American Journal of Transplantation 2015; 15: 993–1002 Wiley Periodicals Inc.
C
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13124
Lung Transplantation With Donation After Circulatory Determination of Death Donors and the Impact of Ex Vivo Lung Perfusion T. N. Machuca, O. Mercier, S. Collaud, J. Tikkanen, T. Krueger, J. C. Yeung, M. Chen, S. Azad, L. Singer, K. Yasufuku, M. de Perrot, A. Pierre, T. K. Waddell, S. Keshavjee and M. Cypel* Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada Corresponding author: Marcelo Cypel, [email protected]
The growing demand for suitable lungs for transplantation drives the quest for alternative strategies to expand the donor pool. The aim of this study is to evaluate the outcomes of lung transplantation (LTx) with donation after circulatory determination of death (DCDD) and the impact of selective ex vivo lung perfusion (EVLP). From 2007 to 2013, 673 LTx were performed, with 62 (9.2%) of them using DCDDs (seven bridged cases). Cases bridged with mechanical ventilation/extracorporeal life support were excluded. From 55 DCDDs, 28 (51%) underwent EVLP. Outcomes for LTx using DCDDs and donation after neurological determination of death (DNDD) donors were similar, with 1 and 5-year survivals of 85% and 54% vs 86% and 62%, respectively (p ¼ 0.43). Although comparison of survival curves between DCDD þ EVLP vs DCDD-no EVLP showed no significant difference, DCDD þ EVLP cases presented shorter hospital stay (median 18 vs. 23 days, p ¼ 0.047) and a trend toward shorter length of mechanical ventilation (2 vs. 3 days, p ¼ 0.059). DCDDs represent a valuable source of lungs for transplantation, providing similar results to DNDDs. EVLP seems an important technique in the armamentarium to safely increase lung utilization from DCDDs; however, further studies are necessary to better define the role of EVLP in this context. Abbreviations: BMI, body mass index; BP, blood pressure; DCDD, donation after circulatory determination of death; DNDD, donation after neurological determination of death; ECLS, extracorporeal life support; EVLP, ex vivo lung perfusion; FiO2, fraction of inspired oxygen; ICU, intensive care unit; LTx, lung transplantation; OR, operating room; PaO2, partial arterial pressure of oxygen; P/F, partial arterial pressure of oxygen/fraction of inspired oxygen; PEEP, positive end expiratory pressure; PGD, primary graft
dysfunction; PGE, prostaglandin; US, United States; WLST, withdrawal of life sustaining therapies Received 05 August 2014, revised 28 October 2014 and accepted for publication 29 October 2014
Introduction The preclinical foundations for lung donation after circulatory determination of death (DCDD) were revisited by Egan et al in 1991. His group initially showed that non-ventilated canine lungs procured 1 hour after cardiac arrest could sustain life for at least 8 hours once transplanted into a recipient with the contra-lateral pulmonary artery ligated (1). The same group further highlighted the importance of oxygen ventilation in order to maintain cell viability for hours after circulatory arrest (2,3). Clinically, successful lung transplantation (LTx) using controlled DCDDs was first reported by Love et al, in 1993 (4). In the late 90s early 2000s, several reports and small series followed, supporting the use of DCDD lungs but also suggesting caution with the use of organs prone to a series of injuries (such as hypotension, hypoxia, aspiration and warm ischemia), especially during the interval between withdrawal of life sustaining therapies (WLST) and organ recovery (5). Despite the increasing number of LTxs performed each year (6), the clear imbalance between patients being listed and the number of suitable donor lungs available for transplantation still generates considerable waitlist mortality (7,8). Although more recent series have described the growing worldwide successful experience with the use of DCDDs (9,10), its promise as a source of donor lungs with real potential to address the striking inequality between supply and demand is still modest: while 1617 kidney transplants were performed from DCDDs in the United States in 2012 (14.4% of all deceased donor kidney transplants), there were only 32 contemporary DCDD LTxs (1.9% of all deceased donor lung transplants) (11,12). Ex vivo lung perfusion (EVLP) is a modern preservation technique to assess and treat high-risk donor lungs (13). It was first utilized clinically by Steen et al in 2001 to further assess DCDD lungs (14). At that time, EVLP was used for a ‘‘quick check’’ (65 minutes) of donor lungs with 993
Machuca et al
questionable function. Cypel et al, from the Toronto Lung Transplant Program, further mastered the methodology to allow for prolonged perfusion periods (up to 12 hours) and repeated functional assessments (15). The clinical experience has been repeatedly reported as successful, with high-risk donor lungs presenting similar outcomes to those lungs from standard criteria donors (16,17). We report herein our experience with DCDD LTxs and describe how it compares to our donation after neurological determination of death (DNDD) donor contemporaneous cohort. However, our main study objective is focused on the use of EVLP to evaluate DCDD lungs and its impact on outcomes. To the best of our knowledge, this paper encompasses one of the largest single-center experiences to date with DCDD LTx.
Methods This is a retrospective analysis of a prospective database comprising LTxs performed from January 2007 to November 2013. The Research Ethics Board of University Health Network approved this study and consent from patients was waived due its retrospective nature. All patients were informed about the possibility of receiving DCDD lungs at the time of informed consent for the LTx procedure. Moreover, at this same clinic visit, signed consent to utilize EVLP lungs was granted until 2011. After 2011 Health Canada approved the use of EVLP and therefore recipients did not require specific consent. Every recipient in our waiting list was a candidate to receive DCDD lungs and EVLP lungs. All DCDDs were Maastricht category III (donors awaiting cardiac arrest).
Donor selection From February 2009 to January 2010, every DCDD donor lung was included in the EVLP arm of our Human ex vivo Lung Perfusion clinical trial (n ¼ 8 cases). Subsequently, indications of high-risk DCDD donor lungs that required EVLP included any of the following: (1) last PaO2/FiO2 (P/F) < than 300 mmHg; (2) pulmonary edema detected on chest X-ray or during examination of the lungs at procurement; (3) poor lung compliance during examination of the lungs at procurement; (4) high-risk history (e.g. multiple blood transfusions, questionable history of aspiration)(16,17); (5) interval between WLST and arrest >60 minutes.
Donor procedure The DCDD donor procedure is performed by members of the Toronto Lung Transplant Program. Different from DNDDs, when we send only one procurement surgeon, two surgeons are involved in the DCDD donor operation in order to minimize the warm ischemic time and also to facilitate reintubation and bronchoscopy while the first surgeon is performing the sternotomy/cannulation. Current DCDD protocols entail that WLST is to be done in the ICU, in the postanesthetic care unit or in the OR, depending on local policies. In our cases, more than 90% this occurred in the ICU environment. Five minutes before WLST, the patient is heparinized with at least 300 units/kg. The patient is then extubated and any vasoactive drug is discontinued. After death is confirmed by two intensive care physicians, there is a ‘‘no touch’’ period of 5 minutes for confirmation of absent vital signs. Finally, the donor is taken to the procurement OR. The donor is reintubated, ventilation is resumed with a tidal volume of 7 mL/kg, 5 cm H2O of PEEP and 50% FiO2. A bronchoscopy is then
994
performed to assess for signs of aspiration, purulence or anatomical abnormalities. A bronchial washing is collected for culture and sensitivities. Concomitant with the bronchoscopy, the first procurement surgeon performs a median sternotomy, cannulates the pulmonary artery and injects 500 mcg of PGE1 into it, followed by five manual cardiac compressions for drug distribution. The subsequent steps are the same as for a DNDD donors. Briefly, 4 L of perfadex solution are flushed antegradely followed by cardiectomy and then a retrograde flush with 250 mL per pulmonary vein. Careful macroscopic inspection is performed after the lungs are removed out of the thoracic cavity.
Ex vivo lung perfusion (EVLP) EVLP was performed according to the technique previously described(16). Briefly, donor lungs were preserved and transported to the recipient site using cold static preservation. In the Organ Regeneration Laboratory, a dedicated organ perfusion room at Toronto General Hospital operating room, they were prepared with cannulation of the left atrium and pulmonary artery followed by intubation of the trachea. Lungs were perfused with Steen solution (with the addition of 3000 UI of heparin, 500 mg of methylprednisolone and 500 mg of imipenem/cilastatin). Temperature and flow were gradually increased up to 378C and 40% of the predicted donor cardiac output, respectively. Ventilation was resumed with 7 mL/kg, PEEP 5 cm H2O, 7 breaths/minute and 30% FiO2 when a temperature of 338C was reached. Decision as to whether to transplant the lungs or not was made based on sequential hourly assessments (with ventilation increased to 10 mL/kg, 10 breaths/minute and 100% FiO2 for 5 minutes prior to each assessment) comprised of pulmonary artery pressure, pulmonary compliance, airway pressures and perfusate pO2. Chest x-ray and bronchoscopic evaluation performed at 1 hour and 3 hours were also used in the decisionmaking process. Acceptance criteria for EVLP included a P/F > 400 mmHg at the last hour and improving or stable (
C
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13124
Lung Transplantation With Donation After Circulatory Determination of Death Donors and the Impact of Ex Vivo Lung Perfusion T. N. Machuca, O. Mercier, S. Collaud, J. Tikkanen, T. Krueger, J. C. Yeung, M. Chen, S. Azad, L. Singer, K. Yasufuku, M. de Perrot, A. Pierre, T. K. Waddell, S. Keshavjee and M. Cypel* Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, ON, Canada Corresponding author: Marcelo Cypel, [email protected]
The growing demand for suitable lungs for transplantation drives the quest for alternative strategies to expand the donor pool. The aim of this study is to evaluate the outcomes of lung transplantation (LTx) with donation after circulatory determination of death (DCDD) and the impact of selective ex vivo lung perfusion (EVLP). From 2007 to 2013, 673 LTx were performed, with 62 (9.2%) of them using DCDDs (seven bridged cases). Cases bridged with mechanical ventilation/extracorporeal life support were excluded. From 55 DCDDs, 28 (51%) underwent EVLP. Outcomes for LTx using DCDDs and donation after neurological determination of death (DNDD) donors were similar, with 1 and 5-year survivals of 85% and 54% vs 86% and 62%, respectively (p ¼ 0.43). Although comparison of survival curves between DCDD þ EVLP vs DCDD-no EVLP showed no significant difference, DCDD þ EVLP cases presented shorter hospital stay (median 18 vs. 23 days, p ¼ 0.047) and a trend toward shorter length of mechanical ventilation (2 vs. 3 days, p ¼ 0.059). DCDDs represent a valuable source of lungs for transplantation, providing similar results to DNDDs. EVLP seems an important technique in the armamentarium to safely increase lung utilization from DCDDs; however, further studies are necessary to better define the role of EVLP in this context. Abbreviations: BMI, body mass index; BP, blood pressure; DCDD, donation after circulatory determination of death; DNDD, donation after neurological determination of death; ECLS, extracorporeal life support; EVLP, ex vivo lung perfusion; FiO2, fraction of inspired oxygen; ICU, intensive care unit; LTx, lung transplantation; OR, operating room; PaO2, partial arterial pressure of oxygen; P/F, partial arterial pressure of oxygen/fraction of inspired oxygen; PEEP, positive end expiratory pressure; PGD, primary graft
dysfunction; PGE, prostaglandin; US, United States; WLST, withdrawal of life sustaining therapies Received 05 August 2014, revised 28 October 2014 and accepted for publication 29 October 2014
Introduction The preclinical foundations for lung donation after circulatory determination of death (DCDD) were revisited by Egan et al in 1991. His group initially showed that non-ventilated canine lungs procured 1 hour after cardiac arrest could sustain life for at least 8 hours once transplanted into a recipient with the contra-lateral pulmonary artery ligated (1). The same group further highlighted the importance of oxygen ventilation in order to maintain cell viability for hours after circulatory arrest (2,3). Clinically, successful lung transplantation (LTx) using controlled DCDDs was first reported by Love et al, in 1993 (4). In the late 90s early 2000s, several reports and small series followed, supporting the use of DCDD lungs but also suggesting caution with the use of organs prone to a series of injuries (such as hypotension, hypoxia, aspiration and warm ischemia), especially during the interval between withdrawal of life sustaining therapies (WLST) and organ recovery (5). Despite the increasing number of LTxs performed each year (6), the clear imbalance between patients being listed and the number of suitable donor lungs available for transplantation still generates considerable waitlist mortality (7,8). Although more recent series have described the growing worldwide successful experience with the use of DCDDs (9,10), its promise as a source of donor lungs with real potential to address the striking inequality between supply and demand is still modest: while 1617 kidney transplants were performed from DCDDs in the United States in 2012 (14.4% of all deceased donor kidney transplants), there were only 32 contemporary DCDD LTxs (1.9% of all deceased donor lung transplants) (11,12). Ex vivo lung perfusion (EVLP) is a modern preservation technique to assess and treat high-risk donor lungs (13). It was first utilized clinically by Steen et al in 2001 to further assess DCDD lungs (14). At that time, EVLP was used for a ‘‘quick check’’ (65 minutes) of donor lungs with 993
Machuca et al
questionable function. Cypel et al, from the Toronto Lung Transplant Program, further mastered the methodology to allow for prolonged perfusion periods (up to 12 hours) and repeated functional assessments (15). The clinical experience has been repeatedly reported as successful, with high-risk donor lungs presenting similar outcomes to those lungs from standard criteria donors (16,17). We report herein our experience with DCDD LTxs and describe how it compares to our donation after neurological determination of death (DNDD) donor contemporaneous cohort. However, our main study objective is focused on the use of EVLP to evaluate DCDD lungs and its impact on outcomes. To the best of our knowledge, this paper encompasses one of the largest single-center experiences to date with DCDD LTx.
Methods This is a retrospective analysis of a prospective database comprising LTxs performed from January 2007 to November 2013. The Research Ethics Board of University Health Network approved this study and consent from patients was waived due its retrospective nature. All patients were informed about the possibility of receiving DCDD lungs at the time of informed consent for the LTx procedure. Moreover, at this same clinic visit, signed consent to utilize EVLP lungs was granted until 2011. After 2011 Health Canada approved the use of EVLP and therefore recipients did not require specific consent. Every recipient in our waiting list was a candidate to receive DCDD lungs and EVLP lungs. All DCDDs were Maastricht category III (donors awaiting cardiac arrest).
Donor selection From February 2009 to January 2010, every DCDD donor lung was included in the EVLP arm of our Human ex vivo Lung Perfusion clinical trial (n ¼ 8 cases). Subsequently, indications of high-risk DCDD donor lungs that required EVLP included any of the following: (1) last PaO2/FiO2 (P/F) < than 300 mmHg; (2) pulmonary edema detected on chest X-ray or during examination of the lungs at procurement; (3) poor lung compliance during examination of the lungs at procurement; (4) high-risk history (e.g. multiple blood transfusions, questionable history of aspiration)(16,17); (5) interval between WLST and arrest >60 minutes.
Donor procedure The DCDD donor procedure is performed by members of the Toronto Lung Transplant Program. Different from DNDDs, when we send only one procurement surgeon, two surgeons are involved in the DCDD donor operation in order to minimize the warm ischemic time and also to facilitate reintubation and bronchoscopy while the first surgeon is performing the sternotomy/cannulation. Current DCDD protocols entail that WLST is to be done in the ICU, in the postanesthetic care unit or in the OR, depending on local policies. In our cases, more than 90% this occurred in the ICU environment. Five minutes before WLST, the patient is heparinized with at least 300 units/kg. The patient is then extubated and any vasoactive drug is discontinued. After death is confirmed by two intensive care physicians, there is a ‘‘no touch’’ period of 5 minutes for confirmation of absent vital signs. Finally, the donor is taken to the procurement OR. The donor is reintubated, ventilation is resumed with a tidal volume of 7 mL/kg, 5 cm H2O of PEEP and 50% FiO2. A bronchoscopy is then
994
performed to assess for signs of aspiration, purulence or anatomical abnormalities. A bronchial washing is collected for culture and sensitivities. Concomitant with the bronchoscopy, the first procurement surgeon performs a median sternotomy, cannulates the pulmonary artery and injects 500 mcg of PGE1 into it, followed by five manual cardiac compressions for drug distribution. The subsequent steps are the same as for a DNDD donors. Briefly, 4 L of perfadex solution are flushed antegradely followed by cardiectomy and then a retrograde flush with 250 mL per pulmonary vein. Careful macroscopic inspection is performed after the lungs are removed out of the thoracic cavity.
Ex vivo lung perfusion (EVLP) EVLP was performed according to the technique previously described(16). Briefly, donor lungs were preserved and transported to the recipient site using cold static preservation. In the Organ Regeneration Laboratory, a dedicated organ perfusion room at Toronto General Hospital operating room, they were prepared with cannulation of the left atrium and pulmonary artery followed by intubation of the trachea. Lungs were perfused with Steen solution (with the addition of 3000 UI of heparin, 500 mg of methylprednisolone and 500 mg of imipenem/cilastatin). Temperature and flow were gradually increased up to 378C and 40% of the predicted donor cardiac output, respectively. Ventilation was resumed with 7 mL/kg, PEEP 5 cm H2O, 7 breaths/minute and 30% FiO2 when a temperature of 338C was reached. Decision as to whether to transplant the lungs or not was made based on sequential hourly assessments (with ventilation increased to 10 mL/kg, 10 breaths/minute and 100% FiO2 for 5 minutes prior to each assessment) comprised of pulmonary artery pressure, pulmonary compliance, airway pressures and perfusate pO2. Chest x-ray and bronchoscopic evaluation performed at 1 hour and 3 hours were also used in the decisionmaking process. Acceptance criteria for EVLP included a P/F > 400 mmHg at the last hour and improving or stable (
