D. Nakajima

Ex Vivo Perfusion Treatment of Infection in Human Donor Lungs

Ex vivo lung perfusion (EVLP) is a platform to treat infected donor lungs with antibiotic therapy before lung transplantation. Human donor lungs that were rejected for transplantation because of clinical concern regarding infection were randomly assigned to two groups. In the antibiotic group (n = 8), lungs underwent EVLP for 12 h with high‐dose antibiotics (ciprofloxacin 400 mg or azithromycin 500 mg, vancomycin 15 mg/kg, and meropenem 2 g). In the control group (n = 7), lungs underwent EVLP for 12 h without antibiotics. A quantitative decrease in bacterial counts in bronchoalveolar lavage (BAL) was found in all antibiotic‐treated cases but in only two control cases. Perfusate endotoxin levels at 12 h were significantly lower in the antibiotic group compared with the control group. EVLP with broad‐spectrum antibiotic therapy significantly improved pulmonary oxygenation and compliance and reduced pulmonary vascular resistance. Perfusate endotoxin levels at 12 h were strongly correlated with levels of perfusates tumor necrosis factor α, IL‐1β and macrophage inflammatory proteins 1α and 1β at 12 h. In conclusion, EVLP treatment of infected donor lungs with broad‐spectrum antibiotics significantly reduced BAL bacterial counts and endotoxin levels and improved donor lung function.

Extension of donor lung preservation with hypothermic storage after normothermic ex vivo lung perfusion

BACKGROUND Ex vivo lung perfusion (EVLP) allows normothermic evaluation and treatment of donor lungs not currently acceptable for transplant and improves organ use. Donor lungs undergo a period of cold preservation before (cold ischemic time [CIT]-1) and after (CIT-2) EVLP. We investigated the effect of an extended CIT-2 on lung function after transplantation. METHODS Explanted pig lungs, preserved in low-potassium dextran flush (Perfadex) at 4°C for 10 hours, were subjected to 6 hours of EVLP. They were subsequently allocated to 2 groups: short CIT-2 (CIT-2 = 2 hours; n = 5), and long CIT-2 (CIT-2 = 10 hours; n = 5). In a control group (n = 6), explanted lungs were placed in cold static preservation for 24 hours without EVLP. After the total preservation period, the left lung was transplanted in all groups. RESULTS After 4 hours of reperfusion, oxygenation function, acute lung injury score, inflammatory markers, and cell death pathway markers were similar between short and long CIT-2 groups. Both EVLP groups fared significantly better than the control group in oxygenation function (p < 0.05). CONCLUSIONS The intervention of EVLP improved lung function after transplantation, and this was not affected by a prolonged cold static preservation time after EVLP. These results provide the basis for a practical prolonged lung preservation strategy using a combination of cold and warm preservation techniques, which may improve lung transplantation logistics and outcomes.

Importance of left atrial pressure during ex vivo lung perfusion

BACKGROUND Ex vivo lung perfusion (EVLP) allows for the evaluation and treatment of donor lungs before transplant. Different EVLP strategies have been described using either an open left atrium (LA) (pressure of 0 mm Hg) or closed LA (pressure of 5 mm Hg). We hypothesized that maintaining a physiologic positive LA pressure during EVLP is protective to the lung. METHODS Pig lungs were flushed with Perfadex, retrieved and stored at 4°C for 4 hours [short cold ischemic time (CIT), n = 10] or 18 hours (prolonged CIT, n = 8). Subsequently, lungs underwent normothermic EVLP for 12 hours using either an open or closed LA technique. A linear mixed effect model was used to compare functional parameters between the 2 groups. RESULTS After short CIT, 12-hour EVLP could not be completed in 4 of 5 open atrium cases due to significant pulmonary edema. Lung injury was evident in this group after 7 hours of EVLP, demonstrating an increase in pulmonary vascular resistance (p < 0.001) and peak inspiratory pressure (p = 0.001), and a decrease in lung compliance (p < 0.001) and perfusate oxygenation (p = 0.04). In contrast, in the closed atrium group, all lungs completed 12 hours of EVLP with stable functional parameters. At the end of the experiment, the wet/dry ratio (p = 0.015) and lung edema score (p = 0.02) were significantly worse in the open LA group compared with the closed LA EVLP group. Similar findings were observed in the prolonged CIT group. CONCLUSION The use of a closed atrial technique to create a controlled positive LA during EVLP leads to significantly less edema and superior lung physiology.

Soluble Adhesion Molecules During Ex Vivo Lung Perfusion Are Associated With Posttransplant Primary Graft Dysfunction

Ex vivo lung perfusion (EVLP) enables assessment of marginal donor lungs for transplantation. We aimed to discover biomarkers in EVLP perfusate that could predict development of primary graft dysfunction (PGD). From September 2008 to August 2013, 100 clinical EVLPs were performed. Eleven patients developed PGD grade 3 within 72 h after transplant. The non‐PGD group consisted of 34 patients without PGD grade 3. Nonbilateral lung transplants or transplant after extracorporeal life support were excluded from analyses. Soluble intercellular adhesion molecule 1 (sICAM‐1), soluble VCAM‐1 (sVCAM‐1), and soluble E selectin (sE‐selectin) levels, as markers of endothelial activation, were measured in the perfusate of EVLP by enzyme‐linked immunosorbent assay and were correlated with clinical outcome. Levels of sICAM‐1 at 1 h and sVCAM‐1 at 1 and 4 h were significantly higher in the PGD group compared with the non‐PGD group. The sE selectin levels were not statistically different between the study groups. Higher levels of sVCAM‐1 at 1 and 4 h were statistically significantly associated with PGD either alone or after adjustment for other PGD risk factors. These adhesion molecules may help identify donor lungs at higher risk of PGD during EVLP.