Impact of time interval between donor brain death and cold preservation on long-term outcome in lung transplantation

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1 European Journal of Cardio-Thoracic Surgery 50 (2016) doi: /ejcts/ezw028 Advance Access publication 17 February 2016 ORIGINAL ARTICLE Cite this article as: Pecoraro Y, Tsushima Y, Opitz I, Benden C, Schüpbach R, Lenherr R et al. Impact of time interval between donor brain death and cold preservation on long-term outcome in lung transplantation. Eur J Cardiothorac Surg 2016;50: a Impact of time interval between donor brain death and cold preservation on long-term outcome in lung transplantation Ylenia Pecoraro a, Yukio Tsushima a, Isabelle Opitz a, Christian Benden b, Reto Schüpbach c, Renato Lenherr c, Wolfgang Jungraithmayr a, Walter Weder a and Ilhan Inci a, * Department of Thoracic Surgery, Zurich University Hospital, Zurich, Switzerland b Division of Pulmonary Medicine, Zurich University Hospital, Zurich, Switzerland c Division of Surgical Intensive Care, Zurich University Hospital, Zurich, Switzerland * Corresponding author. Department of Thoracic Surgery, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. Tel: ; fax: ; ilhan.inci@usz.ch (I. Inci). Received 2 November 2015; received in revised form 1 January 2016; accepted 11 January 2016 Abstract OBJECTIVES: Brain death (BD) is associated with various systemic responses and a cascade of inflammatory reactions. It is still unknown how the time interval from BD to cold preservation (CP) affects outcome after lung transplantation (LTx). This report investigates the impact of the time interval from BD to CP on long-term outcome in LTx. METHODS: We reviewed 250 consecutive recipients who underwent LTx at our institution between January 2000 and December In (n = 212), the time interval from BD to CP was <24 h, and in I (n = 38) >24 h. Cox proportional hazard regression analysis was performed to determine the risk factors affecting survival. RESULTS: The median time from BD to CP was 18.6 h (range 9 65). The rate of postoperative complications was comparable (P = 0.8). The 30-day mortality rate was 7.5% in and 0% in I. The 5-year survival rate was better in I [70% (95% CI: %)] than in [66% (95% CI: %)] without statistical significance (P = 0.3). Intraoperative extracorporeal membrane oxygenation (ECMO) use was identified as a significant risk factor for survival [HR = 1.7, (95% CI: ), P = 0.01]. CONCLUSION: In our cohort, the time interval from BD to CP had no impact on long-term outcome after LTx. Keywords: Brain death Lung transplantation Cold ischaemic time Outcome Cold preservation Survival INTRODUCTION Lung transplantation (LTx) is a well-established therapy for patients with end-stage lung disease. The expansion of indications for LTx has resulted in a steady increase in the number of patients waiting for a transplant. In contrast, the number of lung donors has remained stable, with only 20% of the multiorgan donors having lungs suitable for transplantation [1]. At present, donation after brain death (BD) continues to be the major donor source for LTx [2]. BD, defined by the American Academy of Neurology as an injury to the brain stem with complete irreversible loss of their functions, is usually caused by major haemorrhage, anoxia or metabolic dysregulation [3] and is associated with severe haemodynamic changes, extensive hormonal alterations and intense inflammatory activity, leading to lung injury. Alpha-adrenergic stimulation, which results from the catecholamine storm, causes haemodynamic stress failure of the pulmonary capillaries and also directly increases pulmonary Presented at the 21st European Conference on General Thoracic Surgery, Birmingham, UK, May capillary permeability [4], producing the so-called neurogenic pulmonary oedema, a form of pulmonary oedema resulting from central nervous system injury or stimulation [1]. The hormone-depleted state of BD, with relative reduction in circulating catecholamines, corticosteroids and thyroid hormones, down-regulates alveolar fluid clearance [5]. The process of BD also initiates a systemic inflammatory response, reflected by cellular infiltrates, inflammatory cytokines and adhesion molecules expressed on both leucocytes and endothelial cells [6]. This could lead to the development of acute lung injury (ALI), or it could initiate subclinical inflammation, which could be amplified by the insult of ischaemia reperfusion injury and result in primary graft dysfunction, a post-transplant complication that is the major cause of short-term mortality, but also affects long-term survival. It seems clear that the systemic consequences of BD impact on the integrity and the quality of the lungs and their potential utility for transplantation. The impact of donor causes of brain death (DCBD) on the outcome after LTx has been investigated, but without finding a strong correlation between the mode of donor death and the outcome after LTx [7 10]. The possible influence of the time The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 Y. Pecoraro et al. / European Journal of Cardio-Thoracic Surgery 265 interval between BD and organ retrieval on graft function has also been investigated [11 13], but it remains undetermined how the time interval from BD to cold preservation (CP) affects the outcome in LTx. In the present study, we compared lung retrievals performed within and after 24 h of brain death, trying to investigate the impact of the time interval from BD to CP on long-term outcome in LTx. MATERIALS AND METHODS We retrospectively reviewed 250 consecutive patients who underwent LTx at the Zurich University Hospital from January 2000 to December A total of 238 bilateral LTx and 12 unilateral LTx were performed. Patients were distributed in two study groups: (n = 212), which consisted of recipients who received lungs retrieved within the first 24 h after BD (BD-CP <24 h) and I (n = 38), which consisted of those who received lungs retrieved after 24 h of BD (BD-CP 24 h). The median follow-up was 38 months [interquartile range (IQR) 16 87]. We also looked at different time points: <12 vs >12 h; >10 vs vs >20 h; <48 vs >48 h; <24 vs vs vs >96 h. There were no differences and the number of cases was not ideal for statistical evaluation. For this reason, we took the cut-off as 24 h. Donors and recipients were selected according to the guidelines of the International Society for Heart and Lung Transplantation (ISHLT) [14, 15]. Causes of BD were cerebral bleeding (n = 187), trauma (n =22), anoxia (n = 18), suicide (n =15) and others (n = 8). The median time from BD to CP was 18.6 h (range 9 65). Indications for LTx were cystic fibrosis (n = 84), emphysema (n = 67), idiopathic pulmonary fibrosis (n = 56), primary pulmonary hypertension (n = 16) and others (n = 2). Thirteen patients were retransplanted due to chronic lung allograft dysfunction. Hundred twenty-two cases were carried out with intraoperative extracorporeal membrane oxygenation (ECMO) use. The ECMO device is implemented routinely in patients with preoperatively known pulmonary artery hypertension or if the mean pulmonary artery pressure after clamping the pulmonary artery exceeds 40 mmhg in addition to right ventricular dysfunction. To provide both cardiac and respiratory support, we use the veno-arterial mode intraoperatively. For central cannulation, we use the ascending aorta, and for peripheral cannulation, we use the femoral artery or axillary artery. Donor characteristics such as age, sex, DCBD and PaO 2 /FiO 2 ratio, recipient characteristics such as age, sex, diagnosis and wait list time, perioperative data and postoperative complications were compared in the two study groups. Donor characteristics are given in Table 1. The median age was 55 years in vs 56 years in I. There were 125 males vs 87 females in and 28 males vs 10 females in I. Causes of BD were cerebral bleeding (161 in vs 26 in I), trauma (17 in vs 5 in I), anoxia (15 in vs 3 in I), suicide (11 in vs 4 in I) and others (8 in vs 0 in I). The mean (±standard deviation) PaO 2 /FiO 2 ratio (kpa) was 42 ± 16.5 in vs 40.5 ± 14.8 in I. There was no statistically significant difference between the two groups for any of the variables mentioned above. Recipient characteristics are given in Table 2. The median age was 36 in vs 34 in I. There were 114 males vs 98 females in, but in I there was equal gender distribution. The main diagnosis was cystic fibrosis (75 in vs 9 in I), emphysema (54 in vs 13 in I), idiopathic pulmonary fibrosis (47 in vs 9 in I), primary pulmonary hypertension (13 in vs 3 in I) and others (1 in both groups). The median wait list time was 160 days in vs 138 days in I. There was no statistically significant difference between the two groups regarding any of these variables. Statistical analysis For statistical analysis, the IBM SPSS version 21 (SPSS IBM, New York, USA) software package was used. Data are presented as median and range or IQR if non-normally distributed, and in case of normally distributed data, means and standard deviations (SDs) were expressed for continuous variables, and as frequency and percentage for discrete variables. Categorical variables were compared using χ 2 tests. The Mann Whitney test was used to compare continuous variables. Cox proportional hazard regression analysis (stepwise backward regression) was performed to determine the risk factors on survival. The Kaplan Meier method (log-rank test) was used to calculate unadjusted survival rate. A of <0.05 was considered as the threshold for statistical significance. TX & MCS Table 1: Donor characteristics I Donor age Median (years, range) 55 (14 79) 56 (11 76) 0.7 Donor sex Female 87 (41%) 10 (26%) 0.2 Male 125 (59%) 28 (74%) Donor cause of death Cerebral bleeding 161 (76%) 26 (68%) 0.9 Trauma 17 (8%) 5 (14%) Anoxia 15 (7%) 3 (7%) Suicide 11 (5%) 4 (11%) Others 8 (4%) 0 Donor blood gas, kpa (PaO 2 /FiO 2 ratio) (mean ± SD) 42 ± ± kpa: kilo pascal; PaO 2 /FiO 2 : ratio of arterial oxygen partial pressure/fraction of inspired oxygen.

3 266 Y. Pecoraro et al. / European Journal of Cardio-Thoracic Surgery Table 2: Recipient characteristics I Recipient age Median (years, range) 36 (15 56) 34 (17 54) 0.6 Recipient sex Female 98 (46%) 19 (50%) 0.7 Male 114 (54%) 19 (50%) Diagnosis Cystic fibrosis 75 (35%) 9 (24%) 0.6 Emphysema 54 (26%) 13 (34%) Idiopathic pulmonary fibrosis 47 (22%) 9 (24%) Idiopathic pulmonary hypertension 13 (6%) 3 (8%) Others 23 (11%) 4 (11%) Wait list time (days) Mean ± SD 42 ± ± Table 3: Perioperative data Table 4: Postoperative complications a I I Mode of transplantation Bilateral lobar 18 (8.5%) 5 (13%) 0.7 One-side lobar 42 (20%) 9 (23.6%) Bilateral 142 (67%) 22 (57.8%) Unilateral 10 (4.7%) 2 (5%) Retransplantation 10 (4.7%) 3 (7.8%) 0.4 Intraoperative ECMO use 106 (50%) 16 (42%) 0.4 Cold ischaemic time (min) Mean ± SD (right/left) 244 ± 85/ 311 ± ± 102/ 330 ± 108 Total operation time (min) Mean ± SD 419 ± ± ICU stay (days) Mean ± SD 12 ± 24 9 ± day mortality (N) 16 (7.5%) Thoracic hernia 6 (0.9%) Lymphocele 14 (6.6%) 3 (7.6%) 0.4 Primary graft dysfunction 25 (11.7%) 1 (2.6%) 0.1 Pleural complications 50 (23.5%) 10 (26.3%) 0.2 Abdominal complications 15 (7%) 3 (7.6%) 0.9 Phrenic nerve injury 4 (1.8%) 1 (2.6%) 0.5 a Patients may have had more than one complication ECMO: extracorporeal membrane oxygenation; ICU: intensive care unit; N: number. RESULTS Perioperative data are presented in Table 3. Ten patients in Group I and 3 in I were retransplanted. Intraoperative ECMO was used in 106 recipients in vs 16 in I. The mean (standard deviation) cold ischaemic time, respectively, for the right and the left side, was 244 ± 85/311 ± 89 min in vs 241 ± 102/330 ± 108 min in I. The mean total operation time was 419 ± 99 min in vs 432 ± 128 min in I. The mean ICU stay was 12 ± 24 days in vs 9 ± 14 days in I. The 30-day mortality rate was 7.5% (16 patients) in vs 0% in I. There was no statistically significant difference between the two groups regarding these variables. The rate of postoperative complications was comparable between the two groups, without any statistically significant difference (P = 0.8, Table 4). Fifty patients in and 10 in I had tracheostomy. Figure 1: Unadjusted survival curve using the Kaplan Meier method. The 5-year survival rate was 70% in I ( 24 h, 95% CI: %) and 66% in (<24 h, 95% CI: %, P = 0.3, log-rank test). Overall survival from surgery to death was analysed by multivariable Cox proportional hazard regression analysis. The unadjusted survival curve for the two groups is illustrated in Fig. 1. The5-year

4 Y. Pecoraro et al. / European Journal of Cardio-Thoracic Surgery 267 survival rate was superior in I [69.9% (95% CI: %)] to that in [65.9% (95% CI: %), P = 0.3]. A stepwise backward regression analysis was performed to determine the risk factors (diagnosis, intraoperative ECMO use and size-reduced transplantation) on survival. Only intraoperative ECMO use (HR 1.7, 95% CI: , P = 0.01) was identified as a significant risk factor for survival (Table 5). DISCUSSION Currently, BD donors remain the main source of grafts for transplantation. However, BD is associated with inferior graft function after kidney, liver, heart and LTx [16, 17]. The lung is especially vulnerable and may not manifest injury until the post-transplant period. Various groups have investigated the impact of donor cause of BD on LTx, with conflicting results. Waller et al. [7] compared the use of traumatic versus non-traumatic donors and concluded that the use of donors involved in major trauma does not increase the risk of early complication after LTx. Ciccone et al. also did not find a difference in hospital outcome or in early survival between traumatic versus non-traumatic brain injury donor groups [8]. Ganesh et al. [9] published the results from a national prospective cohort in the UK including 580 transplants, but even in this large series, one failed to identify a relationship between donor cause of BD and post-transplant survival up to 5 years. Contrary to these authors, Shingal et al. [10] studied the impact of DCBD on transplant outcome based on data from the United Network for Organ Sharing (UNOS) registry with more than donors between 1989 and In univariate analysis, stroke as DBCD was associated with worse graft survival across all organs, including lung recipients from these donors, but lung recipients from anoxic donors showed improved survival and less rejection. The authors concluded that anoxia as DBCD was associated with significantly better outcome in lung recipients from these donors than in those from donors with head trauma or stroke as DCBD. More recently, the possible impact of the time interval between BD and organ retrieval on graft function has also received increasing attention. In 2007, Avlonitis et al. [18] investigated whether early haemodynamic injury during donor brain death in rats increased reperfusion injury after LTx and whether delaying lung recovery increased reperfusion injury further, due to the progressive systemic inflammatory response in the donors. The authors observed that lungs retrieved late after BD presented less damage than those retrieved early, with similar inflammatory markers after reperfusion but significantly lower pulmonary vascular resistance. Subsequently, Wauters et al. [11] tried to find a specific correlation between the time interval from brain injury to brain death (BI-BD) and from brain death to CP (BD-CP) and survival and freedom from bronchiolitis obliterans syndrome (BOS) after LTx, reviewing 400 consecutive donors classified according to DCBD, without any impact on outcome from the length of time between the moment of BI and the diagnosis of BD. Interestingly, the authors described that the length of time between the diagnosis of BD and the moment of organ retrieval affected survival, with more recipients alive at 5 and 10 years transplanted with lungs from donors with such an interval that was longer than 10 h. The survival difference was not seen in the first year after transplantation, but only at a later stage, suggesting that survival benefit was not related to better early graft function and lower incidences of BOS, but probably to other factors [11]. In the report by Wauters et al.[11], which is from a Eurotransplant country, the median time from brain death to CP was 10 h (IQR, 8 12 h). And, this time (median 18.6 h, range 9 65 h) was nearly double in our series. This difference in our country might be due to logistic reasons in the donor hospital such as an available operating room and/or personnel due to emergency operations or other waiting teams outside the country. These might have led to a delay in multiorgan retrieval. Later on in 2013, the same authors studied lung injury at increasing time intervals after BD in a murine model, hypothesizing that markers of lung injury would be more pronounced with increasing time intervals [13]. Study results revealed a statistically significant increase of inflammation and lung injury after 3 h following BD, but not a further increase after 6 h following BD [13]. Moreno et al. [12] presented a study designed to assess whether lung retrieval from traumatic donors performed within the first 24 h of brain injury had a negative impact on graft function and survival after LTx, when compared with those retrieved after 24 h. In contrast to previous studies, the authors showed that early retrieval from traumatic donors performed within the first 24 h after brain injury is not associated with worse graft function and in-hospital outcomes following LTx. In addition, mid- and long-term survivals are not compromised by the use of these grafts. Surprisingly, transplantation of grafts retrieved early from traumatic donors was associated with inferior 5-year survival only in fibrotic recipients [14]. TX & MCS Table 5: Univariate and multivariate logistic regression analyses predicting outcome Covariate of interest Univariate analysis Multivariate analysis HR (95% CI) HR (95% CI) Recipient age 1.03 ( ) ( ) 0.06 Recipient sex 1.25 ( ) ( ) 0.5 Diagnosis 0.83 ( ) ( ) 0.3 Intraoperative ECMO 1.5 ( ) ( ) 0.01 Size reduction 0.99 ( ) ( ) 0.4 CRP at transplant ( ) ( ) 0.18 ICU stay 1.01 ( ) ( ) 0.2 Donor PaO 2 /FiO 2 ratio 0.98 ( ) ( ) 0.7 HR: hazard ratio; CI: confidence interval; ECMO: extracorporeal membrane oxygenation; CRP: C-reactive protein; ICU: intensive care unit; PaO 2 /FiO 2 : ratio of arterial oxygen partial pressure to fraction of inspired oxygen at the time of organ retrieval.

5 268 Y. Pecoraro et al. / European Journal of Cardio-Thoracic Surgery In our study, we analysed our transplant cohort in order to evaluate if the time interval BD-CP influenced survival after LTx. In contrast to previously published reports, we did not find any impact on the long-term outcome in LTx. Only intraoperative ECMO use showed influence on long-term survival. However, our study has some limitations. First, this is a retrospective review, not including homogeneous donor and recipient groups; thus, we cannot exclude a reasonable bias. Unknown confounding factors may have influenced the results. Second, the number of patients included is not large enough to provide definitive results. Third, similarly as in the previous studies, we were unable to provide information about the quality of donor management before and after BD, which can well vary between different donor hospitals. Fourth, the time interval between brain injury and certified BD was unfortunately not documented and could have influenced the results of the present study. Whether lung retrieval teams can safely postpone organ retrieval in relation to other organs depends on the status of the donor. In haemodynamically unstable donors, the retrieval should be as quick as possible (rush and retrieve) as this might lead to loss of organs. On the other hand, a longer and better management of haemodynamic instability, fluid management and improved ventilator settings might reduce neurogenic oedema in the lung graft. Certainly, further research on larger samples is required to provide clearer and definitive results. In conclusion, the time interval from BD to CP had no impact on long-term outcome after LTx. Conflict of interest: none declared. REFERENCES [1] Avlonitis V, Fisher A, Kirby J, Darki J. Pulmonary transplantation: the role of brain death in donor lung injury. Transplantation 2003;75: [2] Thoracic organ: donation, waiting lists, and transplants. In: Rahmel A (ed). Annual Report 2013 of the Eurotransplant International Foundation. Leiden: Eurotransplant International Foundation. [3] Wijdicks EF, Varelas PN, Gronseth G, Greer DM. Evidence-based guidelines update: determining brain death on adults: report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2010;74: [4] Belzberg H, Shoemaker WC, Wo CC, Nicholls TP, Dang AB, Zelman V et al. Hemodynamic and oxygen transport patterns after head trauma and brain death: implications for management of the organ donor. J Trauma 2007;63: [5] Smith M. Physiologic changes during brain stem death lessons for management of the organ donor. J Heart Lung Transplant 2004;23:S [6] Pratschke J, Wilhelm MJ, Kusaka M, Laskowski I, Tilney NL. A model of gradual onset brain death for transplant-associated studies in rats. Transplantation 2000;69: [7] Waller DA, Thompson AM, Wrightson WN, Gould FK, Corris PA, Hilton CJ et al. Does the mode of donor death influence the early outcome of lung transplantation? A review of lung transplantation from donors involved in major trauma. J Heart Lung Transplant 1995;14: [8] Ciccone AM, Stewart KC, Meyers BF, Guthrie TJ, Battafarano RJ, Trulock EP et al. Does donor cause of death affect the outcome of lung transplantation? J Thorac Cardiovasc Surg 2002;123: [9] Ganesh JS, Rogers CA, Banner NR, Bonser RS. Donor cause of death and mid-term survival in lung transplantation. J Heart Lung Transplant 2005; 24: [10] Shingal AK, Sheng X, Drakos SG, Stehlik J. Impact of donor cause of death on transplant outcomes: UNOS registry analysis. Transplant Proc 2009;41: [11] Wauters S, Verleden GM, Belmans A, Coosemans W, De Leyn P, Nafteux P et al. Donor cause of brain death and related time intervals: does it affect outcome after lung transplantation? Eur J Cardiothorac Surg 2011;39: e [12] Moreno P, Alvarez A, Illana J, Espinosa D, Baamonde C, Cerezo F et al. Early lung retrieval from traumatic brain-dead donors does not compromise outcomes following lung transplantation. Eur J Cardiothorac Surg 2013; 43:e [13] Wauters S, Somers J, De Vleeschauwer S, Verbeken E, Verleden GM, van Loon J et al. Evaluating lung injury at increasing time intervals in a murine brain death model. J Surg Res 2013;183: [14] Orens JB, Boehler A, de Perrot M, Estenne M, Glanville AR, Keshavjee S et al. A review of lung transplant donor acceptability criteria. J Heart Lung Transplant 2003;22: [15] Orens JB, Estenne M, Arcasoy S, Conte JV, Corris P, Egan JJ et al. International Guidelines for the Selection of Lung Transplant Candidates: 2006 update a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25: [16] van der Hoeven JA, Molema G, Ter Horst GJ, Freund RL, Wiersema J, van Schilfgaarde R et al. Relationship between duration of brain death and hemodynamic (in)stability on progressive dysfunction and increased immunologic activation of donor kidneys. Kidney Int 2003;64: [17] Floerchinger B, Oberhuber R, Tullius SG. Effects of brain death on organ quality and transplant outcome. Transplant Rev 2012;26:54 9. [18] Avlonitis VS, Wigfield CG, Golledge HD, Kirby JA, Dark JH. Early hemodynamic injury during donor brain death determines the severity of primary graft dysfunction after lung transplantation. Am J Transplant 2007;7:83 90.

Early lung retrieval from traumatic brain-dead donors does not compromise outcomes following lung transplantation

European Journal of Cardio-Thoracic Surgery 43 (2013) e190 e197 doi:10.1093/ejcts/ezt033 Advance Access publication 20 February 2013 ORIGINAL ARTICLE a b Early lung retrieval from traumatic brain-dead