**4. ECMO in the peri- and postoperative period**

#### **4.1 ECMO versus cardiopulmonary bypass**

While partial or full cardiopulmonary support was initially a necessary aspect of lung transplantation, this has become less of a requirement with improvements in ventilation and operative technique. However, for those cases where cardiopulmonary support remains a necessity (such as failure of single lung ventilation, or right heart failure), VA ECMO is playing an increasing role as an alternative to traditional cardiopulmonary bypass. Cardiopulmonary bypass is at least theoretically responsible for the development of pulmonary injury and has been implicated in adult respiratory distress syndrome [40]. Pulmonary injury during cardiopulmonary bypass has been the subject of a significant amount of research over the past 30 years. At this time, it is theorized that lung damage occurs as the result of an inflammatory cascade triggered by a combination of surgical trauma, the interface of blood products with the extracorporeal circuit, and lung reperfusion injury; this triggers the generation of oxygen free radicals that are in turn sequestered within the lung and lead to pulmonary injury [41, 42].

Other issues related to cardiopulmonary bypass include a need for high-dose heparinization, which can lead to intra- and postoperative bleeding complications, and high blood turnover with a high volume of blood necessary to load the circuit. Cardiopulmonary bypass also requires central cannulation that can preclude other interventions in the operative field such as coronary artery bypass grafting. These issues have led providers to seek alternate supportive options. On its face, ECMO has a number of perceived benefits over cardiopulmonary bypass. With this in mind, there have been a number of studies comparing the efficacy of ECMO to cardiopulmonary bypass in the lung transplant setting [43–50].

The first studies of VA ECMO as a replacement therapy were not initially associated with good outcomes. For example, in 2007 a single institute retrospective study, ECMO was found to have a trend toward increased 90-day mortality rate, a higher incidence of severe graft ischemia/reperfusion injury, and a significantly

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reduced 1-year survival compared to cardiopulmonary bypass [45]. However, with increasing experience in using ECMO, results have been more promising. A 2012 retrospective study of outcomes of patients treated using ECMO versus cardiopulmonary bypass demonstrated a higher transfusion requirement in the cardiopulmonary bypass group, as well as a significantly higher incidence of in-hospital mortality, the need for hemodialysis, and new postoperative ECMO support. In this study transplantation with cardiopulmonary bypass was identified as an indepen-

In a 2014 study comparing differences in 47 lung transplant patient outcomes with intraoperative ECMO versus cardiopulmonary bypass, the ECMO group was required fewer transfusions and had less bleeding, fewer reoperations, and less primary graft dysfunction with no 30-day or 1-year survival differences [44]. Similarly, in a 2014 comparison of 271 consecutive patients who underwent lung transplant using either cardiopulmonary bypass or ECMO, there were differences in 30-day or 6-month mortality, and less postoperative complications among the ECMO group [43]. A number of more recent studies similarly comparing VA ECMO to cardiopulmonary bypass have confirmed the finding of a lower perioperative blood product transfusion requirement and lower 90-day mortality among the

Recently, a meta-analysis of the existing evidence to support ECMO versus cardiopulmonary bypass showed beneficial trends of ECMO regarding blood transfusions, duration of ventilator support and intensive care unit length of stay, 3-month and 1-year mortality; these findings, however, were not statistically significant. At this time, while it appears that ECMO is at least non-inferior to cardiopulmonary bypass in the setting of lung transplantation, the superiority of ECMO remains to be determined and will likely require larger multi-center randomized trials [47]. Outcomes compared between patients requiring intraoperative ECMO versus those not requiring any support are less conclusive; in a 2018 study of 53 patients, while patients who underwent ECMO received more intraoperative transfusions, outside of the immediate postoperative period there were no differences in in-hospital and 6-month complications with similar survival between the two groups [50]. In contrast, however, a 2017 single institution study demonstrated 5-year survival to be 52.8% in intraoperative ECMO recipients versus 70.5% in those not requiring ECMO, with multivariate analysis identifying intraoperative ECMO support as

Early primary graft dysfunction, defined as lung injury causing decreased oxygenation during the first 3 days after lung transplant, is a devastating albeit fairly uncommon occurrence. ECMO is a useful adjunct for supporting the patient with primary graft dysfunction, either to recovery or as a bridge to redo transplantation. One-year survival is compromised in patients with severe primary graft dysfunction compared to those without; in addition to the underlying causal factors contributing to dysfunction in the first place, this is often worsened by the high airway pressures and inspired oxygen concentration necessary to adequately oxygenate the patient via mechanical ventilation. ECMO may be desirable for its ability to avoid these risk factors. In a single-institution study of patients with primary graft dysfunction, successful weaning from ECMO was achieved in 96% of patients, with substantially improved long-term outcomes including a 5-year survival of nearly 50%. While allograft function in the ECMO group was worse than in transplant recipients not requiring ECMO, the benefits of ECMO in pulmonary support in the immediate postoperative period is clear [54]. Furthermore,

*DOI: http://dx.doi.org/10.5772/intechopen.83833*

dent risk factor for in-hospital mortality [51].

significant risk factors for overall survival [46].

**4.2 Postoperative ECMO for primary graft dysfunction**

extracorporeal membrane oxygenation cohorts [48, 49, 52, 53].

#### *Advances in Extracorporeal Membrane Oxygenation in the Setting of Lung Transplantation DOI: http://dx.doi.org/10.5772/intechopen.83833*

reduced 1-year survival compared to cardiopulmonary bypass [45]. However, with increasing experience in using ECMO, results have been more promising. A 2012 retrospective study of outcomes of patients treated using ECMO versus cardiopulmonary bypass demonstrated a higher transfusion requirement in the cardiopulmonary bypass group, as well as a significantly higher incidence of in-hospital mortality, the need for hemodialysis, and new postoperative ECMO support. In this study transplantation with cardiopulmonary bypass was identified as an independent risk factor for in-hospital mortality [51].

In a 2014 study comparing differences in 47 lung transplant patient outcomes with intraoperative ECMO versus cardiopulmonary bypass, the ECMO group was required fewer transfusions and had less bleeding, fewer reoperations, and less primary graft dysfunction with no 30-day or 1-year survival differences [44]. Similarly, in a 2014 comparison of 271 consecutive patients who underwent lung transplant using either cardiopulmonary bypass or ECMO, there were differences in 30-day or 6-month mortality, and less postoperative complications among the ECMO group [43]. A number of more recent studies similarly comparing VA ECMO to cardiopulmonary bypass have confirmed the finding of a lower perioperative blood product transfusion requirement and lower 90-day mortality among the extracorporeal membrane oxygenation cohorts [48, 49, 52, 53].

Recently, a meta-analysis of the existing evidence to support ECMO versus cardiopulmonary bypass showed beneficial trends of ECMO regarding blood transfusions, duration of ventilator support and intensive care unit length of stay, 3-month and 1-year mortality; these findings, however, were not statistically significant. At this time, while it appears that ECMO is at least non-inferior to cardiopulmonary bypass in the setting of lung transplantation, the superiority of ECMO remains to be determined and will likely require larger multi-center randomized trials [47].

Outcomes compared between patients requiring intraoperative ECMO versus those not requiring any support are less conclusive; in a 2018 study of 53 patients, while patients who underwent ECMO received more intraoperative transfusions, outside of the immediate postoperative period there were no differences in in-hospital and 6-month complications with similar survival between the two groups [50]. In contrast, however, a 2017 single institution study demonstrated 5-year survival to be 52.8% in intraoperative ECMO recipients versus 70.5% in those not requiring ECMO, with multivariate analysis identifying intraoperative ECMO support as significant risk factors for overall survival [46].

#### **4.2 Postoperative ECMO for primary graft dysfunction**

Early primary graft dysfunction, defined as lung injury causing decreased oxygenation during the first 3 days after lung transplant, is a devastating albeit fairly uncommon occurrence. ECMO is a useful adjunct for supporting the patient with primary graft dysfunction, either to recovery or as a bridge to redo transplantation.

One-year survival is compromised in patients with severe primary graft dysfunction compared to those without; in addition to the underlying causal factors contributing to dysfunction in the first place, this is often worsened by the high airway pressures and inspired oxygen concentration necessary to adequately oxygenate the patient via mechanical ventilation. ECMO may be desirable for its ability to avoid these risk factors. In a single-institution study of patients with primary graft dysfunction, successful weaning from ECMO was achieved in 96% of patients, with substantially improved long-term outcomes including a 5-year survival of nearly 50%. While allograft function in the ECMO group was worse than in transplant recipients not requiring ECMO, the benefits of ECMO in pulmonary support in the immediate postoperative period is clear [54]. Furthermore,

*Advances in Extracorporeal Membrane Oxygenation - Volume 3*

duration of support are widely disparate across centers [37].

therapy as a bridging strategy [39].

**4. ECMO in the peri- and postoperative period**

**4.1 ECMO versus cardiopulmonary bypass**

the lung and lead to pulmonary injury [41, 42].

cardiopulmonary bypass in the lung transplant setting [43–50].

the upper bounds for an acceptable duration of pre-transplant ECMO therapy, and this varied from as little as 10 days to a policy in which ECMO support duration was not bounded. Overall, the institutional criteria for ECMO initiation, age limits, and

A systematic review in 2014 highlighted the inconsistencies in design between these studies; while 82 potential studies of ECMO bridging were identified at the time, the vast majorities were excluded and the broad heterogeneity among the studies precluded any wider meta-analysis. In this analysis, the preoperative mortality rate of patients on ECMO ranged from 10–50%. It was ultimately concluded that ECMO support as a bridge could potentially provide reasonable perioperative and 1-year survival outcomes, but no broader statement could be made owing to a general paucity of high-quality data and significant heterogeneity among studies [38]. While these largely retrospective studies are compelling, it is acknowledged that retrospective studies are not the ideal candidates for definitively proving the efficacy of ECMO compared to mechanical ventilation, which has in tandem with ECMO evolved in the past decade to include more advanced strategies of protective lung ventilation. While the challenges of randomizing patients to different therapies in end-stage respiratory failure are apparent, at this point significant equipoise now exists to justify the randomized comparison of ECMO with standard ventilator

While partial or full cardiopulmonary support was initially a necessary aspect of lung transplantation, this has become less of a requirement with improvements in ventilation and operative technique. However, for those cases where cardiopulmonary support remains a necessity (such as failure of single lung ventilation, or right heart failure), VA ECMO is playing an increasing role as an alternative to traditional cardiopulmonary bypass. Cardiopulmonary bypass is at least theoretically responsible for the development of pulmonary injury and has been implicated in adult respiratory distress syndrome [40]. Pulmonary injury during cardiopulmonary bypass has been the subject of a significant amount of research over the past 30 years. At this time, it is theorized that lung damage occurs as the result of an inflammatory cascade triggered by a combination of surgical trauma, the interface of blood products with the extracorporeal circuit, and lung reperfusion injury; this triggers the generation of oxygen free radicals that are in turn sequestered within

Other issues related to cardiopulmonary bypass include a need for high-dose heparinization, which can lead to intra- and postoperative bleeding complications, and high blood turnover with a high volume of blood necessary to load the circuit. Cardiopulmonary bypass also requires central cannulation that can preclude other interventions in the operative field such as coronary artery bypass grafting. These issues have led providers to seek alternate supportive options. On its face, ECMO has a number of perceived benefits over cardiopulmonary bypass. With this in mind, there have been a number of studies comparing the efficacy of ECMO to

The first studies of VA ECMO as a replacement therapy were not initially associated with good outcomes. For example, in 2007 a single institute retrospective study, ECMO was found to have a trend toward increased 90-day mortality rate, a higher incidence of severe graft ischemia/reperfusion injury, and a significantly

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these trends toward better outcomes after primary graft dysfunction appear to be improving due to ECMO support; in a large database study of the highest-risk transplant patients, patients demonstrate improving outcomes, particularly at high-volume centers [55]. In a review of the UNOS database, the use of postoperative ECMO support for primary graft dysfunction was still associated with a 6-month survival of over 60%, and while the subset of ECMO recipients also requiring dialysis had a only a 25% 6-month survival, if dialysis was not needed survival was over 85% [56].

Unfortunately, while early postoperative ECMO in the setting of primary graft dysfunction is associated with reasonable outcomes, the late implementation of ECMO postoperatively (after 7 days) does not appear to have the same good outcomes. In a 2011 study of late ECMO support in lung transplant patients with infection or graft failure, none of the individuals who received late ECMO support survived to hospital discharge, due to the propagation of uncontrolled infection or organ failure that preempted ECMO support. This suggests that while ECMO can provide early support while awaiting graft recovery, it does not represent a means of reversing complications existing prior to initiation of ECMO [57].

#### **4.3 Routine ECMO prolongation**

With increasing comfort with ECMO as postoperative support, the indications for extending its use have continued to expand. In some institutions, for example, intraoperative extracorporeal membrane oxygenation has been adopted for all unstable lung transplantations. Protocols have been proposed in which ECMO is prophylactically extended into the postoperative period based on graft quality and the preoperative presence of pulmonary hypertension. A recent single-institution analysis of this prophylactic protocol identified patients receiving ECMO as having improved survival compared to non-ECMO patients despite higher levels of medical complexity. Prophylactic ECMO prolongation is being increasingly recognized as a safe option for the routine postoperative support of patients with either marginal graft function or underlying pulmonary hypertension [12].

In the same vein, research has been conducted to identify those patients at increased risk of ECMO weaning failure after lung transplantation, in order to identify those patients who might benefit from continued extracorporeal support. Identified risk factors including older donors, longer periods of donor mechanical ventilation, donor PaO2 prior to organ procurement and longer operative time [58]. In these patients, prophylactic ECMO support postoperatively may be recommended.

#### **4.4 Ex-vivo lung perfusion using ECMO**

Ex vivo lung perfusion is another exciting breakthrough for the reconditioning of poor quality grafts as high risk of postoperative primary graft dysfunction. In this setup, retrieved donor lungs are perfused in an ex vivo circuit. This provides an opportunity for transplant surgeons to reassess graft function before transplantation, providing a more accurate window into the likelihood of success in transplantation with high-risk donor lungs. The use of an ex vivo circuit allows time for toxic waste products and inflammatory cytokines to be filtered out, for more optimal recruitment of collapsed lung areas, and for the fluid-overloaded lung tissue to be dehydrated by the perfusate high oncotic pressure [59]. In a 2015 study, lung transplant recipients who received lungs reconditioned in an ex vivo manner demonstrated significantly shorter hospital stay and trends toward shorter length of mechanical ventilation [48, 49].

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provided the original work is properly cited.

, Suresh Keshavamurthy2

Medicine at Temple University, United States of America

\*Address all correspondence to: skeshavamurthy@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Department of Surgery, Temple University Hospital, Lewis Katz School of

2 Department of Surgery, Division of Cardiovascular Surgery, Temple University Hospital, Lewis Katz School of Medicine at Temple University,

\* and Yoshiya Toyoda<sup>2</sup>

*Advances in Extracorporeal Membrane Oxygenation in the Setting of Lung Transplantation*

Ultimately, recent advances in ECMO have led it to become a critical tool in the armamentarium of the transplant surgeon, in both the preoperative period as a bridging strategy, as a tool for cardiopulmonary support during the operation, and for the rescue of potentially dysfunctional grafts postoperatively. The use of ECMO in lung transplantation has been need-driven in an incredibly complex and medically challenging complication; innovative thinking by basic scientists and transplant surgeons has led to remarkable improvements in patient outcomes. Continued advances in ECMO technologies, deeper experience with the implementation of ECMO in complicated clinical situations, and further high-quality research will help determine the areas where ECMO can help provide a benefit to lung transplant

*DOI: http://dx.doi.org/10.5772/intechopen.83833*

**5. Conclusions**

recipients.

**Author details**

Michael Mazzei1

United States of America

*Advances in Extracorporeal Membrane Oxygenation in the Setting of Lung Transplantation DOI: http://dx.doi.org/10.5772/intechopen.83833*
