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Dynamic contrast-enhanced CT using a lower-viscosity contrast agent in combination with tracer-kinetic analysis by the steepest-slope model improves pulmonary blood flow measurements and assessment of regional distributions of lung perfusion.

We hypothesized that a system that possesses the capacity for ongoing maintenance of its tissues will necessarily also have the capacity to self-heal following a perturbation. We used an agent-based model of tissue maintenance to investigate this idea, and in particular to determine the extent to which the current state of the tissue must influence cell behavior in order for tissue maintenance and self-healing to be stable. We show that a mean level of tissue density is robustly maintained when catabolic agents digest tissue at a rate proportional to local tissue density, but that the spatial heterogeneity of the tissue at homeostasis increases with the rate at which tissue is digested. The rate of self-healing is also increased by increasing either the amount of tissue removed or deposited at each time step by catabolic or anabolic agents, respectively, and by increasing the density of both agent types on the tissue. We also found that tissue maintenance and self-healing are stable with an alternate rule in which cells move preferentially to tissue regions of low density. The most basic form of self-healing can thus be achieved with cells that follow very simple rules of behavior, provided these rules are based in some way on the current state of the local tissue. Straightforward mechanisms can accelerate the rate of self-healing, as might be beneficial to the organism.

Emphysema is a debilitating disease that remodels the lung leading to reduced tissue stiffness. Thus, understanding emphysema progression requires assessing lung stiffness at both the tissue and alveolar scales. Here, we introduce an approach to determine multiscale tissue stiffness and apply it to precision-cut lung slices (PCLS). First, we established a framework for measuring stiffness of thin, disk-like samples. We then designed a device to verify this concept and validated its measuring capabilities using known samples. Next, we compared healthy and emphysematous human PCLS and found that the latter was 50% softer. Through computational network modeling, we discovered that this reduced macroscopic tissue stiffness was due to both microscopic septal wall remodeling and structural deterioration. Lastly, through protein expression profiling, we identified a wide spectrum of enzymes that can drive septal wall remodeling, which, together with mechanical forces, lead to rupture and structural deterioration of the emphysematous lung parenchyma.

Adipocytes regulate tissues through production of adipokines that can act both locally and systemically. Adipocytes also have been found to play a critical role in regulating the healing process. To better understand this role, we developed a three-dimensional human adipocyte spheroid system that has an adipokine profile similar to in vivo adipose tissues. Previously, we found that conditioned medium from these spheroids induces human dermal fibroblast conversion into highly contractile, collagen-producing myofibroblasts through a transforming growth factor beta-1 (TGF-β1) independent pathway. Here, we sought to identify how mature adipocytes signal to dermal fibroblasts through adipokines to induce myofibroblast conversion. By using molecular weight fractionation, heat inactivation and lipid depletion, we determined mature adipocytes secrete a factor that is 30–100 kDa, heat labile and lipid associated that induces myofibroblast conversion. We also show that the depletion of the adipokine adiponectin, which fits those physico-chemical parameters, eliminates the ability of adipocyte-conditioned media to induce fibroblast to myofibroblast conversion. Interestingly, native adiponectin secreted by cultured adipocytes consistently elicited a stronger level of α-smooth muscle actin expression than exogenously added adiponectin. Thus, adiponectin secreted by mature adipocytes induces fibroblast to myofibroblast conversion and may lead to a phenotype of myofibroblasts distinct from TGF-β1-induced myofibroblasts.

Adipocytes regulate tissues through production of adipokines that can act both locally and systemically. Adipocytes also have been found to play a critical role in regulating the healing process. To better understand this role, we developed a 3D human adipocyte spheroid system that has an adipokine profile similar toin vivoadipose tissues. Previously, we found that conditioned medium from these spheroids induces human dermal fibroblast conversion into highly contractile, collagen producing myofibroblasts through a transforming growth factor beta-1 (TGF-β1) independent pathway. Here, we sought to identify how mature adipocytes signal to dermal fibroblasts through adipokines to induce myofibroblast conversion. By using molecular weight fractionation, heat inactivation, and lipid depletion, we determined mature adipocytes secrete a factor that is 30-100 kDa, heat labile, and lipid associated that induces myofibroblast conversion. We also show that depletion of the adipokine adiponectin, which fits those physiochemical parameters, eliminates the ability of adipocyte conditioned media to induce fibroblast to myofibroblast conversion. Interestingly, native adiponectin secreted by cultured adipocytes consistently elicited a stronger level ofα-SMA expression than exogenously added adiponectin. Thus, adiponectin secreted by mature adipocytes induces fibroblast to myofibroblast conversion and may lead to a phenotype of myofibroblasts distinct from TGF-β1 induced myofibroblasts.

The mammalian lung is characterized by heterogeneity in both its structure and function, by incorporating an asymmetric branching airway tree optimized for maintenance of efficient ventilation, perfusion, and gas exchange. Despite potential benefits of naturally occurring heterogeneity in the lungs, there may also be detrimental effects arising from pathologic processes, which may result in deficiencies in gas transport and exchange. Regardless of etiology, pathologic heterogeneity results in the maldistribution of regional ventilation and perfusion, impairments in gas exchange, and increased work of breathing. In extreme situations, heterogeneity may result in respiratory failure, necessitating support with a mechanical ventilator. This review will present a summary of measurement techniques for assessing and quantifying heterogeneity in respiratory system structure and function during mechanical ventilation. These methods have been grouped according to four broad categories: (1) inverse modeling of heterogeneous mechanical function; (2) capnography and washout techniques to measure heterogeneity of gas transport; (3) measurements of heterogeneous deformation on the surface of the lung; and finally (4) imaging techniques used to observe spatially-distributed ventilation or regional deformation. Each technique varies with regard to spatial and temporal resolution, degree of invasiveness, and risk posed to patients, as well as suitability for clinical implementation. Nonetheless, each technique can provide a unique perspective on the manifestations and consequences of mechanical heterogeneity in the diseased lung.

Particle deposition in the lung during inhalation is of interest to a wide range of biomedical sciences due to the noninvasive therapeutic route to deliver drugs to the lung and other organs via the blood stream. Before reaching the alveoli, particles must transverse the bifurcating network of airways. Computational fluid mechanical studies are often used to estimate high-fidelity flow patterns through the large conducting airways, but there is a need for reduced-dimensional modeling that enables rapid parameter optimization while accommodating the complete airway network. Here, we introduce a Markov chain model with each state corresponding to an airway segment in which a particle may be located. The local flows and transition probabilities of the Markov chain, verified against computational fluid dynamics simulations, indicate that the independent effects of three fundamental forces (gravity, fluid drag, diffusion) provide a sufficient approximation of overall particle behavior. The model enables fast computation of how different inhalation strategies, called flow policies, determine total particle escape rates and local particle deposition. In a 3-dimensional airway tree model, the optimal flow policy minimizing the risk of deposition at each generation, compared to other inlet flow waveforms, predicted significantly higher probability of escape defined as the fraction of particles exiting the tree. The model also predicts a small influence of body orientation with respect to a gravitational field on total escape probability, but a significant effect of airway narrowing on regional deposition. In summary, this model provides insight into inhalation strategies for targeted drug delivery.

Background The use of surface disinfection wipes after induction of anesthesia improves anesthesia machine cleaning. We assessed whether anesthesia machine surface redesign improves disinfection wipe cleaning by anesthesia residents. Methods Sixteen anesthesia residents were assigned to 2 cases in series. The first case was randomly assigned to regional knee or hip surgery, a brief or detailed checklist, and the Perseus A500 (redesigned) or GE Aespire 7900 (conventional) machine. The second case was assigned to the opposite for each condition. Setup checklists included cleaning instructions. Eight machine sites representing redesign were contaminated with fluorescent gel prior to setup and reassessed after setup to assess cleaning efficacy. Cleaning was compared by fluorescence quantification of before and after setup images. Our primary hypothesis was that, overall, more sites would be cleaned on the Perseus machine. Our secondary hypothesis was that redesign would affect some sites. Results Overall, the number of sites cleaned did not differ between machines (median 0.74 more sites out of 8 for the Perseus A500; 25th and 75th percentiles, –0.34 and 1.04; P = .093). However, greater cleaning was observed for the work surface and manual bag arm/hose of the Perseus machine (0.58 more sites out of 2; 25th and 75th percentiles, 0.35 and 1.05; P = .0004). Conclusions The number of sites cleaned overall did not differ between the conventional and redesigned Perseus A500 machines. However, the redesigned work surface and smooth manual bag arm features improved resident cleaning with surface disinfection wipes.

Introduction: The use of shared ventilation, or the simultaneous support of multiple patients connected in parallel to a single mechanical ventilator, is receiving considerable interest for addressing the severe shortage of mechanical ventilators available during the novel coronavirus pandemic (COVID-19). In this paper we highlight the potentially disastrous consequences of naive shared ventilation, in which patients are simply connected in parallel to a ventilator without any regard to their individual ventilatory requirements. We then examine possible approaches for individualization of mechanical ventilation, using modifications to the breathing circuit that may enable tuning of individual tidal volumes and driving pressures during either volume-controlled ventilation (VCV) or pressure-controlled ventilation (PCV). Methods: Breathing circuit modifications included a PEEP valve on each expiratory limb for both VCV and PCV, an adjustable constriction and one-way valve on the inspiratory limb for VCV, and a pressure relief valve for peak-inspiratory pressure reduction on the inspiratory limb for PCV. The ability to regulate individual tidal volumes using these breathing circuit modifications was tested both theoretically in computer simulations as well as experimentally in mechanical test lungs. Results: In both the simulations and experimental measurements, naive shared ventilation resulted in large imbalances across individual tidal volume delivery, dependent on imbalances across patient mechanical properties. The proposed breathing circuit modifications for shared VCV and shared PCV enabled optimization of tidal volume distributions. Individual tidal volume for one patient during shared VCV was sensitive to changes in the mechanical properties of other patients. By contrast, shared PCV enabled independent control of individual patient received ventilation. Conclusions: Of the shared ventilation strategies considered, shared PCV, with the inclusion of in-line pressure relief valves in the individual inspiratory and expiratory limbs, offers the greatest degree of safety and lowest risk of catastrophic mechanical interactions between multiple patients connected to a single ventilator.

Emphysema is a progressive disease characterized by irreversible tissue destruction and airspace enlargement, which manifest as low attenuation area (LAA) on CT images. Previous studies have shown that inflammation, protease imbalance, extracellular matrix remodeling and mechanical forces collectively influence the progression of emphysema. Elastic spring network models incorporating force-based mechanical failure have been applied to investigate the pathogenesis and progression of emphysema. However, these models were general without considering the patient-specific information on lung structure available in CT images. The aim of this work was to develop a novel approach that provides an optimal spring network representation of emphysematous lungs based on the apparent density in CT images, allowing the construction of personalized networks. The proposed method takes into account the size and curvature of LAA clusters on the CT images that correspond to a pre-stressed condition of the lung as opposed to a naïve method that excludes the effects of pre-stress. The main findings of this study are that networks constructed by the new method 1) better preserve LAA cluster sizes and their distribution than the naïve method; and 2) predict different course of emphysema progression compared to the naïve method. We conclude that our new method has the potential to predict patient-specific emphysema progression which needs verification using clinical data.

To describe the effects of timing of intubation in COVID-19 patients that fail helmet continuous positive airway pressure (h-CPAP) on progression and severity of disease.COVID-19 patients that failed h-CPAP, required intubation, and underwent chest computed tomography (CT) at two levels of positive end-expiratory pressure (PEEP, 8 and 16 cmHFifty-two patients were included and classified in early (h-CPAP for ≤2 days, N = 26) and late groups (h-CPAP for2 days, N = 26). Patients in the late compared to early intubation group presented: 1) lower respiratory system compliance (median difference, MD -7 mL/cmHIn COVID-19 patients receiving h-CPAP, late intubation was associated with worse clinical presentation at ICU admission and more advanced disease. The possible detrimental effects of delaying intubation should be carefully considered in these patients.

PURPOSE OF REVIEW: Lung imaging is a cornerstone of the management of patients admitted to the intensive care unit (ICU), providing anatomical and functional information on the respiratory system function. The aim of this review is to provide an overview of mechanisms and applications of conventional and emerging lung imaging techniques in critically ill patients. RECENT FINDINGS: Chest radiographs (CXR) provide information on lung structure and have several limitations in the ICU setting; however, scoring systems can be used to stratify patient severity and predict clinical outcome. Computed tomography (CT) is the gold standard for assessment of lung aeration but requires moving the patients to the CT facility. Dual-energy CT has been recently applied to simultaneous study of lung aeration and perfusion in patients with respiratory failure. Lung ultrasound has an established role in the routine bedside assessment of ICU patients, but has poor spatial resolution and largely relies on the analysis of artefacts. Electrical impedance tomography is an emerging technique capable of depicting ventilation and perfusion at the bedside and at the regional level. SUMMARY: Clinicians should be confident with the technical aspects, indications, and limitations of each lung imaging technique to improve patient care.

Inflation of hollow elastic structures can become unstable and exhibit a runaway phenomenon if the tension in their walls does not rise rapidly enough with increasing volume. Biological systems avoid such inflation instability for reasons that remain poorly understood. This is best exemplified by the lung, which inflates over its functional volume range without instability. The goal of this study was to determine how the constituents of lung parenchyma determine tissue stresses that protect alveoli from instability-related overdistension during inflation. We present an analytical model of a thick-walled alveolus composed of wavy elastic fibres, and investigate its pressure–volume behaviour under large deformations. Using second-harmonic generation imaging, we found that collagen waviness follows a beta distribution. Using this distribution to fit human pressure–volume curves, we estimated collagen and elastin effective stiffnesses to be 1247 kPa and 18.3 kPa, respectively. Furthermore, we demonstrate that linearly elastic but wavy collagen fibres are sufficient to achieve inflation stability within the physiological pressure range if the alveolar thickness-to-radius ratio is greater than 0.05. Our model thus identifies the constraints on alveolar geometry and collagen waviness required for inflation stability and provides a multiscale link between alveolar pressure and stresses on fibres in healthy and diseased lungs.

OBJECTIVES It is not known how lung injury progression during mechanical ventilation modifies pulmonary responses to prone positioning. We compared the effects of prone positioning on regional lung aeration in late versus early stages of lung injury. DESIGN Prospective, longitudinal imaging study. SETTING Research imaging facility at The University of Pennsylvania (Philadelphia, PA) and Medical and Surgical ICUs at Massachusetts General Hospital (Boston, MA). SUBJECTS Anesthetized swine and patients with acute respiratory distress syndrome (acute respiratory distress syndrome). INTERVENTIONS Lung injury was induced by bronchial hydrochloric acid (3.5 mL/kg) in 10 ventilated Yorkshire pigs and worsened by supine nonprotective ventilation for 24 hours. Whole-lung CT was performed 2 hours after hydrochloric acid (Day 1) in both prone and supine positions and repeated at 24 hours (Day 2). Prone and supine images were registered (superimposed) in pairs to measure the effects of positioning on the aeration of each tissue unit. Two patients with early acute respiratory distress syndrome were compared with two patients with late acute respiratory distress syndrome, using electrical impedance tomography to measure the effects of body position on regional lung mechanics. MEASUREMENTS AND MAIN RESULTS Gas exchange and respiratory mechanics worsened over 24 hours, indicating lung injury progression. On Day 1, prone positioning reinflated 18.9% ± 5.2% of lung mass in the posterior lung regions. On Day 2, position-associated dorsal reinflation was reduced to 7.3% ± 1.5% (p < 0.05 vs Day 1). Prone positioning decreased aeration in the anterior lungs on both days. Although prone positioning improved posterior lung compliance in the early acute respiratory distress syndrome patients, it had no effect in late acute respiratory distress syndrome subjects. CONCLUSIONS The effects of prone positioning on lung aeration may depend on the stage of lung injury and duration of prior ventilation; this may limit the clinical efficacy of this treatment if applied late.

Fibrotic diseases are characterized by progressive and often irreversible scarring of connective tissue in various organs, leading to substantial changes in tissue mechanics largely as a result of alterations in collagen structure. This is particularly important in the lung because its bulk modulus is so critical to the volume changes that take place during breathing. Nevertheless, it remains unclear how fibrotic abnormalities in the mechanical properties of pulmonary connective tissue can be linked to the stiffening of its individual collagen fibers. To address this question, we developed a network model of randomly oriented collagen and elastin fibers to represent pulmonary alveolar wall tissue. We show that the stress–strain behavior of this model arises via the interactions of collagen and elastin fiber networks and is critically dependent on the relative fiber stiffnesses of the individual collagen and elastin fibers themselves. We also show that the progression from linear to nonlinear stress–strain behavior of the model is associated with the percolation of stress across the collagen fiber network, but that the location of the percolation threshold is influenced by the waviness of collagen fibers.

Acute respiratory distress syndrome (ARDS) consists of acute hypoxemic respiratory failure characterized by massive and heterogeneously distributed loss of lung aeration caused by diffuse inflammation and edema present in interstitial and alveolar spaces. It is defined by consensus criteria, which include diffuse infiltrates on chest imaging—either plain radiography or computed tomography. This review will summarize how imaging sciences can inform modern respiratory management of ARDS and continue to increase the understanding of the acutely injured lung. This review also describes newer imaging methodologies that are likely to inform future clinical decision-making and potentially improve outcome. For each imaging modality, this review systematically describes the underlying principles, technology involved, measurements obtained, insights gained by the technique, emerging approaches, limitations, and future developments. Finally, integrated approaches are considered whereby multimodal imaging may impact management of ARDS.

Primary blast lung injury (PBLI) caused by exposure to high-intensity pressure waves is associated with parenchymal tissue injury and severe ventilation-perfusion mismatch. Although supportive ventilation is often required in patients with PBLI, maldistribution of gas flow in mechanically heterogeneous lungs may lead to further injury due to increased parenchymal strain and strain rate, which are difficult to predict in vivo. In this study, we developed a computational lung model with mechanical properties consistent with healthy and PBLI conditions. PBLI conditions were simulated with bilateral derecruitment and increased perihilar tissue stiffness. As a result of these tissue abnormalities, airway flow was heterogeneously distributed in the model under PBLI conditions, during both conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation. PBLI conditions resulted in over three-fold higher parenchymal strains compared to the healthy condition during CMV, with flow distributed according to regional tissue stiffness. During high-frequency oscillatory ventilation, flow distribution became increasingly heterogeneous and frequency-dependent. We conclude that the distribution and rate of parenchymal distension during mechanical ventilation depend on PBLI severity as well as ventilatory modality. These simulations may allow realistic assessment of the risks associated with ventilator-induced lung injury following PBLI, and facilitate the development of alternative lung-protective ventilation modalities.

Enhanced intrapulmonary gas transport enables oscillatory ventilation modalities to support gas exchange using extremely low tidal volumes at high frequencies. However, it is unknown whether gas transport rates can be improved by combining multiple frequencies of oscillation simultaneously. The goal of this study was to investigate distributed gas transport in vivo during multi-frequency oscillatory ventilation (MFOV) as compared with conventional mechanical ventilation (CMV) or high-frequency oscillatory ventilation (HFOV). We hypothesized that MFOV would result in more uniform rates of gas transport compared to HFOV, measured using contrast-enhanced CT imaging during wash-in of xenon gas. In 13 pigs, xenon wash-in equilibration rates were comparable between CMV and MFOV, but 21 to 39% slower for HFOV. By contrast, the root-mean-square delivered volume was lowest for MFOV, increased by 70% during HFOV and 365% during CMV. Overall gas transport heterogeneity was similar across all modalities, but gravitational gradients and regional patchiness of specific ventilation contributed to regional ventilation heterogeneity, depending on ventilator modality. We conclude that MFOV combines benefits of low lung stretch, similar to HFOV, but with fast rates of gas transport, similar to CMV.

The purpose of this study was to develop a fully-automated segmentation algorithm, robust to various density enhancing lung abnormalities, to facilitate rapid quantitative analysis of computed tomography images. A polymorphic training approach is proposed, in which both specifically labeled left and right lungs of humans with COPD, and nonspecifically labeled lungs of animals with acute lung injury, were incorporated into training a single neural network. The resulting network is intended for predicting left and right lung regions in humans with or without diffuse opacification and consolidation. Performance of the proposed lung segmentation algorithm was extensively evaluated on CT scans of subjects with COPD, confirmed COVID-19, lung cancer, and IPF, despite no labeled training data of the latter three diseases. Lobar segmentations were obtained using the left and right lung segmentation as input to the LobeNet algorithm. Regional lobar analysis was performed using hierarchical clustering to identify radiographic subtypes of COVID-19. The proposed lung segmentation algorithm was quantitatively evaluated using semi-automated and manually-corrected segmentations in 87 COVID-19 CT images, achieving an average symmetric surface distance of $$0.495\pm 0.309$$ 0.495 ± 0.309 mm and Dice coefficient of $$0.985\pm 0.011$$ 0.985 ± 0.011 . Hierarchical clustering identified four radiographical phenotypes of COVID-19 based on lobar fractions of consolidated and poorly aerated tissue. Lower left and lower right lobes were consistently more afflicted with poor aeration and consolidation. However, the most severe cases demonstrated involvement of all lobes. The polymorphic training approach was able to accurately segment COVID-19 cases with diffuse consolidation without requiring COVID-19 cases for training.

Early stages of the novel coronavirus disease (COVID-19) are associated with silent hypoxia and poor oxygenation despite relatively minor parenchymal involvement. Although speculated that such paradoxical findings may be explained by impaired hypoxic pulmonary vasoconstriction in infected lung regions, no studies have determined whether such extreme degrees of perfusion redistribution are physiologically plausible, and increasing attention is directed towards thrombotic microembolism as the underlying cause of hypoxemia. Herein, a mathematical model demonstrates that the large amount of pulmonary venous admixture observed in patients with early COVID-19 can be reasonably explained by a combination of pulmonary embolism, ventilation-perfusion mismatching in the noninjured lung, and normal perfusion of the relatively small fraction of injured lung. Although underlying perfusion heterogeneity exacerbates existing shunt and ventilation-perfusion mismatch in the model, the reported hypoxemia severity in early COVID-19 patients is not replicated without either extensive perfusion defects, severe ventilation-perfusion mismatch, or hyperperfusion of nonoxygenated regions.

Supplemental oxygen is among the most ubiquitous medical therapies used in acute and chronic impairments of the respiratory system, such that little thought is given to its conservation in developed countries. The appropriate amount of oxygen to deliver to a given patient, however, is an important

Early stages of the novel coronavirus disease (COVID-19) are associated with silent hypoxia and poor oxygenation despite relatively minor parenchymal involvement. Although speculated that such paradoxical findings may be explained by impaired hypoxic pulmonary vasoconstriction in infected lung regions, no studies have determined whether such extreme degrees of perfusion redistribution are physiologically plausible, and increasing attention is directed towards thrombotic microembolism as the underlying cause of hypoxemia. Herein, a mathematical model demonstrates that the large amount of pulmonary venous admixture observed in patients with early COVID-19 can be reasonably explained by a combination of pulmonary embolism, ventilation-perfusion mismatching in the noninjured lung, and normal perfusion of the relatively small fraction of injured lung. Although underlying perfusion heterogeneity exacerbates existing shunt and ventilation-perfusion mismatch in the model, the reported hypoxemia severity in early COVID-19 patients is not replicated without either extensive perfusion defects, severe ventilation-perfusion mismatch, or hyperperfusion of nonoxygenated regions., Early stages of the novel coronavirus disease (COVID-19) have been associated with silent hypoxia and poor oxygenation despite relatively small fractions of afflicted lung. Here, the authors present a mathematical model which reproduces the vascular pulmonary mechanisms observed in patients with early COVID-19.

The current coronavirus disease 2019 (Covid-19) pandemia is a highly dynamic situation characterized by therapeutic and logistic uncertainties. Depending on the effectiveness of social distancing, a shortage of intensive care respirators must be expected. Concomitantly, many physicians and nursing staff are unaware of the capabilities of alternative types of ventilators, hence being unsure if they can be used in intensive care patients. Intensive care respirators were specifically developed for the use in patients with pathological lung mechanics. Nevertheless, modern anesthesia machines offer similar technical capabilities including a number of different modes. However, conceptual differences must be accounted for, requiring close monitoring and the presence of trained personnel. Modern transport ventilators are mainly for bridging purposes as they can only be used with 100% oxygen in contaminated surroundings. Unconventional methods, such as "ventilator-splitting", which have recently received increasing attention on social media, cannot be recommended. This review intends to provide an overview of the conceptual and technical differences of different types of mechanical ventilators.