**3. ECMO in the preoperative period**

*Advances in Extracorporeal Membrane Oxygenation - Volume 3*

up to 16% while awaiting organs to become available [3].

**2. VV- and VA-ECMO in lung transplantation**

shortage; there is currently a yearly potential lung transplant recipient mortality of

In tandem with the explosion in lung transplant procedures, a number of support modalities have seen an expanded role. Perhaps one of the most versatile tools in the armamentarium of the pulmonary transplant surgeon is extracorporeal membrane oxygenation (ECMO). This powerful tool is being increasingly implemented in all stages of lung transplantation—from supporting the failing native organ as a bridging tool to transplantation, to stabilizing the patient intraoperatively during the transplant procedure, to rescuing the patient with severe primary graft dysfunction immediately post-transplant. A number of advanced techniques for the application of ECMO in order to optimize the pulmonary transplant procedure are gaining traction—and with ECMO's expanded role in lung transplantation, so to have come a new set of technical and ethical challenges that must also be

The goal of this chapter is to discuss some of the recent advances in the application of ECMO in the setting of lung transplantation. We discuss the application of ECMO in the preoperative, perioperative, and postoperative period, and focus in particular on advances such as the use of awake ECMO and various cannulation strategies. We also briefly discuss some of the ethical issues surrounding ECMO for lung transplantation, including cost, quality of life, and the application of ECMO to

In the setting of lung transplantation, ECMO may be utilized in either a venovenous (VV) or a veno-arterial (VA) configuration. The VV-ECMO modality is used strictly for respiratory support; this review will explore the current frontiers of usage in in the setting of either pre-operative bridge to transplant, as well as for bridging to graft recovery the subset of patients who develop severe post-transplant primary graft dysfunction (PGD). Alternatively, VA-ECMO may be utilized in the subset of patients with either pulmonary arterial hypertension requiring both cardiac and pulmonary support in the preoperative period, recently transplanted patients exhibiting hemodynamic instability, or in the intra-operative period for

Cannulation strategies for VA- and VV-ECMO are listed here. VV-ECMO is typically achieved via outflow and inflow cannulas in the femoral and internal jugular veins, with the tip of the drainage cannula placed to the level of the inferior vena cavaright atria junction and the tip of the return cannula at the right atrium. Alternatively, VV-ECMO may be achieved via a femoral-femoral cannulation strategy, with the tip of the drainage cannula in inferior vena cava and the tip of the outflow cannula is in the right atrium. Alternatively, a one-site cannulation strategy makes use of a dual lumen Avalon cannula (Avalon Elite, Maquet, Rastatt, Germany) percutaneously

VA-ECMO cannulation may be achieved using either a peripheral or central cannulation strategy. In a peripheral cannulation strategy, the femoral vein and artery are cannulated in a percutaneous fashion, with the tip of the arterial cannula placed in the common iliac artery. Alternatively, the arterial inflow cannula can be placed into the right subclavian artery. Because these peripheral strategies may in some cases only transmit arterial blood flow as far as the aortic arch (where blood oxygenated from the patient's native lungs and transmitted by the patient's heart) this may have the effect of poorly perfusing the heart and lungs (known as the Harlequin Syndrome). In this case, central cannulation of VA-ECMO is an option,

placed in the either internal jugular vein or in the subclavian vein [5].

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overcome.

marginal recipients.

cardiopulmonary support [4].

#### **3.1 ECMO as a bridge to lung transplantation**

The first successful use of ECMO in the preoperative period prior to lung transplant may be traced back to 1975, when ECMO was described as being initiated to correct a profound hypercapnia in a 19-year-old boy prior to transplantation. While the patient was successfully removed from the oxygenator and weaned from mechanical ventilation, he ultimately died on the eighteenth postoperative day due to a bronchial dehiscence [6]. For the next 20 years, this modality was occasionally described in the literature in case studies; however, it was associated with dismal outcomes and as a result did not gain widespread use.

In the past decade, however, there have been a number of advances in both the technology surrounding ECMO, and the management of the patient on ECMO, such that institutions are increasingly turning back to preoperative ECMO as an acceptable or even preferred modality for bridging patients with end stage respiratory disease to lung transplantation. This shift in management was preempted by a number of forces. First, the institution of the lung allocation score in 2005 allowed for more efficacious allocation of donor organs to those patients most emergently in need of a transplants rather than just the length of time on the waiting list. This meant that patients receiving continuous mechanical ventilation were listed with scores. ECMO was found to serve as a useful tool to stabilize ventilator-dependent patients approaching transplantation. Additionally, multicenter trials in the non-transplant population began to demonstrate the effectiveness of ECMO in ameliorating severe adult respiratory distress syndrome [7]. With the significant improvement in ECMO technologies, an increasing number retrospective and prospective studies have been conducted that show promising outcomes related to the use of ECMO as a bridging strategy [5, 8–17].

Some of those studies are reported here. Much of the initial research consisted of single-center retrospective studies. One of the first studies to demonstrate the efficacy of this therapy reported 17 bridged patients with a 78% 1-year survival after transplant, among whom allograft function did not differ between patients who did and did not receive ECMO bridging support [8]. A 2012 institutional study of 11 patients demonstrated shorter durations of mechanical support, and shorter post-transplant ICU and hospital stay in patients bridged with ECMO; a 1-year survival rate of over 85% after ECMO compared to 50% in patients with traditional mechanical ventilation was highlighted [15]. In 2013, a retrospective review of the medical records of 39 French patients bridged to lung transplantation on ECMO highlighted successful bridging to transplant in over 80% of the population,

perioperative survival of 75%, and successful discharge from the hospital in 50%. While 2-year survival was largely a function of the underlying disease state, outcomes were largely similar between the ECMO and non-ECMO use groups, supporting the use of ECMO as a bridge to lung in order to preserve a medium-term survival benefit in the critically ill [14].

A large single-institution study retrospectively reviewed 715 consecutive lung transplants performed between the start of LAS implementation in May of 2005 until September 2011, of which 3.4% were performed on patients with attempted pre transplant ECMO. While patients in the pre-transplant ECMO group had significantly higher lung allocation scores, and median hospital stay was nearly double that for the ECMO group compared to the control group there was no difference in survival, with an overall 2-year survival approaching 75% in both cohorts [16]. A 2017 retrospective single-institution study looking particularly at cardiac outcomes in the population bridged to lung transplantation on ECMO identified a successful bridging rate of 60%, with a 1-year survival of over 90%. This study in particular noted right ventricular systolic dysfunction and worsening volume overload to be associated with unsuccessful bridging, but otherwise identified adequate outcomes [18].

In order to overcome some of the weaknesses of small retrospective cohorts, the question of ECMO's efficacy as a bridging strategy to transplant has been additionally queried of large national databases. A 2015 study of the United Network for Organ Sharing (UNOS) database highlighted 119 patients who were bridged to transplantation using extracorporeal membrane oxygenation compared to 12,339 patients who were not. The study period was divided into four 3-year intervals, and this demonstrated both an increasing number of patients bridged per year with ECMO and progressively increasing survival with each period, as did the number of patients bridged using extracorporeal membrane oxygenation. This highlights that short-term survival with the use of extracorporeal membrane oxygenation as a bridge to lung transplantation continues to significantly improve as it is more widely adopted [19].

The use of bridge-to-transplant with ECMO has also been trialed in small cohorts consisting of patient subsets at increased risk due to the presence of comorbidities. For example, this therapy has been demonstrated as effective in patients with cystic fibrosis; the authors of a 2012 case series of this population demonstrate good perioperative outcomes and describe the early initiation of ECMO soon after development of acute respiratory failure requiring mechanical ventilation as an important part of the treatment algorithm for these patients due to their high risk of ventilator-acquired complications [20]. Furthermore, in the subset of patients with advanced interstitial lung disease and secondary pulmonary hypertension, medical management remains complex and mechanical ventilator support are associated with poor outcomes. Small retrospective reviews, however, suggest that this subset had at least a comparable survival when requiring an extracorporeal membrane oxygenation bridge to that of other high acuity patients placed on extracorporeal membrane oxygenation as a bridge to lung transplantation [21]. Taken in sum, these studies suggest that extracorporeal membrane oxygenation is a feasible tool for use as a bridge to lung transplantation.

#### **3.2 Awake and ambulatory ECMO**

One benefit of ECMO compared to normal mechanical ventilation is that extracorporeal membrane oxygenation allows for adequate oxygenation to occur in patients who are awake, spontaneously breathing, and liberated from the ventilator. This could potentially represent a novel bridging strategy in that the complications

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may improve outcomes.

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

associated with prolonged mechanical ventilation, such as ventilator-acquired pneumonia, are avoided. For example, a 2012 retrospective, single-center analysis of consecutive potential lung transplant patients receiving awake ECMO support compared with a historical control group receiving conventional mechanical ventilation demonstrated a 6-month survival after lung transplantation at 80% in the awake ECMO group versus 50% in the mechanical ventilation group. They also

In addition to avoiding mechanical ventilation complications, freedom from the vent also allows for novel rehabilitation efforts, such as ambulation and physical therapy while on ECMO, which could potentially help to stave off deconditioning while awaiting transplantation in the unit. Subjects on awake ECMO usually received a combination of passive and active physiotherapy; emerging research in the field affords preliminary evidence supporting the safety of early mobilization and ambulation in patients on awake ECMO support [22]. For example, a retrospective observational study in which ECMO patients were managed with early aggressive physical therapy, ambulation, and spontaneous breathing led to 30-day, 1-year, and 3-year survival outcomes after transplant of 92, 85, and 80%, respectively [11]. A second retrospective study compared five pre-transplant ECMO patients receiving active rehabilitation and ambulation to patients who were bridged with ECMO but did not receive pre-transplant rehabilitation. A third study of 72 patients receiving ECMO as a bridge to lung transplantation of which daily participation in physical therapy was achieved in 50 patients demonstrated favorable survival in patients receiving ECMO as a bridge to lung transplantation, particularly good outcomes in patients receiving physical therapy and maintaining avoidance of mechanical ventilation, and high rates of successful ambulation and therapy in the overall ECMO group [9]. Pre-transplant physical therapy was associated with shorter mean post-transplant mechanical ventilation, intensive care stay, and overall hospital days [23]. In general, preservation of pre-transplant ambulatory status has been found to improve outcomes in patients bridged to lung transplantation with ECMO [24]. These are encouraging findings support the concept that ambulatory ECMO allows for preservation of vitality while critically ill candidates await donor organs, which

Efforts to ambulate patients on ECMO bridging to lung transplant have been aided by the implementation of single-site, dual-lumen cannulation via an Avalon catheter. In conventional VV-ECMO, the outflow and inflow cannulas are placed percutaneously using the Seldinger technique, most commonly in the femoral and internal jugular veins. Alternatively, a one-site cannulation strategy makes use of a dual lumen Avalon cannula (Avalon Elite, Maquet, Rastatt, Germany) percutaneously placed in the either internal jugular vein or in the subclavian vein, under direct imaging such as fluoroscopy or transesophageal echocardiogram. This approach avoids use of the femoral site, which aids in mobilization and may limit the risk of recirculation and groin infectious complications [5]. Downsides include the need for precise placement and orientation of the catheter, requiring fluoroscopic guidance; femoral-femoral or femoral-jugular cannulation is much more expeditious, and suited to emergency situations. The Avalon catheter is also significantly more expensive than more conventional cannulation strategies [4]. Ultimately, however, the complication rate of this approach is comparable to traditional two-site ECMO in most studies [25], and many centers are now routinely

Awake ECMO has been shown to be particularly effective for those patients at elevated risk of deconditioning. For example, the subset of patients requiring lung re-transplantation is a particularly challenging transplantation cohort because of the critical illness often associated with graft failure, as well as the higher

using single-site ECMO as a first-line cannulation strategy.

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

had shorter postoperative recovery periods [10].

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

associated with prolonged mechanical ventilation, such as ventilator-acquired pneumonia, are avoided. For example, a 2012 retrospective, single-center analysis of consecutive potential lung transplant patients receiving awake ECMO support compared with a historical control group receiving conventional mechanical ventilation demonstrated a 6-month survival after lung transplantation at 80% in the awake ECMO group versus 50% in the mechanical ventilation group. They also had shorter postoperative recovery periods [10].

In addition to avoiding mechanical ventilation complications, freedom from the vent also allows for novel rehabilitation efforts, such as ambulation and physical therapy while on ECMO, which could potentially help to stave off deconditioning while awaiting transplantation in the unit. Subjects on awake ECMO usually received a combination of passive and active physiotherapy; emerging research in the field affords preliminary evidence supporting the safety of early mobilization and ambulation in patients on awake ECMO support [22]. For example, a retrospective observational study in which ECMO patients were managed with early aggressive physical therapy, ambulation, and spontaneous breathing led to 30-day, 1-year, and 3-year survival outcomes after transplant of 92, 85, and 80%, respectively [11]. A second retrospective study compared five pre-transplant ECMO patients receiving active rehabilitation and ambulation to patients who were bridged with ECMO but did not receive pre-transplant rehabilitation. A third study of 72 patients receiving ECMO as a bridge to lung transplantation of which daily participation in physical therapy was achieved in 50 patients demonstrated favorable survival in patients receiving ECMO as a bridge to lung transplantation, particularly good outcomes in patients receiving physical therapy and maintaining avoidance of mechanical ventilation, and high rates of successful ambulation and therapy in the overall ECMO group [9]. Pre-transplant physical therapy was associated with shorter mean post-transplant mechanical ventilation, intensive care stay, and overall hospital days [23]. In general, preservation of pre-transplant ambulatory status has been found to improve outcomes in patients bridged to lung transplantation with ECMO [24]. These are encouraging findings support the concept that ambulatory ECMO allows for preservation of vitality while critically ill candidates await donor organs, which may improve outcomes.

Efforts to ambulate patients on ECMO bridging to lung transplant have been aided by the implementation of single-site, dual-lumen cannulation via an Avalon catheter. In conventional VV-ECMO, the outflow and inflow cannulas are placed percutaneously using the Seldinger technique, most commonly in the femoral and internal jugular veins. Alternatively, a one-site cannulation strategy makes use of a dual lumen Avalon cannula (Avalon Elite, Maquet, Rastatt, Germany) percutaneously placed in the either internal jugular vein or in the subclavian vein, under direct imaging such as fluoroscopy or transesophageal echocardiogram. This approach avoids use of the femoral site, which aids in mobilization and may limit the risk of recirculation and groin infectious complications [5]. Downsides include the need for precise placement and orientation of the catheter, requiring fluoroscopic guidance; femoral-femoral or femoral-jugular cannulation is much more expeditious, and suited to emergency situations. The Avalon catheter is also significantly more expensive than more conventional cannulation strategies [4]. Ultimately, however, the complication rate of this approach is comparable to traditional two-site ECMO in most studies [25], and many centers are now routinely using single-site ECMO as a first-line cannulation strategy.

Awake ECMO has been shown to be particularly effective for those patients at elevated risk of deconditioning. For example, the subset of patients requiring lung re-transplantation is a particularly challenging transplantation cohort because of the critical illness often associated with graft failure, as well as the higher

*Advances in Extracorporeal Membrane Oxygenation - Volume 3*

survival benefit in the critically ill [14].

fied adequate outcomes [18].

as a bridge to lung transplantation.

**3.2 Awake and ambulatory ECMO**

adopted [19].

perioperative survival of 75%, and successful discharge from the hospital in 50%. While 2-year survival was largely a function of the underlying disease state, outcomes were largely similar between the ECMO and non-ECMO use groups, supporting the use of ECMO as a bridge to lung in order to preserve a medium-term

A large single-institution study retrospectively reviewed 715 consecutive lung transplants performed between the start of LAS implementation in May of 2005 until September 2011, of which 3.4% were performed on patients with attempted pre transplant ECMO. While patients in the pre-transplant ECMO group had significantly higher lung allocation scores, and median hospital stay was nearly double that for the ECMO group compared to the control group there was no difference in survival, with an overall 2-year survival approaching 75% in both cohorts [16]. A 2017 retrospective single-institution study looking particularly at cardiac outcomes in the population bridged to lung transplantation on ECMO identified a successful bridging rate of 60%, with a 1-year survival of over 90%. This study in particular noted right ventricular systolic dysfunction and worsening volume overload to be associated with unsuccessful bridging, but otherwise identi-

In order to overcome some of the weaknesses of small retrospective cohorts, the question of ECMO's efficacy as a bridging strategy to transplant has been additionally queried of large national databases. A 2015 study of the United Network for Organ Sharing (UNOS) database highlighted 119 patients who were bridged to transplantation using extracorporeal membrane oxygenation compared to 12,339 patients who were not. The study period was divided into four 3-year intervals, and this demonstrated both an increasing number of patients bridged per year with ECMO and progressively increasing survival with each period, as did the number of patients bridged using extracorporeal membrane oxygenation. This highlights that short-term survival with the use of extracorporeal membrane oxygenation as a bridge to lung transplantation continues to significantly improve as it is more widely

The use of bridge-to-transplant with ECMO has also been trialed in small cohorts consisting of patient subsets at increased risk due to the presence of comorbidities. For example, this therapy has been demonstrated as effective in patients with cystic fibrosis; the authors of a 2012 case series of this population demonstrate good perioperative outcomes and describe the early initiation of ECMO soon after development of acute respiratory failure requiring mechanical ventilation as an important part of the treatment algorithm for these patients due to their high risk of ventilator-acquired complications [20]. Furthermore, in the subset of patients with advanced interstitial lung disease and secondary pulmonary hypertension, medical management remains complex and mechanical ventilator support are associated with poor outcomes. Small retrospective reviews, however, suggest that this subset had at least a comparable survival when requiring an extracorporeal membrane oxygenation bridge to that of other high acuity patients placed on extracorporeal membrane oxygenation as a bridge to lung transplantation [21]. Taken in sum, these studies suggest that extracorporeal membrane oxygenation is a feasible tool for use

One benefit of ECMO compared to normal mechanical ventilation is that extracorporeal membrane oxygenation allows for adequate oxygenation to occur in patients who are awake, spontaneously breathing, and liberated from the ventilator. This could potentially represent a novel bridging strategy in that the complications

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likelihood of deconditioning after transplant failure. In a 2014 study looking specifically at this group, re-transplant patients bridged on awake, ambulatory ECMO support demonstrated a mortality of 0% compared to 39% in the group requiring mechanical ventilation The study concludes that awake ECMO bridging for re-transplantation provides comparable results to elective re-transplantation [26]. Larger retrospective studies have also made use of clinical databases such as the United Network for Organ Sharing database. In 2016, a study of all adult patients undergoing isolated lung transplantation in the last decade were identified based on their need for preoperative support: no support versus ECMO, invasive mechanical ventilation, or both, while 1-year survival was decreased in all patients requiring any type of support, mid-term survival was comparable between patients on ECMO alone and those not requiring support, but significantly worse with patients requiring mechanical ventilation with or without ECMO. This highlights the fact that those patients supported via ECMO with spontaneous breathing demonstrate improved survival compared with mechanical ventilation [27].
