Ann Thorac Surg 2009;87:255-260. doi:10.1016/j.athoracsur.2008.09.049
© 2009 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Clinical Transplantation of Initially Rejected Donor Lungs After Reconditioning Ex Vivo
Richard Ingemansson, MD, PhD,
Atli Eyjolfsson, MD,
Lena Mared, MD,
Leif Pierre, CCP, BSc,
Lars Algotsson, MD, PhD,
Björn Ekmehag, MD, PhD,
Ronny Gustafsson, MD, PhD,
Per Johnsson, MD, PhD,
Bansi Koul, MD, PhD,
Sandra Lindstedt, MD, PhD,
Carsten Lührs, MD,
Trygve Sjöberg, PhD,
Stig Steen, MD, PhD*
Department of Cardiothoracic Surgery, Heart-Lung Division, Lund University Hospital, Lund, Sweden
Accepted for publication September 19, 2008.
* Address correspondence to Dr Steen, Department of Cardiothoracic Surgery, Heart Lung Division, Lund University Hospital, Lund, SE-221 87, Sweden (Email: stig.steen{at}med.lu.se).
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Abstract
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Background: A major problem in clinical lung transplantation is the shortage of donor lungs. Only about 20% of donor lungs are accepted for transplantation. A method to evaluate and recondition lungs ex vivo has been tested on donor lungs that have been rejected for transplantation.
Methods: The donor lungs were reconditioned ex vivo in an extracorporeal membrane oxygenation (ECMO) circuit with STEEN solution (Vitrolife AB, Kungsbacka, Sweden) mixed with erythrocytes. The hyperoncotic solution dehydrates edematous lung tissue. Functional evaluations were performed with deoxygenated perfusate by varying the inspired fraction of oxygen. After the reconditioning, the lungs were kept immersed at 8°C in extracorporeal membrane oxygenation until transplantation was performed.
Results: Six of nine initially rejected donor lungs were reconditioned to acceptable function, and in six recipients, double lung transplantation was performed. Three-month survival was 100%. One patient has since died due to sepsis after 95 days, and one due to rejection after 9 months. Four recipients are alive and well without any sign of bronchiolitis obliterans syndrome 24 months after the transplantation.
Conclusions: The result from the present study is promising, and we continue to transplant reconditioned lungs.
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Introduction
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A major problem in clinical lung transplantation today is the shortage of donor lungs. Despite all improvements in donor management and organ preservation, still only about 20% of potential candidate lungs for transplantation are being transplanted [1]. The number of lung transplantations worldwide has reached a plateau [2, 3], and donor shortage has resulted in deaths on the waiting list, although the real extent of the problem is often disguised by restrictive listing criteria. As the number of patients with chronic obstructive pulmonary disease (COPD) increase, donor shortage can be expected to become worse.
A new method for ex vivo lung evaluation was developed and used for the first time in humans when a lung from a nonheart-beating donor was transplanted by Steen and colleagues in Lund, Sweden, in 2000 [4]. The method, which has been described in detail elsewhere [5, 6], can also be used for reconditioning of initially rejected donor lungs. The first human single lung transplantation of an initially rejected donor lung, after reconditioning ex vivo, was successfully performed in 2005 by Steen and colleagues [7]. The present paper reports the results from the first six double lung transplantations performed with donor lungs that were rejected for transplantation by the Scandiatransplant, Eurotransplant, and UK transplant organizations.
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Material and Methods
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The Donors
Between June 2006 and April 2007 the lungs from nine donors were investigated. The criteria for lungs to undergo reconditioning were the same as for ordinary donor lungs except that we accepted lower partial pressure of oxygen in arterial blood (PaO
2) values. All lungs from the nine donors were initially rejected due to bad oxygenation capacity. In one case (death due to intracerebral bleeding), emphysema and fibrosis were found and therefore reconditioning was never started. To be accepted for transplantation we had, beforehand, decided that the PaO
2 on fraction of inspired oxygen (FiO
2) = 1.0 should be 50 kPa or higher after reconditioning. In two cases (intracerebral bleeding) the PaO
2 was only 38 and 40 kPa, respectively, and no transplantation was done. Twelve lungs from six donors were reconditioned and accepted for double lung transplantation. In Table 1
relevant data for these donors are presented. Donor no. 1 came from England and the other five were from four different hospitals in Sweden. Donor no. 4 had an unwitnessed out-of-hospital cardiac arrest; cardiopulmonary resuscitation (CPR) was successful but brain death was later diagnosed, and the next of kin gave permission for organ donation. Donor 5, a 34-year-old woman, suffered cardiac arrest secondary to an epileptic fit in her home 26 km from our hospital; the patient received bystander CPR before LUCAS-CPR (Lund University Cardiopulmonary Assist System) 8, 9] was started and continued for 40 minutes until the patient achieved spontaneous stable circulation; four days later the patient was declared brain dead and donation was accepted by the next of kin. The other four donors were declared brain dead after intracerebral hemorrhage.
Initial Preservation and Transportation of the Donor Lungs
The lungs from donors 2 through 6 were preserved by cold infusion of the pulmonary artery with Perfadex solution (Vitrolife AB, Kungsbacka, Sweden) with added calcium chloride (0.3 mmol/L), nitroglycerin (5 mg/L), and trihydroxymethylaminomethane-buffer (0.3 mmol/L) [10–12]. The infusion (80 mL/kg body weight) was given with low perfusion pressure (15 to 20 mm Hg). At the retrieval operation a segment (
8 cm) of the descending aorta was also excised. The lungs were immersed in cold Perfadex in a semiinflated state with 100% oxygen together with the aortic segment and transported to our hospital in a cooling box. For donor no. 1, Papworth solution was used for the initial preservation.
Ex Vivo Lung Reconditioning
Figure 1
shows the perfusion circuit. Note the prolongation of the pulmonary artery by a segment of the descending aorta, to make the cannulation easier. All hearts (except the dorsal wall of the left atrium with the pulmonary veins) had been retrieved for the purpose of transplantation or homograft harvesting. During the reconditioning the perfusion solution flowed directly out in the lung reconditioning box, therefore left atrium pressure was always zero.
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Fig 1. Schematic drawing of the ex vivo lung reconditioning system. The lungs are placed in the reconditioning box, connected to the perfusion system and a ventilator. The cannulation is done through a piece of aorta (A), harvested from the donor, and used to prolong the pulmonary artery. The blood coming out from the remaining dorsal part of the left atrium (LA) runs freely out in the box. Pulmonary arterial pressure (PAP) is measured continuously. Blood gases are measured in the blood before and after the lung. The shunt with the tube clamp is used to prime the system with STEEN Solution mixed with erythrocytes to a hematocrit of 10% to 15%.
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The extracorporeal perfusion circuit was delivered by Medtronics (Medtronic AB, Kerkrade, the Netherlands; Ex Vivo Lung Evaluation Set). The system was primed with 2 L of STEEN solution (Vitrolife AB) mixed with 2 units of ABO-compatible erythrocyte concentrate that had been irradiated, leukocyte-filtered, and washed. STEEN solution is a physiologic electrolyte solution containing human serum albumin and dextran, to keep a high colloid osmotic pressure. Imipenem (0.5 g; Tienam, Merck Sharp & Dohme, Sollentuna, Sweden), insulin (20 IU; Actrapid; Novo Nordisk, Bagsvaerd, Denmark), and heparin (10,000 IU; Leo Pharma, Malmö, Sweden) were added, and isotonic trometamol (Addex-Tham, Kabi, Sweden) was used to buffer the mixed solution to a temperature adjusted pH of 7.4. Gas was supplied to the membrane oxygenator; first oxygen and CO2 during the reconditioning phase, and then 93% nitrogen and 7% CO2 during the testing phase, creating a normal venous blood gas in the perfusate to the pulmonary artery (ie, the oxygenator is used to deoxygenate the perfusate). Before the perfusion was started the pulmonary artery cannula was connected to the corresponding tube of the extracorporeal circuit, the air was removed, and the shunt of the circuit was clamped (Fig 1). A low-flow perfusion at 25°C was initiated through the lungs. The lungs were gradually warmed by increasing the temperature of the perfusate. When the temperature of the perfusate from the lungs stabilized at 32°C, careful ventilation was started. The pump flow was gradually increased, but the pulmonary artery pressure was never allowed to exceed 20 mm Hg. After 20 to 30 minutes, normothermia was reached. The positive end expiratory pressure was increased during short intervals to fully expand the lungs and eliminate atelectasis, but otherwise kept at 5 cm H2O. Blood gases were analyzed throughout the perfusion, and when they were acceptable (PaO
2 > 20 kPa on FiO
2 = 0.5), perfusion flow and ventilation were kept constant. For the final evaluation the erythrocyte containing perfusate was deoxygenated and entered the lung circulation through the pulmonary artery. The lungs were ventilated with decreasing oxygen fractions and the oxygenation capacity, obtained from analyzing the perfusate leaving the lung circulation was calculated, as earlier described 4–7]. This method has been approved by the Ethics Committee at Lund University.
Topical Extracorporeal Membrane Oxygenation (ECMO)
When reconditioning and evaluation were completed, the temperature of the ingoing perfusate was reduced to 25°C and when temperature had stabilized the perfusion was stopped. The pulmonary artery cannula and the trachea were clamped with the lungs in a semiinflated state (FiO
2 = 1.0). The lungs were then immersed in the perfusate, to which a buffered Perfadex solution was added. The extracorporeal circuit was then used to perfuse the solution in the box containing the immersed lungs, keeping that medium oxygenated and cooled to 8°C [5].
Transplantation
Double sequential lung transplantation was performed with clam shell incision (4 patients) or bilateral thoracotomy (2 patients) without the support of extracorporeal circulation, except in recipient 5. All relevant data for the recipients are given in Table 2.
Logistics of the Procedures
If the donor lungs arrived after 11 PM they were kept in Perfadex solution at 4°C to 6°C and the reconditioning was postponed until 9 a.m. the following day and then transplanted. If the reconditioning procedure had not been completed before 11 p.m., successfully reconditioned lungs were stored in topical ECMO at 8°C until the transplantation was started at 9 a.m. the next day.
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Results
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During the time period for this study we did eleven lung transplantations (seven double and four single) with donor lungs meeting acceptable standards of quality, compared with the six transplantations with primary rejected but reconditioned lungs presented in the present study. Thus, 35% of the lung transplantations were made with reconditioned lungs.
The essential characteristics for the donors of the six successfully reconditioned lungs are presented in Table 1 and Table 2. Before retrieval the median (range) PaO
2 on FiO
2 = 1.0 was 21.1 kPa (11.5 to 28.7 kPa) (Table 1). After reconditioning, the lungs from these donors produced a median PaO
2 on FiO
2 = 1.0 of 68.7 kPa (51.6 to 79.5) (Table 3). The settings of the extracorporeal circulation system and ventilation together with the variables of the achieved physiology are presented in Table 3. The total times between organ retrieval and transplantation were 16:43 (hours:minutes) and 18:04 for the first and second transplanted lung, respectively (Table 4). The median reconditioning time was 1 hour and 29 minutes (range, 1 hour 6 minutes to 2 hours 1 minute) (Table 4). The 4 patients surviving to the 12-month control showed increased 6-minute walking test values compared with the 3-month control, and forced expiratory volume of air in 1 second increased in 3 and was the same in 1 patient (Table 5).
Double sequential lung transplantations were performed without major surgical complications. In the first five cases the right lung was transplanted first and in the sixth case the left lung was transplanted first. The five recipients who survived 6 months had a postoperative course that in essence did not differ from patients transplanted with primary accepted donor lungs during the same time period. Recipient no. 6 was a man who had good lung function initially, but on postoperative day 2 developed sepsis. Blood culture showed the same bacteria as in an inflamed tooth. He never recovered but died after 95 days due to multiorgan failure. Recipient no. 4 was a woman who was doing well at the 6-month control, but developed side effects of cyclosporine, which necessitated a change in immunosuppressive treatment. She died 9 months after the transplantation due to organ rejection. The surviving four recipients are alive and well without any sign of bronchiolitis obliteranse syndrome approaching the 24-month control at the end of October 2008.
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Comment
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Lungs from the 6 donors that were successfully reconditioned and transplanted were initially all rejected due to bad arterial oxygen tension (Table 1). In many brain-dead donors the arterial oxygen tension deteriorates before organ harvesting can be performed. This deterioration is often caused by pulmonary edema due to excessive intravenous infusion of electrolyte solutions to keep the donor circulation adequate. Replacement therapy for bleeding during the donor operation with crystalloid solutions will hemodilute the donors still more and may reduce the plasma colloid osmotic (oncotic) pressure to a critical low level so that the hydrostatic pressure within the lung capillaries becomes higher than the oncotic pressure, with the consequence that pulmonary edema develops, particularly in the dorsal (most dependent) parts of the lungs. The solution used for the lung reconditioning can be characterized as an artificial hyperoncotic serum containing an optimal amount of dextran to coat the vascular endothelium and the plastic surfaces of the extracorporeal circuit. This solution keeps the lungs dry during perfusion, and dehydrates edematous lung tissue. We believe this is the explanation for the success achieved in reconditioning the donor lungs in the present study. A valuable method to observe the disappearance of edema in a lung ex vivo is to disconnect the tracheal tube from the ventilator. A normal nonedematous lung will then collapse, whereas an edematous lung will stay unchanged and only the nonedematous parts will collapse. After successful reconditioning of an edematous lung, global atelectasis is seen when the collapse test is done. For a more detailed discussion of lung reconditioning ex vivo see References 4 through 7.
In this study, neither reconditioning nor transplantation was started between 11 p.m. and 9 a.m. the next day. This is the explanation for the long time intervals in Table 3. If the transplantation is performed directly after the reconditioning, the reconditioned lungs can be quickly cooled by the heart-lung machine used for the reconditioning; ie, by core cooling. The second lung is kept in topical ECMO until its implantation.
The number of patients who become donors by means of classical brain death criteria are limited 1]. Donors 4 and 5 in the present study represent a special type of donor; namely patients with cardiac arrest who receive effective cardiopulmonary resuscitation (CPR) resulting in return of spontaneous circulation, but later develop brain death due to severe brain injury in connection with the cardiac arrest. Cardiac arrest is the most common cause of death in the Western World with a majority occurring out-of-hospital. It has been estimated that 375,000 persons each year die from cardiac arrest in the United States [8]. The 30-day survival after out-of-hospital cardiac arrest is very poor: less than 5% [7, 8]. With effective mechanical CPR many patients will arrive at the hospital with adequate organ circulation, but a majority of these patients will have irreversible brain damage and may therefore be potential organ donors. In the future we think that victims of cardiac arrest will be common organ donors, either after declaration of brain death, as for donors 4 and 5 in this study, or as nonheart-beating donors [4].
Since the start of our clinical lung transplantation program, initiated in 1990, 80% of the donor lungs have been rejected. A substantial number of these may have been suitable for reconditioning. In the present study, lungs from six of nine donors could be reconditioned and transplanted. However, a longer study period in a larger number of patients is needed, before the method of reconditioning donor lungs ex vivo may become routine.
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Acknowledgments
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This work was supported by grants from Lund University Hospital and the Swedish Heart Lung Foundation.
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References
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- Punch JD, Hayes DH, LaPorte FB, McBride V, Seely MS. Organ donation and utilization in the United States, 1996–2005 Am J Transpl 2007;7:1327-1338.
- Trulock EP, Edwards LB, Taylor DO, Boucek MM, Keck BM, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: twenty-first official adult heart transplant report – 2004 J Heart Lung Transplant 2004;23:804-815.[Medline]
- Maurer JR, Frost AE, Estenne M, Higenbottam T, Glanville AR. International guidelines for the selection of lung transplant candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, The European Respiratory Society. J Heart Lung Transplant 1998;17:703-709.[Medline]
- Steen S, Sjöberg T, Pierre L, Liao Q, Eriksson L, Algotsson L. Transplantation of lungs from a non-heart-beating donor Lancet 2001;357:825-829.[Medline]
- Steen S, Liao Q, Wierup P, Bolys R, Pierre L, Sjöberg T. Transplantation of lungs from non-heart-beating donors after functional assessment ex vivo Ann Thorac Surg 2003;76:244-252.[Abstract/Free Full Text]
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- Steen S, Ingemansson R, Eriksson L, et al. First human transplantation of a nonacceptable donor lung after reconditioning ex vivo Ann Thorac Surg 2007;83:2191-2195.[Abstract/Free Full Text]
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Abstract
Introduction
