P = 0.009) and higher serum oestradiol concentrations (P < 0.03) on the day of HCG administration. In this study, lower follicular 25OHD3 concentrations predicted a better response to ovarian stimulation shown by a greater production of larger follicles and higher serum oestradiol concentrations.

The Role of Multidetector Computed Tomography and the Forced Oscillation Technique in Assessing Lung Damage in Adults With Cystic Fibrosis.

BACKGROUND: With increased survival rates and the consequent emergence of an adult population with cystic fibrosis (CF), developing novel tools for periodic evaluations of these patients has become a new challenge. Thus, we sought to determine the contribution of lung-volume quantification using multidetector computed tomography (CT) in adults with CF and to investigate the association between structural changes and functional abnormalities. METHODS: This was a cross-sectional study in which 21 adults with CF and 22 control subjects underwent lung-volume quantification using multidetector CT. Voxel densities were divided into 4 bands: -1,000 to -900 Hounsfield units (HU) (hyperaerated region), -900 to -500 HU (normally aerated region), -500 to -100 HU (poorly aerated region), and -100 to 100 HU (non-aerated region). In addition, all participants performed pulmonary function tests including spirometry, body plethysmography, diffusion capacity for carbon monoxide, and the forced oscillation technique. RESULTS: Adults with CF had more non-aerated regions and poorly aerated regions with lung-volume quantification using multidetector CT than controls. Despite these abnormalities, total lung volume measured by lung-volume quantification using multidetector CT did not differ between subjects and controls. Total lung capacity (TLC) measured by body plethysmography correlated with both total lung volume (rs = 0.71, P < .001) and total air volume (rs = 0.71, P < .001) as measured with lung-volume quantification using multidetector CT. While the hyperaerated regions correlated with the functional markers of gas retention in the lungs (increased residual volume (RV) and RV/TLC ratio), the poorly aerated regions correlated with the resistive parameters measured by the forced oscillation technique (increased intercept resistance and mean resistance). We also observed a correlation between normally aerated regions and highest pulmonary diffusion values (rs = 0.68, P < .001). CONCLUSIONS: In adults with CF, lung-volume quantification using multidetector CT can destimate the lung volumes of compartments with different densities and determine the aerated and non-aerated contents of the lungs; furthermore, lung-volume quantification using multidetector CT is clearly related to pulmonary function parameters.

Mapping Regional Differences of Local Pressure-Volume Curves With Electrical Impedance Tomography.

OBJECTIVES: Lung-protective mechanical ventilation aims to prevent alveolar collapse and overdistension, but reliable bedside methods to quantify them are lacking. We propose a quantitative descriptor of the shape of local pressure-volume curves derived from electrical impedance tomography, for computing maps that highlight the presence and location of regions of presumed tidal recruitment (i.e., elastance decrease during inflation, pressure-volume curve with upward curvature) or overdistension (i.e., elastance increase during inflation, downward curvature). DESIGN: Secondary analysis of experimental cohort study. SETTING: University research facility. SUBJECTS: Twelve mechanically ventilated pigs. INTERVENTIONS: After induction of acute respiratory distress syndrome by hydrochloric acid instillation, animals underwent a decremental positive end-expiratory pressure titration (steps of 2 cm H2O starting from ≥ 26 cm H2O). MEASUREMENTS AND MAIN RESULTS: Electrical impedance tomography-derived maps were computed at each positive end-expiratory pressure-titration step, and whole-lung CT taken every second steps. Airway flow and pressure were recorded to compute driving pressure and elastance. Significant correlations between electrical impedance tomography-derived maps and positive end-expiratory pressure indicate that, expectedly, tidal recruitment increases in dependent regions with decreasing positive end-expiratory pressure (p < 0.001) and suggest that overdistension increases both at high and low positive end-expiratory pressures in nondependent regions (p < 0.027), supporting the idea of two different scenarios of overdistension occurrence. Significant correlations with CT measurements were observed: electrical impedance tomography-derived tidal recruitment with poorly aerated regions (r = 0.43; p < 0.001); electrical impedance tomography-derived overdistension with nonaerated regions at lower positive end-expiratory pressures and with hyperaerated regions at higher positive end-expiratory pressures (r ≥ 0.72; p < 0.003). Even for positive end-expiratory pressure levels minimizing global elastance and driving pressure, electrical impedance tomography-derived maps showed nonnegligible regions of presumed overdistension and tidal recruitment. CONCLUSIONS: Electrical impedance tomography-derived maps of pressure-volume curve shapes allow to detect regions in which elastance changes during inflation. This could promote individualized mechanical ventilation by minimizing the probability of local tidal recruitment and/or overdistension. Electrical impedance tomography-derived maps might become clinically feasible and relevant, being simpler than currently available alternative approaches.

Integrin αDß2 (CD11d/CD18) mediates experimental malaria-associated acute respiratory distress syndrome (MA-ARDS).

BACKGROUND: Malaria-associated acute respiratory distress syndrome (MA-ARDS) is a potentially lethal complication of clinical malaria. Acute lung injury in MA-ARDS shares features with ARDS triggered by other causes, including alveolar inflammation and increased alveolar-capillary permeability, leading to leak of protein-rich pulmonary oedema fluid. Mechanisms and physiologic alterations in MA-ARDS can be examined in murine models of this syndrome. Integrin αDß2 is a member of the leukocyte, or ß2 (CD18), sub-family of integrins, and emerging observations indicate that it has important activities in leukocyte adhesion, accumulation and signalling. The goal was to perform analysis of the lungs of mice wild type C57Bl/6 (a D (+/+) ) and Knockout C57Bl/6 (a D (-/-) ) with malaria-associated acute lung injury to better determine the relevancy of the murine models and investigate the mechanism of disease. METHODS: C57BL/6 wild type (a D (+/+) ) and deficient for CD11d sub-unit (a D (-/-) ) mice were monitored after infection with 10(5) Plasmodium berghei ANKA. CD11d subunit expression RNA was measured by real-time polymerase chain reaction, vascular barrier integrity by Evans blue dye (EBD) exclusion and cytokines by ELISA. Protein and leukocytes were measured in bronchoalveolar lavage fluid (BALF) samples. Tissue cellularity was measured by the point-counting technique, F4/80 and VCAM-1 expression by immunohistochemistry. Respiratory function was analysed by non-invasive BUXCO and mechanical ventilation. RESULTS: Alveolar inflammation, vascular and interstitial accumulation of monocytes and macrophages, and disrupted alveolar-capillary barrier function with exudation of protein-rich pulmonary oedema fluid were present in P. berghei-infected wild type mice and were improved in αDß2-deficient animals. Key pro-inflammatory cytokines were also decreased in lung tissue from α D (-/-) mice, providing a mechanistic explanation for reduced alveolar-capillary inflammation and leak. CONCLUSIONS: The results indicate that αDß2 is an important inflammatory effector molecule in P. berghei-induced MA-ARDS, and that leukocyte integrins regulate critical inflammatory and pathophysiologic events in this model of complicated malaria. Genetic deletion of integrin subunit αD in mice, leading to deficiency of integrin αDß2, alters lung inflammation and acute lung injury in a mouse model of MA-ARDS caused by P. berghei.

Regional tidal lung strain in mechanically ventilated normal lungs.

Parenchymal strain is a key determinant of lung injury produced by mechanical ventilation. However, imaging estimates of volumetric tidal strain (ε = regional tidal volume/reference volume) present substantial conceptual differences in reference volume computation and consideration of tidally recruited lung. We compared current and new methods to estimate tidal volumetric strains with computed tomography, and quantified the effect of tidal volume (VT) and positive end-expiratory pressure (PEEP) on strain estimates. Eight supine pigs were ventilated with VT = 6 and 12 ml/kg and PEEP = 0, 6, and 12 cmH2O. End-expiratory and end-inspiratory scans were analyzed in eight regions of interest along the ventral-dorsal axis. Regional reference volumes were computed at end-expiration (with/without correction of regional VT for intratidal recruitment) and at resting lung volume (PEEP = 0) corrected for intratidal and PEEP-derived recruitment. All strain estimates demonstrated vertical heterogeneity with the largest tidal strains in middependent regions (P < 0.01). Maximal strains for distinct estimates occurred at different lung regions and were differently affected by VT-PEEP conditions. Values consistent with lung injury and inflammation were reached regionally, even when global measurements were below critical levels. Strains increased with VT and were larger in middependent than in nondependent lung regions. PEEP reduced tidal-strain estimates referenced to end-expiratory lung volumes, although it did not affect strains referenced to resting lung volume. These estimates of tidal strains in normal lungs point to middependent lung regions as those at risk for ventilator-induced lung injury. The different conditions and topography at which maximal strain estimates occur allow for testing the importance of each estimate for lung injury.

Does acute exposure to aldehydes impair pulmonary function and structure?

Mixtures of anhydrous ethyl alcohol and gasoline substituted for pure gasoline as a fuel in many Brazilian vehicles. Consequently, the concentrations of volatile organic compounds (VOCs) such as ketones, other organic compounds, and particularly aldehydes increased in many Brazilian cities. The current study aims to investigate whether formaldehyde, acetaldehyde, or mixtures of both impair lung function, morphology, inflammatory and redox responses at environmentally relevant concentrations. For such purpose, C57BL/6 mice were exposed to either medical compressed air or to 4 different mixtures of formaldehyde and acetaldehyde. Eight hours later animals were anesthetized, paralyzed and lung mechanics and morphology, inflammatory cells and IL-1ß, KC, TNF-α, IL-6, CCL2, MCP-1 contents, superoxide dismutase and catalalase activities were determined. The extra pulmonary respiratory tract was also analyzed. No differences could be detected between any exposed and control groups. In conclusion, no morpho-functional alterations were detected in exposed mice in relation to the control group.

Experimental blunt chest trauma--cardiorespiratory effects of different mechanical ventilation strategies with high positive end-expiratory pressure: a randomized controlled study.

BACKGROUND: Uncertainty persists regarding the optimal ventilatory strategy in trauma patients developing acute respiratory distress syndrome (ARDS). This work aims to assess the effects of two mechanical ventilation strategies with high positive end-expiratory pressure (PEEP) in experimental ARDS following blunt chest trauma. METHODS: Twenty-six juvenile pigs were anesthetized, tracheotomized and mechanically ventilated. A contusion was applied to the right chest using a bolt-shot device. Ninety minutes after contusion, animals were randomized to two different ventilation modes, applied for 24 h: Twelve pigs received conventional pressure-controlled ventilation with moderately low tidal volumes (VT, 8 ml/kg) and empirically chosen high external PEEP (16 cmH2O) and are referred to as the HP-CMV-group. The other group (n = 14) underwent high-frequency inverse-ratio pressure-controlled ventilation (HFPPV) involving respiratory rate of 65 breaths · min(-1), inspiratory-to-expiratory-ratio 2:1, development of intrinsic PEEP and recruitment maneuvers, compatible with the rationale of the Open Lung Concept. Hemodynamics, gas exchange and respiratory mechanics were monitored during 24 h. Computed tomography and histology were analyzed in subgroups. RESULTS: Comparing changes which occurred from randomization (90 min after chest trauma) over the 24-h treatment period, groups differed statistically significantly (all P values for group effect <0.001, General Linear Model analysis) for the following parameters (values are mean ± SD for randomization vs. 24-h): PaO2 (100% O2) (HFPPV 186 ± 82 vs. 450 ± 59 mmHg; HP-CMV 249 ± 73 vs. 243 ± 81 mmHg), venous admixture (HFPPV 34 ± 9.8 vs. 11.2 ± 3.7%; HP-CMV 33.9 ± 10.5 vs. 21.8 ± 7.2%), PaCO2 (HFPPV 46.9 ± 6.8 vs. 33.1 ± 2.4 mmHg; HP-CMV 46.3 ± 11.9 vs. 59.7 ± 18.3 mmHg) and normally aerated lung mass (HFPPV 42.8 ± 11.8 vs. 74.6 ± 10.0 %; HP-CMV 40.7 ± 8.6 vs. 53.4 ± 11.6%). Improvements occurring after recruitment in the HFPPV-group persisted throughout the study. Peak airway pressure and VT did not differ significantly. HFPPV animals had lower atelectasis and inflammation scores in gravity-dependent lung areas. CONCLUSIONS: In this model of ARDS following unilateral blunt chest trauma, HFPPV ventilation improved respiratory function and fulfilled relevant ventilation endpoints for trauma patients, i.e. restoration of oxygenation and lung aeration while avoiding hypercapnia and respiratory acidosis.

CT pulmonary densitovolumetry in patients with acromegaly: a comparison between active disease and controlled disease.

OBJECTIVE: Our purpose was to compare the findings of CT pulmonary densitovolumetry and pulmonary function in patients with active acromegaly and controlled acromegaly and, secondarily, to correlate these findings. METHODS: 11 patients with active acromegaly, 18 patients with controlled acromegaly and 17 control subjects, all non-smokers, underwent quantification of lung volume using multidetector CT (Q-MDCT) and pulmonary function tests. RESULTS: Patients with active acromegaly had larger total lung mass (TLM) values than the controls and larger amounts of non-aerated compartments than the other two groups. Patients with active acromegaly also had larger amounts of poorly aerated compartments than the other two groups, a difference that was observed in both total lung volume (TLV) and TLM. TLV as measured by inspiratory Q-MDCT correlated significantly with total lung capacity, whereas TLV measured using expiratory Q-MDCT correlated significantly with functional residual capacity. CONCLUSION: Patients with active acromegaly have more lung mass and larger amounts of non-aerated and poorly aerated compartments. There is a relationship between the findings of CT pulmonary densitovolumetry and pulmonary function test parameters. ADVANCES IN KNOWLEDGE: Although the nature of our results demands further investigation, our data suggest that both CT pulmonary densitovolumetry and pulmonary function tests can be used as useful tools for patients with acromegaly by assisting in the prediction of disease activity.

Correlation of lung collapse and gas exchange - a computer tomographic study in sheep and pigs with atelectasis in otherwise normal lungs.

BACKGROUND: Atelectasis can provoke pulmonary and non-pulmonary complications after general anaesthesia. Unfortunately, there is no instrument to estimate atelectasis and prompt changes of mechanical ventilation during general anaesthesia. Although arterial partial pressure of oxygen (PaO2) and intrapulmonary shunt have both been suggested to correlate with atelectasis, studies yielded inconsistent results. Therefore, we investigated these correlations. METHODS: Shunt, PaO2 and atelectasis were measured in 11 sheep and 23 pigs with otherwise normal lungs. In pigs, contrasting measurements were available 12 hours after induction of acute respiratory distress syndrome (ARDS). Atelectasis was calculated by computed tomography relative to total lung mass (Mtotal). We logarithmically transformed PaO2 (lnPaO2) to linearize its relationships with shunt and atelectasis. Data are given as median (interquartile range). RESULTS: Mtotal was 768 (715-884) g in sheep and 543 (503-583) g in pigs. Atelectasis was 26 (16-47) % in sheep and 18 (13-23) % in pigs. PaO2 (FiO2 = 1.0) was 242 (106-414) mmHg in sheep and 480 (437-514) mmHg in pigs. Shunt was 39 (29-51) % in sheep and 15 (11-20) % in pigs. Atelectasis correlated closely with lnPaO2 (R2 = 0.78) and shunt (R2 = 0.79) in sheep (P-values<0.0001). The correlation of atelectasis with lnPaO2 (R2 = 0.63) and shunt (R2 = 0.34) was weaker in pigs, but R2 increased to 0.71 for lnPaO2 and 0.72 for shunt 12 hours after induction of ARDS. In both, sheep and pigs, changes in atelectasis correlated strongly with corresponding changes in lnPaO2 and shunt. DISCUSSION AND CONCLUSION: In lung-healthy sheep, atelectasis correlates closely with lnPaO2 and shunt, when blood gases are measured during ventilation with pure oxygen. In lung-healthy pigs, these correlations were significantly weaker, likely because pigs have stronger hypoxic pulmonary vasoconstriction (HPV) than sheep and humans. Nevertheless, correlations improved also in pigs after blunting of HPV during ARDS. In humans, the observed relationships may aid in assessing anaesthesia-related atelectasis.

Repeated intranasal exposure to microcystin-LR affects lungs but not nasal epithelium in mice.

Microcystin-LR (MC-LR) is a harmful cyanotoxin able to induce adverse outcomes in the respiratory system. We aimed to examine the lungs and nasal epithelium of mice following a sub-chronic exposure to MC-LR. Swiss mice were intranasally instilled with 10 µL of distilled water (CTRL, n = 10) or 6.7 ng/kg of MC-LR diluted in 10 µL of distilled water (TOX, n = 8) during 30 consecutive days. Respiratory mechanics was measured in vivo and histology measurements (morphology and inflammation) were assessed in lungs and nasal epithelium samples 24 h after the last intranasal instillation. Despite the lack of changes in the nasal epithelium, TOX mice displayed an increased amount of PMN cells in the lungs (× 10(-3)/µm(2)), higher lung static elastance (cmH2O/mL), resistive and viscoelastic/inhomogeneous pressures (cmH2O) (7.87 ± 3.78, 33.96 ± 2.64, 1.03 ± 0.12, 1.01 ± 0.08, respectively) than CTRL (5.37 ± 4.02, 26.65 ± 1.24, 0.78 ± 0.06, 0.72 ± 0.05, respectively). Overall, our findings suggest that the nasal epithelium appears more resistant than lungs in this model of MC-LR intoxication.

Positive end-expiratory pressure and variable ventilation in lung-healthy rats under general anesthesia.

OBJECTIVES: Variable ventilation (VV) seems to improve respiratory function in acute lung injury and may be combined with positive end-expiratory pressure (PEEP) in order to protect the lungs even in healthy subjects. We hypothesized that VV in combination with moderate levels of PEEP reduce the deterioration of pulmonary function related to general anesthesia. Hence, we aimed at evaluating the alveolar stability and lung protection of the combination of VV at different PEEP levels. DESIGN: Randomized experimental study. SETTING: Animal research facility. SUBJECTS: Forty-nine male Wistar rats (200-270 g). INTERVENTIONS: Animals were ventilated during 2 hours with protective low tidal volume (VT) in volume control ventilation (VCV) or VV and PEEP adjusted at the level of minimum respiratory system elastance (Ers), obtained during a decremental PEEP trial subsequent to a recruitment maneuver, and 2 cmH2O above or below of this level. MEASUREMENTS AND MAIN RESULTS: Ers, gas exchange and hemodynamic variables were measured. Cytokines were determined in lung homogenate and plasma samples and left lung was used for histologic analysis and diffuse alveolar damage scoring. A progressive time-dependent increase in Ers was observed independent on ventilatory mode or PEEP level. Despite of that, the rate of increase of Ers and lung tissue IL-1 beta concentration were significantly lower in VV than in VCV at the level of the PEEP of minimum Ers. A significant increase in lung tissue cytokines (IL-6, IL-1 beta, CINC-1 and TNF-alpha) as well as a ventral to dorsal and cranial to caudal reduction in aeration was observed in all ventilated rats with no significant differences among groups. CONCLUSIONS: VV combined with PEEP adjusted at the level of the PEEP of minimal Ers seemed to better prevent anesthesia-induced atelectasis and might improve lung protection throughout general anesthesia.

Liquid- and air-filled catheters without balloon as an alternative to the air-filled balloon catheter for measurement of esophageal pressure.

BACKGROUND: Measuring esophageal pressure (Pes) using an air-filled balloon catheter (BC) is the common approach to estimate pleural pressure and related parameters. However, Pes is not routinely measured in mechanically ventilated patients, partly due to technical and practical limitations and difficulties. This study aimed at comparing the conventional BC with two alternative methods for Pes measurement, liquid-filled and air-filled catheters without balloon (LFC and AFC), during mechanical ventilation with and without spontaneous breathing activity. Seven female juvenile pigs (32-42 kg) were anesthetized, orotracheally intubated, and a bundle of an AFC, LFC, and BC was inserted in the esophagus. Controlled and assisted mechanical ventilation were applied with positive end-expiratory pressures of 5 and 15 cmH2O, and driving pressures of 10 and 20 cmH2O, in supine and lateral decubitus. MAIN RESULTS: Cardiogenic noise in BC tracings was much larger (up to 25% of total power of Pes signal) than in AFC and LFC (<3%). Lung and chest wall elastance, pressure-time product, inspiratory work of breathing, inspiratory change and end-expiratory value of transpulmonary pressure were estimated. The three catheters allowed detecting similar changes in these parameters between different ventilation settings. However, a non-negligible and significant bias between estimates from BC and those from AFC and LFC was observed in several instances. CONCLUSIONS: In anesthetized and mechanically ventilated pigs, the three catheters are equivalent when the aim is to detect changes in Pes and related parameters between different conditions, but possibly not when the absolute value of the estimated parameters is of paramount importance. Due to a better signal-to-noise ratio, and considering its practical advantages in terms of easier calibration and simpler acquisition setup, LFC may prove interesting for clinical use.

Non-lobar atelectasis generates inflammation and structural alveolar injury in the surrounding healthy tissue during mechanical ventilation.

INTRODUCTION: When alveoli collapse the traction forces exerted on their walls by adjacent expanded units may increase and concentrate. These forces may promote its re-expansion at the expense of potentially injurious stresses at the interface between the collapsed and the expanded units. We developed an experimental model to test the hypothesis that a local non-lobar atelectasis can act as a stress concentrator, contributing to inflammation and structural alveolar injury in the surrounding healthy lung tissue during mechanical ventilation. METHODS: A total of 35 rats were anesthetized, paralyzed and mechanically ventilated. Atelectasis was induced by bronchial blocking: after five minutes of stabilization and pre-oxygenation with FIO2 = 1.0, a silicon cylinder blocker was wedged in the terminal bronchial tree. Afterwards, the animals were randomized between two groups: 1) Tidal volume (VT) = 10 ml/kg and positive end-expiratory pressure (PEEP) = 3 cmH2O (VT10/PEEP3); and 2) VT = 20 ml/kg and PEEP = 0 cmH2O (VT20/zero end-expiratory pressure (ZEEP)). The animals were then ventilated during 180 minutes. Three series of experiments were performed: histological (n = 12); tissue cytokines (n = 12); and micro-computed tomography (microCT; n = 2). An additional six, non-ventilated, healthy animals were used as controls. RESULTS: Atelectasis was successfully induced in the basal region of the lung of 26 out of 29 animals. The microCT of two animals revealed that the volume of the atelectasis was 0.12 and 0.21 cm3. There were more alveolar disruption and neutrophilic infiltration in the peri-atelectasis region than the corresponding contralateral lung (control) in both groups. Edema was higher in the peri-atelectasis region than the corresponding contralateral lung (control) in the VT20/ZEEP than VT10/PEEP3 group. The volume-to-surface ratio was higher in the peri-atelectasis region than the corresponding contralateral lung (control) in both groups. We did not find statistical difference in tissue interleukin-1ß and cytokine-induced neutrophil chemoattractant-1 between regions. CONCLUSIONS: The present findings suggest that a local non-lobar atelectasis acts as a stress concentrator, generating structural alveolar injury and inflammation in the surrounding lung tissue.

Effects of different levels of pressure support on intra-individual breath-to-breath variability.

BACKGROUND: Evidence exists that during pressure support ventilation (PSV), the addition of an extrinsic (ie, ventilator-generated) breath-to-breath variability (BBV) of breathing pattern improves respiratory function. If BBV is beneficial per se, choosing the PS level that maximizes it could be considered a valid strategy for conventional PSV. In this study, we evaluated the effect of different PS levels on intrinsic BBV in acutely ill, mechanically ventilated subjects to determine whether a significant relationship exists between PS level and BBV magnitude. METHODS: Fourteen invasively mechanically ventilated subjects were prospectively studied. PS was adjusted at 20 cm H2O and sequentially reduced to 15, 10, and 5 cm H2O. Arterial blood gas analysis and pressure at 0.1 s after the onset of inspiration (P0.1) were measured at each PS level. Airway and esophageal pressure and air flow were continuously recorded. Peak inspiratory flow, tidal volume (VT), breathing frequency, and pressure-time product (PTP) were calculated on a breath-by-breath basis. The breathing pattern variability was assessed by the coefficient of variation of the time series of VT, peak inspiratory flow, and breathing frequency from ∼ 60 consecutive breath cycles at each PS level. A general linear model for repeated measures was applied, with PS as an independent factor. A significance level of .05 was considered. RESULTS: Despite a large inter-individual difference in all measured variables (P < .001), the coefficient of variation was as low as 30%, and no significant differences in the coefficient of variation of peak inspiratory flow, breathing frequency, and VT between PS levels were observed (P > .15). Additionally, a significant increase in P0.1, PTP, and breathing frequency (P < .01) and a reduction in VT (P < .001) were observed with PS reduction. CONCLUSIONS: Despite a significant increase in spontaneous activity with PS reduction, BBV was not influenced by the PS level and was as low as 30% for all evaluated parameters.

Tidal lung recruitment and exhaled nitric oxide during coronary artery bypass grafting in patients with and without chronic obstructive pulmonary disease.

BACKGROUND: We studied the occurrence of intraoperative tidal alveolar recruitment/derecruitment, exhaled nitric oxide (eNO), and lung dysfunction in patients with and without chronic obstructive pulmonary disease (COPD) undergoing coronary artery bypass grafting (CABG). METHODS: We performed a prospective observational physiological study at a university hospital. Respiratory mechanics, shunt, and eNO were assessed in moderate COPD patients undergoing on-pump (n = 12) and off-pump (n = 8) CABG and on-pump controls (n = 8) before sternotomy (baseline), after sternotomy and before cardiopulmonary bypass (CPB), and following CPB before and after chest closure. Respiratory system resistance (R (rs)), elastance (E (rs)), and stress index (to quantify tidal recruitment) were estimated using regression analysis. eNO was measured with chemiluminescence. RESULTS: Mechanical evidence of tidal recruitment/derecruitment (stress index <1.0) was observed in all patients, with stress index <0.8 in 29% of measurements. Rrs in on-pump COPD was larger than in controls (p < 0.05). Ers increased in controls from baseline to end of surgery (19.4 ± 5.5 to 27.0 ± 8.5 ml cm H(2)O(-1), p < 0.01), associated with increased shunt (p < 0.05). Neither Ers nor shunt increased significantly in the COPD on-pump group. eNO was comparable in the control (11.7 ± 7.0 ppb) and COPD on-pump (9.9 ± 6.8 ppb) groups at baseline, and decreased similarly by 29% at end of surgery(p < 0.05). Changes in eNO were not correlated to changes in lung function. CONCLUSIONS: Tidal recruitment/derecruitment occurs frequently during CABG and represents a risk for ventilator-associated lung injury. eNO changes are consistent with small airway injury, including that from tidal recruitment injury. However, those changes are not correlated with respiratory dysfunction. Controls have higher susceptibility to develop complete lung derecruitment.

On the crucial ventilatory setting adjustment from two- to one-lung ventilation.

Lung mechanics, histology, oxygenation and type-III procollagen (PCIII) mRNA were studied aiming to evaluate the need to readjust ventilatory pattern when going from two- to one-lung ventilation (OLV). Wistar rats were assigned to three groups: the left lung was not ventilated while the right lung received: (1) tidal volume (V(T))=5 ml/kg and positive end-expiratory pressure (PEEP)=2 cm H(2)O (V5P2), (2) V(T)=10 ml/kg and PEEP=2 cm H(2)O (V10P2), and (3) V(T)=5 ml/kg and PEEP=5 cm H(2)O (V5P5). At 1-h ventilation, V5P2 showed hypoxemia, alveolar collapse and impaired lung function. Higher PEEP minimized these changes and prevented hypoxemia. Although high V(T) prevented hypoxemia and maintained a higher specific compliance than V5P2, a morphologically inhomogeneous parenchyma and higher PCIII expression resulted. In conclusion, the association of low V(T) and an adequate PEEP level could be useful to maintain arterial oxygenation without inducing a possible inflammatory/remodeling response.

LASSBio 596 per os avoids pulmonary and hepatic inflammation induced by microcystin-LR.

Cyanobacterial blooms that generate microcystins (MCYSTs) are increasingly recognized as an important health problem in aquatic ecosystems. We have previously reported the impairment of pulmonary structure and function by microcystin-LR (MCYST-LR) exposure as well as the pulmonary improvement by intraperitoneally injected (i.p.) LASSBio 596. In the present study, we aimed to evaluate the usefulness of LASSBio 596 per os on the treatment of pulmonary and hepatic injuries induced by MCYST-LR. Swiss mice received an intraperitoneal injection of 40 µl of saline (CTRL) or a sub-lethal dose of MCYST-LR (40 µg/kg). After 6 h the animals received either saline (TOX and CTRL groups) or LASSBio 596 (50 mg/kg, LASS group) by gavage. Eight hours after the first instillation, lung impedance (static elastance, elastic component of viscoelasticity and resistive, viscoelastic and total pressures) was determined by the end-inflation occlusion method. Left lung and liver were prepared for histology. In lung and hepatic homogenates MCYST-LR, TNF-α, IL-1ß and IL-6 were determined by ELISA. LASSBio 596 per os (LASS mice) kept all lung mechanical parameters, polymorphonuclear (PMN) cells, pro-inflammatory mediators, and alveolar collapse similar to control mice (CTRL), whereas in TOX these findings were higher than CTRL. Likewise, liver structural deterioration (hepatocytes inflammation, necrosis and steatosis) and inflammatory process (high levels of pro-inflammatory mediators) were less evident in the LASS than TOX group. LASS and CTRL did not differ in any parameters studied. In conclusion, orally administered LASSBio 596 prevented lung and hepatic inflammation and completely blocked pulmonary functional and morphological changes induced by MCYST-LR.

Pressure support improves oxygenation and lung protection compared to pressure-controlled ventilation and is further improved by random variation of pressure support.

OBJECTIVES: To explore whether 1) conventional pressure support ventilation improves lung function and attenuates the pulmonary inflammatory response compared to pressure-controlled ventilation and 2) random variation of pressure support levels (noisy pressure support ventilation) adds further beneficial effects to pressure support ventilation. DESIGN: Three-arm, randomized, experimental study. SETTING: University hospital research facility. SUBJECTS: Twenty-four juvenile pigs. INTERVENTIONS: Acute lung injury was induced by surfactant depletion. Animals were randomly assigned to 6 hrs of mechanical ventilation (n = 8 per group) with either 1) pressure-controlled ventilation, 2) pressure support ventilation, or 3) noisy pressure support ventilation. During noisy pressure support ventilation, the pressure support varied randomly, with values following a normal distribution. In all groups, the driving pressures were set to achieve a mean tidal volume of 6 mL/kg. At the end of experiments, animals were killed and lungs extracted for histologic and biochemical analysis. MEASUREMENTS AND MAIN RESULTS: Respiratory, gas-exchange, and hemodynamics variables were assessed hourly. The diffuse alveolar damage and the inflammatory response of lungs were quantified. Pressure support ventilation and noisy pressure support ventilation improved gas exchange and were associated with reduced histologic damage and interleukin-6 concentrations in lung tissue compared to pressure-controlled ventilation. Noisy pressure support ventilation further improved gas exchange and decreased the inspiratory effort while reducing alveolar edema and inflammatory infiltration compared to pressure support ventilation. CONCLUSIONS: In this model of acute lung injury, pressure support ventilation and noisy pressure support ventilation attenuated pulmonary inflammatory response and improved gas exchange as compared to pressure-controlled ventilation. Noisy pressure support ventilation further improved gas exchange, reduced the inspiratory effort, and attenuated alveolar edema and inflammatory infiltration as compared to conventional pressure support ventilation.