Background Mechanical ventilation worsens acute respiratory distress syndrome, but this secondary “ventilator-associated” injury is variable and difficult to predict. The authors aimed to visualize the propagation of such ventilator-induced injury, in the presence (and absence) of a primary underlying lung injury, and to determine the predictors of propagation. Methods Anesthetized rats (n = 20) received acid aspiration (hydrochloric acid) followed by ventilation with moderate tidal volume (VT). In animals surviving ventilation for at least 2 h, propagation of injury was quantified by using serial computed tomography. Baseline lung status was assessed by oxygenation, lung weight, and lung strain (VT/expiratory lung volume). Separate groups of rats without hydrochloric acid aspiration were ventilated with large (n = 10) or moderate (n = 6) VT. Results In 15 rats surviving longer than 2 h, computed tomography opacities spread outward from the initial site of injury. Propagation was associated with higher baseline strain (propagation vs. no propagation [mean ± SD]: 1.52 ± 0.13 vs. 1.16 ± 0.20, P < 0.01) but similar oxygenation and lung weight. Propagation did not occur where baseline strain was less than 1.29. In healthy animals, large VT caused injury that was propagated inward from the lung periphery; in the absence of preexisting injury, propagation did not occur where strain was less than 2.0. Conclusions Compared with healthy lungs, underlying injury causes propagation to occur at a lower strain threshold and it originates at the site of injury; this suggests that tissue around the primary lesion is more sensitive. Understanding how injury is propagated may ultimately facilitate a more individualized monitoring or management.
BackgroundUncertain prediction of outcome in acute respiratory distress syndrome (ARDS) impedes individual patient management and clinical trial design.ObjectivesTo develop a radiological metric of injurious inflation derived from matched inspiratory and expiratory CT scans, calibrate it in a model of experimental lung injury, and test it in patients with ARDS.Methods73 anaesthetised rats (acid aspiration model) were ventilated (protective or non-protective) for up to 4 hours to generate a spectrum of lung injury. CT was performed (inspiratory and expiratory) at baseline each hour, paired inspiratory and expiratory images were superimposed and voxels tracked in sequential scans. In nine patients with ARDS, paired inspiratory and expiratory CT scans from the first intensive care unit week were analysed.ResultsIn experimental studies, regions of lung with unstable inflation (ie, partial or reversible airspace filling reflecting local strain) were the areas in which subsequent progression of injury was greatest in terms of progressive infiltrates (R=0.77) and impaired compliance (R=0.67, p<0.01). In patients with ARDS, a threshold fraction of tissue with unstable inflation was apparent: >28% in all patients who died and ≤28% in all who survived, whereas segregation of survivors versus non-survivors was not possible based on oxygenation or lung mechanics.ConclusionsA single set of superimposed inspiratory–expiratory CT scans may predict progression of lung injury and outcome in ARDS; if these preliminary results are validated, this could facilitate clinical trial recruitment and individualised care.
Prone position limits the radiologic progression of early lung injury. Minimizing unstable inflation in this setting may alleviate the burden of acute respiratory distress syndrome.
Quantitative analysis of computed tomography (CT) is essential to the study of acute lung injury. However, quantitative CT is made difficult by poor lung aeration, which complicates the critical step of image segmentation. To overcome this obstacle, this study sought to develop and validate a semiautomated, multilandmark, registration-based scheme for lung segmentation that is effective in conditions of poor aeration. Expiratory and inspiratory CT images were obtained in rats (n = 8) with surfactant depletion of incremental severity to mimic worsening aeration. Trained operators manually delineated the images to provide a comparative landmark. Semiautomatic segmentation originated from a single, previously segmented reference image obtained at healthy baseline. Deformable registration of the target images (after surfactant depletion) was performed using the symmetric diffeomorphic transformation model with B-spline regularization. Registration used multiple landmarks (i.e., rib cage, spine, and lung parenchyma) to minimize the effect of poor aeration. Then target images were automatically segmented by applying the calculated transformation function to the reference image contour. Semiautomatically and manually segmented contours proved to be highly similar in all aeration conditions, including those characterized by more severe surfactant depletion and expiration. The Dice similarity coefficient was over 0.9 in most conditions, confirming high agreement, irrespective of poor aeration. Furthermore, CT density-based measurements of gas volume, tissue mass, and lung aeration distribution were minimally affected by the method of segmentation. Moving forward, multilandmark registration has the potential to streamline quantitative CT analysis by enabling semiautomatic image segmentation of lungs with a broad range of injury severity.
Inspiratory stretch by mechanical ventilation worsens lung injury. However, it is not clear whether and how the ventilator damages lungs in the absence of preexisting injury. We hypothesized that subtle loss of lung aeration during general anesthesia regionally augments ventilation and distension of ventilated air spaces. In eight supine anesthetized and intubated rats, hyperpolarized gas MRI was performed after a recruitment maneuver following 1 h of volume-controlled ventilation with zero positive end-expiratory pressure (ZEEP), FiO2 0.5, and tidal volume 10 ml/kg, and after a second recruitment maneuver. Regional fractional ventilation (FV), apparent diffusion coefficient (ADC) of (3)He (a measurement of ventilated peripheral air space dimensions), and gas volume were measured in lung quadrants of ventral and dorsal regions of the lungs. In six additional rats, computed tomography (CT) images were obtained at each time point. Ventilation with ZEEP decreased total lung gas volume and increased both FV and ADC in all studied regions. Increases in FV were more evident in the dorsal slices. In each lung quadrant, higher ADC was predicted by lower gas volume and by increased mean values (and heterogeneity) of FV distribution. CT scans documented 10% loss of whole-lung aeration and increased density in the dorsal lung, but no macroscopic atelectasis. Loss of pulmonary gas at ZEEP increased fractional ventilation and inspiratory dimensions of ventilated peripheral air spaces. Such regional changes could help explain a propensity for mechanical ventilation to contribute to lung injury in previously uninjured lungs.
During lung inflation, airspace dimensions are affected nonlinearly by both alveolar expansion and recruitment, potentially confounding the identification of emphysematous lung by hyperpolarized helium-3 diffusion magnetic resonance imaging (HP MRI). This study aimed to characterize lung inflation over a broad range of inflation volume and pressure values in two different models of emphysema, as well as in normal lungs. Elastase-treated rats ( = 7) and healthy controls ( = 7) were imaged with HP MRI. Gradual inflation was achieved by incremental changes to both inflation volume and airway pressure. The apparent diffusion coefficient (ADC) was measured at each level of inflation and fitted to the corresponding airway pressures as the second-order response equation, with minimizing residue (χ < 0.001). A biphasic ADC response was detected, with an initial ADC increase followed by a decrease at airway pressures >18 cmHO. Discrimination between treated and control rats was optimal when airway pressure was intermediate (between 10 and 11 cmHO). Similar findings were confirmed in mice following long-term exposure to cigarette smoke, where optimal discrimination between treated and healthy mice occurred at a similar airway pressure as in the rats. We subsequently explored the evolution of ADC measured at the intermediate inflation level in mice after prolonged smoke exposure and found a significant increase ( < 0.01) in ADC over time. Our results demonstrate that measuring ADC at intermediate inflation enhances the distinction between healthy and diseased lungs, thereby establishing a model that may improve the diagnostic accuracy of future HP gas diffusion studies.
Tyrosine kinase inhibitor therapy is an established standard of care for patients with NSCLC with EGFR mutations, but a worse prognosis has been observed in patients with specific EGFR exon-20 insertion mutations. Mobocertinib (TAK-788) is a novel tyrosine kinase inhibitor developed to target EGFR exon-20 insertion and has exhibited promising response rates and acceptable safety in phase 1 and 2 trials. We report a case of a 59-year-old woman with metastatic NSCLC and EGFR exon-20 mutation responsive to mobocertinib therapy, who developed severe depression and catatonia approximately 4 months after mobocertinib initiation, ultimately necessitating its permanent discontinuation. Given the observed severe depression in this case report, we recommend that, for patients on mobocertinib who develop neuropsychiatric adverse effects, strong consideration should be given for dose interruption or discontinuation.
e18731 Background: Immune checkpoint inhibitors (ICI) constitute the mainstay of treatment in several unresectable locally advanced and metastatic solid cancers. mRNA COVID-19 vaccines are immunogenic and can modulate intrinsic host immunostimulatory properties however the effect of COVID-19 mRNA vaccination on outcomes in patients receiving ICI is not well understood. This study examines the outcomes in cancer patients receiving ICI according to their vaccination status. Methods: From January 2021 to December 2021, we identified adult patients with locally advanced and metastatic solid tumors at the University of Illinois Hospital & Health Sciences System who had received at least one dose of ICI, either as monotherapy or in combination with chemotherapy or targeted therapy, in any line of cancer treatment. Patients were stratified by COVID-19 vaccination status and treatment type (monotherapy versus combined chemoimmunotherapy). Endpoints included immune-related adverse events (IRAEs), progression-free survival (PFS) from ICI initiation and overall survival (OS). Results: Among 89 patients meeting these inclusion criteria, the mean age at diagnosis was 66 years, patient sex was about equally split (female 50.5% to male 49.5%), most patients were minorities (including 58.4% African American), vaccinated (78.7%), had lung cancer (57.3%), were stage IV (71.1%), and had received ICI monotherapy (67.4%). There were no significant differences in the rate of IRAEs between vaccinated and non-vaccinated patients ( p= 0.53). Patients who received ICI monotherapy had higher rates of IRAEs ( p< 0.001). There was no difference in PFS between vaccinated and non-vaccinated patients ( p= 0.7) and no difference in OS between vaccinated and non-vaccinated patients ( p= 0.59). Conclusions: In this real-world sample of patients with advanced solid cancers who received ICI there were no significant differences in IRAEs, PFS or OS between vaccinated and non-vaccinated patients, which may be due to the relatively small sample size. Larger real-world datasets with long-term follow-up are needed to study the effect of mRNA COVID-19 vaccination on outcomes in advanced cancer patients receiving ICI.
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