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Applications of Out of Body Lung Perfusion

Posted Feb 28, 2019 Updated Apr 10, 2023
By Bing Zhu MD , Yoshikazu Suzuki MD , Thomas DiSanto BA , Samantha Rubin BS , Zachary Penfil BA , Ralph A. Pietrofesa MS , Shampa Chatterjee PhD , Melpo Christofidou-Solomidou PhD , Edward Cantu MD MSCE
9 min read

Rationale and Objectives

Out of body organ perfusion is a concept that has been around for a long time. As technology has evolved, so have the systems available for out of body perfusion making whole organ preservation for extended evaluation, resuscitation, and discovery routine.

Materials and Methods

Clinical use of ex vivo lung perfusion (EVLP) systems has continued to expand as evidence has accumulated to suggest EVLP transplants experience similar mortality, ICU length of stay, length of mechanical ventilation, hospital length of stay, and rates of primary graft dysfunction as conventional lung transplants. In 2017, more lung transplants were performed than any previous year in the US history.

Results

Early success of EVLP has motivated groups to evaluate additional donor types and methods for expanding the donor pool. The ability to keep a lung alive in a physiologically neutral environment opens the ability to better understand organ quality, define pathophysiology in certain disease conditions, and provides a platform for interventions to prevent or repair injury.

Conclusion

The next several years will usher in significant changes in understanding and interventions focused on lung injury. This manuscript highlights applications of EVLP to clarify how this system can be used for basic and translational research.

Introduction

Lung transplantation is an effective therapy for patients with end-stage lung disease. However, a major challenge facing this therapeutic option is the limited availability of suitable organs for transplantation ( ). As a consequence of this limitation, strategies have been employed to increase the number of lung transplants by expanding the donor pool through improved donor management strategies, use of extended criteria donors and ex vivo lung perfusion (EVLP) technologies ( ). As experience in lung transplantation with EVLP has continued to expand, further interest in use of this technology for use in other contexts has become increasingly common. Our group has utilized this technology to create a high-fidelity human lung model for basic and translational work in drug discovery pipelines, toxicant research, and molecular characterization of acute lung injury. For the purposes of this manuscript, we will describe the closed atrium acellular method of EVLP to highlight clinical and research applications of out-of-body perfusion. Our intent is to provide a basic understanding of out of body perfusion in order to facilitate basic and translational research efforts that capitalize from clinical experience and expand the multidisciplinary potential of this technology.

History of out of body lung perfusion

The first experimental lung transplant was performed by Vladamir Demikhov in 1947. Almost 20 years passed before the first human technical success was reported by James Hardy and almost 40 years before the first clinical success reported by Joel Cooper in 1983. Significant progress had been made in lung transplant, but there are still too few organs for transplant. This reinvigorated interest in out of body perfusion techniques proposed by Lindbergh and Carrel in the 1930s ( ). The concept of out of body whole organ perfusion for organ evaluation had been previously described by the French physiologist Le Gallois in 1812 but was not successfully realized until Lindbergh and Carrel in 1935. Their success was in part due to surgical innovation to allow for organ procurement without organ damage, improved aseptic techniques and the development of an apparatus that could be sterilized and perfuse an organ indefinitely ( ). Though successful, this technique for whole organ perfusion was not used clinically and remained a relatively infrequently used research technique. With increasing numbers of patients waiting for transplant and limited numbers of suitable donor available for transplant, efforts were made to identify new methods for expanding the donor pool. A promising solution for this organ shortage was to use organs from nonbrain dead donors whom had elected to have a natural death and donate their organs to help other patients in need. Donation after cardiac death donors present unique challenges since the assessment of such donors can be significantly limited. To overcome these limitations, Stig Steen, used a low potassium dextran augmented blood-based perfusate and a modified perfusions system to successfully perfuse and transplant the first patient to use this technology in 2000 ( Fig 1 ) ( ). This report encouraged other groups to investigate similar methods but with slight modifications to the specific procedures. These innovations led to the current era of EVLP for use for evaluation, preservation, and rehabilitation of organs for transplant. The conceptual framework of EVLP in most cases is to allow for risk assessment for extended criteria organs. This is important because improper organ selection can increase the risk of primary graft dysfunction (PGD) which is the most common cause of death in the first 90 days and impacts short, long and functional outcomes after transplant( ). For this reason, safe donor pool expansion through use of EVLP has stimulated significant enthusiasm and innovation in clinical lung transplantation.

Figure 1, Timeline of events in lung transplantation leading to out of body organ perfusion. Images of Charles Lindbergh and Alexis Carrel courtesy of Wikipedia. Images of James Hardy and the Lindbergh and Carrel perfusion pump courtesy of Pinterest. Image of Joel Cooper courtesy of the University of Pennsylvania. Images of Stig Steen and his ex vivo perfusion chamber courtesy of Stig Steen.

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Technical Aspects of EVLP

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Figure 2, Standard cannulation for EVLP. Funnel shaped cannulas are sutured to the left atrium and pulmonary artery using a monofilament polypropylene suture. Care is taken to avoid inadvertent obstruction of the pulmonary artery or veins by placing cannulas on tension as illustrated. An endotracheal tube is secured using umbilical tapes.

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Figure 3, Circuit diagram of EVLP. Blue depicts deoxygenated and red oxygenated perfusate. Starting from the left atrium, oxygenated perfusate is returned to the hard-shell reservoir then pumped through an oxygenator and leukocyte filter before reentering the pulmonary artery. In this set up, the oxygenator deoxygenates the perfusate to facilitate evaluation of lung oxygenation potential. The ventilator maintains respiration and controls the concentration of oxygen delivery. Typically, the lungs are ventilated with room air (21% oxygen) and only delivered 100% when an oxygen challenge is performed to gauge maximal potential of the organ to oxygenate the perfusate.

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Organ Assessment

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Clinical Results

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Figure 4, Conceptual framework of EVLP. Images at the top of the figure demonstrate the variation in organ injury from minimal on the far left to severe at the far right. The goal of EVLP is to make more organs available for transplant by extending the evaluation of less ideal organs and demonstrating adequate function for transplantation (arrow depicts the level of risk being shifted to the right by EVLP). The means of determining adequate function for transplantation is demonstrated in the bottom table.

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Applications for research

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Figure 5, Potential experimental EVLP configurations. There are multiple EVLP configurations possible that can be individualized to the questions to be addressed. With respect to a lung block, a left and right lung from the same donor, there are four potential configurations: (a) independently perfused and ventilated lungs; (b) commonly perfused and ventilated lungs; (c) commonly ventilated but independently perfused lungs; and (d) independently ventilated but commonly perfused lungs. Note: in single perfusion systems perfusate leaves the left atrium and returns via the main pulmonary artery while in independently perfused systems perfusate leaves the pulmonary vein confluence and returns via the branch pulmonary artery.

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Experimental Design 1: Understanding Kinetics of Agent Delivery Method

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Figure 6, Kinetics of LGM2605 delivered by aerosol. LGM2605 concentrations from perfusate, BAL fluid and tissue biopsies are depicted serially over time in a common perfusate independent ventilation configuration. Aerosolized LGM2605 delivered to the left lung (blue line) quickly traverses the epithelial and endothelial membranes to be found in the circulating perfusate (black line). BAL fluid from the left lung demonstrates persistence of LGM2605 in the airway up to six hours (gray line). Off target delivery is seen in the right lung tissue (red line) with delayed kinetics.

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Figure 7, Transcriptomic response of lung tissue to LGM2605. Effects of LGM2605 (blue line) were compared to vehicle (red line) in a common perfusate independent ventilation configuration. Decreased proinflammatory gene expression was demonstrated in IL-1β (a); IL-6 (b); and COX-2 (c) transcripts as early as 30 minutes after delivery of LGM2605 in the treated lung and subsequently in the bystander lung after a short delay. Levels of target gene mRNA are reported as the mean fold change from baseline (time zero). Statistically significant differences were determined by two-way analysis of variance (ANOVA) followed by Tukey's multiple comparisons tests (vehicle versus LGM2605) using GraphPad Prism version 6.00 for Windows, GraphPad Software, La Jolla, California, www.graphpad.com . Results are reported as the mean ± the standard error of the mean (SEM). Asterisks shown in figures indicate statistically significant differences between vehicle and LGM2605 (* = p < 0.05, ** = p < 0.01, *** = p < 0.001 and **** = p < 0.0001).

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Experimental Design 2: Defining Efficacy for an Inhalational Agent

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Figure 8, Physiologic response to aerosolized LGM2605. (a) Partial pressure of arterial oxygen to the fractional inspired oxygen ratio (P/F) and (b) static compliance are graphed in the treated lung. The arrows highlight the effect of an oxygen challenge with 100% oxygen. The red blocks demonstrate the delivery interval of aerosolized LGM2605. Dotted lines highlight trends in oxygenation and compliance. Note: when the oxygenation and compliance deterioratethey do not later improve.

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Future

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Figure 9, Real-time confocal microscopy of ex vivo lungs for reactive oxygen species (ROS) during reperfusion. The ROS sensitive dye dihydrodifluorofluorescein (H2DFFDA, 10 μM) (Invitrogen, Molecular Probes, Oregon) was added to the perfusate for five to ten minutes prior to reperfusion. Images were acquired using a 10× lens on a Zeiss LSM 510 microscope. (a) Standard cannulation for continuous perfusion. (b) Stage preparation on the movable stage of Zeiss LSM 510 microscope for image acquisition. (c) Real-time imaging of ROS as detected by the green fluorescence of the oxidized H2DFFDAreactive oxygen species (d) A magnification of the box in c. (e). Polymorphonuclear Neutrophils (PMN) were labeled with red dye (CellTracker Red CMTPX, ThermoFisher Scientific, Waltham, Massachusetts) and injected into the perfusate. After reperfusion, the lungs were washed and the PMN as detected by red fluorescence were observed sticking to the alveolar (Alv) and perivascular regions of the lungs.

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Acknowledgments

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Academic Radiology, Volume 26, Issue 3
Journals General Radiology
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