The impact of alteplase on pulmonary graft function in donation after circulatory death - An experimental study

Abstract

Objective: Lung transplantation is hampered by the lack of organs resulting in deaths on the waiting list. The usage of donation after circulatory death (DCD) lungs would dramatically increase donor availability. The most optimal organ preservation method, and the need for antithrombotic and fibrinolytic treatment to prevent thrombosis in the donor lungs is currently on debate. The present study investigated, in a simulated clinical DCD situation, whether the addition of alteplase in the flush-perfusion solution at the time of pulmonary graft harvesting could prevent thrombosis in the donor lung and thereby improve pulmonary graft function.

Methods: Twelve Swedish domestic pigs were randomized into two groups. All animals underwent ventricular fibrillation and were then left untouched for 1 h after declaration of death. None of the animals received heparin. The lungs were then harvested and flush-perfused with Perfadex^® solution and the organs were then stored at 8 °C for 4 h. In one group alteplase was added to the Perfadex^® solution (donation after cardiac death with alteplase (DCD-A)) and in the other, it was not (DCD). Lung function was evaluated, using ex vivo lung perfusion (EVLP), with blood gases at different oxygen levels, pulmonary vascular resistance (PVR), lung weight, and macroscopic appearance.

Results: During EVLP, there were no significant differences between groups in PaO₂ at any investigated FiO₂ level (1.0, 0.5, or 0.21). At FiO₂ 1.0, the PaO₂ in the DCD and DCD-A was 51.7 ± 2.05 kPa and 60.3 ± 3.67 kPa, respectively (p = 0.1320). There were no significant differences between groups PVR levels, in the DCD (372 ± 31 dyne x s/cm⁵) and in the DCD-A (297 ± 37 dyne x s/cm⁵) groups (p = 0.1720). There was no significant difference between groups in macroscopic appearance.

Conclusions: All the lungs showed excellent blood gases after EVLP, and they all meet the criteria's for clinical lung transplantation. The use of alteplase did not seem to have any obvious benefit to the donor lungs in a DCD situation. The donor lungs treated with alteplas showed slightly better blood gases and slightly lower PVR compared to the group without alteplas, however the difference was not significant. DCD appears to be a safe and effective method to expand the donor pool.

Keywords: DCD; EVLP; Lung transplantation; Pulmonary graft.

Fig. 1

The figure shows a timeline of the experimental setup for the different groups: donation after circulatory death without alteplas (DCD) and with alteplase (DCD-A). The time for each procedural step is given as mean and SEM. In the DCD-A group the lungs were perfused with Perfadex with the addition of alteplase. Ex Vivo Lung Perfusion is mentioned as EVLP in the timeline.

Fig. 2

The mean pulmonary artery flow (PAF) (±SEM) after Ex Vivo Lung Perfusion (EVLP) is illustrated for the three different groups: donation after circulatory death without alteplas (DCD) and with alteplase (DCD-A) at different fractions of inspired oxygen (FiO₂). Statistical analysis was performed using Mann-Whitney test. Significance was defined as p < 0.05 (*), p < 0.01 (**), p < 0.001 (***) and p > 0.05 (n.s.).

Fig. 3

The mean pulmonary artery pressure (PAP) (±SEM) after Ex Vivo Lung Perfusion (EVLP) is illustrated for the different groups: donation after circulatory death without alteplas (DCD) and with alteplase (DCD-A) at different fractions of inspired oxygen (FiO₂). Statistical analysis was performed using Mann-Whitney. Significance was defined as p < 0.05 (*), p < 0.01 (**), p < 0.001 (***) and p > 0.05 (n.s.).

Fig. 4

The mean pulmonary vascular resistance (PVR) (±SEM) after Ex Vivo Lung Perfusion (EVLP) is illustrated for the different groups: donation after circulatory death without alteplas (DCD) and with alteplase (DCD-A) at different fractions of inspired oxygen (FiO₂). Statistical analysis was performed using Mann-Whitney test. Significance was defined as p < 0.05 (*), p < 0.01 (**), p < 0.001 (***) and p > 0.05 (n.s.).