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= Ex Vivo Lung Perfusion = Ex vivo lung perfusion, abbreviated as EVLP, is a form of machine perfusion aimed at sustaining the active aerobic cellular metabolism of donor lungs outside the donor's body prior to lung transplantation. This medical preservation technique typically occurs within a specialised machine called the EVLP dome, engineered to closely mimic the natural circulatory system. During EVLP, the lungs are maintained at normothermia, supplied with either blood-based or acellular perfusate, and ventilated using a protective mechanical ventilator. These components work together to provide essential nutrients and oxygen to the donor lung, supporting metabolic functions and allowing for prolonged preservation up to 12 hours. Moreover, EVLP has proven effective in rendering initially rejected donor lungs suitable for transplantation through reassessment and damage repair, thus widening the donor lung pools. The extended preservation period and the capacity to increase the pool of potential donor lungs have established EVLP as a reliable system for evaluating and managing donor lung viability before transplantation.

Procedure
The EVLP technique is implemented in clinical practice according to specific EVLP protocols. The three primary EVLP protocols utilised are the Toronto protocol, Lund protocol, and Organ Care System protocol.

Toronto Protocol
The Toronto Protocol is currently one of the most widely adopted EVLP protocol, esteemed for its established performance and safety record.

Eligibility Criteria
Both lungs obtained from brain death donors and donors after cardiac death undergo the Toronto protocol if they meet the listed eligibility criteria. Donor lungs exhibiting insufficient oxygenation, as indicated by a PaO2/FiO2 ratio below 300 mmHg, due to factors such as infection or aspiration, are subject to reevaluation and conditioning through EVLP to improve their suitability for transplantation. However, some donor lungs with extreme damages were often excluded from assessment across various clinical studies.

The current eligibility criteria for the selection of donor lungs include:


 * Best PaO2/FiO2 is less than 300 mmHg.
 * Signs of pulmonary oedema either on chest X-ray or physical examination at the donor site.
 * Poor lung compliance during examination at procurement operation.
 * High-risk history, such as more than 10 units of blood transfusion or questionable history of aspiration.
 * Donation after cardiac death with more than 60 min interval from withdrawal life support to cardiac arrest interval.

Apparatus
It is a low flow strategy that targets to reach 40% of the expected cardiac output to reduce the likelihood of oedema formation. To avoid haemolysis, the Toronto Protocol opts for the use of an acellular Steen solution rather than the blood-based Steen solution. Extracorporeal membrane oxygenation (ECMO) machine is frequently used as a protective ventilator, and centrifugal pumps are used to pump the perfusates.

Procedures
First, cannulas are inserted into the pulmonary artery and left atrium, followed by intubation of the trachea or main bronchus. The EVLP circuit is then primed with a solution containing methylprednisolone, heparin, and antibiotics. Next, the lung is connected to the EVLP circuit and ventilator. Perfusion is initiated at a low flow rate, gradually increasing to the target flow of 40%. Meanwhile, the perfusate temperature is raised to body temperature. Ventilation begins once the perfusate reaches normothermia, with some adjustments made to ensure adequate circulation and ventilation. Throughout the process, the lung's condition is closely monitored to optimise its function for transplantation.

Lund Protocol
The Lund protocol, or the Vivoline LS1 system, was first high-functioning EVLP protocol introduced by Stig Steen from the University Hospital in Lund in 2000.

Eligibility Criteria
Out of the donor lungs that do not meet the requirements for lung donor, the exclusion criteria are applied. The exclusion criteria of the Lund protocol are the presence of any severe lung damages, malignant cells except brain tumours, and signs of hepatitis and HIV.

Apparatus
The Lund protocol utilises a roller pump, blood-based perfusate, and an ECMO ventilator. Red blood cells account for 14% of the Steen perfusate–that is, haematocrit level is kept at 14%. The Lund protocol achieves a target flow, which is 100% of the cardiac output. This level of flow closely mimics the post-reperfusion conditions encountered by transplanted lungs.

Procedures
In the Lund protocol, the main procedures involve reconditioning and assessment. During the reconditioning phase, various measures are taken to improve lung function. This includes recruiting atelectasis, controlling inflammation using a leukocyte filter, and circulating antimicrobials and glucocorticoids during perfusion, which typically lasts for 1 to 2 hours. After the reconditioning phase, the lungs undergo assessment to ascertain their suitability for transplantation. If the lungs meet the necessary standards, they proceed to preparation for transplant. However, if the reconditioning results are unsatisfactory, perfusion continues to provide the lungs with additional time for recovery. Should inadequate reconditioning persist, the donor lung is considered unsuitable for transplantation and is subsequently discarded.

The Organ Care System Protocol
The Organ Care System (OCS) protocol is the first portable EVLP system designed to assess the donor lung functionality during the transportation of donated organs.

Apparatus
Throughout the OCS protocol, the left atrium remains open, a characteristic shared with the Lund protocol. Both protocols employ a blood-based perfusate, although the OCS solution maintains a higher haematocrit, ranging from 15-25%. Bellows pump is used for ventilation, and pulsatile pump is used for perfusion. The target flow of the OCS protocol ranges from 2 to 2.5 litres per minute.

Significance
In both the Toronto and Lund systems, the donor lung is subject to low temperature cryopreservation from the point of harvest until it is linked to the EVLP circuit upon arrival at the recipient's hospital. This cryopreservation period adds to the cold ischemia time, which, if prolonged, can lead to substantial lung injury in the recipient, potentially resulting in transplant rejection. OCS protocol offers a solution to this issue by minimising cold ischemia time, as the OCS lungs are kept at 37˚C throughout the ex vivo ventilation and perfusion process.

Outcomes
On one hand, study findings indicate that lungs preserved with the OCS protocol demonstrate short-term outcomes similar to those preserved using standard cold storage techniques. However, the study also suggests that long-term mortality rates might be notably lower among recipients who receive lungs preserved with the OCS protocol compared to those preserved via standard cold storage methods. It is noted by researchers that further investigation into the outcomes associated with the OCS protocol is needed.

Advantages
The utilisation of EVLP may offer several advantages.

Effective Rehabilitation of Marginal Donor Lungs
EVLP serves as a valuable tool for rehabilitating marginal donor lungs. By providing a platform for their assessment and potential optimisation before transplantation, EVLP enhances post-transplant outcomes and improves the overall success rate of lung transplants.

Increasing the Donor Lung Pool
By enabling the evaluation and utilisation of donor lungs that have previously been deemed unsuitable for transplantation, EVLP addresses the critical shortage of donor organs and improves accessibility to lung transplantation for patients in need.

Targeting Endothelial Protection
EVLP interventions focus on endothelial protection, as demonstrated in various studies. Incorporating heparanase inhibitors, sphingosine-1-phosphate, and endothelin receptor antagonists into the EVLP perfusate enhances organ preservation, improves lung graft quality, and prevents physiological deterioration. These interventions optimise lung performance and contribute to successful transplant outcomes.

Risks and Complications
EVLP also introduces challenges such as inflammatory responses and metabolic alterations that necessitate further investigation and optimisation for improved transplant outcomes.

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Inflammatory Responses  ====== Addressing lung oedema post-EVLP or lung transplantation presents a challenge for transplant surgeons and perfusionists, as EVLP may trigger an inflammatory reaction similar to ischemia-induced injuries. Additionally, exposure to EVLP apparatuses (e.g., ventilator, pumps) can create an adverse pro-inflammatory milieu for the lungs. While EVLP restores ventilation, circulation, and normothermia to donor lungs, the environment remains non-physiological due to the lack of hepatic or renal clearance mechanisms and interaction with recipient blood cells or proteins, potentially inducing inflammatory responses in the recipient.

Induction of Metabolic Changes
The introduction of EVLP may induce metabolic changes in donor lungs, prompting further investigation to facilitate the restoration of lung homeostasis. During EVLP, donor lungs were found to exhibit unfavourable glucose consumption as a result of glycolysis, which correlated strongly with the development of lung oedema. This emphasises the importance of continuously supplementing fresh perfusate during the EVLP procedure to counteract glucose depletion and its related complications, potentially adding to the substantial costs associated with EVLP.