Publications by authors named "Marcelo Cypel"

182 Publications

Commentary: To die or not to die-rescuing lung cells from ischemia-reperfusion injury.

J Thorac Cardiovasc Surg 2021 Jan 30. Epub 2021 Jan 30.

Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.01.091DOI Listing
January 2021

Successful lung transplantation from lungs procured 12 hours after withdrawal of life-sustaining therapy: Changing the paradigm of controlled DCD donors?

J Heart Lung Transplant 2021 Jan 23. Epub 2021 Jan 23.

Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1016/j.healun.2021.01.1389DOI Listing
January 2021

Commentary: Bruised donor lungs-they may not be pretty, but they will still work.

J Thorac Cardiovasc Surg 2021 Jan 23. Epub 2021 Jan 23.

Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.12.045DOI Listing
January 2021

Safety of continuous 12-hour delivery of antimicrobial doses of inhaled nitric oxide during ex vivo lung perfusion.

J Thorac Cardiovasc Surg 2020 Dec 10. Epub 2020 Dec 10.

Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Introduction: High-dose nitric oxide (NO) has been shown effective against a variety of micro-organisms in vitro, including common bacteria found in donor organs. However, clinical obstacles related to its implementation in vivo are the formation of methemoglobin and the accumulation of toxic nitrogen compounds. Ex vivo lung perfusion (EVLP) is a platform that allows for organ maintenance with an acellular perfusion solution, thus overcoming these limitations. The present study explores the safety of continuous high-dose inhaled (iNO) during EVLP for an extended period of 12 hours.

Methods: Lungs procured from Yorkshire pigs were randomized into control (standard ventilation) and treatment (standard ventilation + 200 ppm iNO) groups, then perfused with an acellular solution for 12 hours (n = 4/group). Lung physiology and biological markers were evaluated.

Results: After 12 hours of either standard EVLP or EVLP + 200 ppm iNO, we did not notice any significant physiologic difference between the groups: pulmonary oxygenation (P = .586), peak airway pressures (P = .998), and dynamic (P = .997) and static (P = .908) lung compliances. In addition, no significant differences were seen among proinflammatory cytokines measured in perfusate and lung tissue. Importantly, most common toxic compounds were kept at safe levels throughout the treatment course.

Conclusions: High-dose inhaled NO delivered continuously over 12 hours appears to be safe without inducing any significant pulmonary inflammation or deterioration in lung function. These findings support further efficacy studies to explore the use of iNO for the treatment of infections in donor lungs during EVLP.
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http://dx.doi.org/10.1016/j.jtcvs.2020.11.150DOI Listing
December 2020

Conquer, not Divide: A Case for Desensitization in Seeking Parity for Sensitized Candidates.

Ann Thorac Surg 2021 Jan 6. Epub 2021 Jan 6.

Department of Cardiothoracic Surgery, NYU Langone Health, 530 First Ave, Suite 9V New York, NY 10016. Electronic address:

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http://dx.doi.org/10.1016/j.athoracsur.2020.10.068DOI Listing
January 2021

Commentary: Gift of life in the time of COVID-19.

J Thorac Cardiovasc Surg 2020 Nov 28. Epub 2020 Nov 28.

Division of Thoracic Surgery, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1016/j.jtcvs.2020.11.081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695944PMC
November 2020

Donor ventilation parameters as predictors for length of mechanical ventilation after lung transplantation: Results of a prospective multicenter study.

J Heart Lung Transplant 2021 Jan 28;40(1):33-41. Epub 2020 Oct 28.

Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: The evaluation of donor lungs heavily depends on the subjective judgment of the retrieval surgeon. As a consequence, acceptance rates vary significantly among transplant centers. We aimed to determine donor ventilation parameters in a prospective study and test if they could be used as objective quality criteria during organ retrieval.

Methods: A prospective evaluation of lung donors was performed in 3 transplant centers. Ventilation parameters were collected at the time of retrieval using a standardized ventilation protocol. Recipient length of mechanical ventilation (LMV) was defined as the primary end point, and collected data was used to build linear models predicting LMV.

Results: In total, 166 donors were included in this study. Median LMV after transplantation was 32 hours (interquartile range: 20-63 hours). Peak inspiratory pressure and dynamic compliance (C) at the time of retrieval, but not the partial pressure of oxygen/fraction of inspired oxygen (P/F) ratio, correlated with recipient LMV in Spearman correlations (r = 0.280, p = 0.002; r = -0.245, p = 0.003; and r = 0.064, p = 0.432, respectively). Linear models were built to further evaluate the impact of donor ventilation parameters on LMV. The first model was based on donor P/F ratio, donor age, donor intubation time, donor smoking history, donor partial pressure of carbon dioxide, aspiration, chest trauma, and pathologic chest X-ray. This model performed poorly (multiple R-squared = 0.063). In a second model, donor ventilation parameters were included, and C was identified as the strongest predictor for LMV. The third model was extended by recipient factors, which significantly improved the robustness of the model (multiple R-squared = 0.293).

Conclusion: In this prospective evaluation of donor lung parameters, currently used donor quality criteria poorly predicted recipient LMV. Our data suggest that C is a strong donor-bound parameter to predict short-term graft performance; however, recipient factors are similarly relevant.
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http://dx.doi.org/10.1016/j.healun.2020.10.008DOI Listing
January 2021

Comment on Let's Build Bridges to Recovery in COVID-19 ARDS, not Burn Them!

Ann Surg 2020 Nov 17. Epub 2020 Nov 17.

Division of Thoracic Surgery, University of Florida, Gainesville, FL Division of Thoracic Surgery, University of Toronto, Toronto, Canada Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL.

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http://dx.doi.org/10.1097/SLA.0000000000004623DOI Listing
November 2020

Ventilation parameters and early graft function in double lung transplantation.

J Heart Lung Transplant 2021 Jan 13;40(1):4-11. Epub 2020 Oct 13.

Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: Currently, the primary graft dysfunction (PGD) score is used to measure allograft function in the early post-lung transplant period. Although PGD grades at later time points (T48 hours and T72 hours) are useful to predict mid- and long-term outcomes, their predictive value is less relevant within the first 24 hours after transplantation. This study aimed to evaluate the capability of PGD grades to predict prolonged mechanical ventilation (MV) and compare it with a model derived from ventilation parameters measured on arrival at the intensive care unit (ICU).

Methods: A retrospective single-center analysis of 422 double lung transplantations (LTxs) was performed. PGD was assessed 2 hours after arrival at ICU, and grades were associated with length of MV (LMV). In addition, peak inspiratory pressure (P), ratio of the arterial partial pressure of oxygen to fraction of inspired oxygen (P/F ratio), and dynamic compliance (cDyn) were collected, and a logistic regression model was created. The predictive capability for prolonged MV was calculated for both (the PGD score and the model). In a second step, the created model was externally validated using a prospective, international multicenter cohort including 102 patients from the lung transplant centers of Vienna, Toronto, and Budapest.

Results: In the retrospective cohort, a high percentage of extubated patients was reported at 24 hours (35.1%), 48 hours (68.0%), and 72 hours (80.3%) after transplantation. At T0 (time point defined as 2 hours after arrival at the ICU), patients with PGD grade 0 had a shorter LMV with a median of 26 hours (interquartile range [IQR]: 16-47 hours) than those with PGD grade 1 (median: 42 hours, IQR: 27-50 hours), PGD grade 2 (median: 37.5 hours, IQR: 15.5-78.5 hours), and PGD grade 3 (median: 46 hours, IQR: 27-86 hours). However, IQRs largely overlapped for all grades, and the value of PGD to predict prolonged MV was poor. A total of 3 ventilation parameters (P, cDyn, and P/F ratio), determined at T0, were chosen on the basis of clinical reasoning. A logistic regression model including these parameters predicted prolonged MV (>72 hours) with an optimism-corrected area under the curve (AUC) of 0.727. In the prospective validation cohort, the model proved to be stable and achieved an AUC of 0.679.

Conclusions: The prediction model reported in this study combines 3 easily obtainable variables. It can be employed immediately after LTx to quantify the risk of prolonged MV, an important early outcome parameter.
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http://dx.doi.org/10.1016/j.healun.2020.10.003DOI Listing
January 2021

Transcriptomic investigation reveals donor specific gene signatures in human lung transplants.

Eur Respir J 2020 Oct 29. Epub 2020 Oct 29.

Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.

Rationale: Transplantation of lungs from donation after circulatory death (DCD) in addition to donation after brain death (DBD) became routine worldwide to address the global organ shortage. The development of ex vivo lung perfusion (EVLP) for donor lung assessment and repair contributed to the increased use of DCD lungs. We hypothesise that better understanding of the differences between lungs from DBD and DCD donors, and between EVLP and directly transplanted (non-EVLP) lungs, will lead to discovery of the injury specific targets for donor lung repair and reconditioning.

Methods: Tissue biopsies from human DBD (n=177) and DCD (n=65) donor lungs assessed with or without EVLP, were collected at the end of cold ischemic time. All samples were processed with microarray assay. Gene expression, network and pathway analyses were performed using R, Ingenuity Pathway Analysis and STRING. Results were validated with protein assay, multiple logistic regression and 10-fold cross validation.

Results: Our analyses showed that lungs from DBD donors have up-regulation of inflammatory cytokines and pathways. In contrast, DCD lungs display a transcriptome signature of pathways associated with cell death, apoptosis and necrosis. Network centrality revealed specific drug targets to rehabilitate the DBD lungs. Moreover, in DBD lungs, TNFR1/2 signalling pathways and macrophage migration inhibitory factor associated pathways were activated in the EVLP group A panel of genes that differentiate the EVLP from non-EVLP group in DBD lungs was identified.

Conclusion: The examination of gene expression profiling indicates that DBD and DCD lungs have distinguishable biological transcriptome signatures.
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http://dx.doi.org/10.1183/13993003.00327-2020DOI Listing
October 2020

Veno-venous ECMO as a platform to evaluate lung lavage and surfactant replacement therapy in an animal model of severe ARDS.

Intensive Care Med Exp 2020 Oct 27;8(1):63. Epub 2020 Oct 27.

Latner Thoracic Surgery Research Laboratories, Toronto, Canada.

Background: There are limited therapeutic options directed at the underlying pathological processes in acute respiratory distress syndrome (ARDS). Experimental therapeutic strategies have targeted the protective systems that become deranged in ARDS such as surfactant. Although results of surfactant replacement therapy (SRT) in ARDS have been mixed, questions remain incompletely answered regarding timing and dosing strategies of surfactant. Furthermore, there are only few truly clinically relevant ARDS models in the literature. The primary aim of our study was to create a clinically relevant, reproducible model of severe ARDS requiring extracorporeal membrane oxygenation (ECMO). Secondly, we sought to use this model as a platform to evaluate a bronchoscopic intervention that involved saline lavage and SRT.

Methods: Yorkshire pigs were tracheostomized and cannulated for veno-venous ECMO support, then subsequently given lung injury using gastric juice via bronchoscopy. Animals were randomized post-injury to either receive bronchoscopic saline lavage combined with SRT and recruitment maneuvers (treatment, n = 5) or recruitment maneuvers alone (control, n = 5) during ECMO.

Results: PaO/FiO after aspiration injury was 62.6 ± 8 mmHg and 60.9 ± 9.6 mmHg in the control and treatment group, respectively (p = 0.95) satisfying criteria for severe ARDS. ECMO reversed the severe hypoxemia. After treatment with saline lavage and SRT during ECMO, lung physiologic and hemodynamic parameters were not significantly different between treatment and controls.

Conclusions: A clinically relevant severe ARDS pig model requiring ECMO was established. Bronchoscopic saline lavage and SRT during ECMO did not provide a significant physiologic benefit compared to controls.
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http://dx.doi.org/10.1186/s40635-020-00352-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591687PMC
October 2020

Effect of Driving Pressure Change During Extracorporeal Membrane Oxygenation in Adults With Acute Respiratory Distress Syndrome: A Randomized Crossover Physiologic Study.

Crit Care Med 2020 Dec;48(12):1771-1778

1Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada. 2Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Toronto, ON, Canada. 3Extracorporeal Life Support Program, Toronto General Hospital, University of Toronto, Toronto, ON, Canada. 4Department of Medicine, Division of Respirology, University Health Network and Sinai Health System, Toronto, ON, Canada. 5Institute for Health Policy, Management, and Evaluation, University of Toronto, Toronto, ON, Canada. 6Department of Medicine, University Health Network and Sinai Health System, Toronto, ON, Canada. 7Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada. 8Keenan Research Center at the Li-Ka-Shing Knowledge Institute of St. Michael´s Hospital, Toronto, ON, Canada. 9Toronto General Hospital Research Institute, Toronto, ON, Canada.

Objectives: Venovenous extracorporeal membrane oxygenation is an effective intervention to improve gas exchange in patients with severe acute respiratory distress syndrome. However, the mortality of patients with severe acute respiratory distress syndrome supported with venovenous extracorporeal membrane oxygenation remains high, and this may be due in part to a lack of standardized mechanical ventilation strategies aimed at further minimizing ventilator-induced lung injury. We tested whether a continuous positive airway pressure ventilation strategy mitigates ventilator-induced lung injury in patients with severe acute respiratory distress syndrome on venovenous extracorporeal membrane oxygenation, compared with current ventilation practice that employs tidal ventilation with limited driving pressure. We used plasma biomarkers as a surrogate outcome for ventilator-induced lung injury.

Design: Randomized crossover physiologic study.

Setting: Single-center ICU.

Patients: Ten patients with severe acute respiratory distress syndrome supported on venovenous extracorporeal membrane oxygenation.

Interventions: The study included four phases. After receiving pressure-controlled ventilation with driving pressure of 10 cm H2O for 1 hour (phase 1), patients were randomly assigned to receive first either pressure-controlled ventilation 20 cm H2O for 2 hours (phase 2) or continuous positive airway pressure for 2 hours (phase 3), and then crossover to the other phase for 2 hours; during phase 4 ventilation settings returned to baseline (pressure-controlled ventilation 10 cm H2O) for 4 hours.

Measurements And Main Results: There was a linear relationship between the change in driving pressure and the plasma concentration of interleukin-6, soluble receptor for advanced glycation end products, interleukin-1ra, tumor necrosis factor alpha, surfactant protein D, and interleukin-10.

Conclusions: Ventilator-induced lung injury may occur in acute respiratory distress syndrome patients on venovenous extracorporeal membrane oxygenation despite the delivery of volume- and pressure-limited mechanical ventilation. Reducing driving pressure to zero may provide more protective mechanical ventilation in acute respiratory distress syndrome patients supported with venovenous extracorporeal membrane oxygenation. However, the risks versus benefits of such an approach need to be confirmed in studies that are designed to test patient centered outcomes.
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http://dx.doi.org/10.1097/CCM.0000000000004637DOI Listing
December 2020

Ex vivo lung perfusion for donor lung assessment and repair: a review of translational interspecies models.

Am J Physiol Lung Cell Mol Physiol 2020 12 30;319(6):L932-L940. Epub 2020 Sep 30.

Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada.

For patients with end-stage lung disease, lung transplantation is a lifesaving therapy. Currently however, the number of patients who require a transplant exceeds the number of donor lungs available. One of the contributing factors to this is the conservative mindset of physicians who are concerned about transplanting marginal lungs due to the potential risk of primary graft dysfunction. Ex vivo lung perfusion (EVLP) technology has allowed for the expansion of donor pool of organs by enabling assessment and reconditioning of these marginal grafts before transplant. Ongoing efforts to optimize the therapeutic potential of EVLP are underway. Researchers have adopted the use of different large and small animal models to generate translational preclinical data. This includes the use of rejected human lungs, pig lungs, and rat lungs. In this review, we summarize some of the key current literature studies relevant to each of the major EVLP model platforms and identify the advantages and disadvantages of each platform. The review aims to guide investigators in choosing an appropriate species model to suit their specific goals of study, and ultimately aid in translation of therapy to meet the growing needs of the patient population.
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http://dx.doi.org/10.1152/ajplung.00295.2020DOI Listing
December 2020

Strategies to prolong homeostasis of ex vivo perfused lungs.

J Thorac Cardiovasc Surg 2020 Aug 13. Epub 2020 Aug 13.

Latner Thoracic Research Laboratories, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Objectives: Ex vivo lung perfusion provides an innovative method to assess and repair donor lungs. The current Toronto ex vivo lung perfusion protocol can reliably and reproducibly preserve lungs for 12 hours. A longer ex vivo lung perfusion preservation time could enable the application of more advanced repair therapies and the rescue of more donor lungs for lung transplant. Our objective was to achieve stable 24-hour normothermic ex vivo lung perfusion.

Methods: We systematically examined 3 modifications of ex vivo lung perfusion perfusate administration in a large animal 24-hour ex vivo lung perfusion model. Pig lungs were assigned to 4 groups (n = 5 per group): (1) control; (2) continuous replacement of ex vivo lung perfusion perfusate; (3) modified feed, which used a modified solution to maintain perfusate osmolality by adjusting glucose and sodium levels; and (4) total parenteral nutrition, in which we added parenteral nutrition to the perfusate.

Results: Only 1 lung in the control group completed 24-hour ex vivo lung perfusion. However, 24-hour perfusion was achieved in 4 lungs in the continuous replacement group, 3 lungs in the modified feed group, and 4 lungs in the total parenteral nutrition group. The total parenteral nutrition group achieved significantly longer stable perfusion time compared with control (P = .03). Lung function was significantly improved and inflammatory cytokine production was reduced in the continuous replacement and total parenteral nutrition groups compared with control.

Conclusions: Modifications of ex vivo lung perfusion perfusate toward achieving a stable homeostatic state can extend perfusion time for up to 24 hours. Although these modifications allow for prolonged ex vivo lung perfusion, further research will be required to develop stable lung support beyond 24 hours.
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http://dx.doi.org/10.1016/j.jtcvs.2020.07.104DOI Listing
August 2020

Ex-vivo delivery of monoclonal antibody (Rituximab) to treat human donor lungs prior to transplantation.

EBioMedicine 2020 Oct 16;60:102994. Epub 2020 Sep 16.

Ajmera Transplant Center, University Health Network, PMB 11-175, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada. Electronic address:

Background: Ex-vivo lung perfusion (EVLP) is an innovative platform for assessing donor lungs in the pre-transplant window. In this study, we demonstrate an extension of its utility by administering the anti-CD20 monoclonal antibody, Rituximab, during EVLP. We hypothesized that this would lead to targeted depletion of allograft B-cells which may provide significant clinical benefit, including the potential to reduce latent Epstein-Barr virus (EBV) and decrease the incidence of post-transplant lymphoproliferative malignancies.

Methods: Twenty human donor lungs rejected for transplantation were placed on EVLP with (n = 10) or without (n = 10) 500 mg of Rituximab. Safety parameters such as lung physiology and inflammatory cytokines were evaluated. We measured the delivery efficacy through flow cytometry, immunohistochemistry and ELISA. An in-vitro culture assay, in the presence of complement, was further conducted to monitor whether B-cell depletion would occur in Rituximab-perfused samples.

Findings: Rituximab was successfully delivered to human lungs during EVLP as evidenced by flow cytometric binding assays where lung tissue and lymph node biopsies demonstrated occupied CD20 epitopes after perfusion with the antibody. Lymph nodes from Rituximab perfusions demonstrated a 10.9 fold-reduction in CD20+ staining compared to controls (p = 0.0003). In lung tissue, Rituximab resulted in an 8.75 fold-reduction in CD20+ staining relative to controls (p = 0.0002). This decrease in CD20+ binding illustrates the successful delivery and occupation of epitopes after perfusion with the Rituximab. No apparent safety concerns were seen as exhibited by markers associated with acute cell injury (e.g., proinflammatory cytokines), cell death (e.g., TUNEL staining), or pulmonary physiology. In a post-perfusion tissue culture model, the addition of complement (human serum) resulted in evidence of B-cell depletion consistent with what would be expected with posttransplant activation of bound Rituximab.

Interpretation: Our experiments illustrate the potential of EVLP as a platform to deliver monoclonal antibody therapies to treat donor lungs pretransplant with the goal of eliminating a latent virus responsible for considerable morbidity after lung transplantation.

Funding: Supported by the University Health Network Transplant Center.
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http://dx.doi.org/10.1016/j.ebiom.2020.102994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501077PMC
October 2020

The impact of concordance with a lung cancer diagnosis pathway guideline on treatment access in patients with stage IV lung cancer.

J Thorac Dis 2020 Aug;12(8):4327-4337

Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Ontario, Canada.

Background: Timely access to treatment of lung cancer is dependent on efficient and appropriate patient assessment and early referral for diagnostic workup. This study assesses the impact of Cancer Care Ontario (CCO) Lung Cancer Diagnostic Pathway Guideline (LCDPG) concordance on access to treatment of stage IV lung cancer patients referred to the Diagnostic Assessment Program (DAP) at a Canadian tertiary cancer centre.

Methods: This retrospective cohort study includes patients diagnosed with clinical stage IV lung cancer referred to the DAP at a Canadian tertiary cancer centre between November 1, 2015 and May 31, 2017. Referral concordance was determined based on CCO LCDPG. The primary outcome; time to treatment from initial healthcare presentation; was compared between the concordant and discordant referrals.

Results: Two hundred patients were referred for clinical stage IV lung cancer during the study period. Of these referrals, 151 (75.5%) were assessed and referred in concordance with LCDPG. Guideline concordant referrals were associated with reduced time to treatment from first healthcare presentation compared with guideline discordant referrals (55.3 108.8 days, P<0.001). Time to diagnostic procedure (32.2 86.7 days, P<0.001) and decision to treat (38.5 93.8 days, P<0.001) were also reduced with guideline concordance. The most common reason for discordant assessment and referral was delayed or inadequate investigation of symptoms in a high risk patient (32.7% of discordant referrals).

Conclusions: Guideline concordant assessment and referral of stage IV lung cancer patients results in reduced time to diagnosis and treatment. Future research and education should focus on improving factors that delay DAP referral.
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http://dx.doi.org/10.21037/jtd-20-157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475595PMC
August 2020

Cell-free DNA in human ex vivo lung perfusate as a potential biomarker to predict the risk of primary graft dysfunction in lung transplantation.

J Thorac Cardiovasc Surg 2020 Aug 11. Epub 2020 Aug 11.

Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Cell-free DNA (cfDNA), such as mitochondrial DNA (mtDNA) and nuclear DNA (nuDNA), are known to be released from injured cells and as such have been explored as biomarkers for tissue injury in different clinical settings. Ex vivo lung perfusion (EVLP) has been developed as an effective technique for marginal donor lung functional assessment. We hypothesized that the level of cfDNA in EVLP perfusate may reflect tissue injury and thus can be developed as a biomarker to quantify the degree of donor lung injury or predict the development of primary graft dysfunction (PGD) after lung transplantation (LTx).

Methods: The perfusate from 62 donor lungs transplanted at our institution between May 2010 and December 2015 was sampled for cfDNA at 1 and 4 hours of perfusion. Sequences of genes encoding nicotinamide adenine dinucleotide dehydrogenase 1 (NADH-1) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were used to represent mtDNA and nuDNA, respectively. Levels were quantified by real-time polymerase chain reaction and correlated with clinical outcome after LTx.

Results: In our entire cohort, 14 patients developed PGD grade 3 (PGD3) within 72 hours after LTx. The non-PGD group included 48 patients (PGD0-1). Concentrations of mtDNA in the perfusate of the PGD3 group were significantly higher than those in non-PGD group at 1 hour of EVLP (1874 ± 844 vs 1259 ± 885 copies/μL; P = .011). The perfusate of the PGD3 group had significantly higher levels of nuDNA compared with the non-PGD group at both 1 hour (1498 ± 1895 vs 675 ± 391 copies/μL; P = .008) and 4 hours (4521 ± 5810 vs 1764 ± 1494 copies/μL; P = .001). In donation after cardiac death (DCD) cases, mtDNA levels were significantly higher in the PGD3 group compared with the non-PGD group at 1 hour of EVLP (2060 ± 997 vs 1184 ± 782 copies/μL; P = .040), and the levels of nuDNA were significantly higher in the PGD3 group compared with the non-PGD group at both 1 hour (1021 ± 495 vs 606 ± 305 copies/μL; P = .041) and 4 hours (2358 ± 1028 vs 1185 ± 967 copies/μL; P = .006). In donation after brain death (DBD) cases, cfDNA scores did not show a significant difference.

Conclusions: We found that the amount of cfDNA, especially nuDNA, in EVLP perfusate was higher in the severe PGD group (PGD3) compared with the non-PGD group. This proof-of-concept study supports the concept that the analysis of cfDNA levels in EVLP perfusate can help estimate the damage to donor lungs before implantation. Larger studies are needed to validate this concept.
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http://dx.doi.org/10.1016/j.jtcvs.2020.08.008DOI Listing
August 2020

Ex vivo perfusion in lung transplantation and removal of HCV: the next level.

Transpl Int 2020 Dec 22;33(12):1589-1596. Epub 2020 Sep 22.

Latner Thoracic Surgery Research Laboratories, University Health Network, Toronto, ON, Canada.

The large gap between high demand and low availability of lungs is still a limiting factor for lung transplantation which leads to important mortality rates on the waiting list. In the last years, with the advent of potent direct-acting antivirals (DAAs), donors carrying active hepatitis C (HCV) infection became an important source in expanding the donor pool. Recent clinical trials exploring different treatment regimens post-transplantation when using HCV-positive abdominal and thoracic organs into HCV-negative recipients have shown encouraging results. Although early data shows no toxicity and similar survival rates when compared to non-HCV organ transplantation, long-term outcomes evaluating the effect of either the transmission of HCV into the recipients or the deliberate use of DAAs to treat the virus remains absent. An important and innovative strategy to overcome this limitation is the possibility of mitigating viral transmission with the use of ex vivo donor organ treatment prior to transplantation. Recent pre-clinical and clinical studies explore the use of ex vivo perfusion and the removal of HCV prior to transplantation with the addition of other innovative therapies, which will be reviewed in this article.
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http://dx.doi.org/10.1111/tri.13730DOI Listing
December 2020

When to consider lung transplantation for COVID-19.

Lancet Respir Med 2020 10 25;8(10):944-946. Epub 2020 Aug 25.

Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto Lung Transplant Program, Toronto, ON M5G 2C4, Canada.

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http://dx.doi.org/10.1016/S2213-2600(20)30393-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447224PMC
October 2020

Lung donation after medical assistance in dying at home.

Am J Transplant 2021 01 10;21(1):415-418. Epub 2020 Sep 10.

Department of Surgery, Toronto Lung Transplant Program and Multiorgan Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.

Organ donation after medical assistance in dying (MAID) has only been possible for patients having the MAID procedure performed at a hospital facility due to prohibitive warm ischemic times. Herein, we describe a protocol for lung donation following MAID at home and demonstrate excellent postoperative outcomes. Lung donation following MAID at home is possible and should be considered by transplant programs.
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http://dx.doi.org/10.1111/ajt.16267DOI Listing
January 2021

International Society for Heart and Lung Transplantation consensus statement for the standardization of bronchoalveolar lavage in lung transplantation.

J Heart Lung Transplant 2020 Jul 15. Epub 2020 Jul 15.

Lung Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Bronchoalveolar lavage (BAL) is a key clinical and research tool in lung transplantation (LTx). However, BAL collection and processing are not standardized across LTx centers. This International Society for Heart and Lung Transplantation-supported consensus document on BAL standardization aims to clarify definitions and propose common approaches to improve clinical and research practice standards. The following 9 areas are covered: (1) bronchoscopy procedure and BAL collection, (2) sample handling, (3) sample processing for microbiology, (4) cytology, (5) research, (6) microbiome, (7) sample inventory/tracking, (8) donor bronchoscopy, and (9) pediatric considerations. This consensus document aims to harmonize clinical and research practices for BAL collection and processing in LTx. The overarching goal is to enhance standardization and multicenter collaboration within the international LTx community and enable improvement and development of new BAL-based diagnostics.
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http://dx.doi.org/10.1016/j.healun.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361106PMC
July 2020

Impact of donor time to cardiac arrest in lung donation after circulatory death.

J Thorac Cardiovasc Surg 2020 Jun 16. Epub 2020 Jun 16.

Toronto Lung Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.jtcvs.2020.04.181DOI Listing
June 2020

Deceased-donor lobar lung transplant: A successful strategy for small-sized recipients.

J Thorac Cardiovasc Surg 2020 May 23. Epub 2020 May 23.

Toronto Lung Transplant Program, Division of Thoracic Surgery, Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Objectives: Lobar lung transplantation (LLTx) from deceased donors is a potential solution for donor-recipient size mismatch for small sized recipients. We reviewed our institutional experience to compare outcomes after LLTx to standard lung transplantation (LTx).

Methods: We retrospectively reviewed transplants in our institution from January 2000 to December 2017. LLTx early- and long-term outcomes were compared with LTx. Additional analysis of outcomes was performed after dividing the cohort into 2 eras (era 1, 2000-2012; era 2, 2013-2017).

Results: Among the entire cohort (1665), 75 were LLTx (4.5%). Compared with LTx, LLTx were more frequently bridged to transplant with extracorporeal life support or mechanical ventilation and were transplanted in a rapidly deteriorating status (respectively, 20% vs 4.4%, P = .001; 22.7% vs 7.9, P < .001; and 41.3% vs 26.5%, P = .013). LLTx had longer intensive care unit and hospital lengths of stay (respectively, median 17 vs 4 days, and 45 vs 23, both P < .001), and greater 30-day mortality (13.3% vs 4.3%, P = .001) and 90-day mortality (17.3% vs 7.2%, P = .003). In era 2, despite a significantly greater 30-day mortality (10.8% vs 2.8%, P = .026), there was no significant difference in 90-day mortality between LLTx and LTx (13.5% vs 5.1%, P = .070). Overall survival at 1, 3, and 5 years was not significantly different between LLTx and LTx (73.2% vs 84.4%, 56.9% vs 68.4% and 50.4% vs 55.8, P = .088).

Conclusions: Although LLTx is a high-risk procedure, both mid- and long-term survival are comparable with LTx in all cohorts in the modern era. LLTx therefore represents a valuable surgical option for small-sized recipients.
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http://dx.doi.org/10.1016/j.jtcvs.2020.04.166DOI Listing
May 2020

Video-Assisted Thoracic Surgery as the Future of Pulmonary Metastasectomy: Reply.

Ann Thorac Surg 2020 09 18;110(3):1096-1097. Epub 2020 Jul 18.

Division of Thoracic Surgery, Toronto General Hospital, 200 Elizabeth St, 9N969, Toronto, Ontario M5G 2C4, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.athoracsur.2020.05.112DOI Listing
September 2020

Immunosuppressive Therapy in Lung Transplantation.

Curr Pharm Des 2020 ;26(28):3385-3388

Lung Transplantation, University of Toronto, Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto ON M5G2C4, Canada.

Long term survival and quality of life after lung transplantation are still affected by the development of chronic lung graft dysfunction (CLAD). CLAD is the number one cause of death one year after transplant; and there is no effective therapy available to date. Transplant centers' approaches include perioperative immunosuppression, maintenance immunosuppression, and the treatment of eventual rejection. This review will focus on maintenance immunosuppression and the available data that support these strategies, as well as a brief description of our desensitization protocol and immunologic risk stratification. Optimization of immunosuppression is key to increase survival and graft function in transplant recipients, mostly through the combination of drugs. Since the therapeutic options to manage CLAD are still very limited, more studies are necessary to test new therapies and to clarify the potential role of new agents.
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http://dx.doi.org/10.2174/1381612826666200628023150DOI Listing
January 2021

Protective Mechanical Ventilation in Organ Donors: A Lifesaving Maneuver.

Am J Respir Crit Care Med 2020 07;202(2):167-169

Interdepartmental Division of Critical Care MedicineUniversity of TorontoToronto, Ontario, Canadaand.

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http://dx.doi.org/10.1164/rccm.202005-1559EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365355PMC
July 2020

Management of the neurologically deceased organ donor: A Canadian clinical practice guideline.

CMAJ 2020 04;192(14):E361-E369

Departments of Medicine (Ball), Internal Medicine (Basmaji) and Surgery (Luke), Western University, London, Ont.; Children's Hospital of Eastern Ontario Research Institute (Hornby); Deceased Donation (Hornby, Shemie, Wilson), Canadian Blood Services, Ottawa, Ont.; Department of Medicine (Division of Critical Care) and Department of Health Research Methods, Evidence and Impact (Rochwerg, Meade), McMaster University, Hamilton, Ont.; Faculté de médecine (Weiss), Université Laval; Transplant Quebec (Weiss), Québec, Que.; Canadian Blood Services (Gillrie), Ottawa, Ont.; Department of Medicine and School of Public Health (Chassé), University of Montreal, Montréal, Que.; Department of Anesthesiology, Faculty of Medicine and Health Sciences (D'Aragon), University of Sherbrooke, Sherbrooke, Que.; Critical Care (Soliman), Queen's University, Kingston, Ont.; Latner Thoracic Surgery Research Laboratories, Institute of Medical Sciences (Ali), University of Toronto, Toronto, Ont.; Northern Ontario School of Medicine (Arora), Thunder Bay, Ont.; Department of Medicine (Neurology) and Critical Care, Centre for Neuroscience Studies (Boyd), Queen's University, Kingston, Ont.; Department of Medicine (Cantin), Université Laval, Québec, Que.; Gerald Bronfman Department of Oncology (Cantin), McGill University, Montréal, Que.; Departments of Surgery (Cypel) and Medicine (Singh), University of Toronto, Toronto, Ont.; Division of Cardiac Surgery (Freed), University of Alberta, Edmonton, Alta.; Faculty of Pharmacy (Frenette), University of Montreal, Montréal, Que.; Alberta Health Services (Hruska), Calgary, Alta.; Department of Critical Care Medicine (Karvellas), University of Alberta, Edmonton, Alta.; BC Transplant (Keenan), Vancouver, BC; Division of Critical Care (Keenan), University of British Columbia, Vancouver, BC; Departments of Critical Care Medicine and Clinical Neurosciences, Hotchkiss Brain Institute (Kramer), University of Calgary, Calgary, Alta.; Faculty of Medicine and Dentistry (Kutsogiannis), University of Alberta, Edmonton, Alta.; Department of Medicine (Lien), University of Alberta, Edmonton, Alta.; London Health Sciences Centre (Luke), London, Ont.; Department of Pediatrics (Mahoney), University of Calgary, Calgary, Alta.; Division of Infectious Diseases (Wright), University of British Columbia, Vancouver, BC; Division of Nephrology (Zaltzman), University of Toronto, Toronto, Ont.; Department of Pediatrics (Shemie), McGill University, Montréal, Que.

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http://dx.doi.org/10.1503/cmaj.190631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145376PMC
April 2020

Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study.

Lancet Gastroenterol Hepatol 2020 07 6;5(7):649-657. Epub 2020 May 6.

Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.

Background: An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors.

Methods: HCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6-12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing.

Findings: 30 patients (23 men and seven women; median age 61 years (IQR 48-66) received transplants (13 lung, ten kidney, six heart, and one kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 logIU/mL (IQR 4·55-5·63) and at least three HCV genotypes were represented (nine [50%] donors with genotype 1, two [11%] with genotype 2, five [28%] with genotype 3, and two [11%] with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant [IQR 25-47]). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV.

Interpretation: Ezetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors.

Funding: Canadian Institutes of Health Research; the Organ Transplant Program, University Health Network.
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http://dx.doi.org/10.1016/S2468-1253(20)30081-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391837PMC
July 2020

A model to assess acute and delayed lung toxicity of oxaliplatin during in vivo lung perfusion.

J Thorac Cardiovasc Surg 2020 Mar 21. Epub 2020 Mar 21.

Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada. Electronic address:

Objectives: To determine the dose-limiting toxicity of oxaliplatin chemotherapy delivered by in vivo lung perfusion (IVLP). To allow assessment of subacute toxicities, we aimed to develop a 72-hour porcine IVLP survival model.

Methods: In total, 12 Yorkshire male pigs were used. Left lung IVLP was performed for 3 hours. At 72 hours postoperatively, computed tomography imaging of the lungs was performed before the pigs were killed. Lung physiology, airway dynamics, gross appearance, and histology were assessed before and during IVLP, at reperfusion, and when the pigs were euthanized. An accelerated titration dose-escalation study design was employed whereby oxaliplatin doses were sequentially doubled provided no clinically significant toxicity was observed, defined as an arterial partial pressure of oxygen to fraction of inspired oxygen ratio <300 mm Hg or severe acute lung injury on biopsy.

Results: After an initial training phase, no mortality or adverse events related to the procedure were observed. There was no lung injury observed at the time of IVLP for any case. At sacrifice, clinically significant lung injury was observed at 80 mg/L oxaliplatin, with an arterial partial pressure of oxygen to fraction of inspired oxygen ratio of 112 mm Hg. Mild and subclinical lung injury was observed at 40 mg/L, with this dose being repeated to confirm safety.

Conclusions: A stable and reproducible porcine 3-day IVLP survival model was established that will allow toxicity assessment of agents delivered by IVLP. Oxaliplatin delivered by IVLP showed delayed-onset toxicity that was not apparent at the time of reperfusion, with a maximal-tolerated dose of 40 mg/L. This information will inform initiation of a clinical trial examining IVLP delivery of oxaliplatin at our institution.
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http://dx.doi.org/10.1016/j.jtcvs.2020.03.033DOI Listing
March 2020

An extracellular oxygen carrier during prolonged pulmonary preservation improves post-transplant lung function.

J Heart Lung Transplant 2020 06 10;39(6):595-603. Epub 2020 Apr 10.

Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, Ontario, Canada. Electronic address:

Background: The use of a novel extracellular oxygen carrier (EOC) preservation additive known as HEMOLife has recently been shown to lead to a superior preservation of different types of solid organs. Our study aimed to investigate the effect of this EOC on extending lung preservation time and its mechanism of action.

Methods: Donor pigs were randomly allocated to either of the following 2 groups (n = 6 per group): (1) 36 hours cold preservation or (2) 36 hours cold preservation with 1 g/liter of EOC. The lungs were evaluated through 12 hours of normothermic ex vivo lung perfusion (EVLP) followed by a left-single lung transplant into a recipient pig. Grafts were reperfused for 4 hours, followed by right pulmonary artery clamping to assess graft oxygenation function.

Results: During EVLP assessment, EOC-treated lungs showed improvements in physiologic parameters, whereas the control lungs deteriorated. After a total of 48 hours of preservation (36 hours cold + 12 hours normothermic EVLP), transplanted grafts in the treatment group displayed significantly better oxygenation than in the controls (PaO/FiO: 437 ± 36 mm Hg vs 343 ± 27 mm Hg, p = 0.041). In addition, the use of EOC led to significantly less edema formation (wet-to-dry ratio: 4.95 ± 0.29 vs 6.05 ± 0.33, p = 0.026), less apoptotic cell death (p = 0.041), improved tight junction preservation (p = 0.002), and lower levels of circulating IL-6 within recipient plasma (p = 0.004) compared with non-use of EOC in the control group after transplantation.

Conclusion: The use of an EOC during an extended pulmonary preservation period led to significantly superior early post-transplant lung function.
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http://dx.doi.org/10.1016/j.healun.2020.03.027DOI Listing
June 2020