Successful Lung Transplantation After Donor Lung Reconditioning With Urokinase in Ex Vivo Lung Perfusion System

Acute pulmonary embolism is considered a contraindication to lung donation for transplantation as it might result in graft dysfunction. Ex vivo lung perfusion (EVLP) is a novel method to assess and recondition a questionable donor graft before transplantation. In this report we present a case of successful bilateral lung transplant after donor lung assessment and treatment with a fibrinolytic agent, urokinase, during EVLP. Acute pulmonary embolism is considered a contraindication to lung donation for transplantation as it might result in graft dysfunction. Ex vivo lung perfusion (EVLP) is a novel method to assess and recondition a questionable donor graft before transplantation. In this report we present a case of successful bilateral lung transplant after donor lung assessment and treatment with a fibrinolytic agent, urokinase, during EVLP. Despite improvements in both donor management and organ preservation, only a limited number of potential donor lungs are considered acceptable for transplantation. This leads to high waiting list mortality for lung transplant recipients. Ex vivo lung perfusion (EVLP) is a novel technique proposed for the assessment, resuscitation, and repair of extended donor lungs [1Cypel M. Yeung J.C. Liu M. et al.Normothermic ex vivo lung perfusion in clinical lung transplantation.N Engl J Med. 2011; 14: 1431-1440Crossref Scopus (816) Google Scholar, 2Wierup P. Haraldsson A. Nilsson F. et al.Ex vivo evaluation of nonacceptable donor lungs.Ann Thorac Surg. 2006; 81: 460-466Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar]. Similar early outcomes have been reported in recipients who underwent transplantation after EVLP to those with conventionally selected and transplanted lungs [1Cypel M. Yeung J.C. Liu M. et al.Normothermic ex vivo lung perfusion in clinical lung transplantation.N Engl J Med. 2011; 14: 1431-1440Crossref Scopus (816) Google Scholar, 2Wierup P. Haraldsson A. Nilsson F. et al.Ex vivo evaluation of nonacceptable donor lungs.Ann Thorac Surg. 2006; 81: 460-466Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 3Aigner C. Slama A. Hötzenecker K. et al.Clinical ex vivo lung perfusion–pushing the limits.Am J Transplant. 2012; 12: 1839-1847Crossref PubMed Scopus (145) Google Scholar]. We report successful bilateral lung transplantation after donor lung treatment and assessment in the EVLP system with a fibrinolytic agent, urokinase. Recipient was a 27-year-old male suffering with end-stage cystic fibrosis (176 cm, 75 kg, body mass index 24 kg/m2), diagnosed in childhood due to recurrent respiratory symptoms and found to have a delta F508 homozygous cystic fibrosis genotype. Forced expiratory volume in 1 second (FEV1) and forced vital capacity were 1.7 l, 40% predicted and 3.38 l, 64% predicted, respectively. Informed consent was obtained from the patient. The donor was a 45-year-old female (180 cm, 98 kg) who was hospitalized for spine surgery. At postoperative day 4 she had suffered diffuse arterial and venous emboli. She underwent femoral arterial embolectomy and received intravenous lytic treatment for pulmonary emboli. Thereafter she developed intracranial bleeding resulting in brain death. She was declared brain dead after developing intracranial bleeding. Her arterial oxygen partial pressure at the time of retrieval was 360 mm Hg. Chest X-ray revealed bilateral infiltrations. Thorax computed tomography (CT) scan could not rule out persistent segmental arterial lung emboli. The lung was accepted for EVLP and reconditioning during EVLP with urokinase. Acellular normothermic EVLP [1Cypel M. Yeung J.C. Liu M. et al.Normothermic ex vivo lung perfusion in clinical lung transplantation.N Engl J Med. 2011; 14: 1431-1440Crossref Scopus (816) Google Scholar] was performed. At 37°C 100,000 IU urokinase was added into the reservoir. During EVLP for the functional assessment, tidal volume was set at 10 mL per kilogram of donor body weight and 10 breaths per minute, with fraction of inspired oxygen at 1.0. Lung function was evaluated hourly during EVLP according to the following calculations: Delta Po2 (partial pressure of oxygen) = [left atrial Po2 – pulmonary-artery Po2 (in mm Hg)], and pulmonary vascular resistance = [(pulmonary-artery pressure – left atrial pressure)] ÷ pulmonary-artery flow (in Wood Units), dynamic compliance (in mL/cm H20), and peak inspiratory pressure (in cm H2O). The lung was functionally evaluated for 3 hours and then cooled down to 20°C (Table 1). Then the lung block was placed in a bag filled with 1 L of cold Perfadex (Vitrolife, Göteburg, Sweden) and stored in cold saline until transplantation. The cold ischemic time after EVLP was 3 hours for the right and 5 hours for the left lung. Total operation time was 5 hours and 30 minutes. The recipient did not receive any blood transfusion. The patient was extubated 6 hours after the transplantation. Intensive care unit stay was 3 days. Primary graft dysfunction score at postoperative time 48 hours and 72 hours was 0. The last chest tube was removed at postoperative day 6. The patient was discharged from the hospital at postoperative day 21. The FEV1 at discharge was 2.8 l (64%). The patient is alive and follow-up time is 6 weeks posttransplant.Table 1Parameters During Ex Vivo Lung PerfusionTime (hour)PVRC-DynDelta Po2PiPLactate14.972278141.424.973322152.533.774280153.1C-Dyn = dynamic lung compliance (mL/cm H2O); PiP = peak inspiratory pressure (cm H2O); Po2 = partial pressure of oxygen; PVR = pulmonary vascular resistance (Wood Units). Open table in a new tab C-Dyn = dynamic lung compliance (mL/cm H2O); PiP = peak inspiratory pressure (cm H2O); Po2 = partial pressure of oxygen; PVR = pulmonary vascular resistance (Wood Units). We report a successful lung transplantation after reconditioning and treatment with urokinase during EVLP. Perfusion of grafts from non-heart-beating donors (NHBD) shows typically high resistance and inadequate microperfusion suggesting the presence of thrombi and fibrin deposition in the microcirculation [4Inci I. Zhai W. Arni S. et al.Fibrinolytic treatment improves the quality of lungs retrieved from non-heart-beating donors.J Heart Lung Transplant. 2007; 26: 1054-1060Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. Plasminogen activators are such agents utilized for this purpose. Adding a plasminogen activator, urokinase, into the perfusion solution during ex vivo perfusion and evaluation after 3 hours of warm ischemia resulted in improved graft function and significant reduction of pulmonary vascular resistance (PVR) [4Inci I. Zhai W. Arni S. et al.Fibrinolytic treatment improves the quality of lungs retrieved from non-heart-beating donors.J Heart Lung Transplant. 2007; 26: 1054-1060Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. This effect of urokinase has been attributed to reconditioning of the graft by dissolving microthrombi [4Inci I. Zhai W. Arni S. et al.Fibrinolytic treatment improves the quality of lungs retrieved from non-heart-beating donors.J Heart Lung Transplant. 2007; 26: 1054-1060Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. Improvements in pH, Po2, and partial pressure of carbon dioxide with EVLP all may have led to reductions in PVR in addition to the effect of urokinase, which has contributed to the dissolving of microthrombi. In our case, the donor had initially central pulmonary emboli, which were treated by an intravenous thrombolytic agent. Thorax CT scan, which was performed for donor evaluation, showed lyses of central emboli but persistent peripheral arterial lung emboli could not be ruled out. For this reason, we added urokinase into the perfusion solution during EVLP. As seen in Table 1, PVR dropped from 4.9 to 3.7 Wood Units, as well as excellent lung compliance. Lung compliance during retrieval was 42 mL/cm H2O, improved to 74 mL/H2O, and was stable during EVLP. Oxygenation remained stable. Reduction of PVR is a very important indicator for dissolving microemboli [4Inci I. Zhai W. Arni S. et al.Fibrinolytic treatment improves the quality of lungs retrieved from non-heart-beating donors.J Heart Lung Transplant. 2007; 26: 1054-1060Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. In the early postoperative period, we did not observe any problems such as allergic or toxic effects, or bleeding-related complications to urokinase. Primary graft dysfunction score at 48 and 72 hours was 0, showing an excellent graft function. In a research project the use of EVLP to evaluate a donor lung graft with acute pulmonary embolism has been recently reported [5Brown C.R. Brozzi N.A. Vakil N. et al.Donor lungs with pulmonary embolism evaluated with ex vivo lung perfusion.ASAIO J. 2012; 58: 432-434Crossref PubMed Scopus (8) Google Scholar]. The authors observed decreased PVR, increased lung compliance, and oxygenation during EVLP. In conclusion, our case report may encourage other groups which utilize NHBD category 1 or 2 donors (other than brain death donors with pulmonary embolism) to add urokinase in the perfusion solution during EVLP. The authors thank Mrs Laurie Theurer for reading and correcting language and syntax errors.