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Ex-vivo lung perfusion (EVLP) has improved organ utilization for lung transplantation, but it is not yet known whether the benefits of this technology offset its additional costs. We compared the institutional costs of lung transplantation before vs after EVLP was available to identify predictors of costs and determine the health-economic impact of EVLP.We performed a retrospective, before-after, propensity-score weighted cohort study of patients wait-listed for lung transplant at University Health Network (UHN) in Ontario, Canada, between January 2005 and December 2019 using institutional administrative data. We compared costs, in 2019 Canadian Dollars ($), between patients referred for transplant before EVLP was available (Pre-EVLP) to after (Modern EVLP). Cumulative costs were estimated using a novel application of multistate survival models. Predictors of costs were identified using weighted log-gamma generalized linear regression.A total of 1,199 patients met inclusion criteria (352 Pre-EVLP; 847 Modern EVLP). Mean total costs for the transplant hospitalization were $111,878 ($94,123-$130,767) in the Pre-EVLP era and $110,969 ($87,714-$136,000) in the Modern EVLP era. Cumulative five-year costs since referral were $278,777 ($82,575-$298,135) in the Pre-EVLP era and $293,680 ($252,832-$317,599) in the Modern EVLP era. We observed faster progression to transplantation when EVLP was available. EVLP availability was not a predictor of waitlist (cost ratio [CR] 1.04 [0.81-1.37]; p = 0.354) or transplant costs (CR 1.02 [0.80-1.29]; p = 0.425) but was associated with lower costs during posttransplant years 12 (CR 0.75 [0.58-1.06]; p = 0.05) and posttransplant years 3+ (CR 0.43 [0.26-0.74]; p = 0.001).At our center, EVLP availability was associated with faster progression to transplantation at no significant marginal cost.

Our recent work has challenged 4°C as an optimal lung preservation temperature by showing storage at 10°C to allow for the extension of preservation periods. Despite these findings, the impact of 10°C storage has not been evaluated in the setting of injured donor lungs.Aspiration injury was created through bronchoscopic delivery of gastric juice (pH: 1.8). Injured donor lungs (n = 5/group) were then procured and blindly randomized to storage at 4°C (on ice) or at 10°C (in a thermoelectric cooler) for 12 hours. A third group included immediate transplantation. A left lung transplant was performed thereafter followed by 4 hours of graft evaluation.After transplantation, lungs stored at 10°C showed significantly better oxygenation when compared to 4°C group (343 ± 43 mm Hg vs 128 ± 76 mm Hg, p = 0.03). Active metabolism occurred during the 12 hours storage period at 10°C, producing cytoprotective metabolites within the graft. When compared to lungs undergoing immediate transplant, lungs preserved at 10°C tended to have lower peak airway pressures (p = 0.15) and higher dynamic lung compliances (p = 0.09). Circulating cell-free mitochondrial DNA within the recipient plasma was significantly lower for lungs stored at 10°C in comparison to those underwent immediate transplant (p = 0.048), alongside a tendency of lower levels of tissue apoptotic cell death (p = 0.075).We demonstrate 10°C as a potentially superior storage temperature for injured donor lungs in a pig model when compared to the current clinical standard (4°C) and immediate transplantation. Continuing protective metabolism at 10°C for donor lungs may result in better transplant outcomes.

A paucity of data supports the use of transesophageal echocardiography (TEE) for bedside extracorporeal membrane oxygenation (ECMO) cannulation. Concerns have been raised about performing TEEs in patients with COVID-19. The authors describe the use and safety of TEE guidance for ECMO cannulation for COVID-19.Single-center retrospective cohort study.The study took place in the intensive care unit of an academic tertiary center.The authors included 107 patients with confirmed SARS-CoV-2 infection who underwent bedside venovenous ECMO (VV ECMO) cannulation under TEE guidance between May 2020 and June 2021.TEE-guided bedside VV ECMO cannulation.Patient characteristics, physiologic and ventilatory parameters, and echocardiographic findings were analyzed. The primary outcome was the number of successful TEE-guided bedside cannulations without complications. The secondary outcomes were cannulation complications, frequency of cannula repositioning, and TEE-related complications.TEE-guided cannulation was successful in 99% of the patients. Initial cannula position was adequate in all but 1 patient. Fourteen patients (13%) required cannula repositioning during ECMO support. Forty-five patients (42%) had right ventricular systolic dysfunction, and 9 (8%) had left ventricular systolic dysfunction. Twelve patients (11%) had intracardiac thrombi. One superficial arterial injury and 1 pneumothorax occurred. No pericardial tamponade, hemothorax or intraabdominal bleeding occurred in the authors' cohort. No TEE-related complications or COVID-19 infection of healthcare providers were reported during this study.Bedside TEE guidance for VV ECMO cannulation is safe in patients with severe respiratory failure due to COVID-19. No tamponade or hemothorax, nor TEE-related complications were observed in the authors' cohort.

The 8th TNM edition classifies stage III-N2 disease as IIIA and IIIB based on a tumor size cutoff of 5 cm. However, the importance of tumor size on survival in patients with resectable stage III-N2 disease has not been analyzed systematically.Survival analysis based on tumor size (5 cm vs ≤ 5 cm) for 255 consecutive patients with nonbulky (maximal lymph node diameter of 1.5 cm) stage III-N2 non-small cell lung cancer treated with surgery in our institution.Ninety patients (35.3%) underwent induction chemoradiation therapy (n = 72, 28%) or induction chemotherapy (n = 18, 7%), and 165 patients underwent primary surgery followed by adjuvant chemotherapy (n = 52, 32%), adjuvant chemoradiation therapy (n = 47, 29%), or adjuvant radiation therapy (n = 14, 13.2%). After a median follow-up of 6.5 years, the overall survival was 46.5% at 5 years and 28.9% at 10 years. In tumors 5 cm or less, there was no difference in survival between patients treated with induction or adjuvant therapy. However, in tumors greater than 5 cm, the survival was significantly better after induction therapy compared with adjuvant therapy or surgery alone. Pathologic multi-station N2 disease was more frequently detected in tumors greater than 5 cm (31% vs 18% in tumors ≤5 cm, P = .042), and the rate of R1 resection was lower after induction therapy (2.2% vs 8.5% in primary surgery, P = .048).These results support the redefinition of tumors greater than 5 cm with resectable N2 disease to stage IIIB. This change should help to refine the multimodality approach for stage III-N2 lung cancer.

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.

Background Weaning from venovenous extracorporeal membrane oxygenation (VV-ECMO) has not been not well studied. VV-ECMO can be discontinued when patients tolerate noninjurious mechanical ventilation (MV) during a sweep gas-off trial (SGOT). However, predictors of safe liberation are unknown. Research Question Can safe liberation from VV-ECMO be predicted at the bedside? Study Design and Methods Two observational studies of adults weaned from VV-ECMO for severe ARDS at Toronto General Hospital were conducted. MV settings, respiratory mechanics, and clinical variables were analyzed to predict safe liberation from VV-ECMO, defined a priori as avoida7ce of ECMO recannulation, increased MV support, need for rescue therapy, or hemodynamic instability developed within 48 h following decannulation. Results During both studies, 83 patients were weaned from VV-ECMO, 21 (25%) of whom did not meet the criteria for safe liberation. In the retrospective study, higher tidal volume per predicted body weight (OR, 1.58; 95% CI, 1.05-2.40; P = .03) and heart rate (OR, 1.07; 95% CI, 1.022-1.15; P = .01) at the end of SGOT were significantly associated with increased odds of unsafe liberation when adjusted for age (OR, 1.02; 95% CI, 0.95-1.09; P = .63) and sequential organ failure assessment score (OR, 1.16; 95% CI, 0.86-1.56; P = .34). Change in ventilatory ratio had an imprecise association (OR, 2.7; 95% CI, 0.94-7.95; P = .06) with unsafe liberation when adjusted for age (OR, 1.03; 95% CI, 0.96-1.10; P = .42), sequential organ failure assessment score (OR, 1.11; 95% CI, 0.81-1.51; P = .52), and heart rate (OR, 1.07; 95% CI, 1.01-1.13; P = .02). In the prospective study, patients who had unsafe liberation from VV-ECMO also had significantly higher inspiratory efforts (esophageal pressure swings, 9 [7-13] vs 18 [7-25] cm H2O; P = .03) and worse outcomes (longer MV duration, ICU and hospital length of stay). Interpretation Patients with higher tidal volume, heart rate, ventilatory ratio, and esophageal pressures swings during SGOT were less likely to achieve safe liberation from VV-ECMO.

Ex vivo lung perfusion (EVLP) has being increasingly used for the pretransplant assessment of extended-criteria donor lungs. Mathematical models to predict lung acceptance during EVLP have not been reported so far. Thus, we hypothesized that predictors of lung acceptance could be identified and used to develop a mathematical model describing the clinical decision-making process used in our institution. Donor lungs characteristics and EVLP physiologic parameters included in our EVLP registry were examined (derivation cohort). Multivariable logistic regression analysis was performed to identify predictors independently associated with lung acceptance. A mathematical model (EX vivo lung PerfusIon pREdiction [EXPIRE] model) for each hour of EVLP was developed and validated using a new cohort (validation cohort). Two hundred eighty donor lungs were assessed with EVLP. Of these, 186 (66%) were accepted for transplantation. ΔPO2 and static compliance/total lung capacity were identified as independent predictors of lung acceptance and their respective cut-off values were determined. The EXPIRE model showed a low discriminative power at the first hour of EVLP assessment (AUC: 0.69 [95% CI: 0.62-0.77]), which progressively improved up to the fourth hour (AUC: 0.87 [95% CI: 0.83-0.92]). In a validation cohort, the EXPIRE model demonstrated good discriminative power, peaking at the fourth hour (AUC: 0.85 [95% CI: 0.76-0.94]). The EXPIRE model may help to standardize lung assessment in centers using the Toronto EVLP technique and improve overall transplant rates.

Background Ex vivo lung perfusion (EVLP) is an isolated organ assessment technique that has revolutionized the field of lung transplantation and enabled a safe increase in the number of organs transplanted. The objective of this study was to develop a protein-based assay that would provide a precision medicine approach to lung injury assessment during EVLP. Methods Perfusate samples collected from clinical EVLP cases performed from 2009 to 2019 were separated into development (n=281) and validation (n=57) sets to derive and validate an inflammation score based on IL-6 and IL-8 protein levels in perfusate. The ability of an inflammation score to predict lungs suitable for transplantation and likely to produce excellent recipient outcomes (time on ventilator ≤ three days) was assessed. Inflammation scores were compared to conventional clinical EVLP assessment parameters and associated with outcomes, including primary graft dysfunction and patient care in the ICU. Results An inflammation score accurately predicted the decision to transplant (AUROC 68% [95% CI 62-74]) at the end of EVLP and those transplants associated with short ventilator times (AUROC 73% [95% CI 66-80]). The score identified lungs more likely to develop primary graft dysfunction at 72-hours post-transplant (OR 4.0, p=0.03). A model comprised of the inflammation score and ∆PO2 was able to determine EVLP transplants that were likely to have excellent recipient outcomes, with an accuracy of 87% [95% CI 83-92]. Conclusions The adoption of an inflammation score will improve accuracy of EVLP decision-making and increase confidence of surgical teams to determine lungs that are suitable for transplantation, thereby improving organ utilization rates and patient outcomes.

Lobar lung transplant is a technique that allows for large-sized donor lungs to be implanted into small-sized adult and pediatric recipients. Often, these recipients have longer waiting list times due to a shortage of appropriately sized donors, with the potential for increased waiting list mortality. Lobar lung transplant involves implanting a single lobe from each lung instead of the usual full-lung implant, thus ameliorating the size difference between donor and recipient. The first important step in this procedure involves proper donor-recipient size-matching, using calculation of total lung capacity using the bronchopulmonary segments to choose the appropriate lobes for the recipient. The preferred lobes to use are the lower lobes (or right lower lobe and right middle lobe, depending on sizing) as they are usually larger lobes and have a larger vascular bed. The surgery should ideally be done at experienced centres with high volume thoracic surgery where surgeons are very familiar with the pulmonary anatomy. Once the lungs are split, careful dissection is performed in order to ensure that the cuffs on the vein, artery and bronchus of the lobe to be used are of adequate length and undamaged during the dissection. The implantation must be performed on cardio-pulmonary support (preferably veno-arterial extra-corporeal membrane oxygenation) in order protect the lobes during the periods of reperfusion.

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 (PIP), 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 (PIP, 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.

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.

Uncontrolled donation after cardiac death (uDCD) has the potential to ameliorate the shortage of suitable lungs for transplant. To date, no lung transplant data from these donors are available from North America. We describe the successful use of these donors using a simple method of in situ lung inflation so that the organ can be protected from warm ischemic injury. Forty-four potential donors were approached, and family consent was obtained in 30 cases (68%). Of these, the lung transplant team evaluated 16 uDCDs on site, and 14 were considered for transplant pending ex vivo lung perfusion assessment. Five lungs were ultimately used for transplant (16.7% use rate from consented donors). The mean warm ischemic time was 2.8 hours. No primary graft dysfunction grade 3 was observed at 24, 48, or 72 hours after transplant. Median intensive care unit stay was 5 days (range: 2-78 days), and median hospital stay was 17 days (range: 8-100 days). The 30-day mortality was 0%. Four of 5 patients are alive at a median of 651 days (range: 121-1254 days) with preserved lung function. This study demonstrates the proof of concept and the potential for uDCD lung donation using a simple donor intervention.

BACKGROUND The contribution of lung transplantation to the treatment of patients with end-stage cystic fibrosis (CF) has been debated. We aimed to describe achievable outcomes from high-volume CF and lung transplant programs. This study reports on the largest single-center experience of lung transplantation for adult and pediatric patients with CF. It also highlights the evolution of practice and outcomes over time. METHODS A retrospective analysis of the prospectively collected Toronto Lung Transplant database was carried out. Post-transplant survival in CF was calculated using the Kaplan–Meier method and analyzed with log-rank tests. RESULTS From 1983 to 2016, a total of 1,885 transplants were performed at our institution, where 364 (19.3%) were CF recipients and another 39 (2.1%) were CF retransplants. The mean age at first transplant was 29.5 ± 9.7 years where 56.6% were males and 91.5% were adults. Pre-transplantation, 88 patients (24.2%) were Burkholderia cepacia complex (BCC)-positive, 143 (39.3%) had diabetes mellitus, and the mean forced expiratory volume in one second was 26.0 ± 7.2%, as predicted at listing. The 1-, 5-, and 10-year probabilities of survival in adults who were BCC-negative were 94%, 70%, and 53%, respectively. Pediatric, BCC-positive, and retransplant recipients had worse survival than adult patients who were BCC-negative. Strategies to improve the donor pool did not affect survival but possibly reduced waitlist mortality. For the entire cohort, the most common causes of death after lung transplant were infection and chronic lung allograft dysfunction. CONCLUSIONS Lung transplantation for CF provides excellent short- and long-term outcomes. These results strongly support lung transplantation as the standard of care for patients with CF having advanced lung disease.

Background The use of a novel extracellular oxygen carrier (EOC) preservation additive known as HEMO2Life 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 (PaO2/FiO2: 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.

Cadaveric lobar lung transplantation is an alternative for patients whose chest cavities have small dimensions. We present here a case where 1 donor was used for bilateral lobar transplantations in 2 high-risk patients. Coordination between the graft preparation at the back table and the 2 concomitant lung transplant teams was necessary to minimize the ischemic injury of the grafts and to plan for adequate vascular and bronchial cuffs for both implantations.

Background There is still controversy whether full lung palpation is required for patients undergoing pulmonary metastasectomy. We aimed to compare pulmonary ipsilateral recurrence (IR) after video-assisted thoracic surgery (VATS) or open surgery. Methods A retrospective study of all patients who underwent surgery for colorectal cancer lung metastases between 2003 and 2012 was performed. IR rate was compared between the 2 groups after adjusting for a propensity score matching based on age, sex, disease-free interval, number of metastases, type of resection, presence of a cardiovascular risk factor, presence of a respiratory risk factor, as well as the interaction between the number of metastases and the disease-free interval. The propensity score was used for matched and weighted comparisons of VATS and open patients. Results A total of 211 patients underwent surgery for colorectal cancer lung metastases. Of these, 75 (35.5%) were performed via VATS and 136 (64.5%) via open surgery. Before matching, 118 (55.9%) were male and the median age at the time of metastases diagnosis was 61 (range, 49.8-72.2) years. Median disease free-interval was 20 (19.7 ± 28.3) months; 22 (21.6 ± 28.5) months in VATS and 19 (19.0 ± 28.3) months in open surgery. In total, 19 (25.3%) developed IR in VATS, and 39 (28.7%) in open surgery. Five-year overall survival was 53.1% (61.9% VATS; 49.2% open). In the matched sample, IR was 23.6% in VATS vs 26.2% in open surgery (95% confidence interval for risk reduction with VATS: –22.6% to 17.5%; P = .80). Conclusions No significant difference was observed in IR rates between VATS and open surgery in the treatment of colorectal cancer lung metastases.

The study objective was to determine whether donor substance abuse (opioid overdose death, opioid use, cigarette or marijuana smoking) impacts lung acceptance and recipient outcomes.Donor offers to a single center from 2013 to 2019 were reviewed to determine if lung acceptance rates and recipient outcomes were affected by donor substance abuse.There were 3515 donor offers over the study period. A total of 154 offers (4.4%) were opioid use and 117 (3.3%) were opioid overdose deaths. A total of 1744 donors (65.0%) smoked cigarettes and 69 donors (2.6%) smoked marijuana. Of smokers, 601 (35.0%) had less than 20 pack-year history and 1117 (65.0%) had more than 20 pack-year history. Substance abuse donors were younger (51.5 vs 55.2 P .001), more often male (65.6 vs 54.8%, P .001), more often White (86.2 vs 68.7%, P .001), and had hepatitis C (8.3 vs 0.8%, P .001). Donor acceptance was significantly associated with brain dead donors (odds ratio, 1.56, P .001), donor smoking history (odds ratio, 0.56, P .001), hepatitis C (odds ratio, 0.35, P .001), younger age (odds ratio, 0.98, P .001), male gender (odds ratio, 0.74, P = .004), and any substance abuse history (odds ratio, 0.50, P .001), but not opioid use, opioid overdose death, or marijuana use. Recipient survival was equivalent when using lungs from donors who had opioid overdose death, who smoked marijuana, or who smoked cigarettes for less than 20 patient-years or more than 20 patient-years, and significantly longer in recipients of opioid use lungs. There was no significant difference in time to chronic lung allograft dysfunction for recipients who received lungs from opioid overdose death or with a history of opioid use, marijuana smoking, or cigarette smoking.Donor acceptance was impacted by cigarette smoking but not opioid use, opioid overdose death, or marijuana use. Graft outcomes and recipient survival were similar for recipients of lungs from donors who abused substances.

Summary Background A substantial proportion of organ donors test positive for hepatitis C virus (HCV) infection. To date, only a few studies have evaluated the safety of using lungs from these donors for transplantation, and no direct interventions to donor organs have been done with the aim of preventing HCV transmission via organ transplantation. We aimed to assess the safety and efficacy of lung transplantation in humans from HCV-positive donors to HCV-negative recipients after application of ex-vivo lung perfusion (EVLP) plus ultraviolet C (UVC) perfusate irradiation. Methods We did a single centre, prospective, open-label, non-randomised trial in which donor lungs from HCV-viraemic donors (HCV-positive) were transplanted into HCV-negative recipients at Toronto General Hospital, University Health Network (Toronto, ON, Canada). Donors were younger than 65 years old and tested positive for HCV by nucleic acid testing. Donors who tested positive for hepatitis B virus, HIV, human T-lymphotropic virus 1 or 2 were excluded. Recipients were on the lung transplant waiting list without significant liver disease (stage 2 fibrosis or higher were excluded) or active HCV infection. Before implantation, all HCV-positive donor lungs were treated with EVLP with or without UVC perfusate irradiation to reduce the concentration of HCV RNA and infectivity. For the first week after transplantation, patients' HCV RNA blood concentrations were measured once daily, then once per week for 12 weeks. All patients received 12 weeks of oral sofosbuvir 400 mg plus velpatasvir 100 mg, starting at least 2 weeks after transplantation. The primary endpoint was a composite of survival and HCV-free status at 6 months after transplantation in all patients who received HCV-positive lungs. Patient outcomes such as survival, time in hospital, and incidence of acute rejection were compared between those receiving HCV-positive lungs and all patients who received HCV-negative lung transplants during the study period. The study is registered with ClinicalTrials.gov, NCT03112044. Findings From Oct 1, 2017, to Nov 1, 2018, 209 patients had a transplantation; of 27 donors who were HCV-positive and initially considered, 22 were suitable for transplantation. The remaining 187 donors were HCV-negative. Before implantation, 11 of the HCV-positive donor lungs were treated with EVLP alone and the other 11 were treated with EVLP plus UVC. Lung disease, urgency status, and positive donor-recipient HLA crossmatch were similar between the patients who received HCV-positive and HCV-negative lungs. 20 (91%) patients in the HCV-positive group developed HCV viraemia within the first week after transplantation and had sofosbuvir plus velpatasvir treatment, starting at a median of 21 days after transplantation (IQR 16·76–24·75). Donor organ treatment with EVLP plus UVC was associated with significantly lower recipient viral loads in blood within the first week after transplantation than with EVLP alone (median of 167 IU/mL [IQR 20–12 000] vs 4390 IU/mL [1170–112 000] at day 7; p=0·048) and prevented transmission in two (18%) of 11 patients. All 20 infected patients achieved negative HCV PCR within 6 weeks of treatment initiation. The primary endpoint of survival and HCV-free status at 6 months after transplantation was achieved in 19 (86%) of 22 patients in the HCV-positive group. 6-month survival was 95% in recipients receiving lungs from HCV-viraemic donors versus 94% in recipients receiving lungs from HCV-negative donors. The most common grade 3–4 adverse events in the HCV-positive group were respiratory complications (five [23%]) and infections (four [18%]). Serious adverse events requiring admission to hospital occurred in ten (45%) patients. One (5%) patient who did not develop HCV infection died at day 31 from multiorgan failure related to pseudomonas sepsis. Two patients presented with HCV relapse within 3 months after sofosbuvir plus velpatasvir completion and required retreatment. Interpretation Early and intermediate clinical outcomes were not significantly different between patients receiving viraemic HCV donor lungs and HCV-negative donor lungs. Donor organ treatment with UVC perfusate irradiation during EVLP significantly decreased HCV viral loads within the first 7 days after transplantation and shows the proof-of-concept for a novel approach of minimising viral load ex vivo before transplantation, with intent of preventing donor–recipient transmission. Funding Canadian Institutes of Health Research.

BACKGROUND: This study aimed to examine intermediate-term outcomes of lung transplantation (LTx) recipients from donors after circulatory death (DCD).METHODS: We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry data for patients transplanted between January 2003 and June 2017 at 22 centers in North America, Europe, and Australia participating in the DCD Registry. The distribution of continuous variables was summarized as median and interquartile range (IQR) values. Wilcoxon rank sum test was used to compare distribution of continuous variables and chi-square or Fisher's exact test for categorical variables. Kaplan-Meier survival rates after LTx from January 2003 to June 2016 were compared between DCD-III (Maastricht category III withdrawal of life-sustaining therapy [WLST]) only and donors after brain death (DBD) using the log-rank test. Risk factors for 5-year mortality were investigated using Cox multivariate proportional-hazards model.RESULTS: The study cohort included 11,516 lung transplants, of which 1,090 (9.5%) were DCD lung transplants with complete data. DCD-III comprised 94.1% of the DCD cohort. Among the participating centers, the proportion of DCD-LTx performed each year increased from 0.6% in 2003 to 13.5% in 2016. DCD donor management included extubation in 91%, intravenous heparin in 53% and pre-transplant normothermic ex vivo donor lung perfusion in 15%. The median time interval from WLST to cardiac arrest was 15 minutes (IQR: 11-22 minutes) and to cold flush 32 minutes (IQR: 26-41minutes). Compared with DBD, donor age was higher in DCD-III donors (46 years [IQR: 34-55] vs 40 years [IQR: 24-52]), bilateral LTx was performed more often (88.3% vs 76.6%), and more recipients had chronic obstructive pulmonary disease and emphysema as their transplant indication. Five-year survival rates were comparable (63% vs 61%, p = 0.72). In multivariable analysis, recipient and donor ages, indication diagnosis, procedure type (single vs bilateral and double LTx), and transplant era (2003-2009 vs 2010-2016) were independently associated with survival (p CONCLUSION: This ISHLT DCD Registry report with 5-year follow-up demonstrated similar favorable long-term survival in DCD-III and DBD lung donor recipients at 22 experienced centers globally. These data indicate that more extensive use of DCD-LTx would increase donor organ availability and may reduce waiting list mortality. (C) 2019 International Society for Heart and Lung Transplantation. All rights reserved.

A large proportion of controlled donation after circulatory death (cDCD) donor lungs are declined because cardiac arrest does not occur within a suitable time after the withdrawal of life-sustaining therapy. Improved strategies to preserve lungs after asystole may allow the recovery team to arrive after death actually occurs and enable the recovery of lungs from more cDCD donors. The aim of this study was to determine the effect of donor positioning on the quality of lung preservation after cardiac arrest in a cDCD model. Cardiac arrest was induced by withdrawal of ventilation under anesthesia in pigs. After asystole, animals were divided into 2 groups based on body positioning (supine or prone). All animals were subjected to 3 hours of warm ischemia. After the observation period, donor lungs were explanted and preserved at 4°C for 6 hours, followed by 6 hours of physiologic and biological lung assessment under normothermic ex vivo lung perfusion. Donor lungs from the prone group displayed significantly greater quality as reflected by better function during ex vivo lung perfusion, less edema formation, less cell death, and decreased inflammation compared with the supine group. A simple maneuver of donor prone positioning after cardiac arrest significantly improves lung graft preservation and function.

Background Moderate to severe depressive symptoms occur in up to one-third of patients at 1 year following ICU discharge, negatively affecting patient outcomes. This study evaluated patient and caregiver factors associated with the development of these symptoms. Methods This study used the Rehabilitation and Recovery in Patients after Critical Illness and Their Family Caregivers (RECOVER) Program (Phase 1) cohort of 391 patients from 10 medical/surgical university-affiliated ICUs across Canada. We determined the association between patient depressive symptoms (captured by using the Beck Depression Inventory II [BDI-II]), patient characteristics (age, sex, socioeconomic status, Charlson score, and ICU length of stay [LOS]), functional independence measure (FIM) motor subscale score, and caregiver characteristics (Caregiver Assistance Scale and Center for Epidemiologic Studies-Depression Scale) by using linear mixed models at time points 3, 6, and 12 months. Results BDI-II data were available for 246 patients. Median age at ICU admission was 56 years (interquartile range, 45-65 years), 143 (58%) were male, and median ICU LOS was 19 days (interquartile range, 13-32 days). During the 12-month follow-up, 67 of 246 (27.2%) patients had a BDI-II score ≥ 20, indicating moderate to severe depressive symptoms. Mixed models showed worse depressive symptoms in patients with lower FIM motor subscale scores (1.1 BDI-II points per 10 FIM points), lower income status (by 3.7 BDI-II points; P = .007), and incomplete secondary education (by 3.8 BDI-II points; P = .009); a curvilinear relation with age (P = .001) was also reported, with highest BDI-II at ages 45 to 50 years. No associations were found between patient BDI-II and comorbidities (P = .92), sex (P = .25), ICU LOS (P = .51), or caregiver variables (Caregiver Assistance Scale [P = .28] and Center for Epidemiologic Studies Depression Scale [P = .74]). Conclusions Increased functional dependence, lower income, and lower education are associated with increased severity of post-ICU depressive symptoms, whereas age has a curvilinear relation with symptom severity. Knowledge of risk factors may inform surveillance and targeted mental health follow-up. Early mobilization and rehabilitation aiming to improve function may serve to modify mood disorders.

Background: Effective treatment of respiratory infections continues to be a major challenge. In high doses (³160 ppm), inhaled Nitric Oxide (iNO) has been shown to act as a broad-spectrum antimicrobial agent in preliminary studies. However, the safety of prolonged in vivo implementation of high-dose iNO therapy has not been studied. Herein we aim to explore the feasibility and safety of delivering continuous high-dose iNO over an extended period of time using an in vivo animal model. Methods: Yorkshire pigs were randomized to one of the following two groups: group 1, standard ventilation; and group 2, standard ventilation + continuous iNO 160 ppm + methylene blue (MB) as intravenous bolus, whenever required, to maintain metHb

BACKGROUND Venovenous (VV) extracorporeal membrane oxygenation (ECMO) is the preferred configuration for bridging respiratory failure patients while awaiting lung transplantation. However, there is no consensus on intraoperative extracorporeal cardiopulmonary support during lung transplantation in these patients. METHODS The configuration of the intraoperative extracorporeal circuit after VV ECMO bridge was reviewed and correlated with clinical outcomes. This retrospective cohort study performed at our university hospital included 34 patients who were successfully bridged solely with VV ECMO to lung transplantation during the period 2007 to 2016. Indications to switch to intraoperative venoarterial (VA) ECMO were hemodynamic compromise (systemic hypotension or mean pulmonary artery pressure >40 mm Hg) or when this scenario was thought to be highly likely. RESULTS The median duration of bridging was 12 (IQR 7 to 19) days. Intraoperatively, 3 patients (8.8%) required cardiopulmonary bypass. Twenty patients (58.8%) stayed on VV ECMO and 11 (32.3%) were switched to central VA ECMO. Between the 2 types of intraoperative ECMO (VV vs VA), there were no significant differences in post-operative ECMO duration, chest reopening for bleeding, or renal replacement therapy. There was no significant difference in 90-day mortality (0% and 9.0%, p = 0.35) or in long-term survival (p = 0.59). The intraoperative transfusion of red blood cells tended to be higher in the VA group (5 [4 to 9] vs 8 [6 to 13] units, p = 0.06). Use of intraoperative VA ECMO was associated with the use of low-flow VV device bridging and lobar transplantation. CONCLUSIONS Using the existing VV ECMO bridge intraoperatively during lung transplantation is feasible and provides comparable outcomes to patients converted to central VA ECMO for compromised hemodynamics.

Background Increasing evidence indicates that regulated necrosis plays a critical role during cell death caused by ischemia-reperfusion (IR) injury. Necroptosis is one form of regulated necrosis. Necrostatin-1 (Nec-1), an inhibitor of receptor-interacting protein kinase 1 (RIPK1), is known to reduce necroptosis. We investigated the effect of Nec-1 treatment on IR-induced lung injury in a rat lung transplant model. Methods Lewis rats were divided into 4 groups (n = 6 each): (1) Control (no treatment), (2) Donor treatment (D), (3) Recipient treatment (R), and (4) Donor plus Recipient treatment (D+R) groups. Donor lungs were flushed and preserved for 18 hours at 4oC before transplantation. Recipient animals underwent a left single lung transplant. After 2 hours of reperfusion, we assessed the physiologic function, cytokine expression, pathway activation, and the extent of necrosis. Results Pulmonary gas exchange in D+R group was significantly better than in the other 3 groups ( p = 0.003). Lung edema was significantly lower in the D+R group compared with the Control group (p = 0.006). The expression of interleukin-6 in lung tissue and plasma was significantly reduced in the D+R group compared with the Control group (p = 0.036). The percentage of necrotic cells in D+R group was significantly lower than in the Control and D groups (p = 0.01), indicating Nec-1inhibited regulated necrosis. Conclusions The administration of Nec-1 to both donor and recipient improved graft function after lung transplantation through the reduction of necroptosis. The inhibition of regulated necrosis appears to be a promising strategy to attenuate IR lung injury after lung transplantation.

The study aim is to compare the diagnostic yield, safety, and cost of outpatient awake thoracoscopy (AT) with video-assisted thoracoscopic surgery (VATS) pleural biopsy in undiagnosed pleural effusions.The diagnostic yield of pleural biopsy performed by AT or VATS in patients with undiagnosed exudative pleural effusions at a tertiary thoracic surgery center in Canada between 2011 and 2015 was retrospectively evaluated. Test sensitivity, specificity, positive predictive value, and negative predictive value were compared. Procedure safety, hospital length of stay, additional pleural-based interventions, and procedure-related costs were compared.Patients underwent either AT (n = 78) or VATS (n = 99) during the study period. Sensitivity, specificity, positive predictive value, and negative predictive value were 85%, 100%, 100%, and 79% for AT and 93%, 94%, 99%, and 76% for VATS, with no significant difference in diagnostic test performance. There was no difference in the rate of major complications (2 AT [2.6%] versus 4 VATS [4.0%], p = 0.696), minor complications (14 AT [17.9%] versus 16 VATS [16.2%], p = 0.841) or need for additional pleural-based procedures (20 AT [25.6%] versus 18 VATS [18.2%], p = 0.270). The VATS was associated with longer median hospital stay (VATS 3 days [interquartile range: 1 to 4] versus AT 0 days [interquartile range: 0 to 1], z = 6.98, p0.001) and a higher procedure-related average cost (VATS Canadian dollars $7,962 [95% confidence interval: $7,134 to $8,790] versus AT Canadian dollars $2,815 [95% confidence interval: $2,010 to $3,620], p0.001).Awake thoracoscopy and VATS have similar diagnostic yield and safety profiles in the assessment of undiagnosed pleural effusions; however, AT is associated with shorter length of stay and lower average per-procedure cost. In the appropriate clinical setting, AT may be the diagnostic test of choice.

The fast and sensitive determination of concentrations of anticancer drugs in specific organs can improve the efficacy of chemotherapy and minimize its adverse effects. In this paper, ex vivo solid-phase microextraction (SPME) coupled to LC-MS/MS as a method for rapidly quantitating doxorubicin (DOX) in lung tissue was optimized. Furthermore, the theoretical and practical challenges related to the real-time monitoring of DOX levels in the lung tissue of a living organism (in vivo SPME) are presented. In addition, several parameters for ex vivo/in vivo SPME studies, such as extraction efficiency of autoclaved fibers, intact/homogenized tissue differences, critical tissue amount, and the absence of an internal standard are thoroughly examined. To both accurately quantify DOX in solid tissue and minimize the error related to the lack of an internal standard, a calibration method at equilibrium conditions was chosen. In optimized ex vivo SPME conditions, the targeted compound was extracted by directly introducing a 15 mm (45 µm thickness) mixed-mode fiber into 15 g of homogenized tissue for 20 min, followed by a desorption step in an optimal solvent mixture. The detection limit for DOX was 2.5 µg g−1 of tissue. The optimized ex vivo SPME method was successfully applied for the analysis of DOX in real pig lung biopsies, providing an averaged accuracy and precision of 103.2% and 12.3%, respectively. Additionally, a comparison between SPME and solid-liquid extraction revealed good agreement. The results presented herein demonstrate that the developed SPME method radically simplifies the sample preparation step and eliminates the need for tissue biopsies. These results suggest that SPME can accurately quantify DOX in different tissue compartments and can be potentially useful for monitoring and adjusting drug dosages during chemotherapy in order to achieve effective and safe concentrations of doxorubicin.

Background Ex-vivo lung perfusion (EVLP), a technique for donor lung assessment, also represents a platform for donor lung repair and immunomodulation. α 1 -Anti-trypsin (A1AT), a medication used to treat emphysema in A1AT-deficient patients, has anti-inflammatory properties and has been shown to attenuate ischemia–reperfusion injury in rat and pig lung transplants . The objective of this study was to determine whether administration of A1AT during EVLP can improve donor lung quality after prolonged hypothermic preservation. Methods Pig donor lungs were retrieved, preserved at 4°C for 24 hours, and then subjected to normothermic EVLP for 12 hours using the Toronto protocol. The treatment group (n = 6) received 3 mg/ml A1AT (Zemaira) in the EVLP perfusate, acellular Steen solution. The control group (n = 6) was perfused with Steen solution only. Physiologic functions and gas exchange were measured hourly. Pulmonary edema, lung injury, apoptosis and inflammatory mediators were evaluated in lung tissues and perfusate. Results A1AT treatment significantly reduced pulmonary arterial pressure , pulmonary vascular resistance and airway pressure changes from the baseline when compared with controls. A1AT treatment significantly improved both dynamic and static pulmonary compliance , and change in partial pressure of oxygen (ΔPO 2 ) between the left atrium and the pulmonary artery. Furthermore, A1AT treatment also significantly reduced pulmonary edema (wet-to-dry ratio), pulmonary cell apoptosis and pro-inflammatory cytokine levels (interleukin-1α and -8) in the perfusate. Conclusion Treatment of 24-hour-preserved pig donor lungs with A1AT during EVLP resulted in improved physiologic function, reduced pulmonary edema and inflammation and decreased cell death. Our findings suggest that treatment of donor lungs during EVLP with A1AT is a promising strategy to attenuate early lung injury and improve donor lung function before lung transplantation.

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.

Purpose CD4+CD25highFoxp3+ regulatory T cells (Treg) can establish immunologic tolerance in animal models but are hampered by immunosuppressive drugs. IL-2-anti-IL-2 complexes (IL-2c) promote Treg expansion in vivo even with concomitant calcineurin inhibitor administration. Here, we combined recipient IL-2c therapy with pre-transplant Treg administration during ex vivo lung perfusion (EVLP), to test the hypothesis that this strategy would facilitate expansion and function of the Tregs within the graft. Methods We performed rat orthotopic left lung transplantation (OLT) experiments using Fischer 344 (F344, RT-1lv1) donors and Wistar Kyoto (WKy, RT-1l) recipients. Expanded WKy Tregs were administered to the F344 donor lungs during EVLP. Some animals received IL-2c (30 ug recombinant mouse IL-2 and 150 ug anti-mouse IL-2, given i.p. once on day 0) and/or Tacrolimus (Tac, 0.1mg/kg/day, 7 days). Treatment groups were: no treatment (n=7), Tac (n=5), IL-2c/Tac (n=4), Treg (n=6), and Treg/IL-2c/Tac (n=5). Necropsy was performed 7 days post-transplant. Results Graft CD25highFoxp3+ content increased as a result of Treg therapy (p Conclusion Treg therapy increased intragraft Treg content, and IL-2c/Tac further increased intragraft Tregs 7 days after transplantation, with reductions observed in A and B rejection scores. The combination of graft-directed Treg cell therapy with a Treg-permissive immunosuppressive strategy may be a viable therapeutic approach for effective pre-transplant graft immunomodulation in lung transplantation.

Purpose This study explores feasibility and safety of using enzymes (FpGalNAc deacetylase & FpGalNase) to remove ABO-A antigens from donor lungs during ex vivo lung perfusion (EVLP). The enzymes have been reported to efficiently convert ABO-A blood to O (Withers, Nat Microbiol, 2019). Methods Human lungs (ABO-A1, n=5), declined for transplant, were treated with the enzymes during EVLP. Tissues were sampled before and after. The distribution and expression level of ABO antigens were analyzed by immunohistochemistry and flow cytometry. Lung function was monitored for side-effects. Immediate post-transplant immune response was simulated in an ex vivo model of hyperacute lung rejection, with introduction of ABO-O plasma (carrying ABO antibodies) as the surrogate for the recipient circulation (Fig.1H, n=1). The physiology and histology of lungs were analyzed for anti-A-induced immune responses. Results The histo-blood type A (BTA) antigens in the A1 lungs are observed primarily on endothelial and epithelial cells. BTA were cleared remarkably well from treated lungs (Fig.1A). The enzymes convert vascular BTA to the blood group H (BTH) antigens found in ABO-O tissue (Fig.1B). Over 97% of endothelial BTA antigens were removed within the typical 4h clinical EVLP timeframe using very low dose (1 µg/mL) enzymes (Fig.1C). No acute side-effects were seen (Fig.1D-G). The rejection model showed that the 3-hour treatment of human lung with low dose enzymes prevented the damage triggered by type O plasma (presumably due to anti-A antibodies) as observed in the physiology and histology of the control lung (Fig.1I-J). Conclusion Ex vivo enzymatic treatment can efficiently remove ABO-A antigen in donor lungs without acute side-effects. Preliminary results show that the treatment can prevent ABO mismatch-induced early damages. The treatment can potentially allow expansion of ABO-incompatible lung transplantation, leading to significant improvements in logistics and fairness of organ allocation.