Extracorporeal membrane oxygenation support before lung transplant: A bridge over troubled water

Abstract

Central MessageOutcomes from bridging to lung transplant are comparable with outcomes from standard transplant in cases with appropriate patient selection and "awake" extracorporeal membrane oxygenation.See Commentary on page 155. Outcomes from bridging to lung transplant are comparable with outcomes from standard transplant in cases with appropriate patient selection and "awake" extracorporeal membrane oxygenation. See Commentary on page 155. Every year, lung transplants save the lives of thousands of patients with irreversible end-stage lung disease. Despite an increased awareness of this condition and a trend toward early referral for transplant, an increasing proportion of patients who present for a lung transplant are critically ill.1Valapour M. Lehr C.J. Skeans M.A. Smith J.M. Uccellini K. Goff R. et al.OPTN/SRTR 2018 annual data report: lung.Am J Transplant. 2020; 20: 427-508Crossref PubMed Scopus (82) Google Scholar,2Benazzo A. Schwarz S. Frommlet F. Schweiger T. Jaksch P. Schellongowski P. et al.Twenty-year experience with extracorporeal life support as bridge to lung transplantation.J Thorac Cardiovasc Surg. 2019; 157: 2515-2525.e10Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Even the sickest patients and those who are near death can now benefit from innovative circulatory support strategies that will enable them to survive in good condition and with stable oxygen levels while they wait for an organ to become available. One such strategy, extracorporeal membrane oxygenation (ECMO), allows direct infusion of oxygenated blood into the circulation and clearance of carbon dioxide, irrespective of the condition of the patient's lungs. In the strictest definition, a bridge-to-transplant (BTT) candidate is a patient receiving ECMO who is deemed by the transplant program's multidisciplinary review board to be a candidate for transplant. Bridging to lung transplant with ECMO is becoming more common as devices become safer, transplant candidates become sicker, and surgeons become more comfortable operating on patients bridged with ECMO.3Mattar A. Chatterjee S. Loor G. Bridging to lung transplantation.Crit Care Clin. 2019; 35: 11-25Abstract Full Text Full Text PDF Scopus (12) Google Scholar In addition, since 2005, patients receiving ECMO have been prioritized for lung transplant on the basis of a lung allocation score, which has reduced their time waiting for a lung allograft. Not offering ECMO to a patient with an urgent exacerbation of their lung disease almost always leads to death. With these factors in mind, we present recent studies that have compared survival outcomes from lung allograft recipients bridged with ECMO with outcomes from those not bridged with ECMO. We highlight the opportunities that bridging to lung transplant provides and basic principles for achieving a successful outcome. We end with consideration of ECMO in the context of COVID-19. See Video 1 for an overview of these considerations. Multiple published studies have reported on ECMO as a bridge to lung transplant. Herein, we focus on the 3 most recent single-center experiences (Table 1), because these illustrate the evolution of BTT and associated outcomes in experienced centers. These studies have influenced how we consider BTT for patients with COVID-19, as discussed later in this review.Table 1ECMO as bridge to lung transplant in 3 recent single-center seriesPublicationN∗Patients who underwent lung transplant after BTT.Median duration, daysAwake, %Ambulatory, %MV, %VV, %Survival 1 y after lung transplant, %Langer et al.4Langer F. Aliyev P. Schäfers H.J. Trudzinski F.C. Seiler F. Bals R. et al.Improving outcomes in bridge-to-transplant: extended extracorporeal membrane oxygenation support to obtain optimal donor lungs for marginal recipients.ASAIO J. 2019; 65: 516-521Crossref PubMed Scopus (11) Google Scholar3429 (range, 0-129)18NA829479Tipograf et al.5Tipograf Y. Salna M. Minko E. Grogan E.L. Agerstrand C. Sonett J. et al.Outcomes of extracorporeal membrane oxygenation as a bridge to lung transplantation.Ann Thorac Surg. 2019; 107: 1456-1463Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar7012 (IQR, 5-21)1007686†Seventy-one percent of patients had at least 1 day free from mechanical ventilation.5088Benazzo et al.2Benazzo A. Schwarz S. Frommlet F. Schweiger T. Jaksch P. Schellongowski P. et al.Twenty-year experience with extracorporeal life support as bridge to lung transplantation.J Thorac Cardiovasc Surg. 2019; 157: 2515-2525.e10Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar1076 (IQR, 3-14)28NA100‡Twenty-eight percent of patients were weaned off MV.3469§Estimated from the propensity-matched cohort comparing BTT with non-BTT.MV, Mechanical ventilation; VV, veno-venous extracorporeal membrane oxygenation; IQR, interquartile range; NA, not available.∗ Patients who underwent lung transplant after BTT.† Seventy-one percent of patients had at least 1 day free from mechanical ventilation.‡ Twenty-eight percent of patients were weaned off MV.§ Estimated from the propensity-matched cohort comparing BTT with non-BTT. Open table in a new tab MV, Mechanical ventilation; VV, veno-venous extracorporeal membrane oxygenation; IQR, interquartile range; NA, not available. In a single-center, retrospective analysis of lung transplant patients in Hamburg, Germany, Langer and colleagues4Langer F. Aliyev P. Schäfers H.J. Trudzinski F.C. Seiler F. Bals R. et al.Improving outcomes in bridge-to-transplant: extended extracorporeal membrane oxygenation support to obtain optimal donor lungs for marginal recipients.ASAIO J. 2019; 65: 516-521Crossref PubMed Scopus (11) Google Scholar compared the outcomes of 34 ECMO-bridged patients with outcomes of 54 non-bridged patients. Transplants took place from January 2012 to July 2017. The median BTT time was 29 days (range, 0-129 days). Veno-venous (VV) ECMO was used in 96% of cases, and veno-arterial (VA)-venous ECMO was used in 4% of cases; 18% of the BTT patients did not require mechanical ventilation during ECMO (ie, "awake ECMO"). The percentage of those who were ambulatory during ECMO (ie, "ambulatory ECMO") was not reported. Post-transplant survival rates were similar among the BTT patients and non-BTT patients (at 1 year, 79% vs 86%, respectively; at 3 years, 63% vs 71%).4Langer F. Aliyev P. Schäfers H.J. Trudzinski F.C. Seiler F. Bals R. et al.Improving outcomes in bridge-to-transplant: extended extracorporeal membrane oxygenation support to obtain optimal donor lungs for marginal recipients.ASAIO J. 2019; 65: 516-521Crossref PubMed Scopus (11) Google Scholar These results were encouraging, considering the acuity of this patient population. In another single-center analysis, Tipograf and colleagues5Tipograf Y. Salna M. Minko E. Grogan E.L. Agerstrand C. Sonett J. et al.Outcomes of extracorporeal membrane oxygenation as a bridge to lung transplantation.Ann Thorac Surg. 2019; 107: 1456-1463Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar at Columbia University Medical Center reviewed outcomes from patients who underwent lung transplant between 2009 and 2018. Only selected patients who were already on the transplant wait list were deemed candidates for BTT, with few exceptions. Patients with irreversible disease and end-organ damage were often delisted after ECMO was initiated, because of their low chance of survival after transplant. Ultimately, 70/121 ECMO patients (59%) were successfully bridged to lung transplant. The median BTT time was 12 days; 50% of patients had VV ECMO. Although most patients required some form of mechanical ventilation, 14% were never intubated, 20% had a tracheostomy, and 76% achieved ambulatory ECMO status. All patients in this series participated in physical therapy, and 71% had at least 1 day free of mechanical ventilation. The 1-year and 3-year survival rates of 88% and 83% for the BTT patients did not differ statistically from those of the 545 non-BTT patients in log rank and propensity-matched analyses. Renal replacement therapy, cerebrovascular accident, and elevated Simplified Acute Physiology II score were risk factors for mortality on the wait list, whereas ambulation was the only factor independently associated with survival to transplant. Another recent study of BTT patients came from Benazzo and colleagues,2Benazzo A. Schwarz S. Frommlet F. Schweiger T. Jaksch P. Schellongowski P. et al.Twenty-year experience with extracorporeal life support as bridge to lung transplantation.J Thorac Cardiovasc Surg. 2019; 157: 2515-2525.e10Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar who reviewed 120 patients who met strict criteria for BTT at the Medical University of Vienna over a 20-year period ending in 2017. The study time frame was divided into 3 segments, each encompassing approximately 5 to 7 years. The number of patients who required BTT in the most recent time segment was sevenfold higher than that in the earliest segment; the overall transplant rate among BTT candidates was 89%. Thirteen percent of patients were weaned from mechanical ventilation during ECMO. The study did not report length of time of mechanical ventilation before being weaned, nor did it delineate successful ambulatory ECMO cases. Survival to discharge after BTT improved steadily over time. The authors noted greater use of VV ECMO over the study period and greater achievement of awake ECMO status. VV ECMO was used in 37% of all cases, with the rest using VA ECMO, interventional lung assist, VA-venous ECMO, or a combination of strategies. The 5-year survival after lung transplant was approximately 63% for BTT patients and approximately 75% for non-BTT patients, on the basis of Kaplan–Meier analysis of propensity-matched cohorts. This difference was reported to be statistically significant, although excluding deaths before 90 days eliminated any differences in post-transplant outcomes between the 2 groups. This underscores the importance of patient selection, because BTT patients who have a high likelihood of surviving the first 90 days may expect long-term survival outcomes that are similar to those of non-BTT patients. Patients who undergo lung transplant after ECMO are at high risk for post-transplant complications and require heightened levels of vigilance, resources, and expertise.6Shafii A.E. Mason D.P. Brown C.R. Vakil N. Johnston D.R. McCurry K.R. et al.Growing experience with extracorporeal membrane oxygenation as a bridge to lung transplantation.ASAIO J. 2012; 58: 526-529Crossref PubMed Scopus (48) Google Scholar Despite the excellent outcomes achieved at experienced lung transplant centers, not all BTT patients can expect similar results. Thankfully, a reasonable amount of published data on prognostic indicators is available to guide physicians in selecting patients for BTT. Many centers that achieve good results with transplants after ECMO will use specific criteria to ensure that the patient has a reasonable chance of survival. A 2017 publication by our group reported on prognostic factors associated with outcomes after lung transplant in BTT patients.7Loor G. Simpson L. Parulekar A. Bridging to lung transplantation with extracorporeal circulatory support: when or when not?.J Thorac Dis. 2017; 9: 3352-3361Crossref PubMed Scopus (22) Google Scholar On the basis of available data and our own experience, we identified the following favorable factors for post-transplant survival after BTT: age younger than 50 years, normal or marginally elevated bilirubin level, normal or mildly elevated pulmonary artery pressures, <14-day duration of ECMO, a Sequential Organ Failure Assessment score <6, noninvasive ventilation, and the ability to participate in ambulatory ECMO. Unfavorable factors included age older than 60 years, total bilirubin >3 mg/dL, severe pulmonary hypertension, ECMO duration >14 days, prolonged mechanical ventilation, prolonged immobility during ECMO, Sequential Organ Failure Assessment score >9, major bleeding, infectious complications, end-organ complications during ECMO, and re-transplant within 1 year. The observation regarding duration of ECMO support deserves additional mention. This was based on a 2013 case series by Crotti and colleagues,8Crotti S. Iotti G.A. Lissoni A. Belliato M. Zanierato M. Chierichetti M. et al.Organ allocation waiting time during extracorporeal bridge to lung transplant affects outcomes.Chest. 2013; 144: 1018-1025Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar who showed superior outcomes for patients who underwent transplant with <14 days of ECMO support, along with a mortality hazard ratio of 1.12 for each day of ECMO support. Oh and colleagues9Oh D.K. Hong S.B. Shim T.S. Kim D.K. Choi S. Lee G.D. et al.Effects of the duration of bridge to lung transplantation with extracorporeal membrane oxygenation.PLoS One. 2021; 16: e0253520Crossref Scopus (2) Google Scholar used a 14-day cutoff and achieved similar results. Conceivably, prolonged exposure to mechanical circulatory support increases inflammation and coagulopathy, both of which could be detrimental to post-transplant outcomes. However, in our experience and that of others, successful transplant is possible after months of ECMO support (particularly VV ECMO), if the patient is awake, has limited or no mechanical ventilation, is ambulatory, and has stable end-organ perfusion and hemostasis. In fact, during the current COVID-19 pandemic, it has not been uncommon to evaluate patients for transplant after a month of VV ECMO support. The study by Tipograf and colleagues5Tipograf Y. Salna M. Minko E. Grogan E.L. Agerstrand C. Sonett J. et al.Outcomes of extracorporeal membrane oxygenation as a bridge to lung transplantation.Ann Thorac Surg. 2019; 107: 1456-1463Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar did not show duration of ECMO support as a prognostic factor for successful BTT; however, their median ECMO duration was only 12 days. Waiting for the best possible donor might offset some of the risk associated with duration of ECMO support. Importantly, considering the scant literature on long-duration ECMO before lung transplant, such cases should be individualized and tailored to the recipient's condition and the center's experience. Importantly, patients who are awake during ECMO do better, leading to improved BTT results; thus, awake ECMO is the goal for most BTT cases. Although there is no uniformly accepted definition for "awake ECMO," 3 considerations apply: the degree of sedation, the degree of participation with physical therapy, and the need for mechanical ventilation. A fundamental requirement is that the patient should be, at most, only lightly sedated. The awake ECMO patient should be participating in physical therapy, with or without ambulation. If the patient achieves ambulation, the term "ambulatory ECMO" is applied; this is arguably the most encouraging form of awake ECMO. In addition, ECMO without mechanical ventilatory support is often designated as awake ECMO. Although lack of mechanical ventilatory support is a reasonable surrogate for awake ECMO, it is not a requirement for achieving this designation. Benazzo and colleagues2Benazzo A. Schwarz S. Frommlet F. Schweiger T. Jaksch P. Schellongowski P. et al.Twenty-year experience with extracorporeal life support as bridge to lung transplantation.J Thorac Cardiovasc Surg. 2019; 157: 2515-2525.e10Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar showed that the ability to achieve awake ECMO was the most important factor associated with post-BTT survival. In this state, patients participated with physiotherapy in bed, were able to move from bed to chair 1 to 2 times per day, and in some cases, were ambulatory. These patients were not always extubated. Langer and colleagues4Langer F. Aliyev P. Schäfers H.J. Trudzinski F.C. Seiler F. Bals R. et al.Improving outcomes in bridge-to-transplant: extended extracorporeal membrane oxygenation support to obtain optimal donor lungs for marginal recipients.ASAIO J. 2019; 65: 516-521Crossref PubMed Scopus (11) Google Scholar reported that 100% of BTT patients who were awake without mechanical ventilation at the time of lung transplant were alive 1 year later. Schechter and colleagues10Schechter M.A. Ganapathi A.M. Englum B.R. Speicher P.J. Daneshmand M.A. Davis R.D. et al.Spontaneously breathing extracorporeal membrane oxygenation support provides the optimal bridge to lung transplantation.Transplantation. 2016; 100: 2699-2704Crossref PubMed Scopus (55) Google Scholar reported similar post-transplant survival for patients bridged to lung transplant during ECMO without mechanical ventilation and patients who were not bridged with ECMO. Conversely, bridging with ECMO and mechanical ventilation was associated with worse survival. In the study by Tipograf and colleagues,5Tipograf Y. Salna M. Minko E. Grogan E.L. Agerstrand C. Sonett J. et al.Outcomes of extracorporeal membrane oxygenation as a bridge to lung transplantation.Ann Thorac Surg. 2019; 107: 1456-1463Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar patients who were ambulatory during ECMO had an odds ratio of 7.5 in favor of surviving to transplant (95% CI, 2.15-26.6; P = .002). Patients who survived to transplant and patients who were not bridged had similar outcomes. When feasible, we favor extubation without tracheostomy to avoid bleeding and the need for mechanical ventilation. A study by Harris and colleagues11Harris II, D.D. Shafii A.E. Baz M. Tribble T.A. Ferraris V.A. Increased blood transfusion and its impact in patients having tracheostomy while on extracorporeal membrane oxygenation.Perfusion. 2019; 34: 143-146Crossref Scopus (7) Google Scholar in a nontransplant population showed a small but significant increase in blood transfusion rates in patients receiving VV ECMO with tracheostomy versus those without tracheostomy. Tracheostomy before lung transplant is sometimes unavoidable because of respiratory secretion accumulations and muscle weakness. When tracheostomy is necessary, we hold anticoagulation for at least 8 hours before the procedure and for 24 hours after the procedure when feasible. The use of anticoagulation in VV ECMO is controversial and is discussed further in the section "ECMO Management Challenges." We increase the ECMO flow rates to at least 3 L/min during this time to avoid clotting. In addition, even with tracheostomy, we try aggressively to maintain patients in an awake ECMO state with light sedation and participation in physiotherapy directed by dedicated physical therapy teams. We avoid mechanical ventilation whenever possible and wean the patient to pressure support and a tracheal collar as soon as possible. Habertheuer and colleagues12Habertheuer A. Richards T. Sertic F. Molina M. Vallabhajosyula P. Suzuki Y. et al.Stratification risk analysis in bridging patients to lung transplant on ECMO: the STABLE risk score.Ann Thorac Surg. 2020; 110: 1175-1184Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar at The University of Pennsylvania developed and validated a useful score for identifying post-transplant mortality risk for BTT patients. Using data from 822 BTT lung transplant patients in the United Network for Organ Sharing database, the group used a linear prediction method to construct the Stratification Risk Analysis in Bridging Patients to Lung Transplant on ECMO (STABLE) score. The area under the curve for this tool was 89%, suggesting that it is an accurate prediction model. Univariate and multivariate analyses identified age older than 50 years, >75 days on the wait list, dialysis while on the wait list, mechanical ventilation while on the wait list, and total bilirubin >1.2 mg/dL as predictive of post-transplant mortality. The presence of each of these 5 factors is assigned a weighted score (Table 2). The lowest score is 0 (best outcome) and the highest score is 24 (worst outcome). The higher the score, the greater the odds of mortality; for instance, a score of 0 is associated with a 3% chance of in-hospital mortality after transplant, whereas a score of 24 indicates a 78% chance.Table 2Factors comprising the STABLE scoring system for predicting mortality risk after lung transplantFactorValueSTABLE pointsAge18-50 years0>50 years3Time on wait list1-75 days0>75 days5Dialysis on the wait listNo0Yes6Transplant center volume≥50 lung transplants per year0<50 lung transplants per year3Mechanical ventilation on wait listNo0Yes4Total bilirubin≤1.2 mg/dL0>1.2 mg/dL3Total points24STABLE, Stratification Risk Analysis in Bridging Patients to Lung Transplant on ECMO. Open table in a new tab STABLE, Stratification Risk Analysis in Bridging Patients to Lung Transplant on ECMO. Whether bridging a patient with VA versus VV ECMO support is associated with different outcomes after lung transplant is unknown. However, VV ECMO is the method of choice for isolated respiratory failure.13Kon Z.N. Bittle G.J. Pasrija C. Pham S.M. Mazzeffi M.A. Herr D.L. et al.Venovenous versus venoarterial extracorporeal membrane oxygenation for adult patients with acute respiratory distress syndrome requiring precannulation hemodynamic support: a review of the ELSO Registry.Ann Thorac Surg. 2017; 104: 645-649Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Few studies have compared VA versus VV bridging outcomes after lung transplant. Generally, BTT patients who require VA ECMO have severe pulmonary hypertension and right These patients are to have worse outcomes after lung transplant than patients with for VA ECMO is in patients who are with VV ECMO support because of A. Schwarz S. Frommlet F. Schweiger T. Jaksch P. Schellongowski P. et al.Twenty-year experience with extracorporeal life support as bridge to lung transplantation.J Thorac Cardiovasc Surg. 2019; 157: 2515-2525.e10Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar VA ECMO indicates more severe disease that might be associated with worse post-transplant outcomes. Tipograf and colleagues5Tipograf Y. Salna M. Minko E. Grogan E.L. Agerstrand C. Sonett J. et al.Outcomes of extracorporeal membrane oxygenation as a bridge to lung transplantation.Ann Thorac Surg. 2019; 107: 1456-1463Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar reported that 50% of patients were bridged with VV ECMO and were bridged with VA ECMO, but no of outcomes was Outcomes after lung transplant are most to the factors in both (ie, ambulatory degree of and patient are for the increased of VV ECMO over VA ECMO for bridging to lung transplant. The VV for ambulatory ECMO are with a This ambulation, although and oxygenation can be at VA ECMO the patient to from the in the and the in VA ECMO is in with the greater of anticoagulation are often Bridging with VA ECMO is as an ambulatory can be The VA should be to ensure a good likelihood of while good oxygenation and organ or bleeding complications should be and if at all possible. center is an important of outcomes. In an analysis of United Network for Organ Sharing and A. J. membrane oxygenation as a bridge to lung might we from and Cardiovasc Thorac Surg. 2016; PubMed Scopus Google Scholar reported that centers transplants per had a higher 1-year mortality compared with centers transplants per were noted in the of the STABLE A. Richards T. Sertic F. Molina M. Vallabhajosyula P. Suzuki Y. et al.Stratification risk analysis in bridging patients to lung transplant on ECMO: the STABLE risk score.Ann Thorac Surg. 2020; 110: 1175-1184Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar The goal during ECMO is for patients to be ambulatory and is not always possible to achieve this for a of If the patient is critically and ECMO standard VV with oxygenated in the and from the is the and G. Simpson L. Parulekar A. Bridging to lung transplantation with extracorporeal circulatory support: when or when not?.J Thorac Dis. 2017; 9: 3352-3361Crossref PubMed Scopus (22) Google Scholar can be at the with or without If is not or should be used to guide and the patient is achieving awake ECMO is if the standard VV are with a in the if a patient is for BTT early and is not it is reasonable to use a from the should be in a and with and the or the can be We first of the the and to this for A.E. McCurry K.R. of the for extracorporeal membrane Thorac Surg. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar the and is more comfortable for the patient while awake and a during ambulation. 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Mazzeffi M.A. Herr D.L. et al.Venovenous versus venoarterial extracorporeal membrane oxygenation for adult patients with acute respiratory distress syndrome requiring precannulation hemodynamic support: a review of the ELSO Registry.Ann Thorac Surg. 2017; 104: 645-649Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar in of all BTT cases in the series by Tipograf and colleagues,5Tipograf Y. Salna M. Minko E. Grogan E.L. Agerstrand C. Sonett J. et al.Outcomes of extracorporeal membrane oxygenation as a bridge to lung transplantation.Ann Thorac Surg. 2019; 107: 1456-1463Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar which included VA and VV ECMO cases in approximately If a patient has right we an when P. J.M. et of

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