Effects of immediate versus delayed ex-vivo lung perfusion in a porcine cardiac arrest donation model

Objective:Ex-vivo lung perfusion is a promising tool to evaluate and recondition marginal donor lungs usually after a cold static preservation. The concept of continuous organ perfusion is supposed to reduce ischemic damage; however, the optimal perfusion protocol has not been established yet. The aim of this study was to compare immediate ex-vivo lung perfusion (I-EVLP) to delayed ex-vivo lung perfusion (D-EVLP) after a certain cold static preservation period on lung function in a large animal model.Methods:In a porcine model, lungs were procured after circulatory death and 60 min of no-touch warm ischemia. Lungs were preserved with single-flush cold low potassium dextran solution and prepared either for I-EVLP (n = 8) or stored cold for 9 h with subsequent D-EVLP (n = 8). Functional outcomes and morphology were compared during 4 h of ex-vivo lung perfusion, using STEEN SolutionTMas perfusion solution.Results:Pulmonary functional data, perfusate activities of lactate dehydrogenase, alkaline phosphatase, and products of lipid peroxidation did not differ significantly. There was a trend toward lower wet–dry ratio (I-EVLP: 13.4 ± 2.9; D-EVLP: 9.1 ± 2.5) and higher ΔpO2in D-EVLP group (I-EVLP: 209 ± 51.6 mmHg; D-EVLP: 236.3 ± 47.3 mmHg).Conclusion:In this donation-after-circulatory-death model, 9 h of cold static preservation followed by ex-vivo lung perfusion results in comparable pulmonary function to I-EVLP as indicated by oxygenation capacities and wet–dry ratio. Our findings indicate that prolonged cold static preservation prior to ex-vivo lung perfusion is as safe and effective as I-EVLP in the procurement of donor lungs.

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Cellular and acellular ex vivo lung perfusion preserve functional lung ultrastructure in a large animal model: a stereological study

Respiratory Research ◽

10.1186/s12931-018-0942-5 ◽

2018 ◽

Vol 19 (1) ◽

Cited By ~ 4

Author(s):

Jasmin Steinmeyer ◽

Simon Becker ◽

Murat Avsar ◽

Jawad Salman ◽

Klaus Höffler ◽

...

Keyword(s):

Animal Model ◽

Ex Vivo ◽

Lung Perfusion ◽

Large Animal Model ◽

Large Animal ◽

Ex Vivo Lung Perfusion ◽

Lung Ultrastructure

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Reduced-flow ex vivo lung perfusion to rehabilitate lungs donated after circulatory death

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2019.09.009 ◽

2020 ◽

Vol 39 (1) ◽

pp. 74-82

Author(s):

Jared P. Beller ◽

Matthew R. Byler ◽

Dustin T. Money ◽

William Z. Chancellor ◽

Aimee Zhang ◽

...

Keyword(s):

Ex Vivo ◽

Lung Perfusion ◽

Ex Vivo Lung Perfusion ◽

Circulatory Death ◽

Reduced Flow

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Donation After Circulatory Death Lungs Transplantable Up to Six Hours After Ex Vivo Lung Perfusion

The Annals of Thoracic Surgery ◽

10.1016/j.athoracsur.2016.06.043 ◽

2016 ◽

Vol 102 (6) ◽

pp. 1845-1853 ◽

Cited By ~ 18

Author(s):

Eric J. Charles ◽

Mary E. Huerter ◽

Cynthia E. Wagner ◽

Ashish K. Sharma ◽

Yunge Zhao ◽

...

Keyword(s):

Ex Vivo ◽

Lung Perfusion ◽

Donation After Circulatory Death ◽

Ex Vivo Lung Perfusion ◽

Circulatory Death

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

PLoS ONE ◽

10.1371/journal.pone.0255155 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0255155

Author(s):

Stephan Arni ◽

Tatsuo Maeyashiki ◽

Isabelle Opitz ◽

Ilhan Inci

Keyword(s):

Lung Tissue ◽

Ex Vivo ◽

Lung Perfusion ◽

Atp Content ◽

Donation After Circulatory Death ◽

Immunological Parameters ◽

Ex Vivo Lung Perfusion ◽

Ischemic Time ◽

Physiological Variables ◽

Circulatory Death

Use of normothermic ex vivo lung perfusion (EVLP) was adopted in clinical practice to assess the quality of marginal donor lungs. Subnormothermic perfusion temperatures are in use among other solid organs to improve biochemical, clinical and immunological parameters. In a rat EVLP model of donation after circulatory death (DCD) lung donors, we tested the effect of four subnormothermic EVLP temperatures that could further improve organ preservation. Warm ischemic time was of 2 hours. EVLP time was of 4 hours. Lung physiological data were recorded and metabolic parameters were assessed. Lung oxygenation at 21°C and 24°C were significantly improved whereas pulmonary vascular resistance and edema formation at 21°C EVLP were significantly worsened when compared to 37°C EVLP. The perfusate concentrations of potassium ions and lactate exiting the lungs with 28°C EVLP were significantly lower whereas sodium and chlorine ions with 32°C EVLP were significantly higher when compared to 37°C EVLP. Also compared to 37°C EVLP, the pro-inflammatory chemokines MIP2, MIP-1α, GRO-α, the cytokine IL-6 were significantly lower with 21°C, 24°C and 28°C EVLP, the IL-18 was significantly lower but only with 21°C EVLP and IL-1β was significantly lower at 21°C and 24°C EVLP. Compared to the 37°C EVLP, the lung tissue ATP content after 21°C, 24°C and 28°C EVLP were significantly higher, the carbonylated protein content after 28°C EVLP was significantly lower and we measured significantly higher myeloperoxidase activities in lung tissues with 21°C, 24°C and 32°C. The 28°C EVLP demonstrated acceptable physiological variables, significantly higher lung tissue ATP content and decreased tissue carbonylated proteins with reduced release of pro-inflammatory cytokines. In conclusion, the 28°C EVLP is a non inferior setting in comparison to the clinically approved 37°C EVLP and significantly improve biochemical, clinical and immunological parameters and may reduce I/R injuries of DCD lung donors.

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A method for translational rat ex vivo lung perfusion experimentation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00256.2019 ◽

2020 ◽

Vol 319 (1) ◽

pp. L61-L70

Author(s):

Akihiro Ohsumi ◽

Takashi Kanou ◽

Aadil Ali ◽

Zehong Guan ◽

David M. Hwang ◽

...

Keyword(s):

Lung Function ◽

Ex Vivo ◽

Left Lung ◽

Lung Compliance ◽

Lung Perfusion ◽

Arterial Oxygen ◽

Large Animal ◽

Ex Vivo Lung Perfusion ◽

Ischemic Time ◽

Cold Ischemic Time

The application of ex vivo lung perfusion (EVLP) has significantly increased the successful clinical use of marginal donor lungs. While large animal EVLP models exist to test new strategies to improve organ repair, there is currently no rat EVLP model capable of maintaining long-term lung viability. Here, we describe a new rat EVLP model that addresses this need, while enabling the study of lung injury due to cold ischemic time (CIT). The technique involves perfusing and ventilating male Lewis rat donor lungs for 4 h before transplanting the left lung into a recipient rat and then evaluating lung function 2 h after reperfusion. To test injury within this model, lungs were divided into groups and exposed to different CITs (i.e., 20 min, 6 h, 12 h, 18 h and 24 h). Experiments involving the 24-h-CIT group were prematurely terminated due to the development of severe edema. For the other groups, no differences in the ratio of arterial oxygen partial pressure to fractional inspired oxygen ([Formula: see text]/[Formula: see text]) were observed during EVLP; however, lung compliance decreased over time in the 18-h group ( P = 0.012) and the [Formula: see text]/[Formula: see text] of the blood from the left pulmonary vein 2 h after transplantation was lower compared with 20-min-CIT group ( P = 0.0062). This new model maintained stable lung function during 4-h EVLP and after transplantation when exposed to up to 12 h of CIT.

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Nicotinamide Adenine Dinucleotide (NAD+) improves lung function in rat lung ex-vivo lung perfusion model

British Journal of Surgery ◽

10.1093/bjs/znab202.079 ◽

2021 ◽

Vol 108 (Supplement_4) ◽

Author(s):

J P Ehrsam ◽

S Arni ◽

J Chen ◽

H Rodriguez Cetina Biefer ◽

I Opitz ◽

...

Keyword(s):

Lung Function ◽

Ex Vivo ◽

Lung Perfusion ◽

Male Rats ◽

Interleukin 12 ◽

Large Animal ◽

Ex Vivo Lung Perfusion ◽

Long Term Outcome ◽

Anti Inflammatory ◽

The Impact

Abstract Objective Ischemia-reperfusion injury compromises short- and long-term outcome after lung transplantation. The scarce existing data on the natural co-enzyme NAD+ suggest an antagonistic effect on hypoxia induced vasoconstriction, removal capacity on reactive oxygen species, and anti-inflammatory effects. We therefore investigated the impact of NAD+ on ischemic rat lungs during ex-vivo lung perfusion (EVLP). Methods Lungs were retrieved from 12 outbred Sprague Dawley male rats and exposed to 14 hours of cold ischemic storage. All lungs were then perfused in a rat EVLP system for 4 hours. Lung grafts were injected after 1, 2 and 3 hours with 2000 uM NAD + (N = 6) or placebo (N = 6) in the perfusate in proximity of the pulmonary artery. EVLP physiology and biochemistry were monitored. Results During the 4 hours of EVLP, the lung function increased significantly in the NAD+ group when compared to the placebo group. We monitored a higher vascular flow (p = 0.018), a lower mean pulmonary pressure (p = 0.007) and increased oxygenation capacity (p = 0.003). Lung compliance and weight were comparable. Tissue inflammation measured by myeloperoxidase was significantly lower in the NAD+ group (p = 0.015). In the perfusate, we observed in the NAD+ group significantly lower levels of pro-inflammatory interleukin-18 (p = 0.033) and a trend towards high levels of anti-inflammatory interleukin-10 (p = 0.080) and low levels of pro-inflammatory interleukin-12 (p = 0.146). Conclusion Findings from this preliminary study demonstrated that NAD+ is a promising agent with both anti-inflammatory properties and the ability to improve ischemic lung function. This observation should be validated in a large animal model.

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