ISHLT special report

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part V: Predictors and Outcomes

Ex vivo lung perfusion (EVLP) allows for a reassessment of lung grafts initially deemed unsuitable for transplantation, increasing the available donor pool; however, this requires a pre- and post-EVLP period of cold ischemic time (CIT). Paucity of data exists on how the sequence of cold normothermic–cold preservations affect outcomes.

A total of 110 patients were retrospectively analyzed. Duration of 3 preservation phases was measured: cold pre-EVLP, EVLP, and cold post-EVLP. The donor and recipient clinical data were collected. Primary graft dysfunction (PGD) and survival were monitored. Risk of mortality or PGD was calculated using Cox proportional hazards and logistic regression models to adjust for baseline characteristics.

Using the highest quartile, patients were stratified into extended vs non-extended pre-EVLP (<264 vs ≥264 minutes) and post-EVLP (<287 vs ≥287 minutes) CIT. The rates of 1-year mortality (8.4% vs 29.6%, p = 0.013), PGD 2-3 (20.5% vs 52%, p = 0.002), and PGD 3 (8.4% vs 29.6%, p = 0.005) at 72 hours were increased in the extended post-EVLP CIT group. After adjusting for baseline risk factors, the extended group remained an independent predictor of PGD ≥2 (odd ratio: 6.18, 95% CI: 1.88–20.3, p = 0.003) and PGD 3 (odd ratio: 20.4, 95% CI: 2.56–161.9, p = 0.004) at 72 hours and 1-year mortality (hazard ratio: 17.9, 95% CI: 3.36–95.3, p = 0.001). Cold pre-EVLP was not a significant predictor of primary outcomes.

Extended cold post-EVLP preservation is associated with a risk for PGD and 1-year mortality. Pre-EVLP CIT does not increase mortality or high-grade PGD. These findings from a multicenter trial should caution on the implementation of extended cold preservation after EVLP.

Primary graft dysfunction (PGD) represents ischemia‒reperfusion injury in the lung allograft, and elevated left ventricular end-diastolic pressure (LVEDP) may contribute to capillary leak. We tested whether pre-transplant LVEDP or pulmonary capillary wedge pressure (mPCWP) are related to PGD risk. We hypothesized that elevated LVEDP and mPCWP would increase PGD risk.

We reviewed adult double lung transplant recipients at the University of Alberta Hospital from 2004 to 2016 with pre-transplant LVEDP measurements. The primary outcome was Grade 3 PGD at 48 to 72 hours post-transplant. We used regression analysis to assess the association between LVEDP and mPCWP with Grade 3 PGD risk, as well as agreement between these measurements.

Three hundred thirty double lung transplant recipients were included in the study, and 63 (19%) developed Grade 3 PGD at 48 or 72 hours. Mean LVEDP was 16 ± 7 mm Hg in the Grade 3 PGD group and 12 ± 5 mm Hg in the non-PGD group (p < 0.0001). LVEDP >15 mm Hg was associated with an adjusted odds ratio (OR) of 3.83 (95% confidence interval [CI] 1.90 to 7.73, p < 0.0001), whereas mPCWP >15 mm Hg showed similar findings (adjusted OR 4.25 [1.83 to 9.86], p = 0.0008). Correlation and agreement between LVEDP and mPCWP were fair.

Elevated pre-transplant LVEDP increases the risk of severe PGD after lung transplant, as does elevated mPCWP. These measurements appear to be complementary as markers of prospective PGD risk.

Indications for pediatric lung transplantation vary by age, with some conditions leading to transplant throughout childhood (e.g., pulmonary hypertension) and others predominating in younger (e.g., surfactant disorders) or older (e.g., cystic fibrosis) children. The use of the “Lung Allocation System” has resulted in shorter waiting list times and also in sicker children proceeding to lung transplant. The number of absolute contraindications to transplant has diminished as centers develop greater expertise. Strategies such as extracorporeal membrane oxygenation (ECMO) are being used as a “bridge” to transplant in some patients with severe lung disease. Patients who undergo lung transplant require lifetime immunosuppression, which increases their ongoing risk of infection. Acute rejection can occur in the period immediately following transplant. Medication side effects, particularly renal dysfunction, become increasingly common over the years following transplant. Malignancies are relatively uncommon as a complication of transplant, but posttransplant lymphoproliferative disorder (PTLD), a form of lymphoma often associated with Epstein-Barr virus (EBV), can occur months or years following transplant. Complications such as chronic lung allograft dysfunction (CLAD) become increasingly common in the years following transplant. Treatment for CLAD is challenging, and this complication limits long-term allograft survival. Average survival in pediatric lung transplantation is just over five years. Extending patient survival and improving organ supply will be vital to the future of the field.