Tilo Winkler

Background

Low-dose inhaled carbon monoxide (iCO) has demonstrated significant therapeutic potential in preclinical studies, and its safety has been established in human studies. However, the safety of delivering personalized iCO concentrations of 200 to 500 ppm in ventilated patients with pneumonia and ARDS, targeting 7% HbCO at 90 min of exposure, remains unknown.
Methods

Personalized iCO concentrations needed to reach a plasma HbCO of 7% at 90 min were determined using a Coburn-Forster-Kane (CFK) calculator, utilizing baseline and 20-minute (20-min) arterial HbCO measurements at an iCO test concentration of 200 ppm. The personalized iCO concentration was administered for the remainder of the 90 min with HbCO measurements performed at 60-, 75-, and 90-minutes.
Results

There were no safety incidents observed during the study, and all exposed subjects were alive and well at 6-month follow-up. Surprisingly, we found significant deviations between measured and predicted HbCO levels at 90 min for individualized exposures with iCO of 220 to 425 ppm (p < 0.001), which were more discrepant at higher iCO doses. However, fitting the CFK model to the 20- to 90-minute HbCO measurements confirmed the validity of the CFK model and revealed significant deviations for baseline HbCO (p < 0.001), suggesting pulmonary vascular responses to iCO during the 20-min test exposure, confirmed by observed changes in DLCO.
Conclusions

Pulmonary vasodilation in response to iCO can affect early HbCO kinetics, which is relevant to refining protocols for reliable, personalized iCO administration that optimize pulmonary iCO concentrations, thereby increasing the benefits of therapeutic iCO administration in lung diseases.

In obesity, excess weight of the chest and abdomen (mass loading) decreases lung volume and can worsen acute hypoxemic respiratory failure (AHRF). We investigated whether positive end-expiratory pressure (PEEP) fully reverses the effects of mass loading on lung volume and respiratory mechanics in an AHRF swine model. Eighteen Yorkshire pigs were studied: six healthy, eight pre- and post-injury, and four post-injury only. We randomly tested three mass loading conditions: without mass loading, with abdominal loading (6kg weight), and with combined abdominal and chest mass loading (12kg total weight). We performed a recruitment maneuver in each condition followed by a decremental PEEP trial and identified the best-PEEP as that with the greatest respiratory system compliance (C
). Airway pressure, esophageal pressure, and thoracic impedance by electrical impedance tomography) were continuously monitored. After lung injury, best-PEEP increased with loading. C
at best-PEEP decreased from 20.6 ± 3.4 ml/cmH
O without loading to 17.7 ± 3.0 ml/cmH
O with abdominal loading (mean difference 2.9, 95% CI 1.6-4.2) and to 14.2 ± 2.8 ml/cmH
O with abdominal and chest loading (mean difference 6.3, 95% CI 5.0-7.7). Any amount of loading decreased end-expiratory lung volume assessed by computed tomography (CT) at best-PEEP and PEEP 3 cmH
O. Combined abdominal-chest loading decreased the vertical lung dimension on CT compared to unloaded and abdominal loading at both levels of PEEP. With mass loading, PEEP did not restore values of C
and lung aeration to their unloaded values. In AHRF with mass loading, geometrical constraints may limit PEEP efficacy even when optimally titrated.

Background:Pulmonary capillary blood volume is a major determinant of lung gas transport efficiency and also potentially related to ventilator-induced lung injury. However, knowledge on how lung expansion influences pulmonary blood volume in injured lungs is scant. The hypothesis was that lung expansion produced by positive end-expiratory pressure (PEEP) modulates the global and regional spatial distribution of pulmonary blood volume. Methods:In a lung injury model exposed to distinct lung expansion within clinical range (PEEP of 5 to 20 cm H2O), this study aimed to determine whole-lung and regional blood volume, their dynamic changes, and association with gas volume changes. Seven healthy sheep were subjected to 3 h of low-lung volume mechanical ventilation at a PEEP of 0 cm H2O and systemic endotoxemia. PEEP values of 5 (low), 20 (high), and 12 (intermediate) cm H2O were applied to produce distinct lung expansion. Respiratory-gated positron emission tomography with 11C-labeled carbon monoxide and four-dimensional computed tomography were obtained to quantify blood volume and aeration. Results: Transpulmonary pressures were lowest at a PEEP of 12 cm H2O. Changes in whole-lung blood volume correlated with gas volume changes between PEEP of 5 and 12 cm H2O at end expiration (P < 0.001) and end inspiration (P < 0.001) but not between 12 and 20 cm H2O. Tissue-normalized blood volume ( V B t i s s u e ) was heterogeneously distributed, with mean values in nondependent regions ( B- t i s s u e = 0.116 +/- 0.055) approximately seven times smaller than those in mid-dependent regions ( V B- t i s s u e = 0.832 +/- 0.132). A positive end-expiratory pressure of 12 cm H2O resulted in the most homogeneous V B- t i s s u e distribution, with the largest means in mid-dependent regions and inspiratory 10th percentile, a measure of lowest values, throughout the lung. V B t i s s u e increased with inspiration at PEEP of 5 and 12 cm H2O but decreased with a PEEP of 20 cm H2O in mid-nondependent regions. Conclusions: During low-volume mechanical ventilation and systemic endotoxemia, lung blood volume is markedly heterogeneously distributed, and modulated by PEEP. Nondependent regions are susceptible to low blood volume and capillary closure. Recruitment of pulmonary vascular blood volume with gas volume is nonlinear, limited at an intermediate PEEP, indicating its advantage to spatial distribution of blood volume.

Mechanical ventilation exposes the lung to injurious stresses and strains that can negatively affect clinical outcomes in acute respiratory distress syndrome or cause pulmonary complications after general anesthesia. Excess global lung strain, estimated as increased respiratory system driving pressure, is associated with mortality related to mechanical ventilation. The role of small-dimension biomechanical factors underlying this association and their spatial heterogeneity within the lung are currently unknown. Using four-dimensional computed tomography with a voxel resolution of 2.4 cubic millimeters and a multiresolution convolutional neural network for whole-lung image segmentation, we dynamically measured voxel-wise lung inflation and tidal parenchymal strains. Healthy or injured ovine lungs were evaluated as the mechanical ventilation positive end-expiratory pressure (PEEP) was titrated from 20 to 2 centimeters of water. The PEEP of minimal driving pressure (PEEPDP) optimized local lung biomechanics. We observed a greater rate of change in nonaerated lung mass with respect to PEEP below PEEPDP compared with PEEP values above this threshold. PEEPDP similarly characterized a breaking point in the relationships between PEEP and SD of local tidal parenchymal strain, the 95th percentile of local strains, and the magnitude of tidal overdistension. These findings advance the understanding of lung collapse, tidal overdistension, and strain heterogeneity as local triggers of ventilator-induced lung injury in large-animal lungs similar to those of humans and could inform the clinical management of mechanical ventilation to improve local lung biomechanics.Mechanical ventilation exposes the lung to injurious stresses and strains that can negatively affect clinical outcomes in acute respiratory distress syndrome or cause pulmonary complications after general anesthesia. Excess global lung strain, estimated as increased respiratory system driving pressure, is associated with mortality related to mechanical ventilation. The role of small-dimension biomechanical factors underlying this association and their spatial heterogeneity within the lung are currently unknown. Using four-dimensional computed tomography with a voxel resolution of 2.4 cubic millimeters and a multiresolution convolutional neural network for whole-lung image segmentation, we dynamically measured voxel-wise lung inflation and tidal parenchymal strains. Healthy or injured ovine lungs were evaluated as the mechanical ventilation positive end-expiratory pressure (PEEP) was titrated from 20 to 2 centimeters of water. The PEEP of minimal driving pressure (PEEPDP) optimized local lung biomechanics. We observed a greater rate of change in nonaerated lung mass with respect to PEEP below PEEPDP compared with PEEP values above this threshold. PEEPDP similarly characterized a breaking point in the relationships between PEEP and SD of local tidal parenchymal strain, the 95th percentile of local strains, and the magnitude of tidal overdistension. These findings advance the understanding of lung collapse, tidal overdistension, and strain heterogeneity as local triggers of ventilator-induced lung injury in large-animal lungs similar to those of humans and could inform the clinical management of mechanical ventilation to improve local lung biomechanics.

Regional pulmonary perfusion (Q) has been investigated using blood volume (F ) imaging as an easier-to-measure surrogate. However, it is unclear if changing pulmonary conditions could affect their relationship. We hypothesized that vascular changes in early acute respiratory distress syndrome (ARDS) affect Q and F differently. Five sheep were anesthetized and received lung protective mechanical ventilation for 20 h while endotoxin was continuously infused. Using dynamic F-FDG and NN Positron Emission Tomography (PET), regional F and Q were analysed in 30 regions of interest (ROIs) and normalized by tissue content (F and Q , respectively). After 20 h, the lung injury showed characteristics of early ARDS, including gas exchange and lung mechanics. PET images of F and Q showed substantial differences between baseline and lung injury. Lung injury caused a significant change in the F -Q relationship compared to baseline (p < 0.001). The best models at baseline and lung injury were F  = 0.32 + 0.690Q and F  = 1.684Q -0.538Q , respectively. Endotoxine-associated early ARDS changed the relationship between F and Q, shifting from linear to curvilinear. Effects of endotoxin exposure on the vasoactive blood flow regulation were most likely the key factor for this change limiting the quantitative accuracy of F imaging as a surrogate for regional Q.

Pulmonary functional imaging modalities such as computed tomography, magnetic resonance imaging and nuclear imaging can quantitatively assess regional lung functional parameters and their distributions. These include ventilation, perfusion, gas exchange at the microvascular level and biomechanical properties, among other variables. This review describes the rationale, strengths and limitations of the various imaging modalities employed for lung functional imaging. It also aims to explain some of the most commonly measured parameters of regional lung function. A brief review of evidence on the role and utility of lung functional imaging in early diagnosis, accurate lung functional characterisation, disease phenotyping and advancing the understanding of disease mechanisms in major respiratory disorders is provided.

Background Positive end-expiratory pressure (PEEP) individualized to a maximal respiratory system compliance directly implies minimal driving pressures with potential outcome benefits, yet, raises concerns on static and dynamic overinflation, strain and cyclic recruitment. Detailed accurate assessment and understanding of these has been hampered by methodological limitations. We aimed to investigate the effects of a maximal compliance- guided PEEP strategy on dynamic lung aeration, strain and tidal recruitment using current four-dimensional computed tomography (CT) techniques and analytical methods of tissue deformation in a surfactant depletion experimental model of acute respiratory distress syndrome (ARDS). Methods ARDS was induced by saline lung lavage in anesthetized and mechanically ventilated healthy sheep (n = 6). Animals were ventilated in a random sequence with: (1) ARDSNet low-stretch protocol; (2) maximal compliance PEEP strategy. Lung aeration, strain and tidal recruitment were acquired with whole-lung respiratory-gated high-resolution CT and quantified using registration-based techniques. Results Relative to the ARDSNet low-stretch protocol, the maximal compliance PEEP strategy resulted in: (1) improved dynamic whole-lung aeration at end-expiration (0.456 +/- 0.064 vs. 0.377 +/- 0.101, P = 0.019) and end-inspiration (0.514 +/- 0.079 vs. 0.446 +/- 0.083, P = 0.012) with reduced non-aerated and increased normally-aerated lung mass without associated hyperinflation; (2) decreased aeration heterogeneity at end-expiration (coefficient of variation: 0.498 +/- 0.078 vs. 0.711 +/- 0.207, P = 0.025) and end-inspiration (0.419 +/- 0.135 vs. 0.580 +/- 0.108, P = 0.014) with higher aeration in dorsal regions; (3) tidal aeration with larger inspiratory increases in normally-aerated and decreases in poorly-aerated areas, and negligible in hyperinflated lung (Aeration x Strategy: P = 0.026); (4) reduced tidal strains in lung regions with normal-aeration (Aeration x Strategy: P = 0.047) and improved regional distributions with lower tidal strains in middle and ventral lung (Region-of-interest [ROI] x Strategy: P < 0.001); and (5) less tidal recruitment in middle and dorsal lung (ROI x Strategy: P = 0.044) directly related to whole-lung tidal strain (r = 0.751, P = 0.007). Conclusions In well-recruitable ARDS models, a maximal compliance PEEP strategy improved end-expiratory/inspiratory whole-lung aeration and its homogeneity without overinflation. It further reduced dynamic strain in middleventral regions and tidal recruitment in middle-dorsal areas. These findings suggest the maximal compliance strategy minimizing whole-lung dynamically quantified mechanisms of ventilator-induced lung injury with less cyclic recruitment and no additional overinflation in large heterogeneously expanded and recruitable lungs.