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PET imaging with 18 F-FDG followed by mathematic modeling of the pulmonary uptake rate (K i ) is the gold standard for assessment of pulmonary inflammation in experimental studies of acute respiratory distress syndrome (ARDS). However, dynamic PET requires long imaging and allows the assessment of only 1 cranio-caudal field of view (∼15 cm). We investigated whether static 18 F-FDG PET/CT and analysis of SUV or standardized uptake ratios (SUR stat , uptake time-corrected ratio of 18 F-FDG concentration in lung tissue and blood plasma) might be an alternative to dynamic 18 F-FDG PET/CT and Patlak analysis for quantification of pulmonary inflammation in experimental ARDS. Methods: ARDS was induced by saline lung lavage followed by injurious mechanical ventilation in 14 anesthetized pigs (29.5-40.0 kg). PET/CT imaging sequences were acquired before and after 24 h of mechanical ventilation. K i and the apparent volume of distribution were calculated from dynamic 18 F-FDG PET/CT scans using the Patlak analysis. Static 18 F-FDG PET/CT scans were obtained immediately after dynamic PET/CT and used for calculations of SUV and SUR stat Mean K i values of the whole imaged field of view and of 5 ventro-dorsal lung regions were compared with corresponding SUV and SUR stat values, respectively, by means of linear regression and concordance analysis. The variability of the 18 F-FDG concentration in blood plasma (arterial input function) was analyzed. Results: Both for the whole imaged field of view and ventro-dorsal subregions, K i was linearly correlated with SUR stat ( r 2 ≥ 0.84), whereas K i -SUV correlations were worse ( r 2 ≤ 0.75). The arterial input function exhibited an essentially invariant shape across all animals and time points and can be described by an inverse power law. Compared with K i , SUR stat and SUV tracked the same direction of change in regional lung inflammation in 98.6% and 84.3% of measurements, respectively. Conclusion: The K i -SUR stat correlations were considerably stronger than the K i -SUV correlations. The good K i -SUR stat correlations suggest that static 18 F-FDG PET/CT and SUR stat analysis provides an alternative to dynamic 18 F-FDG PET/CT and Patlak analysis, allowing the assessment of inflammation of whole lungs, repeated measurements within the period of 18 F-FDG decay, and faster data acquisition., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Obese patients are at higher risk of developing acute respiratory distress syndrome (ARDS); however, their survival rates are also higher compared to those of similarly ill non-obese patients. We hypothesized that obesity would not only prevent lung inflammation, but also reduce remodeling in moderate endotoxin-induced acute lung injury (ALI). Obesity was induced by early postnatal overfeeding in Wistar rats in which the litter size was reduced to 3 pups/litter (Obese, n = 18); Control animals ( n = 18) were obtained from unculled litters. On postnatal day 150, Control, and Obese animals randomly received E. coli lipopolysaccharide (ALI) or saline (SAL) intratracheally. After 24 h, echocardiography, lung function and morphometry, and biological markers in lung tissue were evaluated. Additionally, mediator expression in neutrophils and macrophages obtained from blood and bronchoalveolar lavage fluid (BALF) was analyzed. Compared to Control-SAL animals, Control-ALI rats showed no changes in echocardiographic parameters, increased lung elastance and resistance, higher monocyte phagocytic capacity, collagen fiber content, myeloperoxidase (MPO) activity, and levels of interleukin (IL-6), tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and type III (PCIII), and I (PCI) procollagen in lung tissue, as well as increased expressions of TNF-α and monocyte chemoattractant protein (MCP)-1 in blood and BALF neutrophils. Monocyte (blood) and macrophage (adipose tissue) phagocytic capacities were lower in Obese-ALI compared to Control-ALI animals, and Obese animals exhibited reduced neutrophil migration compared to Control. Obese-ALI animals, compared to Obese-SAL, exhibited increased interventricular septum thickness ( p = 0.003) and posterior wall thickness ( p = 0.003) and decreased pulmonary acceleration time to pulmonary ejection time ratio ( p = 0.005); no changes in lung mechanics, IL-6, TNF-α, TGF-β, PCIII, and PCI in lung tissue; increased IL-10 levels in lung homogenate ( p = 0.007); reduced MCP-1 expression in blood neutrophils ( p = 0.009); decreased TNF-α expression in blood ( p = 0.02) and BALF ( p = 0.008) neutrophils; and increased IL-10 expression in monocytes ( p = 0.004). In conclusion, after endotoxin challenge, obese rats showed less deterioration of lung function, secondary to anti-inflammatory and anti-fibrotic effects, as well as changes in neutrophil and monocyte/macrophage phenotype in blood and BALF compared to Control rats.

Purpose of Review: We aimed at providing the most recent and relevant evidence regarding spontaneous breathing activity during mechanical ventilation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Both clinical and experimental data are depicted., Recent Findings: The use of unsupported spontaneous breathing has been associated with the most beneficial effects reported to date, but recent data favors also pressure-supported breathing activity in experimental ALI. In patients with ALI/ARDS, unsupported spontaneous breathing in combination with mandatory cycles has been shown to improve lung function, reduce the need for sedation and cardiocirculatory drug therapy, and speed weaning, with no effect on mortality. On the other hand, strong clinical evidence shows that the use of neuromuscular blocking agents in the first 48 h of mechanical ventilation with the volume assist-control ventilation mode reduces morbidity and mortality in severe ARDS compared to placebo., Summary: In our opinion, spontaneous breathing activity should be avoided in the first 48 h of mechanical ventilation in patients with severe ARDS (PaO2/FIO2 <120 mmHg), but it may be useful in less severe ARDS and ALI. Clearly, further clinical and experimental investigations on the use of different ventilation modes of supported/unsupported spontaneous breathing in ALI/ARDS are needed.

Objective: To investigate the effects of the rate of airway pressure increase and duration of recruitment maneuvers on lung function and activation of inflammation, fibrogenesis, and apoptosis in experimental acute lung injury., Design: Prospective, randomized, controlled experimental study., Setting: University research laboratory., Subjects: Thirty-five Wistar rats submitted to acute lung injury induced by cecal ligation and puncture., Interventions: After 48 hrs, animals were randomly distributed into five groups (seven animals each): 1) nonrecruited (NR); 2) recruitment maneuvers (RMs) with continuous positive airway pressure (CPAP) for 15 secs (CPAP15); 3) RMs with CPAP for 30 secs (CPAP30); 4) RMs with stepwise increase in airway pressure (STEP) to targeted maximum within 15 secs (STEP15); and 5) RMs with STEP within 30 secs (STEP30). To perform STEP RMs, the ventilator was switched to a CPAP mode and positive end-expiratory pressure level was increased stepwise. At each step, airway pressure was held constant. RMs were targeted to 30 cm H2O. Animals were then ventilated for 1 hr with tidal volume of 6 mL/kg and positive end-expiratory pressure of 5 cm H2O., Measurements and Main Results: Blood gases, lung mechanics, histology (light and electronic microscopy), interleukin-6, caspase 3, and type 3 procollagen mRNA expressions in lung tissue. All RMs improved oxygenation and lung static elastance and reduced alveolar collapse compared to NR. STEP30 resulted in optimal performance, with: 1) improved lung static elastance vs. NR, CPAP15, and STEP15; 2) reduced alveolar-capillary membrane detachment and type 2 epithelial and endothelial cell injury scores vs. CPAP15 (p < .05); and 3) reduced gene expression of interleukin-6, type 3 procollagen, and caspase 3 in lung tissue vs. other RMs., Conclusions: Longer-duration RMs with slower airway pressure increase efficiently improved lung function, while minimizing the biological impact on lungs.

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.

Introduction: Quantitative computed tomography (qCT)-based assessment of total lung weight (Mlung) has the potential to differentiate atelectasis from consolidation and could thus provide valuable information for managing trauma patients fulfilling commonly used criteria for acute lung injury (ALI). We hypothesized that qCT would identify atelectasis as a frequent mimic of early posttraumatic ALI., Methods: In this prospective observational study, Mlung was calculated by qCT in 78 mechanically ventilated trauma patients fulfilling the ALI criteria at admission. A reference interval for Mlung was derived from 74 trauma patients with morphologically and functionally normal lungs (reference). Results are given as medians with interquartile ranges., Results: The ratio of arterial partial pressure of oxygen to the fraction of inspired oxygen was 560 (506 to 616) mmHg in reference patients and 169 (95 to 240) mmHg in ALI patients. The median reference Mlung value was 885 (771 to 973) g, and the reference interval for Mlung was 584 to 1164 g, which matched that of previous reports. Despite the significantly greater median Mlung value (1088 (862 to 1,342) g) in the ALI group, 46 (59%) ALI patients had Mlung values within the reference interval and thus most likely had atelectasis. In only 17 patients (22%), Mlung was increased to the range previously reported for ALI patients and compatible with lung consolidation. Statistically significant differences between atelectasis and consolidation patients were found for age, Lung Injury Score, Glasgow Coma Scale score, total lung volume, mass of the nonaerated lung compartment, ventilator-free days and intensive care unit-free days., Conclusions: Atelectasis is a frequent cause of early posttraumatic lung dysfunction. Differentiation between atelectasis and consolidation from other causes of lung damage by using qCT may help to identify patients who could benefit from management strategies such as damage control surgery and lung-protective mechanical ventilation that focus on the prevention of pulmonary complications.

Inhalation of perfluorohexane vapor (PFH) and high-frequency oscillatory ventilation (HFOV) both have been shown to improve lung function in acute lung injury (ALI). Their combination implies synergistic action. The authors investigated technical aspects of PFH vaporization during HFOV and effects on gas exchange in a pilot study of experimental ALI. Eighteen anesthetized sheep were randomly assigned to HFOV or HFOV with PFH inhalation after oleic acid-induced ALI. HFOV was set to a continuous distending pressure of 25 cm H₂O, and an oscillation of 80 to 100 cm H₂O at a frequency of 5 Hz. PFH vapor was delivered by means of bypassed high-flow oxygen through a thin endotracheal tube. PFH concentration was measured by infrared absorption. Blood gases and hemodynamic data were taken. PaO₂ significantly increased from 9.1 ± 0.9 to 32.7 ± 9.5 kPa (mean ± SEM) in the HFOV group and from 12.5 ± 1.1 to 27.0 ± 6.8 kPa in the HFOV PFH group. PaCO₂ significantly decreased from 6.3 ± 0.3 to 5.5 ± 0.5 kPa in the HFOV group and from 5.7 ± 0.4 to 4.9 ± 0.5 kPa in the HFOV PFH group. Changes in gas exchange were not different between groups. These results show that the inhalation of PFH during HFOV is technically feasible, but did not enhance gas exchange in a 210-minute observation period of experimental ALI.

Introduction: Recruitment maneuvers (RMs) seem to be more effective in extrapulmonary acute lung injury (ALI), caused mainly by sepsis, than in pulmonary ALI. Nevertheless, the maintenance of adequate volemic status is particularly challenging in sepsis. Since the interaction between volemic status and RMs is not well established, we investigated the effects of RMs on lung and distal organs in the presence of hypovolemia, normovolemia, and hypervolemia in a model of extrapulmonary lung injury induced by sepsis., Methods: ALI was induced by cecal ligation and puncture surgery in 66 Wistar rats. After 48 h, animals were anesthetized, mechanically ventilated and randomly assigned to 3 volemic status (n = 22/group): 1) hypovolemia induced by blood drainage at mean arterial pressure (MAP) approximately 70 mmHg; 2) normovolemia (MAP approximately 100 mmHg), and 3) hypervolemia with colloid administration to achieve a MAP approximately 130 mmHg. In each group, animals were further randomized to be recruited (CPAP = 40 cm H2O for 40 s) or not (NR) (n = 11/group), followed by 1 h of protective mechanical ventilation. Echocardiography, arterial blood gases, static lung elastance (Est,L), histology (light and electron microscopy), lung wet-to-dry (W/D) ratio, interleukin (IL)-6, IL-1beta, caspase-3, type III procollagen (PCIII), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) mRNA expressions in lung tissue, as well as lung and distal organ epithelial cell apoptosis were analyzed., Results: We observed that: 1) hypervolemia increased lung W/D ratio with impairment of oxygenation and Est,L, and was associated with alveolar and endothelial cell damage and increased IL-6, VCAM-1, and ICAM-1 mRNA expressions; and 2) RM reduced alveolar collapse independent of volemic status. In hypervolemic animals, RM improved oxygenation above the levels observed with the use of positive-end expiratory pressure (PEEP), but increased lung injury and led to higher inflammatory and fibrogenetic responses., Conclusions: Volemic status should be taken into account during RMs, since in this sepsis-induced ALI model hypervolemia promoted and potentiated lung injury compared to hypo- and normovolemia.

Purpose: There is growing interest in the use of both variable and pressure-controlled ventilation (PCV). The combination of these approaches as "noisy PCV" requires adaptation of the mechanical ventilator to the respiratory system mechanics. Thus, we developed and evaluated a new control system based on the least-mean-squares adaptive approach, which automatically and continuously adjusts the driving pressure during PCV to achieve the desired variability pattern of tidal volume (V (T))., Methods: The controller was tested during numerical simulations and with a physical model reproducing the mechanical properties of the respiratory system. We applied step changes in respiratory system mechanics and mechanical ventilation settings. The time needed to converge to the desired V (T) variability pattern after each change (t (c)) and the difference in minute ventilation between the measured and target pattern of V (T) (DeltaMV) were determined., Results: During numerical simulations, the control system for noisy PCV achieved the desired variable V (T) pattern in less than 30 respiratory cycles, with limited influence of the dynamic elastance (E*) on t (c), except when E* was underestimated by >25%. We also found that, during tests in the physical model, the control system converged in <60 respiratory cycles and was not influenced by airways resistance. In all measurements, the absolute value of DeltaMV was <25%., Conclusion: The new control system for noisy PCV can prove useful for controlled mechanical ventilation in the intensive care unit.

Introduction: There is an increasing interest in biphasic positive airway pressure with spontaneous breathing (BIPAP+SBmean), which is a combination of time-cycled controlled breaths at two levels of continuous positive airway pressure (BIPAP+SBcontrolled) and non-assisted spontaneous breathing (BIPAP+SBspont), in the early phase of acute lung injury (ALI). However, pressure support ventilation (PSV) remains the most commonly used mode of assisted ventilation. To date, the effects of BIPAP+SBmean and PSV on regional lung aeration and ventilation during ALI are only poorly defined., Methods: In 10 anesthetized juvenile pigs, ALI was induced by surfactant depletion. BIPAP+SBmean and PSV were performed in a random sequence (1 h each) at comparable mean airway pressures and minute volumes. Gas exchange, hemodynamics, and inspiratory effort were determined and dynamic computed tomography scans obtained. Aeration and ventilation were calculated in four zones along the ventral-dorsal axis at lung apex, hilum and base., Results: Compared to PSV, BIPAP+SBmean resulted in: 1) lower mean tidal volume, comparable oxygenation and hemodynamics, and increased PaCO2 and inspiratory effort; 2) less nonaerated areas at end-expiration; 3) decreased tidal hyperaeration and re-aeration; 4) similar distributions of ventilation. During BIPAP+SBmean: i) BIPAP+SBspont had lower tidal volumes and higher rates than BIPAP+SBcontrolled; ii) BIPAP+SBspont and BIPAP+SBcontrolled had similar distributions of ventilation and aeration; iii) BIPAP+SBcontrolled resulted in increased tidal re-aeration and hyperareation, compared to PSV. BIPAP+SBspont showed an opposite pattern., Conclusions: In this model of ALI, the reduction of tidal re-aeration and hyperaeration during BIPAP+SBmean compared to PSV is not due to decreased nonaerated areas at end-expiration or different distribution of ventilation, but to lower tidal volumes during BIPAP+SBspont. The ratio between spontaneous to controlled breaths seems to play a pivotal role in reducing tidal re-aeration and hyperaeration during BIPAP+SBmean.

Abstract: Rationale: We investigated the effects of vaporized perfluorohexane (PFH) on pulmonary vascular tone, pulmonary vascular resistance and peak inspiratory pressure as well as lipid mediator formation in the treatment of calcium ionophore induced lung injury in a model of the isolated perfused and ventilated rabbit lungs. Methods: Lung injury was induced in isolated perfused and ventilated rabbit lungs by calcium ionophore A23187. Lungs were treated with either 4.5 vol.% (4.5 vol.% PFH; n = 6) or 18 vol.% (18 vol.% PFH; n = 6) PFH. Six lungs remained untreated (Control). In addition 5 lungs (PFH-sham) remained uninjured receiving 18 vol.% PFH only. Mean pulmonary artery pressure (mPAP), peak inspiratory pressure (P max), and lung weight (weight) were monitored for 120 min. Experiments were terminated before when the increase in lung weight exceeded 40 g. Perfusate samples were taken at regular intervals for analysis of TXB2, 6-keto-PGF1 and LTB4. Results: Controls reached the study end point significantly earlier than both PFH groups. Significant differences were found for a weight gain of 10 g and 20 g between the control and the 4.5 vol.% PFH and the 18 vol.% PFH. Differences in mPAP were more pronounced in the 4.5 vol.% PFH. However increases in P max were more marked in 4.5 vol.% PFH. TXA2-, PGI2-, and LTB4-levels were significantly lower in PFH groups. Uninjured lungs remained unaffected by the presence of 18 vol.% PFH. Conclusion: Inflammatory lung injury was attenuated by the treatment with 4.5 vol.% PFH and 18 vol.% PFH vapor in the isolated perfused rabbit lung. Therapeutic effects were more pronounced with a concentration of 4.5 vol.% PFH. [ABSTRACT FROM AUTHOR]