The U-shaped association of post-lung transplant mortality with pretransplant eGFR underscores possible limitations of creatinine-based estimation equations for risk stratification.

BACKGROUND: Pre-existing chronic kidney disease (CKD) may have an impact on post-lung transplant survival and the development of end stage kidney disease (ESKD). METHODS: We analyzed the US transplant database from 2006 to 2020. Adult patients who received their first lung transplant and were not on dialysis were included. Multivariable Cox regression was used to assess the effect of pretransplant eGFR on mortality and cumulative incidence competing risk was used to explore the effect on ESKD. RESULTS: The adjusted hazard ratio (aHR) for mortality showed a "U" shaped association with eGFR with a rising mortality at <60 and >100 ml/min/1.73m2. The increase in mortality with higher eGFR was only seen in those <30 year and were primarily in whites with a lower body mass index and in patients with cystic fibrosis (CF). The aHR for ESKD increased below an eGFR of 100 rising to 1.74 at an eGFR of 60. Any decrease in eGFR between listing and transplant >10% was associated with higher risk of ESKD. CONCLUSIONS: The U-shaped association of pretransplant eGFR with post-transplant mortality correlated with younger age, lower BMI and a diagnosis of CF. The aHR for ESKD following lung transplantation increased exponentially with worsening eGFR pretransplant.

Case Studies in Physiology: Untangling the cause of hypoxemia in a patient with obesity with acute leukemia.

Diagnosing the cause of hypoxemia and dyspnea can be complicated in complex patients with multiple comorbidities. This "Case Study in Physiology" describes an man with obesity admitted to the hospital for relapse of acute lymphoblastic leukemia, who experienced progressive hypoxemia, shortness of breath, and dyspnea on exertion during his hospitalization. After initial empirical treatment with diuresis and antibiotics failed to improve his symptoms and because an arterial blood gas measurement was not readily available, we applied a novel, recently described physiological method to estimate the arterial partial pressure of oxygen from the peripheral saturation measurement and calculate the alveolar-arterial oxygen difference to discern the source of his hypoxemia and dyspnea. Using basic physiological principles, we describe how hypoventilation, anemia, and the use of a ß blocker and furosemide, collaborated to create a "perfect storm" in this patient that impaired oxygen delivery and limited utilization. This case illustrates the application of innovative physiology methodology in medicine and provides a strong rationale for continuing to integrate physiology education in medical education.NEW & NOTEWORTHY Discerning the cause of dyspnea and hypoxemia in complex patients can be difficult. We describe the "real world" application of an innovative methodology to untangle the underlying physiology in a patient with multiple comorbidities. This case further demonstrates the importance of applying physiology to interrogate the underlying cause of a patient's symptoms when treatment based on probability fails.

Multimodal and palliative treatment of patients with pulmonary metastases.

Pulmonary metastasectomy has become an important part of the multimodality treatment. Surgical practice is based on observational studies published during the last decades, since no randomized clinical trials exist on the topic. However, the overall survival can be improved after pulmonary metastasectomy in carefully selected patients. The objective of resection of pulmonary metastases is to remove all tumor while preserving as much normal pulmonary parenchyma as possible and reduce invasiveness. Contrary, nonsurgical local treatment options for pulmonary metastases include thermal ablation techniques and stereotactic ablative body radiation. Thermal ablation techniques include microwave, cryotherapy and radiofrequency ablation. The present review article gives an overview on the topic and should help thoracic surgeons to make the right decisions in their daily practice.

Preserved Ratio Impaired Spirometry in a Spirometry Database.

BACKGROUND: Spirometry results can yield a diagnosis of normal air flow, air flow obstruction, or preserved ratio impaired spirometry (PRISm), defined as a reduced FEV1 or FVC in the setting of preserved FEV1/FVC. Previous studies have estimated the prevalence of PRISm to be 7-12%. Our objective was to examine the prevalence of PRISm in a spirometry database and to identify factors associated with PRISm. METHODS: We performed a retrospective analysis of 21,870 spirometries; 1,616 were excluded because of missing data or extremes of age, height, or weight. We calculated the prevalence of PRISm in prebronchodilator and postbronchodilator pulmonary function tests. Subsequently, we calculated the prevalence of PRISm by various age, race, body mass index, and diagnosis categories, as well as by gender and smokers versus nonsmokers. Finally, in the subset of the cohort with FEV1 < lower limit of normal, we performed a multivariable logistic regression analysis to identify factors associated with PRISm. RESULTS: We identified 18,059 prebronchodilator spirometries, and 22.3% of these yielded a PRISm diagnosis. This prevalence remained stable in postbronchodilator spirometries (17.7%), after excluding earlier pulmonary function tests for subjects with multiple pulmonary function tests (20.7% in prebronchodilator and 24.3% in postbronchodilator), and when we limited the analysis to prebronchodilator spirometries that met American Thoracic Society criteria (20.6%). The PRISm prevalence was higher in subjects 45-60 y old (24.4%) and in males (23.7%) versus females (17.9%). The prevalence rose with body mass index and was higher for those with a referral diagnosis of restrictive lung disease (50%). PRISm prevalence was similar between races and smokers versus nonsmokers. In a multivariable analysis, higher % of predicted FEV1 (odds ratio 1.51, 95% CI 1.42-1.60), body mass index (odds ratio 1.52, 95% CI 1.39-1.68), and restrictive lung disease (odds ratio 4.32, 95% CI 2.54-7.57) were associated with a diagnosis of PRISm. Smoking was inversely associated (odds ratio 0.55, 95% CI 0.46-0.65) with PRISm. CONCLUSIONS: In a spirometry database at an academic medical center, the PRISm prevalence was 17-24%, which is higher than previously reported.

Survival of Pregnant Coronavirus Patient on Extracorporeal Membrane Oxygenation.

A 27-year-old woman presented at 23 weeks' 6 days' gestation who tested positive for the coronavirus disease 2019 (COVID-19). Despite mechanical ventilation and paralysis, she remained hypoxic and was emergently cannulated for veno-venous extracorporeal membrane oxygenation (VV-ECMO). The patient ambulated while intubated and on VV-ECMO. She was decannulated and extubated. An ultrasound demonstrated an appropriately grown fetus without abnormalities. She was discharged to home and gave birth to a healthy baby girl at 39 weeks' gestation. Using VV-ECMO, this patient and her fetus survived acute hypoxemic respiratory failure due to COVID-19.

Standard and extended sleeve resections of the tracheobronchial tree.

Anatomic resections with bronchial and/or vascular resections and reconstruction, so called sleeve resections were originally performed in patients with impaired cardio-pulmonary reserves. Nowadays, sleeve resections are established surgical procedures of first choice for tracheobronchial pathologies, whenever anatomically and oncologically feasible. Experienced thoracic surgeons have a broad surgical armentarium to avoid a pneumonectomy and the morbidity and mortality associated with it. Sleeve resections are associated with better outcomes in all aspects. Thus, sleeve resection is not an alternative for pneumonectomy and vice versa. In this review article we set out to provide a contemporary overview on this topic.

The Peak Index: Spirometry Metric for Airflow Obstruction Severity and Heterogeneity.

Rationale: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation. Spirometry loops are not smooth curves and have undulations and peaks that likely reflect heterogeneity of airflow.Objectives: To assess whether the Peak Index, the number of peaks adjusted for lung size, is associated with clinical outcomes.Methods: We analyzed spirometry data of 9,584 participants enrolled in the COPDGene study and counted the number of peaks in the descending part of the expiratory flow-volume curve from the peak expiratory flow to end-expiration. We adjusted the peaks count for the volume of the lungs from peak expiratory flow to end-expiration to derive the Peak Index. Multivariable regression analyses were performed to test associations between the Peak Index and lung function, respiratory morbidity, structural lung disease on computed tomography (CT), forced expiratory volume in 1 second (FEV1) decline, and mortality.Results: The Peak Index progressively increased from Global Initiative for Chronic Obstructive Lung Disease stage 0 through 4 (P < 0.001). On multivariable analysis, the Peak Index was significantly associated with CT emphysema (adjusted ß = 0.906; 95% confidence interval [CI], 0.789 to 1.023; P < 0.001) and small airways disease (adjusted ß = 1.367; 95% CI, 1.188 to 1.545; P < 0.001), St. George's Respiratory Questionnaire score (adjusted ß = 1.075; 95% CI, 0.807 to 1.342; P < 0.001), 6-minute-walk distance (adjusted ß = -1.993; 95% CI, -3.481 to -0.506; P < 0.001), and FEV1 change over time (adjusted ß = -1.604; 95% CI, -2.691 to -0.516; P = 0.004), after adjustment for age, sex, race, body mass index, current smoking status, pack-years of smoking, and FEV1. The Peak Index was also associated with the BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index and mortality (P < 0.001).Conclusions: The Peak Index is a spirometry metric that is associated with CT measures of lung disease, respiratory morbidity, lung function decline, and mortality.Clinical trial registered with www.clinicaltrials.gov (NCT00608764).

Diode-pumped neodymium:yttrium aluminum garnet laser effects on the visceral pleura in an ex vivo porcine lung model†.

OBJECTIVES: Resection of tumour spread on a very thin visceral pleura might be challenging, and collateral damage to the lung parenchyma might occur. We aimed to develop an operative technique, which might facilitate the parenchyma-sparing destruction of the visceral pleura. This experimental work investigated the effects of a neodymium:yttrium aluminum garnet (Nd:YAG) laser on the visceral pleura in an ex vivo porcine lung model. METHODS: We used a diode-pumped Nd:YAG laser (Limax® 120, KLS Martin, Tuttlingen, Germany) to investigate the effects on the visceral pleural in 20 porcine lungs. The laser was applied on a standardized length in 4 different settings: Group I (80 W, 6 s), Group II (80 W, 12 s), Group III (120 W, 6 s) and Group IV (120 W, 12 s). All specimens were analysed histologically. RESULTS: The mean thickness of the visceral pleura was 81 ± 10 µm. Increasing power levels and longer application duration resulted in significantly enhanced laser destruction effects. The mean depths of the carbonization zone were 142 ± 42 µm, 378 ± 137 µm, 607 ± 155 µm and 1371 ± 271 µm for Groups I-IV, respectively (P < 0.001). The ratio of carbonization zone to pleural thickness was measured for each section (C/P ratio) to quantify the thermal effects. The corresponding C/P ratio for Groups I-IV were 1.72 ± 0.55, 4.98 ± 1.96, 7.11 ± 1.61 and 17.35 ± 4.35, respectively (P < 0.001). CONCLUSIONS: Our study showed that increasing power levels and application duration of the laser lead to a significantly increased carbonization and destruction zones. Further in vivo human studies should evaluate the feasibility of laser application for a potential translational relevance for human use.

Secondary Lingular Sleeve Resection to Avoid Pneumonectomy Following Bronchial Anastomotic Dehiscence after Left Lower Lobe Sleeve Resection for Destroyed Lung Syndrome.

Bronchial sleeve resections are technically demanding procedures compared with lobectomies. In case of bronchial anastomotic dehiscence, secondary pneumonectomy is the treatment of choice. However, a secondary pneumonectomy is usually associated with high morbidity and mortality. Here, we first report, to the best of our knowledge, a secondary lingular sleeve resection following bronchial anastomotic dehiscence after left lower lobe sleeve resection in a patient with a destroyed lobe syndrome due to a pseudotumor. This approach enabled the avoidance of secondary pneumonectomy, hence reducing the possible pneumonectomy-associated complications.

Depletion of Airway Submucosal Glands and TP63+KRT5+ Basal Cells in Obliterative Bronchiolitis.

RATIONALE: Obliterative bronchiolitis (OB) is a major cause of mortality after lung transplantation. Depletion of airway stem cells (SCs) may lead to fibrosis in OB. OBJECTIVES: Two major SC compartments in airways are submucosal glands (SMGs) and surface airway p63 (also known as TP63 [tumor protein 63])-positive/K5 (also known as KRT5 [keratin 5])-positive basal cells (BCs). We hypothesized that depletion of these SC compartments occurs in OB. METHODS: Ferret orthotopic left lung transplants were used as an experimental model of OB, and findings were corroborated in human lung allografts. Morphometric analysis was performed in ferret and human lungs to evaluate the abundance of SMGs and changes in the expression of phenotypic BC markers in control, lymphocytic bronchiolitis, and OB airways. The abundance and proliferative capacity of proximal and distal airway SCs was assessed using a clonogenic colony-forming efficiency assay. MEASUREMENTS AND MAIN RESULTS: Ferret allografts revealed significant loss of SMGs with development of OB. A progressive decline in p63+/K5+ and increase in K5+/K14+ and K14+ BC phenotypes correlated with the severity of allograft rejection in large and small ferret airways. The abundance and proliferative capacity of basal SCs in large allograft airways declined with severity of OB, and there was complete ablation of basal SCs in distal OB airways. Human allografts mirrored phenotypic BC changes observed in the ferret model. CONCLUSIONS: SMGs and basal SC compartments are depleted in large and/or small airways of lung allografts, and basal SC proliferative capacity declines with progression of disease and phenotypic changes. Global airway SC depletion may be a mechanism for pulmonary allograft failure.

Incomplete fissures are associated with increased alveolar ventilation via spiracles in severe emphysema.

OBJECTIVES: In emphysema, air can flow preferentially via collateral pathways, which can connect an entire lung when incomplete fissures are present. Spiracles are openings through the chest wall into the lung parenchyma. We previously observed increased alveolar ventilation (VA) in subjects with severe emphysema, when spiracles occurred during lung transplant operations. In this study, we set out to identify a computed tomography (CT) imaging phenotype associated with improved VA via spiracles in severe emphysema. METHODS: We retrospectively reviewed 4 patients with severe emphysema who exhaled ≥75% of the inhaled tidal volume via transpleural spiracles during a lung transplant operation. We used quantitative image analysis via VIDA VISION CT software to describe emphysema severity and distribution and fissure integrity from pretransplant CT scans of the chest. We analysed partial pressure of carbon dioxide and calculated estimates of VA at baseline and during spiracle ventilation. RESULTS: All 4 subjects demonstrated severe hyperinflation (total lung capacity 148 ± 24%predicted, residual volume 296 ± 79% predicted). On CT imaging, severe emphysema was present, with an average 38.7 ± 9% (range 28-50%) of lung parenchyma showing low-attenuation areas of - 950 Hounsfield units or less. Lung fissure integrity analysis demonstrated evidence of incomplete fissures (average detectable fissure integrity 67 ± 19%, range 40 ± 11-90 ± 10%). During spiracle ventilation on unchanged ventilator settings, there was a significant reduction in partial pressure of carbon dioxide (61 ± 4-35 ± 4 mmHg, P < 0.001) and increase in estimated VA (2.1 ± 0.5-3.8 ± 0.8 l/min, P < 0.001). CONCLUSIONS: Incomplete lung fissures on quantitative CT analysis seem to be a key image phenotype associated with substantial improvements in VA during transpleural ventilation via spiracles in severe emphysema.

Higher BMI is associated with higher expiratory airflow normalised for lung volume (FEF25-75/FVC) in COPD.

INTRODUCTION: The obesity paradox in chronic obstructive pulmonary disease (COPD), whereby patients with higher body mass index (BMI) fare better, is poorly understood. Higher BMIs are associated with lower lung volumes and greater lung elastic recoil, a key determinant of expiratory airflow. The forced expiratory flow (25-75) (FEF25-75)/forced vital capacity (FVC) ratio reflects effort-independent expiratory airflow in the context of lung volume and could be modulated by BMI. METHODS: We analysed data from the COPDGene study, an observational study of 10 192 subjects, with at least a 10 pack-year smoking history. Data were limited to subjects with BMI 20-40 kg/m2 (n=9222). Subjects were stratified according to forced expiratory volume in 1 s (FEV1) (%predicted)-quintiles. In regression analyses and Cox proportional hazard models, we analysed the association between BMI, the FEF25-75/FVC ratio, the imaging phenotype, COPD exacerbations, hospitalisations and death. RESULTS: There was no correlation between BMI and FEV1(%predicted). However, a higher BMI is correlated with a higher FEF25-75/FVC ratio. In CT scans, a higher BMI was associated with less emphysema and less air trapping. In risk-adjusted models, the quintile with the highest FEF25-75/FVC ratio was associated with a 46% lower risk of COPD exacerbations (OR 0.54, p<0.001) and a 40% lower risk of death (HR 0.60, p=0.02), compared with the lowest quintile. BMI was not independently associated with these outcomes. CONCLUSIONS: A higher BMI is associated with lower lung volumes and higher expiratory airflows when normalised for lung volume, as quantified by the FEF25-75/FVC ratio. A higher FEF25-75/FVC ratio is associated with a lower risk of COPD exacerbations and death and might quantify functional aspects of the paradoxical effect of higher BMIs on COPD.

Perioperative single-site veno-venous extracorporeal CO2 removal for minimally invasive giant bulla resection.

Giant pulmonary bullae are rare and surgical management of patients with severe emphysema and advanced chronic obstructive lung disease (COPD) presenting with giant bullae can be very challenging. Previously, perioperative, two-site, high-flow, veno-venous extracorporeal membrane oxygenation (ECMO) was successfully utilized during giant bulla resection. Here we report the perioperative application of single-site, low-flow extracorporeal CO2 removal (ECCO2R) for minimally invasive thoracoscopic giant bulla resection. This approach of low-flow, veno-venous ECCO2R, which is less invasive than conventional ECLS approaches, has enabled the safe performance of surgery and facilitated protective intraoperative single-lung ventilation while avoiding possible complications of aggressive mechanical ventilation.