The impact and relevance of techniques and fluids on lung injury in machine perfusion of lungs

Abstract

Primary graft dysfunction (PGD) is a common complication after lung transplantation. A plethora of contributing factors are known and assessment of donor lung function prior to organ retrieval is mandatory for determination of lung quality. Specialized centers increasingly perform ex vivo lung perfusion (EVLP) to further assess lung functionality and improve and extend lung preservation with the aim to increase lung utilization. EVLP can be performed following different protocols. The impact of the individual EVLP parameters on PGD development, organ function and postoperative outcome remains to be fully investigated. The variables relate to the engineering and function of the respective perfusion devices, such as the type of pump used, functional, like ventilation modes or physiological (e.g. perfusion solutions). This review reflects on the individual technical and fluid components relevant to EVLP and their respective impact on inflammatory response and outcome. We discuss key components of EVLP protocols and options for further improvement of EVLP in regard to PGD. This review offers an overview of available options for centers establishing an EVLP program and for researchers looking for ways to adapt existing protocols.

Keywords: EVLP; PGD; ex vivo; organ perfusion; techniques; transplantation.

Figure 1

Overview of EVLP and PGD connections. EVLP, ex vivo lung perfusion, PGD, primary graft dysfunction.

Figure 2

Visualization of the extrinsic and intrinsic apoptosis pathway. APAF1, apoptotic peptidase activating factor 1; BAK, BCL2 antagonist/killer 1; BAX, BCL2 associated X; BCL-2, BCL2 apoptosis regulator; BCL-XL, B-cell lymphoma-extra large (encoded by the BCL2 like 1 gene); BH3, BCL2 homology region 3; BID, BH3 interacting domain death antagonist; FADD, Fas associated via death domain; FAS receptor, Fas cell surface death receptor; MCL 1, MCL1 apoptosis regulator; ROS, reactive oxygen species; SMAC, second mitochondria-derived activator of caspase; tBID, truncated BID; XIAP, X-linked inhibitor of apoptosis.

Figure 3

Visualization of ischemia reperfusion injury. NK-Cell, Natural Killer Cell.

Figure 4

Basic EVLP setup.

Figure 5

Ferroptosis Signaling Pathway. Cys, cysteine; DMT1, divalent metal transporter 1; FE, iron; GCL, glutamate-cysteine ligase; Gln, glutamine; GLS, glutaminase; Glu, glutamate; Gly, glycine; GPX4, glutathione peroxidase 4; GSH, glutathione; GSS, glutathione synthetase; PUFA, polyunsaturated fatty acid; SLC1A5, solute carrier family 1 member 5; STEAP3, six-transmembrane epithelial antigen of prostate.

Figure 6

Visualization of atelectrauma through repeated recruitment and derecruitement of functional lung airway units.

Figure 7

Aspects of the influence of ventilation during EVLP on the lungs. EVLP, ex vivo lung perfusion; FCV, flow-controlled ventilation; FiO2, fraction of inspired oxygen; ICU, intensive care unit; IL-6, interleukin 6; IL-8, interleukin 8; NPV, negative pressure ventilation; PEEP, positive end expiratory pressure; TNF-α, tumor necrosis factor-α; ROS, reactive oxygen species.