Subnormothermic Ex Vivo Lung Perfusion Temperature Improves Graft Preservation in Lung Transplantation

Abstract

Normothermic machine perfusion is clinically used to assess the quality of marginal donor lungs. Although subnormothermic temperatures have proven beneficial for other solid organ transplants, subnormothermia-related benefits of ex vivo lung perfusion (EVLP) still need to be investigated. Material and Methods: In a rat model, we evaluated the effects of 28 °C temperature on 4-h EVLPs with subsequent left lung transplantation. The recipients were observed for 2 h postoperatively. Lung physiology data were recorded and metabolic parameters were assessed. Results: During the 4-h subnormothermic EVLP, the lung oxygenation was significantly higher (p < 0.001), pulmonary vascular resistance (PVR) lower and dynamic compliance (Cdyn) higher when compared to the 37 °C EVLP. During an end-of-EVLP stress test, we recorded significantly higher flow (p < 0.05), lower PVR (p < 0.05) and higher Cdyn (p < 0.01) in the 28 °C group when compared to the 37 °C group. After the left lung transplantation, Cdyn and oxygenation improved in the 28 °C group, which were comparable to the 37 °C group. Chemokines RANTES, MIP-3α, MIP-1α MCP-1 GRO/KC and pro-inflammatory mediators GM-CSF, G-CSF and TNFα were significantly lower after the 28 °C EVLP and remained low in the plasma of the recipient rats after transplantation. The lungs of the 28 °C group showed significantly lowered myeloperoxidase activity and lowered levels of TNFα and IL-1β. Conclusions: Compared to the normothermic perfusion, the 28 °C EVLP improved Cdyn and PVR and reduced both the release of pro-inflammatory cytokines and myeloperoxidase activity in lung tissue. These observations were also observed after the left lung transplantation in the subnormothermic group. The 28 °C EVLP significantly improved biochemical, physiological and inflammatory parameters in lung donors.

Temperature-Related Effects of Myocardial Protection Strategies in Swine Hearts after Prolonged Warm Ischemia

“…To make DCD transplantation a routine approach, considering the inevitable prolonged no-touch period before the organ can be procured, it is necessary to develop new organ reconditioning strategies to restore organ function immediately after collection. As a matter of fact, extracorporeal reperfusion of explanted organs is already a clinical reality, although it represents a potential source of damage itself (IRI) [2,30], especially in hearts, as it initiates a complex cascade of events that generates a sudden increase in free radicals and tissue inflammatory response [31]. Therefore, an ex-vivo reconditioning strategy, capable of protecting the heart harvested after DCD, and limiting its exposure to ischemic damage and IRI, could lead to a higher availability of organs suitable for transplantation.…”

Subnormothermic ex vivo lung perfusion attenuates ischemia reperfusion injury from donation after circulatory death donors

“…Normothermic perfusion temperature is the current standard for machine perfusion assessment of the lung before transplantation. However, subnormothermic perfusion temperature settings are already in human clinical use among several human solid organs or tested in animals [ 6 – 11 , 14 , 15 ]. In order to evaluate if subnormothermic temperatures might impact the physiological, biochemical and immunological parameters of the lungs, we exposed rat lungs for 2 hours of warm ischemic time at room temperature and then performed subnormothermic machine perfusion for 4 hours at 32°C, 28°C, 24°C and 21°C with a dedicated rat EVLP platform.…”

“…Recently, Gloria et al presented evidences after a 2-hour reperfusion time in transplanted recipient rats, that lung grafts treated pre-transplantation without EVLP but exposed to a 4-hour cold ischemic time have a worst outcome than their three experimental groups of undamaged lungs pretreated before transplantation with EVLP temperature set at either 25°C, 30°C or 37°C [ 14 ]. We recently published a study [ 15 ] where all the rat HBD lungs were pre-damaged by exposure to a 1-hour cold ischemic time to mimic as close as possible a clinical situation. In this study, and compared to the control 37°C normothermic EVLP setting, the HBD damaged lungs showed improved physiological parameters and attenuated I/R injuries after both the 28°C subnormothermic for 4-hour EVLP time alone or in a combination of the 28°C subnormothermic for 4-hour EVLP time followed by a 2-hour time with left lung transplantation.…”

“…Decreasing the ex vivo perfusate temperature has been already used in clinical practice in other solid organs such as liver [6][7][8][9][10] and kidney [11] and has been shown to reduce tissue metabolism and effectively protect from ischemiareperfusion (I/R) injury [7,11,12]. Nevertheless, few investigators have studied which perfusion temperature might be useful during EVLP [12][13][14][15].…”

Perfluorocarbon-Based Oxygen Carriers and Subnormothermic Lung Machine Perfusion Decrease Production of Pro-Inflammatory Mediators

“…Recently, Gloria et al [ 43 ] and our group [ 44 , 45 ] presented evidences that rat lung grafts treated either with normothermic EVLP or without EVLP have a worst outcome than lung grafts treated before transplantation with subnormothermic EVLP temperatures. In this article, at 28 °C with or without PFCOC, we recorded a significantly lower amount of a selection of pro-inflammatory mediators (i.e., TNFα, IL-6, IL-7) and of chemokines (MIP-3α, MIP-1α, MCP-1, GRO/KC) in the perfusates.…”