Ann Thorac Surg 2007;83:2191-2194
© 2007 The Society of Thoracic Surgeons
New Technology
First Human Transplantation of a Nonacceptable Donor Lung After Reconditioning Ex Vivo
Stig Steen, MD, PhDa,*,
Richard Ingemansson, MD, PhDa,
Leif Eriksson, MD, PhDa,
Leif Pierre, CPPa,
Lars Algotsson, MD, PhDa,
Per Wierup, MD, PhDb,
Qiuming Liao, MDa,
Atli Eyjolfsson, MDa,
Ronny Gustafsson, MD, PhDa,
Trygve Sjöberg, PhDa
a Department of Cardiothoracic Surgery, Heart and Lung Division, Lund University Hospital, Lund, Sweden
b Department of Cardiothoracic Surgery, Skejby Hospital, Aarhus University, Aarhus, Denmark
Accepted for publication January 22, 2007.
* Address correspondence to Dr Steen, Department of Cardiothoracic Surgery, Heart and Lung Division, Lund University Hospital, Lund, SE-221 85, Sweden (Email: stig.steen{at}med.lu.se).
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Abstract
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Purpose: This article describes an ex vivo method to recondition and transplant rejected donor lungs.
Description: A 19-year-old man was brain dead after a traffic accident. A roentgenogram showed bilateral lung contusion. He had ongoing intratracheal bleeding. After optimizing ventilator treatment and suctioning the airways, PaO
2 was 9 kPa (67.5 mm Hg) on FiO2 = 0.7. The lungs were rejected by all transplantation centers in the Nordic countries. We harvested the lungs for research. The right lung was severely injured. The left lung was edematous with bleeding spots in the lower lobe, and the mediobasal segment was atelectatic. The left lung was reconditioned ex vivo and kept in topical extracorporeal membrane oxygenation until it was transplanted into a 70-year-old man with chronic obstructive pulmonary disease 17 hours later.
Evaluation: The transplanted lung functioned very well, and the patient recovered uneventfully. At 3 months control, a computed tomographic thoracic scan and transbronchial biopsies showed a normal left lung, and the patient was in very good clinical condition, only to succumb to death from unrelated events 11 months after the transplantation.
Conclusions: Rejected donor lungs may be successfully transplanted after being reconditioned ex vivo.
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Introduction
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In May 22, 2005, a 19-year-old man was hit on his right side by a car. He had severe head and thoracic injuries and was in a deep coma. The victim was intubated and blood was suctioned from the endotracheal tube. A chest roentgenogram showed bilateral lung contusions, most excessive on the right side. A brain computed tomographic scan showed severe contusion, and after a few hours brain death was declared and permission for organ donation was obtained. The patient’s PaO
2 had been low at all measurements. The last value measured before the organ donation operation started was 9 kPa (67.5 mm Hg) on FiO2 = 0.7. The lungs were deemed nonacceptable for donation due to poor blood gases combined with severe lung contusion and ongoing bleeding into the airways. However one of the doctors in contact with the donor knew of the research program at Lund University Hospital on nonacceptable donor lungs and therefore had contacted us. The responsible doctor in the donor hospital then decided to offer the lungs to Scandia Transplant. The lungs were rejected by all lung transplantation centers (ie, Copenhagen, Gothenburg, Oslo, and Helsinki). Then we were offered the lungs at 2:00 PM. When our team arrived at 5:00 PM, the heart, liver, and kidneys were to be urgently preserved by other teams due to severe hypotension of the donor. There was no time to inspect the lungs, which we preserved in a semi-inflated state with a cold pulmonary artery perfusion with Perfadex (Vitrolife AB, Kungsbacka, Sweden). The lungs were transported to Lund, and arrived at 7:00 PM. Blood samples from the donor were delivered to our blood bank, and 4 units of erythrocyte concentrate (leukocyte filtered and irradiated) were ordered. Our method to evaluate, recondition, and transplant donor lungs was approved by the Ethics Committee at Lund University.
The right lung was severely injured with intraparenchymal hematoma (Fig 1). Small bleeding spots could also be seen in the lower lobe of the left lung. When the trachea was opened the spongy left upper lobe collapsed normally, the left lower lobe that had a semi-solid consistence did not collapse well, and the mediobasal segment was atelectatic. The right lung had a large central hematoma and did not collapse at all. Coagulated blood almost occluded the right main bronchus. A smaller amount of coagulated blood clots were suctioned from the left main bronchus; we judged this blood to have come from the right lung. We decided to evaluate only the left lung. The right lung was excised, preserving the proximal part of the right pulmonary artery.
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Fig 1. Anterior view of the donor lungs. The right lung was severely injured. Small bleeding spots are seen in the lower lobe of the left lung.
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Technology
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A 28-French venous cannula was placed with its tip in the proximal left pulmonary artery through the proximal part of the right pulmonary artery. The stump of the pulmonary trunk was oversewn. A baby feeding catheter was placed in the pulmonary artery to measure the perfusion pressure. The equipment used for the ex vivo perfusion and the method used to recondition the lungs have been described in detail elsewhere [1–3].
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Technique
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After removing the air from the pulmonary artery, a slow perfusion (perfusion pressure <20 mm Hg) was started at 25°C. The temperature in the perfusate was gradually increased to 37°C during the next 15 minutes. The gases to the oxygenator were mixed to get perfusate gas values (temperature corrected) of PO
2 
15 kPa and PCO
2 5 kPa. After 20 minutes the temperature of the perfusate from the lung was 37°C. The end-expiratory pressure was kept at 5 cm H2O, except when it was increased temporarily to 10 cm H2O, then the atelectasis in the mediobasal segment disappeared. Ten minutes later the ventilation was fixed at 3.5 L/min (ie, half of 100 mL/kg, the estimated optimum for two lungs, 12 breaths/min) and the perfusion flow was kept at 2.5 L/min ( half of 70 mL/kg). During the next 20 minutes, with stable ventilator settings and perfusion flow, the pulmonary artery pressure decreased from 12 mm Hg to 7 mm Hg, where it stabilized.
The Assessment
The gas mixture to the oxygenator was now shifted to 7% CO2 and 93% N2. Blood gases of the perfusate were taken before and after passing through the lung after 10 minutes exposure of FiO
2 of 0.5, 1.0, and 0.21, respectively. The results are shown in Table 1. Then a collapse test was done, which consists of observing the lung after a sudden disconnection of the endotracheal tube from the ventilator. In a normal lung the whole lung should collapse (global atelectasis). We deemed the collapse test to be normal and judged the lung acceptable for transplantation in spite of the bleeding spots still present in the lower lobe.
Topical Extracorporeal Membrane Oxygenation Until Next Day Transplantation
The temperature of the ingoing perfusate was reduced to 25°C and when that temperature was reached in the perfusate coming from the lung, the perfusion was stopped. The pulmonary artery cannula and the trachea were clamped with the lung in a semi-inflated state. The lung was then immersed in the perfusate with added buffered Perfadex (Vitrolife AB), and topical extracorporeal membrane oxygenation (ECMO) at 8°C was started at 11:30 PM.
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Clinical Experience
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Left Lung Transplantation
The recipient was called from abroad and arrived with an ordinary air flight. He was a 70-year-old man with chronic obstructive pulmonary disease who had been on 24-hour oxygen therapy for the last three years. He had signed a document stating that he would agree to be transplanted with a nonacceptable donor lung if a successful reconditioning could be done. His forced expiratory volume in 1 second was less than 20% of predicted during the last year, and during the last month his health had severely deteriorated. The implantation of the donor lung was performed without difficulty. Reperfusion of the lung was started at 10:00 AM, which was 17 hours after the harvesting procedure.
Follow-Up
The postoperative course was uneventful. His chest roentgenogram was normal (Fig 2). He left for his home country 6 weeks after the transplantation in very good condition.
Three months after the transplantation, the following status was documented by the responsible doctor at home: good general condition, blood pressure of 120/70, cyclosporine in serum of 200 to 150 µg/L, creatinine of 91 µmol/L, normal liver tests, C-reactive protein of 9 mg/L, cholesterol of 4.7 mmol/L, glomerular filtration rate of 68 mL/min (85% of predicted value). A computed tomographic thoracic scan showed normal transplanted left lung and emphysema of the right lung. A rigid bronchoscopy with transbronchial biopsies showed no sign of rejection. Spirometry with forced vital capacity of 2.69 L (74% of predicted), forced expiratory volume in 1 second of 1.73 L (62%), carbon monoxide lung diffusion capacity of 5.8 (70%), carbon monoxide transfer coefficient of 1.33 (105%), 6-minute walking test without oxygen at 495 m, pulse oximetric saturation measurement during walking test at 95% to 97%, arterial blood gas (without oxygen), pH 7.47, PCO
2 4.8 kPa, PO
2 9.7 kPa. The cytomegalovirus-polymerase chain reaction was negative in two tests. The conclusion was "very satisfactory condition." The immunosuppressive treatment was cyclosporine (Sandimun; Novartis Sverige AB, Täby, Sweden) of 100 mg x 2, azathioprine (Imurel; GlaxoSmithKline AB, Solna, Sweden) of 50 mg x 1, and prednisolone of 10 mg x 1, which was soon to be reduced.
Eight months after the transplantation the patient was diagnosed with Epstein-Barr virus-positive large cell lymphoma in the transplanted lung. He received four cyclophosphamide, adriamycin, vincristine, prednisone chemotherapy treatments and the tumor disappeared. The patient was socially very active when he acquired acute sepsis and died 11 months after the transplantation.
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Comment
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In many brain-dead donors the arterial oxygen tension deteriorates to nonacceptable values before organ harvesting can be done. Edematous lung tissue, due to excessive intravenous infusions to keep the donor circulation adequate, may contribute to the deterioration of the gas exchange capacity. Replacement of bleeding during the donor operation with crystalloid solutions will hemodilute the donor still more and reduce the plasma colloid osmotic (oncotic) pressure. The lungs, due to their spongy structure, are especially vulnerable to develop edema under these circumstances. In the present case the nonatelectatic part of the left lower lobe was edematous compared with the upper lobe. This could be felt during palpation and could be seen when the trachea was opened and the spongy upper lobe collapsed much more in comparison with the lower lobe.
The solution used for the lung perfusion (Steen Solution, Vitrolife AB) 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 ECMO system. It has the capacity to dehydrate edematous lung tissue during ex vivo perfusion. We have found that the use of a hematocrit around 15% is optimal [1–3]. The use of higher hematocrit will increase the viscosity of the perfusate. A higher perfusion pressure is then needed to perfuse the lungs with adequate flow with the consequence that edematous tissue will not be dehydrated so effectively. The centrifugal pump used to create the ex vivo flow is nontraumatic to the erythrocytes, but gives continuous nonpulsatile flow. In vivo there is pulsatile flow in the pulmonary artery with a low (8 mm Hg) diastolic pressure, which keeps the hydrostatic pressure within the pulmonary capillaries low (7 mm Hg) compared with the plasma oncotic pressure (28 mm Hg). Thus the lungs are kept dry (spongy) by the constant suction force of a normal plasma oncotic pressure [4].
If the ex vivo perfusion is run with pulmonary artery pressures higher than 20 mm Hg, pulmonary edema will develop gradually. In the present case, when full flow at normothermia had been reached after 30 minutes of perfusion, the pulmonary artery pressure was 12 mm Hg, and during the next 20 minutes it gradually decreased to 7 mm Hg. The atelectatic segment of the lower lobe had disappeared after using a positive end-expiratory pressure of 10 cm H2O, and when the collapse test was done at the end of the perfusion both lobes collapsed normally, indicating that a dehydration of the lower lobe had occurred during the perfusion. The excellent blood gases obtained indicated a normalized gas exchange, and the small difference between the arterial and end-tidal carbon dioxide tension indicated a normal ventilation-perfusion relationship [3].
Since this case we have done five clinical double lung transplantations with rejected lungs from brain-dead donors, thus making the recipients 100% dependent on the ex vivo reconditioned lungs from the very first moment of reperfusion. In all these patients the postoperative course has been uncomplicated with an observation period (December 2006) of 3 to 6 months. These ten donor lungs were rejected mainly due to low arterial oxygen tensions in the donors, and no cases involved thoracic trauma. The lungs could be reconditioned during 1 to 2 hours of ex vivo perfusion after which the lungs were kept in topical ECMO at 8°C until transplantation the next day. The time from harvesting until the start of reperfusion of the transplanted second lung was approximately 20 hours in all cases. Postoperative chest roentgenogram did not show any difference between the first and second transplanted lung, indicating that topical ECMO is an excellent lung preservation method. Experimentally we have preserved pig lungs for 24 hours with Perfadex (Vitrolife AB) [5] and for 72 hours with topical ECMO (unpublished data); therefore we did not find it mandatory to perform the lung transplantations at night.
Other investigators have reported favorable experimental results with ex vivo perfusion of the lungs [6–9]. However, long-term follow-up of a lager patient cohort is necessary before this method may become a clinical routine.
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Disclosures and Freedom of Investigation
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This project was supported by grants from the Swedish Heart Lung Foundation and Lund University Hospital. The cost for all equipment was covered by these grants. The authors had full control of the design of the study, the methods used, the outcome measurements, analysis of data, and the production of the written report.
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Acknowledgments
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We want to thank nurses Ann-Christin Nilsson, Evamarie Braf, Camilla Olin, and Birgit Malmros for their skillful help and enthusiastic support before, during, and after the transplantation.
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Footnotes
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Disclaimer The Society of Thoracic Surgeons, the Southern Thoracic Surgical Association, and The Annals of Thoracic Surgery neither endorse nor discourage use of the new technology described in this article.
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References
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- 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]
- 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]
- Wierup P, Haraldsson Å, Nilsson F, et al. Ex vivo evaluation of nonaccepatble donor lungs Ann Thorac Surg 2006;81:460-466.[Abstract/Free Full Text]
- Guyton AC, Hall JE. Textbook of medical physiology. 11th ed.. Philadelphia: Elsevier Saunders; 2006.
- Steen S, Kimblad PO, Sjöberg T, Lindberg L, Ingemansson R, Massa G. Safe lung preservation for twenty-four hours with Perfadex Ann Thorac Surg 1994;57:450-457.[Abstract]
- Van Raemdonk DEM, Rega FR, Neyrinck AP, et al. Non-heart-beating donors Semin Thorac Cardiovasc Surg 2004;16:309-321.[Medline]
- Erasmus ME, Fernhout MH, Elstrodt JM, Rakhorst G. Normothermic ex vivo lung perfusion of non-heart-beating donor lungs in pigs: from pretransplant function analysis towards a 6-h machine preservation Transpl Int 2006;19:589-593.[Medline]
- Snell GI, Oto T, Levvey B, et al. Evaluation of techniques for lung transplantation following donation after cardiac death Ann Thorac Surg 2006;81:2014-2019.[Abstract/Free Full Text]
- Egan TM, Haithcock JA, Nicotra WA, et al. Ex vivo evaluation of human lungs for transplant suitability Ann Thor Surg 2006;81:1205-1213.[Abstract/Free Full Text]
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Abstract
Introduction
