Original Clinical Science
Clinical Outcome of Patients Transplanted with Marginal Donor Lungs via Ex Vivo Lung Perfusion Compared to Standard Lung Transplantation James E. Fildes,1,2 Louise D. Archer,1 John Blaikley,1 Alexandra L. Ball,1,2 John P. Stone,1,2 Trygve Sjöberg,3 Stig Steen,3 and Nizar Yonan1 Background. Lung transplantation is limited by a scarcity of suitable donors resulting in high waiting list mortality. Ex vivo lung perfusion (EVLP) allows the evaluation and reconditioning of marginal donor lungs for use in transplantation. This study aimed to compare clinical outcome of patients transplanted with marginal organs by means of EVLP with a standard lung transplant cohort through a multicenter open trial. Methods. Group 1 (n = 9) included patients transplanted using EVLP reconditioned marginal lungs. Group 2 (n = 46) consisted of date-matched patients transplanted using standard transplantation of acceptable lungs. The primary composite endpoint included acute rejection and infection at 12 months after transplantation. Results. There was no significant difference in the overall incidence of acute rejection (P = 0.754) and the number of treated infection episodes (proven/probable pneumonia; P = 0.857/0.368 and proven/probable tracheobronchitis; P = 0.226/0.529) up to 12 months after transplantation, between group 1 and group 2. Additionally, there was no significant difference in early clinical outcome, including intensive care unit stay, hospital stay, and 1 year mortality between the two groups (P = 0.338, P = 0.112 and P = 0.372, respectively). Discussion. This multicenter study demonstrates that EVLP is associated with no adverse effect on clinical outcome, including the incidence of acute rejection and infection after lung transplantation.
(Transplantation 2015;99: 1078–1083)
S
everal strategies have been proposed to increase the number of donor lungs available for transplantation, including extending donor selection criteria, and more recently, reconditioning donor organs using ex vivo lung perfusion (EVLP). Ex vivo lung perfusion is a novel intervention that allows unusable donor lungs to be assessed in the recipient hospital and potentially reconditioned for successful transplantation.
Received 14 April 2014. Revision requested 9 May 2014. Accepted 26 August 2014. 1 The Transplant Centre, University Hospital of South Manchester, Manchester, United Kingdom. 2
The Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, United Kingdom.
3
Department of Cardiothoracic Surgery, Lund University Hospital, Sweden.
The authors declare no funding or conflicts of interest. L.D.A. and J.B. contributed equally in this article. J.E.F. participated in research design, participated in the performance of the research, participated in writing the article, and participated in data analysis. L.D.A., S.R., J.B., A.B., and J.S. participated in writing the article and participated in data analysis. T.S., S.S., and N.Y. participated in the performance of the research and participated in writing the article. Correspondence: James Fildes, PhD, FSB, The Transplant Centre, University Hospital of South Manchester, Manchester M23 9LT, United Kingdom. ([email protected]) Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9905-1078 DOI: 10.1097/TP.0000000000000462
1078
www.transplantjournal.com
Ex vivo lung perfusion was reported for the first time in 20011 and later described in detail in a porcine model.2 After this, a clinical nonrandomized study has reported a lower incidence of primary graft failure in patients receiving EVLP, reconditioned, suboptimal donor lungs, when compared to patients transplanted with lungs within acceptable donor criteria using standard procedure.3 In this cohort, there were no reports of grade 3 primary graft failure in the EVLP group at 72 hr, despite significant impairment at baseline compared to the control group. This is a relevant finding, suggesting EVLP imparts a physiologically reparative effect on the donor lung. Ex vivo lung perfusion has now become a key research area on a global scale. Yet, to date, the effects of EVLP on early and mid-term outcome, with regards to the incidence of acute rejection and infection at 12 months after transplantation remains unclear. We aimed to comparatively assess clinical outcome of patients transplanted using marginal lungs after EVLP with a standard lung transplant cohort. RESULTS A total of 55 patients were recruited into the study; each receiving a double lung transplant. Nine patients received a marginal donor organ that had been reconditioned using EVLP (group 1). The remaining patients (n=46) underwent standard lung transplantation without EVLP (group 2). There were no statistically significant demographic differences between the two recipient groups (Table 1). There were no demographic differences between the donors, with the Transplantation
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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May 2015
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Volume 99
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Number 5
1079
Fildes et al
© 2014 Wolters Kluwer
TABLE 1.
Recipient and donor demographics table demonstrating that there are no statistically significant recipient demographic differences (age, sex, and diagnosis) between patients receiving EVLP reconditioned lungs and those receiving a standard transplant EVLP (n = 9)
Recipient demographics
Donor demographics
Mean age Sex COPD* Bronchiectasis Cystic fibrosis Primary pulmonary hypertension Idiopathic pulmonary fibrosis Mean age Sex Ventilation time (hours) Mean PaO2 ratio (kPa)
53 (±9.4) 5M, 4F (55.6%, 44.4%) Diagnosis 6 (66.7%) 0 (0%) 1 (11.1%) 1 (11.1%) 1 (11.1%) 54 (±10.1) 5M, 4F (55.6%, 44.4%) 40.6 (± 16.2) 30.5 (± 9.7)
Standard (n = 46)
P
49 (±12.0) 22M, 24F (47.8%, 52.2%)
0.312 0.729
24 (52.2%) 7 (15.2%) 9 (19.6%) 3 (6.5%) 3 (6.5%) 45 (±13.1) 16M, 30F (34.8%, 65.2%) 49.9 (± 41.45) 60.4 (± 11.6)
0.487 0.585 1.000 0.522 0.522 0.067 0.279 0.959 30 kPa on FiO2 of 1.0) • Pulmonary artery pressure < 20 mmHg whilst achieving stable perfusate flow at 37°C • Peak airway pressure < 25 cmH2O whilst achieving adequate ventilation • No pulmonary edema in the endotracheal tube • Easily recruited atelectasis • Stable or improving lung compliance
• Stable or falling lung resistance • Satisfactory assessment on inspection and palpation • Satisfactory deflation test on disconnection of the endotracheal tube
of the airways, specifically for fluid accumulation and subsequent suctioning. In the presence of atelectasis, recruitment manoeuvres could be performed through temporary increases in positive end expiratory pressure (PEEP). After a period of up to 4 hr of perfusion and reconditioning, the EVLP group were then reassessed to determine whether they fulfilled the assessment criteria for transplantation. These criteria were based on improvements in appearance, lung mechanics and ventilatory compliance, and gaseous exchange. Specifically they had to successfully complete a deflation test after disconnection of the endotracheal tube, and achieve a target PaO2 above 300 mm Hg (40 kPa) at FiO2 1.0 and PEEP 5 cm H2O on disconnection of the oxygenator. After transplantation, all patients received standard posttransplant care. On discharge, they were reviewed in outpatient clinic where lung function, chest x-ray, clinical examination, and blood tests were performed. This was done on a weekly basis initially for the first month, and then reduced to two to four weekly and then six to eight weekly appointments dependent on progress within the first year of transplantation. Acute Rejection Incidence
Both EVLP and standard lung transplant patients underwent bronchoscopy with transbronchial biopsies at standardized timepoints posttransplant to determine the presence or absence of acute cellular rejection. All patients had a surveillance bronchoscopy with biopsies at approximately 2 weeks after transplantation. If the biopsy sample revealed evidence of A2 rejection or more, the procedure was repeated after 4 to 6 weeks after appropriate treatment. Repeat procedures were then continually performed over the same time intervals, until there was zero or minimal, (A1) rejection. When zero or A1 rejection was demonstrated on biopsy, repeat
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1082
Transplantation
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May 2015
■
Volume 99
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Number 5
www.transplantjournal.com
FIGURE 1. A, Infections were defined according to the ISHLT guidelines.14 For infections to be characterized as proven pneumonia the patient had to exhibit clinical symptoms, CXR changes and positive culture(s). In the absence of a positive culture, pneumonia was defined as probable. Infections were classified as proven tracheobronchitis if the patient presented clinical symptoms and positive cultures, but failed to demonstrate CXR changes. Again, in the absence of a positive culture, the infection was deemed probable. In addition, patients were classified as having CMV if they presented clinical symptoms, positive CXR and positive viral blood culture results. B–F, Kaplan–Meier plots for infection episode occurrence between lung transplant recipients receiving EVLP reconditioned lungs (group 1) and those receiving a standard lung transplant (group 2), up to 12 months after lung transplantation. No significant difference was found between the two groups for proven pneumonia (P = 0.857; B), probable pneumonia (P = 0.368; C), proven tracheobronchitis (P = 0.226; D), and probable tracheobronchitis (P = 0.529; E). However, there was a significant difference in the overall incidence of symptomatic CMV infection in the EVLP group, compared to the standard lung transplant group, at 12 months after transplantation (P = 0.001; F). EVLP, ex vivo lung perfusion; ISHLT, International Society for Heart and Lung Transplantation; CXR, chest x-ray; CMV, cytomegalovirus.
bronchoscopies and biopsies were only subsequently performed if there was a decline in lung function or the patient experienced increased breathlessness in the absence of an alternative cause, specifically infection. Histologic diagnosis of rejection was determined by a principal histopathologist according to International Society for Heart and Lung Transplantation (ISHLT) guidelines. Acute rejection (grade A2 or A3; excluding A1) was considered as a unique episode until a grade of zero was given (i.e., multiple positive biopsies were considered one episode). Infection Incidence
Infection episodes were defined according to ISHLT guidelines (Fig. 1A), requiring a clinician’s interpretation of the patient’s medical history (clinical signs, symptoms and treatment changes), chest x-rays and microbiologic determination of specimen (BAL, blood, urine) culture results.15 In this way, infections were categorised as either: proven pneumonia,
probable pneumonia, proven bronchitis, probable bronchitis, symptomatic CMV, or other.15 Statistical Analysis
Data normality was determined by assessing the descriptive statistics, mean, standard deviation, skewness, and kurtosis. Parametric data sets were analyzed using the independent t test (including donor-recipient age, donor PaO2, and recipient hospital stay). Nonparametric data sets were analyzed using the Mann-Whitney U test (including; donor ventilation time and recipient ICU stay). Recipient diagnosis, donor-recipient ventilation times and postoperative outcomes at 30, 90, and 365 days (mortality, proven or probable pneumonia, proven or probable tracheobronchitis, CMV infection, and other infections) were analyzed by means of the Pearson chi-square or Fisher exact t test. Mortality and the time to the first infection episode (for each infection classification individually) and rejection episode for each transplant group were
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Fildes et al
© 2014 Wolters Kluwer
1083
FIGURE 2. A and B, Boxplots demonstrating no significant difference in total ICU stay (P = 0.338; standard median, 10 days; IQR, 12.5; EVLP median, 19 days; IQR, 24.5) (A) and total hospital stay (P = 0.112; standard median, 39 days; IQR, 22 days; EVLP median, 54 days; IQR, 15.5) (B) between patients receiving a standard transplant and EVLP reconditioned lungs. C, Kaplan-Meier plot for first rejection episode occurrence between lung transplant recipients receiving EVLP reconditioned lungs (group 1) and those receiving a standard lung transplantation (group 2), up to 12 months after lung transplantation. No significant difference was found between the two groups (P = 0.754). D, Kaplan–Meier plot for mortality occurrence between lung transplant recipients receiving EVLP reconditioned lungs (group 1) and those receiving a standard lung transplant (group 2), up to 12 months after lung transplantation. No significant difference was found between the two groups (P = 0.372). EVLP, ex vivo lung perfusion; IQR, interquartile range; ICU, intensive care unit.
also analyzed using the Kaplan-Meier Survival Test. All P values less than 0.05 were considered statistically significant. ACKNOWLEDGMENTS The authors would like to thank Siobhan Regan for assistance in collecting data for this study. REFERENCES 1. Steen S, Sjoberg T, Pierre L, et al. Transplantation of lungs from a nonheart-beating donor. Lancet 2001;357:825. 2. Steen S, Liao Q, Wierup PN, et al. Transplantation of lungs from nonheart-beating donors after functional assessment ex vivo. Ann Thorac Surg 2003;76:244 discussion 252. 3. Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med 2011;364:1431. 4. Faropoulos K, Apostolakis E. Brain death and its influence on the lungs of the donor: how is it prevented? Transplant Proc 2009;41:4114. 5. Schiavon M, Falcoz PE, Santelmo N, et al. Does the use of extended criteria donors influence early and long-term results of lung transplantation? Interact Cardiovasc Thorac Surg. 2012;14:183. 6. Ingemansson R, Eyjolfsson A, Mared L, et al. Clinical transplantation of initially rejected donor lungs after reconditioning ex vivo. Ann Thorac Surg 2009;87:255.
7. Lindstedt S, Hlebowicz J, Koul B, et al. Comparative outcome of double lung transplantation using conventional donor lungs and nonacceptable donor lungs reconditioned ex vivo. Interact Cardiovasc Thorac Surg 2011;12:162. 8. Cypel M, Yeung JC, Machuca T, et al. Experience with the first 50 ex vivo lung perfusions in clinical transplantation. J Thorac Cardiovasc Surg 2012;144:1200. 9. Aigner C, Slama A, Hotzenecker K, et al. Clinical ex vivo lung perfusion— pushing the limits. Am J Transplant 2012;12:1839. 10. Wallinder A, Steen S, Liden H, et al. Heparin does not improve graft function in uncontrolled non-heart-beating lung donation: an experimental study in pigs. Eur J Cardiothorac Surg 2013;43:413. 11. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-eighth adult lung and heart-lung transplant report—2011. J Heart Lung Transplant 2011;30:1104. 12. Garcıa-Gallo CL, Gil PU, Laporta R, et al. Is gammaglobulin anti-CMV warranted in lung transplantation? Transplant Proc 2005;37:4043. 13. Wierup P, Haraldsson A, Nilsson F, et al. Ex vivo evaluation of nonacceptable donor lungs. Ann Thorac Surg 2006;81:460. 14. Aigner C, Winkler G, Jaksch P, et al. Extended donor criteria for lung transplantation—a clinical reality. Eur J Cardiothorac Surg 2005;27:757. 15. Husain S, Mooney ML, Danziger-Isakov L, et al. A 2010 working formulation for the standardization of definitions of infections in cardiothoracic transplant recipients. J Heart Lung Transplant 30:361.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Clinical Outcome of Patients Transplanted with Marginal Donor Lungs via Ex Vivo Lung Perfusion Compared to Standard Lung Transplantation James E. Fildes,1,2 Louise D. Archer,1 John Blaikley,1 Alexandra L. Ball,1,2 John P. Stone,1,2 Trygve Sjöberg,3 Stig Steen,3 and Nizar Yonan1 Background. Lung transplantation is limited by a scarcity of suitable donors resulting in high waiting list mortality. Ex vivo lung perfusion (EVLP) allows the evaluation and reconditioning of marginal donor lungs for use in transplantation. This study aimed to compare clinical outcome of patients transplanted with marginal organs by means of EVLP with a standard lung transplant cohort through a multicenter open trial. Methods. Group 1 (n = 9) included patients transplanted using EVLP reconditioned marginal lungs. Group 2 (n = 46) consisted of date-matched patients transplanted using standard transplantation of acceptable lungs. The primary composite endpoint included acute rejection and infection at 12 months after transplantation. Results. There was no significant difference in the overall incidence of acute rejection (P = 0.754) and the number of treated infection episodes (proven/probable pneumonia; P = 0.857/0.368 and proven/probable tracheobronchitis; P = 0.226/0.529) up to 12 months after transplantation, between group 1 and group 2. Additionally, there was no significant difference in early clinical outcome, including intensive care unit stay, hospital stay, and 1 year mortality between the two groups (P = 0.338, P = 0.112 and P = 0.372, respectively). Discussion. This multicenter study demonstrates that EVLP is associated with no adverse effect on clinical outcome, including the incidence of acute rejection and infection after lung transplantation.
(Transplantation 2015;99: 1078–1083)
S
everal strategies have been proposed to increase the number of donor lungs available for transplantation, including extending donor selection criteria, and more recently, reconditioning donor organs using ex vivo lung perfusion (EVLP). Ex vivo lung perfusion is a novel intervention that allows unusable donor lungs to be assessed in the recipient hospital and potentially reconditioned for successful transplantation.
Received 14 April 2014. Revision requested 9 May 2014. Accepted 26 August 2014. 1 The Transplant Centre, University Hospital of South Manchester, Manchester, United Kingdom. 2
The Manchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, United Kingdom.
3
Department of Cardiothoracic Surgery, Lund University Hospital, Sweden.
The authors declare no funding or conflicts of interest. L.D.A. and J.B. contributed equally in this article. J.E.F. participated in research design, participated in the performance of the research, participated in writing the article, and participated in data analysis. L.D.A., S.R., J.B., A.B., and J.S. participated in writing the article and participated in data analysis. T.S., S.S., and N.Y. participated in the performance of the research and participated in writing the article. Correspondence: James Fildes, PhD, FSB, The Transplant Centre, University Hospital of South Manchester, Manchester M23 9LT, United Kingdom. ([email protected]) Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0041-1337/15/9905-1078 DOI: 10.1097/TP.0000000000000462
1078
www.transplantjournal.com
Ex vivo lung perfusion was reported for the first time in 20011 and later described in detail in a porcine model.2 After this, a clinical nonrandomized study has reported a lower incidence of primary graft failure in patients receiving EVLP, reconditioned, suboptimal donor lungs, when compared to patients transplanted with lungs within acceptable donor criteria using standard procedure.3 In this cohort, there were no reports of grade 3 primary graft failure in the EVLP group at 72 hr, despite significant impairment at baseline compared to the control group. This is a relevant finding, suggesting EVLP imparts a physiologically reparative effect on the donor lung. Ex vivo lung perfusion has now become a key research area on a global scale. Yet, to date, the effects of EVLP on early and mid-term outcome, with regards to the incidence of acute rejection and infection at 12 months after transplantation remains unclear. We aimed to comparatively assess clinical outcome of patients transplanted using marginal lungs after EVLP with a standard lung transplant cohort. RESULTS A total of 55 patients were recruited into the study; each receiving a double lung transplant. Nine patients received a marginal donor organ that had been reconditioned using EVLP (group 1). The remaining patients (n=46) underwent standard lung transplantation without EVLP (group 2). There were no statistically significant demographic differences between the two recipient groups (Table 1). There were no demographic differences between the donors, with the Transplantation
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
■
May 2015
■
Volume 99
■
Number 5
1079
Fildes et al
© 2014 Wolters Kluwer
TABLE 1.
Recipient and donor demographics table demonstrating that there are no statistically significant recipient demographic differences (age, sex, and diagnosis) between patients receiving EVLP reconditioned lungs and those receiving a standard transplant EVLP (n = 9)
Recipient demographics
Donor demographics
Mean age Sex COPD* Bronchiectasis Cystic fibrosis Primary pulmonary hypertension Idiopathic pulmonary fibrosis Mean age Sex Ventilation time (hours) Mean PaO2 ratio (kPa)
53 (±9.4) 5M, 4F (55.6%, 44.4%) Diagnosis 6 (66.7%) 0 (0%) 1 (11.1%) 1 (11.1%) 1 (11.1%) 54 (±10.1) 5M, 4F (55.6%, 44.4%) 40.6 (± 16.2) 30.5 (± 9.7)
Standard (n = 46)
P
49 (±12.0) 22M, 24F (47.8%, 52.2%)
0.312 0.729
24 (52.2%) 7 (15.2%) 9 (19.6%) 3 (6.5%) 3 (6.5%) 45 (±13.1) 16M, 30F (34.8%, 65.2%) 49.9 (± 41.45) 60.4 (± 11.6)
0.487 0.585 1.000 0.522 0.522 0.067 0.279 0.959 30 kPa on FiO2 of 1.0) • Pulmonary artery pressure < 20 mmHg whilst achieving stable perfusate flow at 37°C • Peak airway pressure < 25 cmH2O whilst achieving adequate ventilation • No pulmonary edema in the endotracheal tube • Easily recruited atelectasis • Stable or improving lung compliance
• Stable or falling lung resistance • Satisfactory assessment on inspection and palpation • Satisfactory deflation test on disconnection of the endotracheal tube
of the airways, specifically for fluid accumulation and subsequent suctioning. In the presence of atelectasis, recruitment manoeuvres could be performed through temporary increases in positive end expiratory pressure (PEEP). After a period of up to 4 hr of perfusion and reconditioning, the EVLP group were then reassessed to determine whether they fulfilled the assessment criteria for transplantation. These criteria were based on improvements in appearance, lung mechanics and ventilatory compliance, and gaseous exchange. Specifically they had to successfully complete a deflation test after disconnection of the endotracheal tube, and achieve a target PaO2 above 300 mm Hg (40 kPa) at FiO2 1.0 and PEEP 5 cm H2O on disconnection of the oxygenator. After transplantation, all patients received standard posttransplant care. On discharge, they were reviewed in outpatient clinic where lung function, chest x-ray, clinical examination, and blood tests were performed. This was done on a weekly basis initially for the first month, and then reduced to two to four weekly and then six to eight weekly appointments dependent on progress within the first year of transplantation. Acute Rejection Incidence
Both EVLP and standard lung transplant patients underwent bronchoscopy with transbronchial biopsies at standardized timepoints posttransplant to determine the presence or absence of acute cellular rejection. All patients had a surveillance bronchoscopy with biopsies at approximately 2 weeks after transplantation. If the biopsy sample revealed evidence of A2 rejection or more, the procedure was repeated after 4 to 6 weeks after appropriate treatment. Repeat procedures were then continually performed over the same time intervals, until there was zero or minimal, (A1) rejection. When zero or A1 rejection was demonstrated on biopsy, repeat
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1082
Transplantation
■
May 2015
■
Volume 99
■
Number 5
www.transplantjournal.com
FIGURE 1. A, Infections were defined according to the ISHLT guidelines.14 For infections to be characterized as proven pneumonia the patient had to exhibit clinical symptoms, CXR changes and positive culture(s). In the absence of a positive culture, pneumonia was defined as probable. Infections were classified as proven tracheobronchitis if the patient presented clinical symptoms and positive cultures, but failed to demonstrate CXR changes. Again, in the absence of a positive culture, the infection was deemed probable. In addition, patients were classified as having CMV if they presented clinical symptoms, positive CXR and positive viral blood culture results. B–F, Kaplan–Meier plots for infection episode occurrence between lung transplant recipients receiving EVLP reconditioned lungs (group 1) and those receiving a standard lung transplant (group 2), up to 12 months after lung transplantation. No significant difference was found between the two groups for proven pneumonia (P = 0.857; B), probable pneumonia (P = 0.368; C), proven tracheobronchitis (P = 0.226; D), and probable tracheobronchitis (P = 0.529; E). However, there was a significant difference in the overall incidence of symptomatic CMV infection in the EVLP group, compared to the standard lung transplant group, at 12 months after transplantation (P = 0.001; F). EVLP, ex vivo lung perfusion; ISHLT, International Society for Heart and Lung Transplantation; CXR, chest x-ray; CMV, cytomegalovirus.
bronchoscopies and biopsies were only subsequently performed if there was a decline in lung function or the patient experienced increased breathlessness in the absence of an alternative cause, specifically infection. Histologic diagnosis of rejection was determined by a principal histopathologist according to International Society for Heart and Lung Transplantation (ISHLT) guidelines. Acute rejection (grade A2 or A3; excluding A1) was considered as a unique episode until a grade of zero was given (i.e., multiple positive biopsies were considered one episode). Infection Incidence
Infection episodes were defined according to ISHLT guidelines (Fig. 1A), requiring a clinician’s interpretation of the patient’s medical history (clinical signs, symptoms and treatment changes), chest x-rays and microbiologic determination of specimen (BAL, blood, urine) culture results.15 In this way, infections were categorised as either: proven pneumonia,
probable pneumonia, proven bronchitis, probable bronchitis, symptomatic CMV, or other.15 Statistical Analysis
Data normality was determined by assessing the descriptive statistics, mean, standard deviation, skewness, and kurtosis. Parametric data sets were analyzed using the independent t test (including donor-recipient age, donor PaO2, and recipient hospital stay). Nonparametric data sets were analyzed using the Mann-Whitney U test (including; donor ventilation time and recipient ICU stay). Recipient diagnosis, donor-recipient ventilation times and postoperative outcomes at 30, 90, and 365 days (mortality, proven or probable pneumonia, proven or probable tracheobronchitis, CMV infection, and other infections) were analyzed by means of the Pearson chi-square or Fisher exact t test. Mortality and the time to the first infection episode (for each infection classification individually) and rejection episode for each transplant group were
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Fildes et al
© 2014 Wolters Kluwer
1083
FIGURE 2. A and B, Boxplots demonstrating no significant difference in total ICU stay (P = 0.338; standard median, 10 days; IQR, 12.5; EVLP median, 19 days; IQR, 24.5) (A) and total hospital stay (P = 0.112; standard median, 39 days; IQR, 22 days; EVLP median, 54 days; IQR, 15.5) (B) between patients receiving a standard transplant and EVLP reconditioned lungs. C, Kaplan-Meier plot for first rejection episode occurrence between lung transplant recipients receiving EVLP reconditioned lungs (group 1) and those receiving a standard lung transplantation (group 2), up to 12 months after lung transplantation. No significant difference was found between the two groups (P = 0.754). D, Kaplan–Meier plot for mortality occurrence between lung transplant recipients receiving EVLP reconditioned lungs (group 1) and those receiving a standard lung transplant (group 2), up to 12 months after lung transplantation. No significant difference was found between the two groups (P = 0.372). EVLP, ex vivo lung perfusion; IQR, interquartile range; ICU, intensive care unit.
also analyzed using the Kaplan-Meier Survival Test. All P values less than 0.05 were considered statistically significant. ACKNOWLEDGMENTS The authors would like to thank Siobhan Regan for assistance in collecting data for this study. REFERENCES 1. Steen S, Sjoberg T, Pierre L, et al. Transplantation of lungs from a nonheart-beating donor. Lancet 2001;357:825. 2. Steen S, Liao Q, Wierup PN, et al. Transplantation of lungs from nonheart-beating donors after functional assessment ex vivo. Ann Thorac Surg 2003;76:244 discussion 252. 3. Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med 2011;364:1431. 4. Faropoulos K, Apostolakis E. Brain death and its influence on the lungs of the donor: how is it prevented? Transplant Proc 2009;41:4114. 5. Schiavon M, Falcoz PE, Santelmo N, et al. Does the use of extended criteria donors influence early and long-term results of lung transplantation? Interact Cardiovasc Thorac Surg. 2012;14:183. 6. Ingemansson R, Eyjolfsson A, Mared L, et al. Clinical transplantation of initially rejected donor lungs after reconditioning ex vivo. Ann Thorac Surg 2009;87:255.
7. Lindstedt S, Hlebowicz J, Koul B, et al. Comparative outcome of double lung transplantation using conventional donor lungs and nonacceptable donor lungs reconditioned ex vivo. Interact Cardiovasc Thorac Surg 2011;12:162. 8. Cypel M, Yeung JC, Machuca T, et al. Experience with the first 50 ex vivo lung perfusions in clinical transplantation. J Thorac Cardiovasc Surg 2012;144:1200. 9. Aigner C, Slama A, Hotzenecker K, et al. Clinical ex vivo lung perfusion— pushing the limits. Am J Transplant 2012;12:1839. 10. Wallinder A, Steen S, Liden H, et al. Heparin does not improve graft function in uncontrolled non-heart-beating lung donation: an experimental study in pigs. Eur J Cardiothorac Surg 2013;43:413. 11. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: twenty-eighth adult lung and heart-lung transplant report—2011. J Heart Lung Transplant 2011;30:1104. 12. Garcıa-Gallo CL, Gil PU, Laporta R, et al. Is gammaglobulin anti-CMV warranted in lung transplantation? Transplant Proc 2005;37:4043. 13. Wierup P, Haraldsson A, Nilsson F, et al. Ex vivo evaluation of nonacceptable donor lungs. Ann Thorac Surg 2006;81:460. 14. Aigner C, Winkler G, Jaksch P, et al. Extended donor criteria for lung transplantation—a clinical reality. Eur J Cardiothorac Surg 2005;27:757. 15. Husain S, Mooney ML, Danziger-Isakov L, et al. A 2010 working formulation for the standardization of definitions of infections in cardiothoracic transplant recipients. J Heart Lung Transplant 30:361.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
