Ex Vivo Lung Perfusion: A Review of Research and Clinical Practices

Abstract

End-stage lung disease is ultimately treated with lung transplantation. However, there is a paucity of organs with an increasing number of patients being diagnosed with end-stage lung disease. Ex vivo lung perfusion has emerged as a potential tool to assess the quality and to recondition marginal donor lungs prior to transplantation with the goal of increasing the donor pool. This technology has shown promise with similar results compared with the conventional technique of cold static preservation in terms of primary graft dysfunction and overall outcomes. This review provides an update on the results and uses of this technology. The review will also summarize clinical studies and techniques in reconditioning and assessing lungs on ex vivo lung perfusion. Last, we discuss how this technology can be applied to fields outside of transplantation such as thoracic oncology and bioengineering.

Keywords

thoracic surgery cardiac anesthesia cardiopulmonary bypass intraoperative assessment noncardiac surgery outcome perioperative system reperfusion injury research therapeutic impact

Introduction

Lung transplantation is the curative treatment for patients who have end-stage lung disease. Over the years, the advances in lung transplantation have allowed it to be applied to a greater number of etiologies.^1,2 In 1983, the very first successful lung transplant with long-term survival was done at the University of Toronto by Dr Joel Cooper in a patient with pulmonary fibrosis after many years of surgical and medical optimization.³ Today, the operation is applied to a multitude of etiologies that include cystic fibrosis and scleroderma.^1,2

Unlike other solid organs such as kidney and liver, only 15% to 25% of lungs from donors are transplanted.⁴ These low percentages are a testament to the delicacy of lungs, as they are quite frequently unsuitable for transplantation due to thoracic trauma, aspiration, barotrauma, pneumonia, neurogenic pulmonary edema, and other issues.⁵ As a result, transplantable lungs are hard to come by. However, multiple studies have shown that the use of marginal lungs may not impair results compared with standard donors.^6,7

Because of the paucity of available lungs and the growing number of patients developing end-stage lung disease, multiple methods have been used to attempt to expand the donor pool such as extended criteria donors, donation after cardiac death (DCD), and lobar transplantation. However, the recent advancement of ex vivo lung perfusion (EVLP) has arguably the greatest impact on revolutionizing the evaluation of donor lungs and expanding the number of lungs suitable for transplantation. When lungs are deemed unusable or marginal, EVLP allows for lungs to be ventilated, oxygenated, and perfused for the surgical team to have a more careful assessment of lung function. It also allows for the possibility of recovery of lung function once explanted from the donor. The US Food and Drug Administration (FDA) approved EVLP using the XVIVO Perfusion System (XPS) in April 2019 and the TransMedics Organ Care System (OCS) in March 2018.

This review aims to summarize current knowledge about EVLP techniques, protocols, and available devices for EVLP along with the rationale behind the method. We will also discuss potential areas of uncertainty. We will review the current clinical experience conducted worldwide with EVLP, ongoing trials, and future research directions.

Evolution of EVLP

Today, organ preservation centers on reducing metabolic demands by cooling topically with ice and the use of intravascular perfusates. Initially, the concept of organ preservation started with ex vivo perfusion in the 1930s when Alexis Carrel and Charles Lindbergh showed they could perfuse several organs such as the heart, kidney, thyroid, ovaries, adrenals, and spleen.⁸ EVLP was then proposed in 1987 by Hardesty and Griffith. They were able to provide pulmonary and coronary blood flow to extend the preservation times for hearts and lungs. Though there were some successes, the results showed that the technology was still several years away.⁹

In the 1990s, Steen and colleagues provided some hope for EVLP by devising an apparatus that can assess the lungs after explanting from the donor. The apparatus and solution they used allowed for the measurement of end-tidal carbon dioxide concentration, blood gases, pulmonary vascular resistance, and ventilation-perfusion assessment. Eventually, this led to the first successful EVLP lung transplantation by Steen and colleagues in 2001 in which lungs from a 54-year-old male were assessed using EVLP for prior to right single-lung implantation into a 54-year-old woman with chronic obstructive pulmonary disease.¹⁰

In EVLP, there are a multitude of variables that can be controlled for regarding the ventilation and perfusion of the donor lungs. The University of Toronto has made significant efforts to optimize and standardize EVLP using the XPS system. Their technique, which will be discussed later in this review, has served as a foundation for many institutional protocols today for EVLP. Using their technique, Cypel and colleagues showed no significant differences in results using EVLP compared with traditional technique. In their study, 30-day mortality, bronchial complications, duration of mechanical ventilation, and length of stay in the intensive care unit (ICU) and hospital were similar. Interestingly, the incidence of primary graft dysfunction (PGD) 72 hours after transplantation was lower in the EVLP group compared with the control group.¹¹

Rationale for EVLP

The goal of any organ preservation technique is to maintain function of the organ and tissue during storage and transportation prior to implantation and reperfusion. With cold static preservation, cellular metabolism, oxygen, and nutrient demands are reduced to maintain the integrity of the organ. Meanwhile, EVLP is used to maintain the physiology of the cells by creating a cellular milieu that allows pulmonary cells and tissues to remain metabolically active and viable for hours after explant. With either cold static preservation or EVLP, organ ischemia and subsequent reperfusion during implantation cannot be avoided. The resultant ischemic-reperfusion injury increases the risk for PGD, which negatively affects short- and long-term morbidity and mortality after transplantation.^12,13 With a perfused and ventilated warm lung using EVLP, ischemic reperfusion is minimized by maintaining a metabolically active cell prior to implantation.

Furthermore, studies have shown that it can potentially lengthen lung preservation in order for further assessment and reconditioning after procurement, especially organs that were not optimal.¹⁴ This has led to increase in utilization of marginal and high-risk donor organs that would have previously been rejected.^15,16 There have been reports of EVLP salvage of lungs from neurogenic pulmonary edema, large-volume atelectasis, traumatic chests, and donations after cardiac death.^17-20 In the present era, EVLP may be indicated in high-risk donor lungs that meet the criteria in Table 1.²¹

Table 1.

Criteria for Ex Vivo Lung Perfusion.

An oxygenation index (partial pressure of arterial oxygen/fraction of inspired oxygen) <300 mm Hg

Pulmonary edema as present on the latest chest X-ray

Collapse or poor lung inflation during procurement

Blood transfusions >10 units

Lungs harvested from a donation after circulatory death donors

Last, the EVLP circuits can be used as platforms for translational research involving lungs in fields of regenerative medicine, stem cell research, and oncology.²²

Types of Circuits

The first effective EVLP circuit was developed by Steen and colleagues and served as a prototype for subsequent circuits. This circuit contained the following components: leukocyte filter, centrifugal pump, hollow-fiber oxygenator heat exchanger, and hard-shell reservoir. An endotracheal tube is used to control the airway. Cannulas are used to connect to the pulmonary artery and left atrial cuff (Figure 1). Steen perfusate, a low-potassium dextran solution, has a high colloidal pressure that prevents the development of pulmonary edema. This solution is driven by a centrifugal pump from the reservoir and reaches the gas exchanger connected to a heating-cooling unit. Here the fluid attains the partial gas pressure and temperature of normal venous blood through deoxygenation and warming. It also passes through a leukocyte filter into the pulmonary artery and lung tissue. Pulmonary venous effluent is recirculated after draining in to the reservoir. Following a rewarming up to 32°C, the lungs are ventilated, and temperature is gradually increased till normal body temperature is attained. This circuit simulates the physiologic conditions of the respiratory tract for reconditioning of donor lungs, giving clinicians the time to reassess and plan accordingly.^10,23

XVIVO Perfusion System

There are 2 predominantly used EVLP systems used in the North America.

The XPS was recently approved by the FDA in April 2019. This system is used on previously unacceptable donor lungs for assessment for potential transplantation. Lungs are procured using standard cold static preservation. The lungs are then brought back to a regionalized center or the recipient institution to be connected to the XPS much similar to the circuit created by Steen and colleagues.

The XPS contains a sterile chamber for the lung, an oxygenator, a volume reservoir, a heater-cooler system, a centrifugal pump, and monitoring screen (Figure 2). At many institutions, the perfusate used will be the Steen solution with potential additives to the solution, such as heparin, steroids, and antibiotics. The protocol used for the XPS system follow the Toronto EVLP Protocol. The surgeon makes 2 anastomoses at the left atrial cuff and pulmonary artery to cuffs of the XPS system. An endotracheal tube is inserted into the trachea and secured with umbilical tape. The lungs are then perfused with 40% of the cardiac output and gradually warmed with the perfusate to 37°C. As the lungs are warmed to 32°C, ventilation is started with a tidal volume of 5 to 7 mL/kg, respiratory rate of 20 breaths/minute, positive end-expiratory pressure of 5 cm H₂O, and fraction of inhaled O₂ (FiO₂) of 21%. The sweep gas flow is aimed at a partial pressure of CO₂ (PCO₂) of 34 to 38 mm Hg. Most centers will keep the donor lungs perfused in the XPS for 4 to 6 hours. At the conclusion of EVLP, the lungs will be separated from the XPS and similar techniques are used from cold static preservation. The lungs will then be cooled to 10°C, inflated and clamped, and stored in cold preservation prior to transplantation.^24,25

Organ Care System

The OCS is a portable EVLP system used to potentially decrease cold ischemic times (Figure 3). The device consists of a sterile chamber for the lungs, oxygenator, volume reservoir, ventilator, pulsatile pump, and heating system. The device is stored at the recipient hospital and transported to the donor hospital. The procurement of lungs is completed using the cold static preservation technique. Prior to the installation of the lungs into the system, the OCS system is primed with 3 units of packed red blood cells mixed with the OCS solution, which is a low-potassium dextran solution with glucose. Additives such as steroids, antibiotics, and others can also be added to the system. The lungs are then placed in the system. The OCS system perfuses the lungs at 1.5 to 2.5 L/min. The lungs are then gradually warmed to a temperature of 37°C. As the lungs are warmed to 34°C, ventilation is started with a tidal volume of 6 to 7 mL/kg, respiratory rate of 10 breaths/minute, positive end-expiratory pressure of 5 to 7 cm of H₂O, and FiO₂ of 21%. The OCS is then transported back to the recipient hospital, while the lungs are being monitored en route. At the recipient hospital, final assessments are made and once the lungs are deemed acceptable, they are flushed with cold perfusate. Essentially, using the OCS allows for minimal cold ischemic times, ~30 to 40 minutes, for instrumentation of the lungs onto the system and ~5 to 10 minutes after cold perfusate flush to the start of the anastomosis.^24,25 The characteristics of both XVIVO and OCS are outlined in Table 2.

Table 2.

XVIVO and OCS Characteristics.

	XVIVO (Modified Toronto Protocol)	OCS
Type of pump	Centrifugal	Piston
Cardiac output	40%	1.5-2.5 L/min
Left atrial pressure	Open	Open
Pulmonary artery pressure	≤20	≤20
Perfusate	Steen + RBCs	OCS solution + RBCs
Tidal volume (mL/kg)	5 to 7	7
Respiratory rate	20	10
PEEP (cm H₂O)	5	5 to 7
FiO₂	50%	12%
Temperature (°C)
Start	32	32
Perfusing	25	32
Evaluation	37	37

Abbreviations: OCS, organ care system; PEEP, positive end-expiratory pressure; FiO₂, fraction of inhaled O₂.

Current and Future Modes of Assessment of Lungs on EVLP

Once the lungs have reached a steady state on EVLP, assessment begins according to the institutional protocol. At most institutions, the lungs are evaluated on an hourly basis in real-time. The parameters include hemodynamic factors (pulmonary artery pressure, left atrial pressure, pulmonary vascular resistance, pulmonary flow), ventilatory factors (lung compliance, peak airway pressures), gas exchange parameters (PaO₂/FiO₂, PCO₂), biochemical values (lactate, blood gas), and tactile inspection as the lungs can be physically inspected and palpated. Bronchoscopy can be done while the lungs are on EVLP to assess the quality (edema, purulence, etc) and amount of secretions. Lung X-rays are done as well to assess consolidation and progression of edema (Figure 4a and b). Currently, criteria of acceptance after EVLP are included in Table 3.

Table 3.

Acceptance Criteria for Ex Vivo Lung Perfusion (EVLP).

Oxygenation index after 4-6 hours of EVLP of at least 400 mm Hg

Stable lung X-ray—no new infiltrates or resolving infiltrates/consolidation

Stable pulmonary arterial pressures, airway pressures, and lung compliance

There have also been some novel techniques to evaluate EVLP lungs. Ayyat and colleagues have proposed evaluating the extravascular lung water of lungs on EVLP of various zones of the lung using a technique called CLUE (direCt Lung Ultrasound Evaluation). Using the CLUE images, taken from lungs on EVLP for 2 hours, the lungs are scored according to the percentage of B-lines, grading the lungs on the degree of edema. The CLUE score is correlated to the weight of the EVLP lungs, which correlated negatively with PaO₂/FiO₂ ratio.²⁶

Biochemical markers may also be important in the assessment of EVLP lungs. After inducing cardiac death in a swine model and waiting an hour at room temperature, Sanchez and colleagues procured lungs and placed them on EVLP. They were able to show that by-products of lipid peroxidation (4-HNE and TBARS) increased with warm ischemia. The same by-products peaked during cold ischemia but normalized to baseline after 4 hours on EVLP.²⁷ Furthermore, Wipper and colleagues have suggested that myeloperoxidase tissue levels produced by neutrophils, monocytes, and macrophages could be used to help determine lung viability.²⁸ Biomarkers of endothelial activation may also play a role in the assessment of lungs on EVLP. Hashimoto and colleagues showed that soluble intercellular adhesion molecule 1 and soluble VCAM-1 (sVCAM-1) were significantly higher in patients who received EVLP lungs that developed PGD grade 3 within 72 hours after lung transplantation.²⁹ Furthermore, Dromparis et al studied the genetic changes in lungs subjected to EVLP and showed that 28 of 53 acute lung injury-related genes were significantly upregulated after 12 hours of EVLP.³⁰ The utility in clinical practice of using these biochemical markers is still undetermined and further research is active.

Clinical Outcomes

After the first successful EVLP lung implantation completed by Steen and colleagues, their group reported 6 successful transplantations between June 2006 and April 2007 from donor lungs, which were previously assumed unsuitable.¹⁰ Three-month survival was 100%. One patient had died due to sepsis after 95 days, and one due to rejection after 9 months. Four recipients were alive and well without any sign of bronchiolitis obliterans syndrome 24 months after the transplantation.³¹

The University of Toronto group not only identified the potential of EVLP for reassessment of donor’s lungs but also identified therapies such as a low-stress perfusion/ventilation strategy to improve outcomes after transplantation. The HELP trial (Human Ex Vivo Lung Perfusion), the first prospective clinical trial using EVLP, was published in the year 2011. The trial compared 20 sets of donors who underwent EVLP with that of a standard group (n = 116), and the findings did not show significant differences in terms of PGD, hospital stay, days on mechanical ventilation after transplant, ICU stays, and 30-day mortality.¹¹

In 2009, another group from London transplanted one donor lung after EVLP as per the Toronto protocol.³² This was followed by transplantation of 6 pairs of lungs with a 46% success rate in 2012.³³ Aigner et al, from Vienna, in 2012, transplanted 9 donor lungs out of 13 that displayed improved parameters after EVLP. No recipient had PGD within the first 3 days. No mortality occurred in 30 days posttransplantation period, and the majority (78%) of recipients survived the first year of transplantation.¹⁹ In 2012, 8 double-lung and 3 single-lung transplants totaling 11 EVLPs were performed at Goteborg University. Three-month survival rate was at 100% in EVLP cases as compared with 94% in standard transplantation. However, ventilation and ICU stay were longer in EVLP patients.³⁴ In their mid-term follow-up they reported PGD grade >1 was present in 14% in the EVLP group and in 12% in the non-EVLP group at 72 hours after transplant. Survival at 1 year was 92% in the EVLP group and 79% in the non-EVLP group. Cumulative survival and freedom from retransplantation or chronic rejection were also comparable between the 2 groups (P = .43) when monitored up to 4 years.³⁴ Similar findings were reported in Milan where 2 EVLP donor lung recipients had 0% mortality in 60 days.³⁵ In 2013, 7 lung transplants after EVLP were done by a group at Turin University.³⁶

The NOVEL trial was the first nonrandomized, multicenter trial (Normothermic ex Vivo lung perfusion as an assessment of Extended/marginal donor Lungs) conducted in North America. Initially, 31 EVLP cases were enrolled, which was later expanded to 42 EVLP in 2014. The study showed initial outcomes and 12-month survival rate were similar to conventional lung transplantation.³⁷ Similarly, Nilsson et al showed no significant difference in survival between patients transplanted with lungs after EVLP at a later stage.³⁸ Many centers have used EVLP to revaluate organs from the substandard lung donor. Yet, only the Toronto lung transplant group have reported long-term data in patients receiving EVLP lungs. Their findings showed that freedom from chronic lung allograft dysfunction, patient survival, allograft survival were not different among lung transplant recipients when comparing standard versus EVLP lungs.^39,40 At the 2013 International Society for Heart and Lung Transplantation meeting, the groups from Toronto, Vienna, and Paris reported their findings. The transplantation rate of donor’s lung after EVLP was 82% (103/125) with a 1-year mortality rate at 12%.⁴⁰ Similarly, a 10-year follow-up study by Fakhro et al reported no significant difference in the conventionally transplanted lungs over EVLP transplants, neither in long-term survival nor pulmonary function performed.⁴¹ Niikawa and colleagues from the Cleveland Clinic slightly altered the Lund protocol for EVLP that uses linear shift-invariant system (Vivoline Medical AB, Lund, Sweden) where they inserted an experimental porcine lung graft in a prone position instead of supine during reconditioning. This study and others had reported a significant improvement in cellular function, cytokine, and pathologic tissue analysis. However, the physiology responsible for this improvement in function is still unclear.^42,43

The efficacy of mobile EVLP is currently being evaluated. The initial experience of using the OCS had been reported by the Hanover and Madrid groups.⁴⁴ A total of 12 patients received lungs from the 12 standard donors whose lungs had been transported under normothermic pulsatile perfusion. The mean EVLP running time was 303 minutes (188-622 minutes) and 30-day survival was 100%. At day 140, 1 patient died due to an unrelated cause. Furthermore, the use of the OCS was reported by the Hartfield and Edmonton groups in Europe to reassess both high-risk donation after brain death and donation after cardiac death with good short- and mid-term outcomes. The efficacy of mobile EVLP for the reduction of cold ischemia and reassessment of high-risk donors has been investigated in 2 e-clinical trials, the INSPIRE and EXPAND trials.^45,46 The INSPIRE trial showed that OCS lungs had shortened ischemic times and decreased incidence of PGD 2 and 3, compared with the control group. However, survival rates at 24 months were similar. Patients who received lungs from OCS had somewhat shorter ventilator times and ICU lengths of stay.⁴⁵ Also, the EXPAND trial showed excellent short and 1-year posttransplant outcomes, with 30-day, 6-month, and 1-year survival being 99%, 93%, and 91%, respectively, with an incidence of bronchiolitis obliterans of 1% at 1 year.⁴⁶ Table 4 shows the outcomes of multiple EVLP studies.

Table 4.

Outcomes of EVLP.

Publications	Timeframe	EVLP Lungs	Standard Lungs	Rejected After EVLP	EVLP/Standard Ratio	Transplanted	Type of Machine
Lindstedt et al	2006-2007	6	15	N/A	0.40	100%	ECMO circuit
Cypel et al	2008-2011	60	265	8	0.23	86.67%	XVIVO
Zych et al	2009-2010	6	—	7	—	46.15%	XVIVO
Aigner et al	2010-2011	13	—	4	—	69.23%	Home made
Wallinder et al	2011-2015	32	145	5	0.22	84.37%	Vivoline
Valenza et al	2011	2	6	0	0.33	100%	Home made
Boffini et al	2011-2013	11	28	3	0.39	72.73%	Home made
Sanchez et al	2011-2013	42	42	34	1.00	55.26%	XVIVO
Nilsson et al	2011-2015	54	271	7	0.20	88.52%	Vivoline
Tikkanen et al	2008-2012	63	340	10	0.19	86.39%	XVIVO
Warnecke et al	2011	12	—	—	—	—	OCS
INSPIRE Trial	2011-2014	151	169	—	—	—	OCS
EXPAND Trial	2014-2016	81	—	12	—	87.09%	OCS

Abbreviations: EVLP, ex vivo lung perfusion; N/A, not applicable; OCS, organ care system.

The safety of a dedicated EVLP facility has been evaluated using the Toronto EVLP system (NCT02234128). In this trial, lungs considered high risk are procured and sent to a dedicated EVLP facility that performs the evaluation. If viable during perfusion, the organ is packed and shipped to the transplant center. The total out of body time and its impact on transplant outcome are currently investigated using animal models.

The Donation after Circulatory Death Register Report was recently published by the International Society for Heart and Lung Transplantation. Between January 2003 and June 2013, 306 lung transplants were performed by 10 institutions using donation after circulatory death with excellent outcomes.^47,48 The study by Machuca et al compared 28 DCD lung transplants after EVLP with 27 DCD without EVLP.⁴⁹ No significant differences were observed in terms of survival. Yet, the EVLP showed a trend toward a lower number of days on the ventilator (2 vs 3 days, P = .059) and shorter hospital stay (median 18 vs 23 days, P = .047). Still, the use of EVLP in controlled DCD is controversial and based mostly on individual center preferences.

Utility of EVLP as a Therapeutic Platform

Currently, EVLP is mostly used as an assessment tool for suboptimal lungs for transplantation. By creating a physiologic and controlled milieu, EVLP can be used as more than an assessment tool. Multiple groups are investigating its use as a therapeutic platform for reconditioning and repairing lungs in order for transplantation. There have been promising results in drug, gene, stem cell, and medical gas therapy.

Drug Therapy

The EVLP system provides an isolated circuit in which medications can be added for directed therapy into the donor lungs, avoiding systemic exposure and toxicity. Using donor lungs that have pulmonary emboli has been controversial despite multiple reports of its success. However, Machuca and colleagues described for the first time the therapeutic ex vivo thrombolysis followed by transplantation. In their case, pulmonary embolism caused pulmonary hemodynamic compromise in the donor. While using the XPS, thrombolysis with alteplase was done followed by multiple retrograde flushes to remove residual embolus.⁵⁰ Inci and colleagues also had some success with therapeutic thrombolysis using urokinase in lungs with a massive pulmonary embolus.⁵¹

Ventilator-associated and aspiration pneumonias are also a major cause of rejection of donor lungs. Nakajima et al demonstrated that high-dose antimicrobial agents added to the perfusate of lungs on EVLP can significantly decrease microbial load.⁵² In a pilot study done by Zinne and colleagues, severe Pseudomonas aeruginosa pneumonia was induced in the lower left lobes of pigs. The lungs were then placed on EVLP and colistin was added to the perfusate. After 2 hours of ex vivo treatment, auto transplantation was performed. They showed that in the EVLP group, there was reduced overall mortality compared with the conventional systemic intravenous antibiotic (colistin) treatment of the pneumonia. Moreover, the clinical symptoms of infection were also less severe in the EVLP group.⁵³ In humans, Andreasson and colleagues treated positive culture lungs with broad-spectrum antimicrobials and showed a reduction of bacterial loads after EVLP. They were ultimately able to transplant 6 lungs out of the 18 lungs assessed, with all the patients surviving to hospital discharge.⁵⁴

Gene Therapy

Similarly, directed gene therapy can also be accomplished on the EVLP circuit. For example, work regarding interleukin (IL)-10, an anti-inflammatory cytokine that inactivates antigen-presenting cells and inhibits the pro-inflammatory cytokine cascade, has been promising. Machuca and colleagues, in a porcine model, showed that gene therapy with IL-10 transfected adenovirus during EVLP is safe and improves posttransplant lung function and outcomes over EVLP alone.⁵⁵ This group also showed similar results in human lungs. Lungs from 10 donors that were deemed unsuitable for transplantation were maintained on EVLP with and without IL-10 gene therapy. The lungs that received the therapy showed improvement in arterial oxygen pressure and pulmonary vascular resistance compared with the controls. There was also a favorable shift from pro-inflammatory to anti-inflammatory cytokine expression and recovery of alveolar-blood barrier integrity.⁵⁶

Stem Cell Therapy

Prior studies in multiple systems have indicated that delivery of mesenchymal stromal (MSC) or multipotent adult progenitor cells (MAPC) therapy might attenuate injury by its paracrine effects on the pro-/anti-inflammatory balance.^57,58 EVLP provides a platform to administer these cells to donor grafts prior to transplantation. Nakajima and colleagues delivered MSCs to lungs via the pulmonary artery on EVLP and showed that cleaved caspase-3 and TUNEL-positive cells were decreased in the MSC group at the end of EVLP compared with the control group. Furthermore, peak airway pressure was significantly decreased during EVLP in the MSC group. Tumor necrosis factor-α and pathological acute lung injury score were significantly decreased in the MSC group compared with the control group.^59,60

Additionally, it has been hypothesized that MAPCs may decrease ischemic-reperfusion injury and, as a result, subsequent PGD. La Francesca et al utilized donor lungs that were not used for transplantation and stored them in cold storage for 8 hours. Following rewarming on EVLP, MAPCs were bronchoscopically instilled into the left lower lobes and vehicle control was instilled into the right lower lobes. The lungs were perfused and ventilated for 4 hours and assessed for histologic injury and for inflammatory markers in bronchoalveolar lavage fluid and lung tissue. The group showed the left lower lobes treated with MAPCs had significantly decreased histological inflammation and decreased inflammatory markers in the bronchoalveolar lavage fluid compared with the right lower lobes.⁶¹

Medical Gas Therapy

The EVLP circuit also allows for isolated therapies to the airways to improve the quality of lung grafts. In a rat model, Noda and colleagues mounted heart-lung blocks onto an acellular normothermic EVLP system for 4 hours and ventilated the block with 2% hydrogen. The use of hydrogen attenuated pro-inflammatory changes during EVLP, promoted mitochondrial biogenesis, and decreased lactate production. There was upregulation of heme oxygenase-1 and the expression of hypoxia-inducible factor-1 was significantly attenuated during EVLP. This led to better posttransplant lung graft function in the recipients of hydrogen-treated lungs.⁶²

Inhaled nitric oxide (NO) is used in postoperative lung transplant management. Some studies have shown that pretransplant NO ventilation may be beneficial. Dong et al, in a rat model on an ex vivo circuit, showed that NO ventilation was associated with significantly reduced wet–dry weight ratio, better oxygenation, and reduced pulmonary vascular resistance. Furthermore, there is reduced increases in tumor necrosis factor-α, which is a driver of inflammation and maintenance of endothelial NO synthase, which is a potent vasodilator.⁶³

EVLP Outside the Realm of Transplantation

Thoracic Oncology

There are many implications of EVLP outside of transplantation. The system can be used to investigate the effects and pharmacokinetics of therapeutic oncologic agents. In 1958, Creech and colleagues used isolated lung perfusion with chemotherapeutic agents to treat pulmonary malignancies on an extracorporeal circuit much like EVLP.⁶⁴ The goal is to prevent systemic dosing of potent chemotherapeutic agents, with a focused perfusion into the lungs, thereby avoiding the systemic toxicity of some of these agents. One that shows promise is in thoracic oncology with the management of pulmonary metastasis. Reck dos Santos and colleagues cannulated the pulmonary artery and veins in pigs in an in vivo lung perfusion circuit. The left lung was perfused for 4 hours with doxorubicin. The group showed feasibility with stable function without evidence of acute lung injury during infusion and homogeneously distributed doxorubicin with no systemic leakage.⁶⁵ There have been phase 1 human studies that have shown efficacy of this modality of treatment with low morbidity while maintaining the patient’s pulmonary function.^66,67 Though promising, further studies are needed to determine is long-term efficacy on local recurrence, toxicity, pulmonary function, and overall survival.

Regenerative Medicine and Bioengineering

Despite the continuous efforts to increase the donor pool with modalities such as extended donor criteria and reconditioning using EVLP, there will continue be a shortage of organs for patient with end-stage lung disease. Organ engineering is a theoretical alternative to address this shortage of organs. Ott and colleagues have showed effective decellularization of lungs from various animals—murine, porcine, and human models. The decellularized lungs have preserved extracellular matrix composition and architecture for the purpose of engineering bio-artificial lungs.^68,69 Their group was able to generate functional pulmonary vasculature by repopulating the vascular compartments of the scaffolds with endothelial and perivascular cells.⁷⁰ EVLP has been proposed as a platform for cellular delivery for the bio-artificial organ, as well as providing a physiological environment for cellular proliferation and assessment of the artificial organ.

Anesthesia Considerations for EVLP

Anesthesiologists are not directly involved in the process of EVLP. However, the purpose of this article is to make them understand the indications, principles, and processes involved in EVLP. It is important to be aware of the reason why the lungs were not considered for standard organ donation so that adequate preparations can be done to address graft dysfunction if it occurs. EVLP assessment takes 3 to 4 hours and anesthesiologists may have to wait for the final decision-making. It is a good clinical practice to follow-up on serial arterial blood gas parameters and hemodynamic and airway indices through EVLP duration. Finally, EVLP is an area for research involvement by anesthesiologists where they can explore various lung protective therapeutic options. Standard lung transplantation anesthesia protocols are used after acceptance of lungs from EVLP.

Conclusion

EVLP is promising technology that has already made a significant impact on the field of lung transplantation. Using EVLP as an assessment tool has increased the number of lung transplants by the utilization of marginal donor lungs. It allows for extending the criteria for donors. Furthermore, the OCS has the unique characteristic of minimizing cold perfusion times. The advantages of this over the current standard of cold static preservation is still unclear. Also, there is promise in the field of reconditioning of donor lungs while on the EVLP circuit. Therapies or interventions can be pursued in order for the lungs to be transplantable or to modulate their immunogenicity. The EVLP systems provide us with a platform for expansion of pulmonary and oncologic research, and tissue bioengineering. Though there have been major advancements in EVLP, evidenced by its FDA approval, its full potential is only beginning to be recognized.

Supplemental Material

EVLP_Figure_Permissions – Supplemental material for Ex Vivo Lung Perfusion: A Review of Research and Clinical Practices

Supplemental material, EVLP_Figure_Permissions for Ex Vivo Lung Perfusion: A Review of Research and Clinical Practices by Patrick G. Chan, Akshay Kumar, Kathirvel Subramaniam and Pablo G. Sanchez in Seminars in Cardiothoracic and Vascular Anesthesia

Supplemental Material

TransMedics_PhotoApproval_1.16.20 – Supplemental material for Ex Vivo Lung Perfusion: A Review of Research and Clinical Practices

Supplemental material, TransMedics_PhotoApproval_1.16.20 for Ex Vivo Lung Perfusion: A Review of Research and Clinical Practices by Patrick G. Chan, Akshay Kumar, Kathirvel Subramaniam and Pablo G. Sanchez in Seminars in Cardiothoracic and Vascular Anesthesia

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Patrick G. Chan

Akshay Kumar

Kathirvel Subramaniam

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