**3.4 Prolonged bridging with ECMO**

Outcomes in the unique subset of patient requiring the prolonged use of ECMO prior to lung transplantation have in recent years become the subject of study. For example, in a 2016 review of 974 patients who required prolonged (>14 days) ECMO in the Extracorporeal Life Support Organization international multiinstitutional registry, 46% of these patients did not sustain native lung recovery; among these, 40 patients (4.1%) underwent lung transplant with a 50% postoperative in-hospital mortality [30]. While 14 days appears to be the consensus after which ECMO is considered to be prolonged, the upper bounds for the length of time for which ECMO can be continued as a bridging method continue to be tested. For example, a recent case report describes a patient remaining on ECMO for as long as 403 days while waiting for a lung transplant. This required changing the membrane oxygenator 23 times and the cannula 10 times; This therapy was ultimately terminated due to a loss of access for cannula insertion. The authors conclude that it is at least technically feasible to maintain patients awaiting lung transplantation on ECMO for extended periods of time, albeit maintaining for than 1-year may be difficult [31]. While case reports have described successful transplantation after many months on ECMO support, ultimately the outcomes remain dismal in this cohort; for example, as late as 2016 there were no recorded cases of pediatric long-term post-transplant survival after more than 52 days on ECMO support [32].

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

With the increasing utilization of ECMO in the lung transplant population, the question of utility is growing in importance. Recent studies have examined the cost associated with the use of extracorporeal membrane oxygenation in the setting of lung transplantation. A 2017 study using the Nationwide Inpatient Sample evaluated hospital charges of patients undergoing lung transplant who required ECMO during their hospital course; represented 4.2% of the patients undergoing lung transplantation overall. Median charges for lung transplant recipients who required ECMO were \$780,391.50 versus \$324,279.80 for non-ECMO recipients; the characteristics particularly associated with exorbitant hospital costs included black recipient race, pulmonary hypertension, and Medicare enrollees [33]. Studies have shown a disproportionately high amount of extracorporeal membrane oxygenation use in the Northeast compared to other parts of the country; this is highlighted as a

The economic impact of ambulatory versus either non-ambulatory ECMO strategies or mechanical ventilation as a bridge to lung transplantation is also of interest. In a retrospective 2016 study at a single center, subjects who were rehabilitated while supported with ECMO before lung transplantation were compared with those who were not rehabilitated during ECMO. When hospital cost data for the month before transplantation through 12 months after initial post-transplant hospital discharge were compared, subjects supported with ambulatory ECMO had a 22% (greater than \$60,000) reduction in total hospital cost, 73% (greater than \$100,000) reduction in post-transplant ICU costs, and 11% (greater than \$30,000) reduction in total costs compared with non-ambulatory ECMO subjects [34].

With the increasing use of extracorporeal membrane oxygenation as a bridge to lung transplantation, the impact of preoperative ECMO on quality of life and depressive symptoms has been additionally targeted as an area of study. This question stems from the possibility that, due to complications after ECMO coupled with critical illness in the period up to transplantation may have adverse effects of quality of life in patients after transplantation. This does not appear to be the case; a 2018 single-institution prospective cohort study found that lung transplantation provides substantial quality of life improvements following lung transplantation, and these were generally similar among patients on pre-operative ECMO compared to those patients brought in for transplantation from the outpatient setting [35]. A second study in 2017 examining quality of life in ECMO-bridge lung transplant recipients demonstrated that outcomes after successful transplantation after ECMO are comparable with the general population undergoing lung transplantation in terms of quality of life, lung function, performance tests, and mortality [36].

The increasing need for multi-institutional analysis of ECMO usage has had the effect of highlighting the dramatic differences in the implementation of ECMO at various programs. A survey of all US lung transplant centers in showed that twothirds of responding centers used of ECMO as a bridge to transplant. Among these, a patient age greater than 65 was a cutoff in nearly half of centers, but otherwise many centers had no official age cutoff. Additionally, there was little consensus on

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

*3.5.1 Cost-effectiveness*

regional disparity [2].

*3.5.2 Quality of life*

*3.5.3 Quality of the data*

**3.5 Selected issues in bridge-to-transplant**

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

#### **3.5 Selected issues in bridge-to-transplant**

### *3.5.1 Cost-effectiveness*

*Advances in Extracorporeal Membrane Oxygenation - Volume 3*

**3.3 CO2 removal in the bridge-to-transplant population**

ated with high transplantation and survival rates [29].

**3.4 Prolonged bridging with ECMO**

cal ventilation [27].

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 mechani-

In patients awaiting lung transplantation, adequate gas exchange may not be sufficiently achieved by ventilation alone if acute respiratory decompensation arises. This may result in a life-threatening hypercapnia. ECMO may serve an additional purpose in patients bridging to lung transplantation as an adjunct for CO2 removal (ECCO2-R). For some patients, increased CO2 clearance may spare them the need for mechanical ventilation [28]. A 2016 study of 20 patients (15 invasively ventilated and five noninvasively ventilated patients) demonstrated effective correction of hypercapnia and acidosis within the first 12 hours of therapy. Nineteen patients were successfully transplanted, and hospital and 1-year survival was 75 and 72%, respectively. This highlights ECCO2-R as a feasible rescue therapy that can be associ-

Outcomes in the unique subset of patient requiring the prolonged use of ECMO

prior to lung transplantation have in recent years become the subject of study. For example, in a 2016 review of 974 patients who required prolonged (>14 days) ECMO in the Extracorporeal Life Support Organization international multiinstitutional registry, 46% of these patients did not sustain native lung recovery; among these, 40 patients (4.1%) underwent lung transplant with a 50% postoperative in-hospital mortality [30]. While 14 days appears to be the consensus after which ECMO is considered to be prolonged, the upper bounds for the length of time for which ECMO can be continued as a bridging method continue to be tested. For example, a recent case report describes a patient remaining on ECMO for as long as 403 days while waiting for a lung transplant. This required changing the membrane oxygenator 23 times and the cannula 10 times; This therapy was ultimately terminated due to a loss of access for cannula insertion. The authors conclude that it is at least technically feasible to maintain patients awaiting lung transplantation on ECMO for extended periods of time, albeit maintaining for than 1-year may be difficult [31]. While case reports have described successful transplantation after many months on ECMO support, ultimately the outcomes remain dismal in this cohort; for example, as late as 2016 there were no recorded cases of pediatric long-term post-transplant survival after more than 52 days on

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ECMO support [32].

With the increasing utilization of ECMO in the lung transplant population, the question of utility is growing in importance. Recent studies have examined the cost associated with the use of extracorporeal membrane oxygenation in the setting of lung transplantation. A 2017 study using the Nationwide Inpatient Sample evaluated hospital charges of patients undergoing lung transplant who required ECMO during their hospital course; represented 4.2% of the patients undergoing lung transplantation overall. Median charges for lung transplant recipients who required ECMO were \$780,391.50 versus \$324,279.80 for non-ECMO recipients; the characteristics particularly associated with exorbitant hospital costs included black recipient race, pulmonary hypertension, and Medicare enrollees [33]. Studies have shown a disproportionately high amount of extracorporeal membrane oxygenation use in the Northeast compared to other parts of the country; this is highlighted as a regional disparity [2].

The economic impact of ambulatory versus either non-ambulatory ECMO strategies or mechanical ventilation as a bridge to lung transplantation is also of interest. In a retrospective 2016 study at a single center, subjects who were rehabilitated while supported with ECMO before lung transplantation were compared with those who were not rehabilitated during ECMO. When hospital cost data for the month before transplantation through 12 months after initial post-transplant hospital discharge were compared, subjects supported with ambulatory ECMO had a 22% (greater than \$60,000) reduction in total hospital cost, 73% (greater than \$100,000) reduction in post-transplant ICU costs, and 11% (greater than \$30,000) reduction in total costs compared with non-ambulatory ECMO subjects [34].

#### *3.5.2 Quality of life*

With the increasing use of extracorporeal membrane oxygenation as a bridge to lung transplantation, the impact of preoperative ECMO on quality of life and depressive symptoms has been additionally targeted as an area of study. This question stems from the possibility that, due to complications after ECMO coupled with critical illness in the period up to transplantation may have adverse effects of quality of life in patients after transplantation. This does not appear to be the case; a 2018 single-institution prospective cohort study found that lung transplantation provides substantial quality of life improvements following lung transplantation, and these were generally similar among patients on pre-operative ECMO compared to those patients brought in for transplantation from the outpatient setting [35]. A second study in 2017 examining quality of life in ECMO-bridge lung transplant recipients demonstrated that outcomes after successful transplantation after ECMO are comparable with the general population undergoing lung transplantation in terms of quality of life, lung function, performance tests, and mortality [36].

#### *3.5.3 Quality of the data*

The increasing need for multi-institutional analysis of ECMO usage has had the effect of highlighting the dramatic differences in the implementation of ECMO at various programs. A survey of all US lung transplant centers in showed that twothirds of responding centers used of ECMO as a bridge to transplant. Among these, a patient age greater than 65 was a cutoff in nearly half of centers, but otherwise many centers had no official age cutoff. Additionally, there was little consensus on

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

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 therapy as a bridging strategy [39].
