Evolution of ECMO as a bridge to lung transplant by decade. Adapted with permission from , © 2013 Diaz-Guzman et al. Published under Wolters Kluwer Health, Inc. DOI: 10.1097/MAT.0b013e31827461c2. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Wolters Kluwer Health.
Lung transplantation is increasing as a widely accepted surgical treatment for certain type of end-stage lung disease. Recent technical improvements in extracorporeal membrane oxygenation (ECMO) have been able to expand the role of ECMO during lung transplantation. The evolution of oxygenators, introduction of the new-type pump and tube, and improvement of percutaneous cannulation including dual lumen single catheter resulted in the technical renaissance of ECMO for lung transplantation. Now, beyond the traditional support for patients with severe primary graft dysfunction, ECMO can be established as essential perioperative roles for patients undergoing lung transplantation, such as preoperative lung protective support as a bridge to transplantation, replacement cardiopulmonary bypass during intraoperative support, and rescue of various life-threatening situations after post-transplant. After all, ECMO will be a fundamental, life-saving modality for patients during lung transplantation.
- Perioperative procedures
- lung transplantation
- Perioperative procedures
- Ventilator-induced lung injury
- Intensive care unit
Recent expanded role of extracorporeal membrane oxygenation (ECMO) is switching the paradigm of organ transplantation, especially in the lung. Traditionally, the role of ECMO in the area of lung transplantation was focused in supporting patients with severe primary graft dysfunction (PGD) after post-transplant; however, as the technical ECMO environments such as new type of pump, oxygenator, catheter and tubing are improving, ECMO is now applied to the whole process of lung transplantation, from “bridge-to-transplant” to “rescue post-transplant” [1, 2].
The prevalence of lung transplantation has also increased over several decades especially in the specific end-stage lung diseases, such as cystic fibrosis, interstitial lung disease, and chronic obstructive lung disease. Contrary to successful early survival rate, the long-term survival rate of lung transplantation has still seen modest improvement. In addition, the mortality of patients on the waiting list is also concerning, consequently the interest in looking for alternative strategies for patients with end-stage lung disease who wait lung transplantation has risen considerably.
Mechanical ventilation has been applied to support the failing lung in peritransplant patients; however, per se can aggravate respiratory failure and hemodynamic instability by increasing the risk of ventilator-associated pneumonia and ventilator-induced lung injury . Traditionally, mechanically ventilated pretransplant patients have been reported to have higher post-transplant mortality rates than nonventilated patients .
At this point, ECMO can be considered an alternative bridging strategy in lung transplantation, and now despite the complexity and side effects, the use of ECMO during lung transplantation has risen by 150% in the recent last 2 years compared to the previous decades (1970–2010; Figure 1). Besides the increase of amount, the characteristics of using ECMO are also evolving (Table 1) .
|Patients listed for lung transplantation on ECMO||1||1||22||104||58|
|Modes of ECLS used||VA||VA||VA||VV, VA, iLA™||VV, VA, iLA™, hybrid|
|Pump configuration||CPB||Roller pump||Roller pump||Centrifugal||Centrifigual|
|Oxygenator membrane||Silicone membrane||Polypropylene and silicone||Polypropylene||PMP||PMP|
|Cannulation approach innovation||Central||Central||Central||Peripheral Novalung®||Peripheral Avalon™|
2. Extracorporeal membrane oxygenation as a bridge to lung transplantation
The first report of the use of ECMO as a bridge-to-transplant was published in the 1970s . The patient was successfully transplanted and wean from ECMO, he died at 10 days of post-transplant. Successful cases were reported in 1993 ; however, still controversies of using ECMO as a bridge-to-transplant were noted at that time because of poor clinical outcomes, for example, the estimated 1-year survival for the transplant of ECMO was only 40%. In addition, the resources have been considerable for a successful transplant through ECMO bridge, such as prolong intensive care and hospital stays, need of tracheostomy, substantial blood requirement, and consequent neuromuscular complications that also required prolonged periods of postoperative rehabilitation.
The lung allocation scoring (LAS) system, begun in 2005, can be attributable to increase the use of ECMO as a bridge-to-transplant. Contrary to it patients before 2005 would receive lungs only based on the length of time on the waiting list, both medical urgency and net benefit from transplantation were incorporated to create a standardized scoring system. Since the adoption of LAS system, patients receiving continuous mechanical ventilation get higher scores, more likely to receive a transplant. Simultaneously, issues were arisen that ventilator-dependent patient before transplantation may be too sick for transplantation, which may affect the post-transplant outcomes. Direct or indirect risk factors could be considered in these patients: one is the increased risk of “ventilator-induced lung injury (VILI)” or “ventilator-associated pneumonia” during waiting period, and the other is “ICU-acquired weakness.”
ECMO has been associated with avoidance of mechanical ventilation and it facilitates perioperative rehabilitation. As far as minimizing VILI when using ECMO as a bridge-to-transplant, ECMO may be beneficial for the patients waiting lung transplantation who have refractory hypercapnic respiratory failure, which was followed by most patients with end-stage lung disease combined with hypoxic respiratory failure. Extracorporeal CO2 removal (ECCO2R), more commonly called as this concept instead of ECMO, reduces mechanical ventilation requirements, enabling the use of low tidal volume and high PEEP at relatively lower respiratory rates. Recently, technological improvements, such as interventional lung-assisted device pumpless venovenous ECMO (NovalungGmbH, Germany), a low-resistance oxygenator that offers good decarboxylation, and the CardioHelp venovenous ECCO2R device (Maquet, Germany), have led to remove CO2 selectively including partial or full oxygenation support .
Compared to the conventional mechanical ventilation strategy, patients who received “awake” ECMO as a bridge-to-transplant can be liberated from bed and participate in a preoperative “active” rehabilitation program, which consequently mitigated ICU-acquired weakness (Figure 2a). For this purpose, new-type single catheters, configured by double lumen, such as “Avalon” (Figure 2b) or “Novatwin” cannula, can be preferable, which facilitate easier patient mobilization to prevent decline in skeletal muscle dysfunction in postoperative period. Although a direct causal relationship between preoperative rehabilitation enhanced by a bridge-to-transplant using ECMO and postoperative exercise tolerance with ultimate clinical outcomes has not been established, it is generally considered a standard of care to enlist all patients into an active pulmonary rehabilitation program before transplantation or a “destination therapy” like that seen with left ventricular-assisted devices in the area of heart transplantation. There appears to be a benefit even in a common selected group of extremely sick conditions before transplant despite the scarcity of data currently .
Until now, there are no randomized controlled trials showing the beneficial effect of ECMO as bridge to lung transplant, several retrospective studies reported acceptable survival and its feasibility. Because most of these analyses were composed of many heterogeneous patients' feature, whether ECMO as an alternative, rather than an adjunction, to invasive mechanical ventilation is a better bridging strategy during lung transplantation still remains an unresolved issue. A meta-analysis of 14 retrospective studies [10–23] reported from 50 to 90% of the post-transplant 1-year survival rate, which was significantly better in spontaneously breathing patients or when the ECMO bridge duration was shorter than 14 days.(Tables 2 and 3) .
|Author, year||Patients, number||Age (years)||Sex male, ||Diagnosis||Ventilation|
|Bridge time (days)||Severity score prebridge|
|Mason, 2010 ||51||39±22||25 (49%)||PF 27%; COPD 1996; CF 12%; PH 9.8%; sarcoidosis 2%; other 20%||na||na||LAS 54±21|
|Bermudez, 2011 ||17||40±14||7 (41%)||PF 35%; Re-LTx 35%; CF 23%; COPD 6%||MV||3.2 (0–49)||na|
|Hammainen, 2011 ||16||41±8a||7 (58%)||PF 37%a; PH 15%a; CF 8%a; ARDS 8%a; IP 8%a; PVOD 8%a; BOS 8%a; PGD 8%a||na||12 (1–59)||na|
|Shafii, 2012 ||19||44 (23–60)||10 (53%)||IP 68%; CF 16%; PH 16%||MV 13||6±5||LAS 87 (64–95)|
|Nosotti, 2012 ||11||34±13||5 (45%)||na|| Awake 7|
|Javidfar, 2012 ||18||34 (22–50)||8 (45%)||CF 44%; PF 33%; PH 11%; Other 11%||Awake 6||11.5 (6–18)||LAS 93(90–94)|
|George, 2012 ||122||48±16||74 (60%)||PF 29.5%; CF 11.5%; COPD 10.7%; PH 2.5%; other 45.8%||na||na||LAS 73.9±21.4|
|Fuehner, 2012 ||26||44 (23–62)||21 (81%)||PF 35%; PH 27%; CF 19%; BOS 12%; sarcoidosis 4%||Awake 19|
|9 (1–45)||SOFA 7 (6–12)|
|Hoopes, 2013 ||31||45±15||21 (67%)||PF 29%; CF 23%; ILD 13%; ARDS 10%;|
PVOD 10%; PH 6%;
BOS 3%; IP 3%; CWP 3%
18 13 VM
|11 (2–53)||LAS > 50|
|Anile, 2013 ||12||na||na||CF 92%; histiocytosis 8%||Awake 2|
|Toyoda, 2013 ||31||46±15a||10 (43%)a||Pf 33%a; CF 21%a; Re-LTx 13%a; scleroderma 13%a; bronchiectasis 8%a; COPD 4%a; sarcoidosis 4%a; PH 4%a||MVa||7.1±10||Las 87±9 a|
|Weig, 2013 ||26||36 (30–51)a||14 (54%)||PF 62%; CF 23%; COPD 4%; Re-LTx 4%; lung cancer 4%; sarcoidosis 4%||na||16 (88–25)a||SOFA 9 (8.5–10.5)a|
|Crotti, 2013 ||25||41±12||na||PF 52%; CF 16%; PH 16%; Re-LTx 12%; ARDS 4%||Awake 10|
|5.8±4.5 versus 29.8±11.5a||SOFA 5.6±1.9|
|36||31 (22–48)||19 (53%)||CF 56%; PF 30%; other 14%||MV||3.5 (2–7)||na|
|Author, year||Ltx/total patients, ||Died before Ltx, ||Type of bypass||Survival at 1 year post-LTx (%)||Length of stay post-LTx (days)||MV (days post-LTx)|
|Mason, 2010 ||51/51||na||na||50%||24 (9–55) H||na|
|Bermudez, 2011 ||14/17||3 (17%): neurologic dysfunction, thrombosis||W, VA||74%||16 (3–40) ICU)||12 (2–20)|
|Hammainen, 2011 ||13/16||3 (19%): septic MOF||W, VA||92%||22 (3–63) ICU||na|
|Shafii, 2012 ||14/19||5 (26%): septic MOF 2, DC 2, and anoxic brain injury 1||W, VA||75%||42 (19–175) H||22 (5–125)|
|Nosotti, 2012 ||11/11||na||W||87% and 50%b||47.6±21.9 H 30±20.4 ICU||27.1±20.7|
|Javidfar, 2012 ||10/18a||8 (44%): pneumonia 1, MOF 6, and CA 1||W, VA||60%||22 (18–33) H 47 (41–52) ICU||na|
|George, 2012 ||122/122||na||na||57.6%||32 (16.5–60) H||na|
|Fuehner, 2012 ||20/26||6 (23%): CA 2, septic MOF 4||W, VA||6 months 80%||38 (20–87) H 18 (1–69) ICU||14 (0–64)|
|Hoopes, 2013 ||31/31||na||VA, W||93%||31 (12–86)eH||na|
|Anile, 2013 ||7/12||5 (41%)||W, VA||85.7%||29 (15–59) H||<5|
|Toyoda, 2013 ||24/31||7(22%)||W, VA||74%||46 median H||na|
|Weig, 2013 ||13/26||13 (50%): acute liver failure 7, thoracic bleeding 3, cerebral hemorrhage 1, and PE 2||W, VA||54%||na||na|
|Crotti, 2013 ||17/25||8 (32%): MOF 3, septic shock 2, cardiogenic shock 2, and intestinal ischemia 1||W, VA||82% and 29%c||na||12.2±11.9d|
|Lafarge, 2013 ||30/36||6 (17%): GI bleeding 1, DIC 1, cerebral hemorrhage 1, CA 1, septic shock 1, and therapeutic limitation 1||W, VA,CPB||66.5%||na||na|
3. Extracorporeal membrane oxygenation during lung transplantation
There is little evidence or protocol about how to manage ECMO during intraoperative situation; however, the intraoperative use of ECMO may be necessary at any stage of developing hypoxia, hypercapnia, and/or hemodynamic instability. In bilateral lung transplantation, ECMO can stabilize hemodynamic variables and prevent “first lung syndrome,” the hyperperfusion of the first implanted lung during implantation of the second lung. In addition, it can also be used at every phase during lung transplantation to enhance a protective ventilation strategy and avoid 100% oxygen so as to mitigate the reperfusion syndrome especially during one-lung ventilation or to support when there was a lung size mismatch, auto-PEEP, and dynamic hyperinflation .
Because of many advantages mentioned earlier, ECMO has replaced CPB as the first option for intraoperative support during lung transplantation in many transplant centers. A recent published study from Germany showed 5-year experience with intraoperative ECMO in lung transplantation since April 2010 . Compared with patients who underwent lung transplantation without ECMO, overall survival at 1 and 4 years was not inferior in patients in whom the indication for ECMO support and the intraoperative use of ECMO did not emerge as a risk factor for mortality. Though small numbers were included, many studies showed overall clinical beneficiary of ECMO over CPB during lung transplantation, such as lesser intraoperative blood transfusion requirement, lesser mechanical ventilation requirement, shorter ICU stay, and higher postoperative complications.
Bermudez et al.  compared 49 VA-ECMOs with 222 CPBs using intraoperative lung transplantation. In this study, there was a higher requirement for reintubation, tracheostomy, and dialysis in the CPB group; however, the lack of significant differences in perioperative blood transfusion requirement and hospital length of stay may have been caused by the ECMO group including a sicker population, such as the higher LAS (73.3 vs. 52.9) and higher pretransplantation ECMO requirement (42.8% vs. 7.2%). Though most of these studies did not show any difference in the survival curve between two groups, one study  revealed the hospital mortality gain of CPB over ECMO (39% vs. 13%); however, it should be considered that there were more planned ECMOs than CPBs (61% vs. 28%) in this study, which may not be ignored showing the different mortality between two groups.
4. Extracorporeal membrane oxygenation as a rescue postlung transplant
In the postopertative setting of lung transplantation, early primary graft dysfunction (PGD), which is a syndrome consisting of lung injury during the first 72 hours following lung transplant defined as a physiologically decreased oxygenation and radiologically diffuse infiltrates, continues to be a major situation of morbidity and mortality. There is no doubt that ECMO has been applied as a pivotal management strategy to support severe PGD because none of interventions to ameliorate the effects of PGD on transplanted lung have been successful, including inhaled nitric oxide and prostaglandins. Although about 5% of lung transplantation requires ECMO support for PGD, this remains the most common indication for ECMO use as a rescue strategy and consequently it is reasonable that the concept of “bridge-to-transplant” has been arisen from the intermittent successes of a bridge to redo transplant in selected patients .
The goal of ECMO for severe PGD after lung transplant, same as mentioned in bridging-to-transplant, should be to minimize ventilator-induced lung injury such as elevated airway pressures or high inspired oxygen concentration by mechanical ventilation with positive pressure. While about this no uniform guidelines exist, one recommendation how to use ECMO to support PGD after lung transplant consists of initiating it when peak inspiratory pressure reaches up to 35 cm H2O or 60% FiO2 . In addition, if possible, it could not be delayed greater than 48 hours to initiate ECMO after transplantation because of alleged worse outcomes. Hartwig et al.  reported surprising survival result in this group patients supported with VV-ECMO. Of the recipients from VV-ECMO following transplant, 96% weaned successfully with a 1-year survival of 64%.
Recently, Biscotti et al. suggested the decision algorithm of how to use ECMO during entire lung transplantation (Figure 3) . Though the details are not described in this chapter, the interhospital transport of lung transplantation candidate during ECMO is also feasible and this is opening a kind of new future episode .
Modern experience with ECMO and reported institutional experience on survival challenge historical assumptions about the treatment of end-stage lung disease and suggest that “bridging” to transplant with ECMO is both technically feasible and logistically viable. It is clear at this point that continued advances in the technologies and further research will help determine how best to include ECMO as a bridging strategy for lung transplantation.
Gulack, B.C., S.A. Hirji, and M.G. Hartwig, Bridge to lung transplantation and rescue post‐transplant: the expanding role of extracorporeal membrane oxygenation.J Thorac Dis, 2014. 6(8): p. 1070–9.
Biscotti, M., J. Sonett, and M. Bacchetta, ECMO as bridge to lung transplant.Thorac Surg Clin, 2015. 25(1): p. 17–25.
Slutsky, A.S. and V.M. Ranieri, Ventilator‐induced lung injury.N Engl J Med, 2013. 369(22): p. 2126–36.
Chiumello, D., et al., Extracorporeal life support as bridge to lung transplantation: a systematic review.Crit Care, 2015. 19: p. 19.
Diaz‐Guzman, E., C.W. Hoopes, and J.B. Zwischenberger, The evolution of extracorporeal life support as a bridge to lung transplantation.ASAIO J, 2013. 59(1): p. 3–10.
Nelems, J.M., et al., Extracorporeal membrane oxygenator support for human lung transplantation.J Thorac Cardiovasc Surg, 1978. 76(1): p. 28–32.
Barankay, A., et al., [Successful resuscitation using extracorporeal perfusion].Orv Hetil, 1975. 116(49): p. 2898–9.
Soluri‐Martins, A., et al., How to minimise ventilator‐induced lung injury in transplanted lungs: The role of protective ventilation and other strategies.Eur J Anaesthesiol, 2015. 32(12): p. 828–36.
Abrams, D. and D. Brodie, Novel Uses of Extracorporeal Membrane Oxygenation in Adults.Clin Chest Med, 2015. 36(3): p. 373–84.
Anile, M., et al., Extracorporeal membrane oxygenation as bridge to lung transplantation.Transplant Proc, 2013. 45.
Bermudez, C.A., et al., Extracorporeal membrane oxygenation as a bridge to lung transplant: midterm outcomes.Ann Thorac Surg, 2011. 92.
Crotti, S., et al., Organ allocation waiting time during extracorporeal bridge to lung transplant affects outcomes.Chest, 2013. 144.
Fuehner, T., et al., Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation.Am J Respir Crit Care Med, 2012. 185.
George, T.J., et al., Outcomes and temporal trends among high‐risk patients after lung transplantation in the United States.J Heart Lung Transplant, 2012. 31.
Hammainen, P., et al., Usefulness of extracorporeal membrane oxygenation as a bridge to lung transplantation: a descriptive study.J Heart Lung Transplant, 2011. 30.
Hoopes, C.W., et al., Extracorporeal membrane oxygenation as a bridge to pulmonary transplantation.J Thorac Cardiovasc Surg, 2013. 145.
Javidfar, J., et al., Extracorporeal membrane oxygenation as a bridge to lung transplantation and recovery.J Thorac Cardiovasc Surg, 2012. 144.
Lafarge, M., et al., Experience of extracorporeal membrane oxygenation as a bridge to lung transplantation in France.J Heart Lung Transplant, 2013. 32.
Mason, D.P., et al., Should lung transplantation be performed for patients on mechanical respiratory support? The US experience.J Thorac Cardiovasc Surg, 2010. 139.
Nosotti, M., et al., Extracorporeal membrane oxygenation with spontaneous breathing as a bridge to lung transplantation.Interact Cardiovasc Thorac Surg, 2013. 16.
Shafii, A.E., et al., Growing experience with extracorporeal membrane oxygenation as a bridge to lung transplantation.ASAIO J, 2012. 58.
Toyoda, Y., et al., Efficacy of extracorporeal membrane oxygenation as a bridge to lung transplantation.J Thorac Cardiovasc Surg, 2013. 145.
Weig, T., et al., Parameters associated with short‐ and midterm survival in bridging to lung transplantation with extracorporeal membrane oxygenation.Clin Transplant, 2013. 27.
Ius, F., et al., Five‐year experience with intraoperative extracorporeal membrane oxygenation in lung transplantation: Indications and midterm results.J Heart Lung Transplant, 2016. 35(1): p. 49–58.
Bermudez, C.A., et al., Outcomes of intraoperative venoarterial extracorporeal membrane oxygenation versus cardiopulmonary bypass during lung transplantation.Ann Thorac Surg, 2014. 98(6): p. 1936–42; discussion 1942–3.
Ius, F., et al., Lung transplantation on cardiopulmonary support: venoarterial extracorporeal membrane oxygenation outperformed cardiopulmonary bypass.J Thorac Cardiovasc Surg, 2012. 144(6): p. 1510–6.
Diaz‐Guzman, E., et al., Lung function and ECMO after lung transplantation.Ann Thorac Surg, 2012. 94(2): p. 686–7; author reply 687.
Hartwig, M.G., et al., Improved survival but marginal allograft function in patients treated with extracorporeal membrane oxygenation after lung transplantation.Ann Thorac Surg, 2012. 93(2): p. 366–71.
Cypel, M., et al., Normothermic ex vivo lung perfusion in clinical lung transplantation.N Engl J Med, 2011. 364(15): p. 1431–40.
Boffini, M., et al., Incidence and severity of primary graft dysfunction after lung transplantation using rejected grafts reconditioned with ex vivo lung perfusion.Eur J Cardiothorac Surg, 2014. 46(5): p. 789–93.
Lee, S.G., et al., The feasibility of extracorporeal membrane oxygenation support for inter‐hospital transport and as a bridge to lung transplantation.Ann Thorac Cardiovasc Surg, 2014. 20(1): p. 26–31.