Abstract
Background
Ischemia–reperfusion injury is a key complication following lung transplantation. The clinical application of ex vivo lung perfusion (EVLP) to assess donor lung function has ...significantly increased the utilization of “marginal” donor lungs with good clinical outcomes. The potential of EVLP on improving organ quality and ameliorating ischemia–reperfusion injury has been suggested.
Methods
To determine the effects of ischemia–reperfusion and EVLP on gene expression in human pulmonary microvascular endothelial cells and epithelial cells, cell culture models were used to simulate cold ischemia (4 °C for 18 h) followed by either warm reperfusion (DMEM + 10% FBS) or EVLP (acellular Steen solution) at 37 °C for 4 h. RNA samples were extracted for bulk RNA sequencing, and data were analyzed for significant differentially expressed genes and pathways.
Results
Endothelial and epithelial cells showed significant changes in gene expressions after ischemia–reperfusion or EVLP. Ischemia–reperfusion models of both cell types showed upregulated pro-inflammatory and downregulated cell metabolism pathways. EVLP models, on the other hand, exhibited downregulation of cell metabolism, without any inflammatory signals.
Conclusion
The commonly used acellular EVLP perfusate, Steen solution, silenced the activation of pro-inflammatory signaling in both human lung endothelial and epithelial cells, potentially through the lack of serum components. This finding could establish the basic groundwork of studying the benefits of EVLP perfusate as seen from current clinical practice.
Although lung transplantation has become a life-saving option for patients with end-stage lung disease, this intervention is hampered by a shortage of lungs in view of the growing number of people on ...the waiting list. Lungs are retrieved from only a small percentage of multiorgan donors, and the transplantation and intensive-care communities have recognised the need to develop innovative methods to expand the donor pool. Advancements in lung-preservation techniques in the preretrieval and postretrieval periods have increased the pool of available donors, and novel research and discoveries in this area have steadily improved post-transplantation adverse events. This Review summarises current best practice and the latest research on intensive-care management of a potential lung donor. We also discuss lung-preservation techniques, including advancements in normothermic ex-vivo lung perfusion, and the potential for a personalised medicine approach to the organ.
Over 2.5% of deaths in Canada occur as a result from medical assisting in dying (MAID), and a subset of these deaths result in organ donation. However, detailed outcomes of lung transplant recipients ...using these donors is lacking. This is a retrospective single center cohort study comparing lung transplantation outcomes after donation using MAID donors compared to neurologically determined death and controlled donation after circulatory death (NDD/cDCD) donors from February 2018 to July 2021. Thirty‐three patients received lungs from MAID donors, and 560 patients received lungs from NDD/cDCD donors. The donor diagnoses leading to MAID provision were degenerative neurological diseases (n = 33) and end stage organ failure (n = 5). MAID donors were significantly older than NDD/cDCD donors (56 IQR 49–64 years vs. 48 32–59; p = .0009). Median ventilation period and 30 day mortality were not significantly different between MAID and NDD/cDCD lungs recipients (ventilation: 1 day 1–3 vs 2 days 1–3; p = .37, deaths 0% 0/33 vs. 2% 11/560, p = .99 respectively). Intermediate‐term outcomes were also similar. In summary, for lung transplantation using donors after MAID, recipient outcomes were excellent. Therefore, where this practice is permitted, donation after MAID should be strongly considered for lung transplantation as a way to respect donor wishes while substantially improving outcomes for recipients with end‐stage lung disease.
The first North American experience transplanting lungs from donors who donated after medical assistance in dying reports excellent outcomes.
IntroductionIdiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown cause characterised by progressive fibrotic formation in lung tissue. We hypothesise that disrupted metabolic ...pathways in IPF contribute to disease pathogenesis.MethodsMetabolomics of human IPF was performed using mass spectroscopy (IPF lung=8; donor lung=8). Gene expression of key metabolic enzymes was measured using microarrays. Of the 108 metabolites whose levels were found altered, 48 were significantly increased, whereas 60 were significantly decreased in IPF samples compared with normal controls.ResultsSpecific metabolic pathways mediating the IPF remodelling were found with a downregulated sphingolipid metabolic pathway but an upregulated arginine pathway in IPF. In addition, disrupted glycolysis, mitochondrial beta-oxidation and tricarboxylic acid cycle, altered bile acid, haem and glutamate/aspartate metabolism were found in IPF samples compared with control.ConclusionsOur results show alterations in metabolic pathways for energy consumption during lung structural remodelling, which may contribute to IPF pathogenesis. We believe that this is the first report of simultaneously and systemically measuring changes of metabolites involving nine metabolic pathways in human severe IPF lungs. The measurement of the metabolites may serve in the future diagnosis and prognosis of IPF.
Acceptance of lungs from donation after circulatory determination of death has been generally restricted to donors who have cardiac arrest within 60 minutes after withdrawal of life-sustaining ...therapies. We aimed to determine the effect of the interval between withdrawal of life-sustaining therapies to arrest and recipient outcomes. Second, we aimed to compare outcomes between donation after circulatory determination of death transplants and donation after neurologic determination of death transplants.
A single-center, retrospective review was performed analyzing the clinical outcomes of transplant recipients who received donation after circulatory determination of death lungs and those who received donation after neurologic determination of death lungs. Donation after circulatory determination of death cases were then grouped on the basis of the interval between withdrawal of life-sustaining therapies and asystole: 0 to 19 minutes (rapid), 20 to 59 minutes (intermediate), and more than 60 minutes (long). Recipient outcomes from each of these groups were compared.
A total of 180 cases of donation after circulatory determination of death and 1088 cases of donation after neurologic determination of death were reviewed between 2007 and 2017. There were no significant differences in the 2 groups in terms of age, gender, recipient diagnosis, and type of transplant (bilateral vs single). Ex vivo lung perfusion was used in 118 of 180 (65.6%) donation after circulatory determination of death cases and 149 of 1088 (13.7%) donation after neurologic determination of death cases before transplantation. The median survivals of recipients who received donation after circulatory determination of death lungs versus donation after neurologic determination of death lungs were 8.0 and 6.9 years, respectively. Time between withdrawal of life-sustaining therapies and asystole was available for 148 of 180 donors (82.2%) from the donation after circulatory determination of death group. Mean and median time from withdrawal of life-sustaining therapies to asystole were 28.6 minutes and 16 minutes, respectively. Twenty donors required more than 60 minutes to experience cardiac arrest, with the longest duration being 154 minutes before asystole was recorded. Recipients of donation after circulatory determination of death lungs who had cardiac arrest at 0 to 19 minutes (90 donors), 20 to 59 minutes (38 donors), and more than 60 minutes (20 donors) did not demonstrate any significant differences in terms of short- and long-term survivals, primary graft dysfunction 2 and 3, intensive care unit stay, mechanical ventilation days, or total hospital stay.
Short- and long-term outcomes in recipients who received donation after neurologic determination of death versus donation after circulatory determination of death lungs are similar. Different withdrawals of life-sustaining therapies to arrest intervals were not associated with recipient outcomes. The maximum acceptable duration of this interval has yet to be established.
Tumour thickness was assessed to determine if this parameter could refine patients' selection for multimodality therapy in malignant pleural mesothelioma.We reviewed 65 consecutive treatment-naïve ...malignant pleural mesothelioma patients undergoing surgery for mesothelioma after radiation therapy (SMART). Total tumour thickness was determined by measuring the maximal thickness on nine predefined sectors on the chest wall, mediastinum and diaphragm.After a median follow-up of 19 months, 40 patients (62%) developed recurrence and 36 died (55%). Total tumour thickness, ranging between 2.4 and 21 cm (median 6.9 cm), correlated with tumour volume (p<0.0001, R
=0.29) and maximum standardised uptake value (p=0.006, R
=0.11). Total tumour thickness had a significant impact on overall survival and disease-free survival in univariate analysis. In multivariate analysis, total tumour thickness remained an independent predictor of survival (p=0.02, hazard ratio (HR) 1.12, 95% CI 1.02-1.23) and disease-free survival (p=0.01, HR 1.13, 95% CI 1.03-1.24) along with epithelial histologic subtype (p<0.0001, HR 0.25, 95% CI 0.13-0.50) and pN2 disease (p=0.03, HR 2.15, 95% CI 1.07-4.33). Diaphragmatic tumour thickness correlated best with time to recurrence (p=0.002, R
=0.22) and time to death (p=0.003, R
=0.2).The impact of tumour thickness on survival and disease-free survival independent of histologic subtypes and nodal disease is extremely encouraging. This parameter could potentially be used to refine the clinical staging of malignant pleural mesothelioma and optimise patient selection for radical treatment.
The evaluation of donor lungs by normothermic ex vivo acellular perfusion has improved the safety of organ utilization. However, this strategy requires a critical re-evaluation of the parameters used ...to assess lungs during ex vivo perfusion compared with those traditionally used to evaluate the donor lung in vivo. Using a porcine model, we studied the physiology of acellular lung perfusion with the aim of improving the accuracy of clinical ex vivo evaluation.
Porcine lungs after 10 hours of brain death and 24 hours of cold ischemia and uninjured control lungs were perfused for 12 hours and then transplanted. PaO2, compliance, airway pressure and pulmonary vascular resistance were measured. Ventilation with 100% nitrogen and addition of red blood cells to the perfusate were used to clarify the physiologic disparities between in vivo blood perfusion and ex vivo acellular perfusion.
During 12 hours of ex vivo perfusion, injured lungs developed edema with decreased compliance and increased airway pressure, but ex vivo PO2 remained stable. After transplantation, injured lungs demonstrated high vascular resistance and poor PaO2. A reduced effect of shunt on ex vivo lung perfusion PO2 was found to be attributable to the linearization of the relationship between oxygen content and PO2, which occurs with acellular perfusate.
Ex vivo PO2 may not be the first indication of lung injury and, taken alone, may be misleading in assessing the ex vivo lung. Thus, evaluation of other physiologic parameters takes on greater importance.
Abstract Objective To assess the cost-effectiveness of various modes of mediastinal staging in non–small cell lung cancer (NSCLC) in a single-payer health care system. Methods We performed a decision ...analysis to compare the health outcomes and costs of 4 mediastinal staging strategies: no invasive staging, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), mediastinoscopy, and EBUS-TBNA followed by mediastinoscopy if EBUS-TBNA is negative. We determined incremental cost effectiveness ratios (ICER) for all strategies and performed comprehensive deterministic sensitivity analyses using a willingness to pay threshold of $80,000/quality adjusted life year (QALY). Results Under the base-case scenario, the no invasive mediastinal staging strategy was least effective (QALY, 5.80) and least expensive ($11,863), followed by mediastinoscopy, EBUS-TBNA, and EBUS-TBNA followed by mediastinoscopy with 5.86, 5.87, and 5.88 QALYs, respectively. The ICER was ∼$26,000/QALY for EBUS-TBNA staging and ∼$1,400,000/QALY for EBUS-TBNA followed by mediastinoscopy. The mediastinoscopy strategy was dominated. Once pN2 exceeds 2.5%, EBUS-TBNA staging is cost-effective (∼$80,000/QALY). Once the pN2 reaches 57%, EBUS-TBNA followed by mediastinoscopy is cost-effective (ICER ∼$79,000/QALY). Once EBUS-TBNA sensitivity exceeds 25%, EBUS-TBNA staging is cost-effective (ICER ∼$79,000/QALY). Once pN2 exceeds 25%, confirmatory mediastinoscopy should be added, in cases of EBUS-TBNA sensitivity ≤ 60%. Conclusions Invasive mediastinal staging in NSCLC is unlikely to be cost-effective in clinical N0 patients if pN2 <2.5%. In patients with probability of mediastinal metastasis between 2.5% and 57% EBUS-TBNA is cost-effective as the only staging modality. Confirmatory mediastinoscopy should be considered in high-risk patients (pN2 > 57%) in case of negative EBUS-TBNA.
Background Sevoflurane is one of the most commonly used volatile anesthetic agents with the fastest onset and offset, replacing isoflurane in modern anesthesiology. Preconditioning and ...postconditioning using volatile anesthetics can attenuate ischemia-reperfusion injury (IRI). However, no previous studies have evaluated the effect of sevoflurane in lung transplantation after cold ischemic injury. We aimed to study the effects of donor and recipient treatment with sevoflurane in a rat lung transplantation model. Methods Lewis rats were allocated to four groups: control, PreC (preconditioning), PostC (postconditioning), and PreC + PostC. Donor rats in the PreC and PreC + PostC groups were exposed to 1.5% sevoflurane for 30 minutes before donor operation. Donor lungs were flushed with Perfadex and stored for 12 hours at 4°C before transplantation. Recipients received orthotopic left lung transplantation. In the PostC and PreC + PostC groups, sevoflurane was initiated 2 minutes before reperfusion and maintained for 30 minutes. Two hours after reperfusion, lung function was evaluated, and samples were collected for histologic, inflammatory, and cell death assessment. Results Preconditioning and postconditioning using sevoflurane significantly improved the oxygenation of lung grafts (partial arterial gas pressure of oxygen: 198 mm Hg in control, 406.5 mm Hg in PreC, 472.4 mm Hg in PostC, and 409.7 mm Hg in PreC + PostC, p < 0.0001) and reduced pulmonary edema. Sevoflurane treatment reduced levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α. Moreover, sevoflurane significantly inhibited apoptotic cells by a decrease in cytochrome c release into cytosol and caspase-3 cleavage. Conclusions Preconditioning or postconditioning of lungs using sevoflurane exhibits a significant protective effect against early phase of ischemia-reperfusion injury in a rat lung transplantation model.
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