Lung transplantation remains the only curative and life-saving intervention for patients with a wide spectrum of end-stage pulmonary disorders. Despite significant advances in medical therapy and changes made in organ allocation policies, organ availability remains a significant obstacle. Consequently, the number of patients awaiting lung transplantation continues to exceed by a large margin the number of transplants performed each year, and the mortality for patients on the waiting list remains unacceptably high.1 On the basis of data from the Organ Procurement and Transplantation Network in 2009, approximately 1,660 patients underwent a lung transplant procedure in the United States and 2,290 new patients were added to the waiting list the same year.2
In an attempt to reduce mortality while patients are on the waiting list, the lung allocation score (LAS) system was modified in 2005 to allow patients to be prioritized based on clinical status and the highest potential benefit from early transplant, instead of time accrued on the waiting list.3 Simply described, the LAS score is reported on a scale of 0–100 (0 is least ill and 100 is most ill.) Although the modification resulted in an overall reduction of the time to transplant,4 the rate of annual death rates per 1,000 patient-years at risk on the waiting list has increased every year since 2005.5 The risk is particularly high in patients with LAS scores > 50, many of whom succumb with progressive hypoxemia or hemodynamic collapse.
The management of patients with end-stage pulmonary disease suffering respiratory failure is complex, as patients with end-stage pulmonary disorders frequently suffer from concomitant pulmonary hypertension or restrictive lung physiology, conditions that complicate conventional medical management with mechanical ventilation.6 Not surprisingly, several studies have shown that pretransplant mechanical ventilation use may be associated with worse outcomes from transplant. A recent analysis of the United Network of Organ Sharing (UNOS) database found that mechanical ventilation use was associated with a two-fold higher risk of death in the first 6 months after lung transplantation and a worse overall survival after long-term follow-up.7
There is an increasing need to improve available technologies to facilitate bridging to lung transplantation in patients with end-stage lung disease that are clinically deteriorating and have a high risk of immediate death. Once considered an absolute contraindication to lung transplantation because of an unacceptable risk/benefit ratio, extracorporeal membrane oxygenation (ECMO) has evolved into several configurations for patients with a wide variety of respiratory disorders, including those patients with respiratory failure awaiting lung transplantation. Our purpose is to provide an overview of the evolution of ECMO technologies that have been used in patients awaiting lung transplantation and to provide an update on recent innovations to improve outcomes in lung transplantation.
History of ECMO in Lung Transplantation
The use of a mechanical pump-oxygenator to support heart-lung transplantation was described first by Webb and Howard in 1957.8 Nevertheless, it was not until 1971 that Kolff, Kolobow, and others demonstrated the successful use of a silicone membrane to allow long-term extracorporeal blood gas exchange away from the operating room in awake lambs.9 Between 1972 and 1977, many centers reported the use of extracorporeal oxygenators in patients who died while awaiting lung transplantation.10 In 1977, the first successful case of ECMO as a bridge to lung transplantation was reported by Vieth,11 who described a patient with post-trauma respiratory failure who underwent bilateral lung transplantation. The patient only survived 10 days and died of infectious complications. Subsequently, in 1982, another case of ECMO as a bridge to lung transplant was reported in a patient with severe paraquat poisoning. Interestingly, the patient was bridged to lung transplantation and successfully weaned from ECMO but after a short period of time had graft failure and required ECMO reinitiation. Approximately 19 days later the patient was successfully bridged to a lung retransplant procedure. This patient died after 3 months of complications related to a trachea-innominate fistulae.12
After these initial negative experiences and the publication of a large national randomized trial suggesting that ECMO use was associated with worse outcomes in patients with acute respiratory failure,13 the use of ECMO either as a bridge to lung transplantation or in patients with respiratory failure was largely abandoned. Many assumed that ECMO use was associated with an increased risk for infectious complications and high incidence of ischemia of the bronchial anastomosis.
Early Successful Experiences with ECMO
The first successful use of ECMO as a bridge to lung transplantation in patients receiving mechanical ventilation was published by Jurmann et al.14 in 1991. The authors described the use of venoarterial (VA) ECMO in two patients who developed severe primary graft dysfunction after lung transplantation and underwent a successful retransplant procedure. A year later, the same group reported successful use of venovenous (VV)-ECMO (femoral vein to internal jugular vein) as a bridge to primary lung transplantation in a patient who developed post-traumatic respiratory distress syndrome; this was also the first reported case of long-term survival (> 12 months) after ECMO in a lung transplant recipient.
Despite these initial successful experiences, the use of ECMO in lung transplantation remained highly controversial given a high mortality rate and associated bleeding, anastomotic leaks, increased rate of infection, prolonged ICU and hospital stay, high incidence of neuromuscular complications, and frequent need for prolonged physical rehabilitation after hospital discharge.
Modern Experience with ECMO
ECMO use as a bridge to lung transplantation has significantly increased during the last 10 years (Table 1). A recent analysis of the UNOS database showed that the use of ECMO at the time of lung transplantation has grown 150% in the last 24 months compared with all previous decades (1970–2010).15 This increase in use is reflected in the growing success reported with the use of different ECMO modalities in patients awaiting lung transplantation.16 Likewise, the increase in worldwide experience appears to be associated with improved short- and long-term outcomes. A previous review of the US experience by Mason et al.,17 which included 51 patients who received transplants while they were on ECMO before 2008, found that the 1-year survival was only 50% compared with 79% for unsupported patients. In contrast to this report, more recent studies show a significant improvement in short- and mid-term outcomes of patients undergoing lung transplantation while supported on ECMO.
Bermudez et al. 18 published a single-center experience with 17 patients bridged on ECMO and reported 30-day, 1-year, and 3-year survivals of 81%, 74%, and 65%, respectively, for patients on ECMO, compared with 93%, 78%, and 62% in the nonsupported patients (p = 0.56). Similarly, Fuehner et al.49 reported their single-center experience in Germany including 26 patients that were bridged to transplant using ECMO and compared the outcomes with patients on conventional mechanical ventilation. The authors reported a 6-month survival of 80% in the awake ECMO group versus 50% in the MV group (p = 0.02). Finally, Lang et al.19 reported their single-center experience in Vienna including 38 patients transplanted between 1998 and 2011. The 1-, 3-, and 5-year survival conditional on 3-month survival for patients bridged with ECMO to lung transplant (78%, 78%, and 63%) was not worse than for other lung transplant patients within the same period of time (90%, 80%, and 72%, respectively, p = 0.09, 0.505, and 0.344). We recently submitted our experience with the use of ambulatory ECMO as a bridge to lung transplantation, reporting the use of ECMO in 31 patients with end-stage lung disease. In our series, all of the patients were awake and the vast majority followed an “algorithm-directed” ECMO management program that involved the use of physical therapy and ambulation in preparation for lung transplant. In our series, the 30-day, 1-year, 3- year, and 5-year survival was 97%, 92%, 83%, and 66%, respectively.20
A summary of a modern series of patients bridged to lung transplant while on ECMO is presented in Table 2.
Indications, Contraindications, Candidate Selection
ECMO was initially considered a “salvage” therapy in patients “dying” from severe respiratory failure refractory to conventional medical therapies (high end-expiratory positive pressure [PEEP], high frequency oscillation, prone ventilation, nitric oxide, etc). Currently, advances in ECMO technology allow application early in the course of the disease with the potential to minimize systemic organ injury associated with the use of conventional mechanical ventilation.21 Furthermore, ECMO use is now being considered in awake and nonintubated patients in order to improve oxygenation, facilitate ambulation, and to improve physical conditioning before transplant.20, 22
Indications for ECMO use as a bridge to lung transplantation include the following:
Patients with irreversible end-stage lung disease presenting with clinical deterioration (refractory hypoxia or hypercapnia) despite the use of invasive or noninvasive mechanical ventilation. The same applies for those who are candidates for mechanical ventilation use because of lack of response to conventional therapy (i.e., high-flow oxygen devices).
Several studies have shown that the use of mechanical ventilation in patients with idiopathic pulmonary fibrosis is not effective and is associated with high mortality rates.23, 24 Delaying initiation of ECMO in an attempt to maximize alternative medical treatments (i.e., prone ventilation, newer modes of mechanical ventilation, and the like) in patients with irreversible alveolar damage (such as idiopathic pulmonary fibrosis) and respiratory failure may result in worsening physical condition, secondary organ dysfunction,25 and jeopardizing their candidacy for possible lung transplantation.
1. Patients with severe pulmonary hypertension refractory to pulmonary vasodilators or hemodynamic deterioration caused by right ventricular failure.26
2. Patients with severe exercise induced pulmonary hypertension associated with advanced lung disease, presenting with clinical deterioration and progressive physical decline and unable to maintain ambulation and good functional status.
In our practice, we consider the following as relative contraindications to the use of ECMO as a bridge to transplant:
1. Active bloodstream infection
2. Acute renal failure not responsive to medical therapy (need for dialysis)
3. Hereditary or acquired coagulation disorders (i.e., blood dyscrasia, heparin-induced thrombocytopenia)
4. Evidence of end-organ failure other than lung
5. Underlying irreversible neurological or neuromuscular disease
Areas of Controversy
Advanced age (> 65 years) is considered by some a relative contraindication for lung transplantation. Nevertheless, several reports have demonstrated that lung transplantation can be performed safely and with good outcomes in patients > 65 years of age.27, 28 In our experience, advanced age does not represent an absolute contraindication for ECMO, although the long-term outcomes in this subgroup of patients remain to be studied.
Another area of debate is the use of ECMO in patients with severe bronchiectasis or cystic fibrosis. A recent report of the use of ambulatory VV-ECMO in patients with cystic fibrosis and hypercapneic respiratory failure, suggests that these patients can be successfully bridged to lung transplantation without an increased risk for infectious complications.29
Finally, a similar concern relates to patients with profound neuromuscular weakness after critical care illness (i.e., critical care polyneuropathy). Several reports in the literature suggest that patients can be successfully bridged to lung transplantation even after prolonged ECMO use. For example, Broomé et al.30 reported good long-term outcome (3 years) after prolonged use of ECMO (57 days) in a patient with polymyositis. Similarly, Iacono et al.31 reported a patient that underwent a double lung transplant with good short-term outcome after 107 days on ECMO. In our experience, the presence of critical care polyneuropathy or myopathy does not represent an absolute contraindication to ECMO use. Nevertheless, it must be pointed out that these patients require a very aggressive multidisciplinary approach to facilitate physical reconditioning both before transplantation (ambulatory ECMO) and after transplant. We recently performed a double lung transplant in a 28-year-old male with diffuse alveolar damage, who was switched to VV-ECMO after 32 days on conventional mechanical ventilation. Neuromuscular testing confirmed the presence of severe critical care polyneuropathy and polymyopathy. After a total of 55 days on VV-ECMO and an intensive physical therapy program, the patient was successfully bridged to lung transplantation. The patient had a full recovery after transplant, regaining normal ambulation and enjoying normal lung function and good quality of life after 1-year follow-up (unpublished report).
Advances in Technology
The oxygenator constitutes one of the key elements of the ECMO circuit. Significant advances in commercially available oxygenator membranes have resulted in improved durability, including patients bridged to lung transplantation after prolonged use of ECMO (> 90 days).31 In 1971, Kolobow demonstrated the use of a membrane made of silicone rubber that enhanced secondary flow and improved gas exchange capability. The silicone membrane oxygenator was quickly used in clinical practice and became one of the preferred oxygenator technologies used for both ECMO and cardiopulmonary bypass.9 Between 1970 and 1980, a microporous hollow-fiber membrane oxygenator was developed. Although this oxygenator provided adequate gas exchange, the membrane was associated with a large amount of leakage through the membrane walls. Subsequently, the technology was improved, and in 1981 the first commercially available hollow-fiber oxygenator (Capiox) with a microporous membrane was developed in Japan.32 Silicone-coated microporous polypropylene was advocated as the best clinically available complex membrane, gained popularity in the United States, and was widely adopted in clinical practice during the years 1980–1990.33 Currently, most ECMO systems have replaced polypropylene with polymethylpentene (PMP) fibers. Compared with silicone and polyproplylene oxygenators, PMP membrane oxygenators are smaller, provide efficient gas exchange without plasma leak, and are associated with faster priming (saving blood and valuable time and making CO2 flushing unnecessary). In addition, the PMP oxygenators are associated with less circuit resistance, are less prone to malfunctioning because of blood trauma or blood clots, and can be functional for several weeks to months.31, 34
Modern ECMO components can be heparin coated, reducing excessive use of heparin, minimizing risk of over-anticoagulation, and reducing the use of blood products.35 Heparin-coated tubing is also associated with a reduction in the rates of leukocytes, platelets, and complement activation.36 In addition, PMP oxygenators can also be heparin coated, leading to better preservation of extrinsic coagulation factors and platelets.34
Earlier ECMO circuits were based on a roller-head pump that used gravity drainage to augment venous return to the circuit. In order to facilitate venous return, the majority of the ECMO centers set up the lowest point in the venous circuit on the floor and implemented elevation of the bed height. This configuration did not allow for patient vertical mobilization or ambulation without significant risks of adverse hemodynamic consequences, rupture, or air emboli. In addition, the roller head required that the tubing frequently (walking the raceway) be moved to prevent disruption to the walls because of shear stress on the tubing. High pressure in the tubing system can accumulate and create tubing rupture if a kink or an occlusion distal to the roller head occurs in the circuit. These factors combine to make roller-head systems incapable to facilitate patient movement, physical therapy, and ambulation. To overcome these problems, centrifugal pumps have been created offering a nonocclusive, demand-regulated pump flow that eliminates the risk of raceway tubing wear and circuit rupture. The availability of centrifugal pumps has made significant impact in our ability to facilitate patient mobilization and ambulation.37
Interventional Lung Assist (Novalung)®
Arteriovenous (AV) gas exchange has been successfully used to bridge patients to lung transplantation using a “pumpless” AV mode (also known as pECLA), in which the device is attached to the systemic circulation via the femoral artery, although central cannulation has also been reported in patients bridged to lung transplantation (PA-LA or PA-PV).38, 39
The interventional lung assist (iLA®), or Novalung® (Heilbronn, Germany) (Figure 1), consists of a low-resistance PMP membrane designed to allow gas exchange by simple diffusion. The device is effective for CO2 removal but is less effective for O2 augmentation as it only receives approximately 15–20% of the cardiac output for extracorporeal gas exchange. Novalung® has been compared with other CO2 removal devices in patients awaiting lung transplantation and all provided similar CO2 clearance.40
Novalung® has been successfully used in patients awaiting lung transplantation with hypercapneic respiratory failure (i.e., end-stage chronic obstructive pulmonary disease (COPD), with bronchiolitis obliterans syndrome, etc)41, 42 and with pulmonary hypertension.43 Fischer et al.42 presented their experience at a single institution in Germany and described the use of Novalung® in 12 patients that were bridged to lung transplantation. In this study, the authors report significant improvements in CO2 removal and modest improvements in oxygenation 6 hours after initiation of iLA®. The 1-year survival rate in this cohort was 80%.
Although studies have found that pECLA is capable of unloading the lung work and facilitates gas exchange in patients with hypercapneic respiratory failure, this modality has significant disadvantages when compared with VV-ECMO. Limited blood flow thus limited gas exchange, increased cardiac workload, the need to maintain high systemic vascular resistance, and the potential to limb ischemia when using the femoral cannulation site44; all contraindicate the application of iLA® in patients with acute hypoxic respiratory failure with severe hypoxia or in patients with hemodynamic instability.
Dual Lumen Cannula (Avalon-Elite)TM
A new type of double lumen cannula (DLC) (Figure 2), offers an alternative to traditional in-series cannulation. The device consists of two pathways: a drainage pathway and an infusion pathway. The cannula is placed percutaneously through the internal jugular vein; the drainage lumen is open to both the superior vena cava and the inferior vena cava, whereas the infusion lumen is open to the right atrium. The blood from systemic circulation flows through the superior vena cava and inferior vena cava into the drainage lumen to the artificial lung device. The blood is oxygenated and returned via the infusion lumen into the right atrium.45
The DLC (Avalon Laboratories LLC, Rancho Dominguez, CA) was approved by the US Food and Drug Administration for adult ECMO use in 2009.46 Compared with traditional ECMO approaches, this device offers important advantages in patients awaiting lung transplantation: it requires single-site cannulation, reduces the risk for complications associated with femoral or central cannulation, and facilitates ambulation by avoiding the use of the femoral site. A significant problem associated with nonambulatory ECMO techniques is the development of profound neuromuscular complications and physical deconditioning that are associated with prolonged hospital length of stay and difficult rehabilitation after lung transplantation.
The DLC cannula has a unique design with improved flexibility (reducing kinking problems associated with rigid cannulas). The infusion lumen of the cannula is an ultra-thin membrane that collapses during insertion to allow space for an atraumatic introducer that facilitates placement. In addition, the cannula wall is reinforced with antikink stainless steel wire around it.46 A major drawback of a DLC design is the propensity for the “recirculation” phenomenon, particularly when it is not properly positioned. Nevertheless, the Avalon DLC has shown recirculation fractions as low as 2% when fluoroscopy or transthoracic echocardiography guidance is used.46, 47
The Avalon DLC was initially advocated by Hoopes to facilitate ambulation during ECMO in awake and nonintubated patients. Garcia et al.48 first reported the use of ambulatory VV-ECMO using a DLC in a patient with COPD with refractory hypercapnia. The patient was able to exercise using a treadmill and a stationary bike while on ECMO and was successfully bridged to lung transplantation approximately 19 days later (Figure 3).
Many other centers have reported similar results and have confirmed the feasibility and safety of the DLC as a bridge to lung transplantation: Fuehner et al.49 reported that 13 patients were treated with VV-ECMO and an “awake” strategy before transplantation. For VV-ECMO, a single-site approach using a DLC was preferred in patients with hypercapnia and preserved oxygenation, whereas a two-site approach was chosen for patients with severe hypoxemia. Bermudez et al.18 presented their single-center experience with 17 patients that were bridged to lung transplantation (including 3 patients bridged using a DLC). The 30-day, 1-year, and 3-year survival rates were not different when compared with nonsupported patients, and the survival was not affected by ECMO type at 2 years. Turner et al.50 reported the use of DLC in three patients with acute respiratory failure that were successfully bridged to lung transplantation after an active rehabilitation program and active ambulation. Hayes et al.29 reported the use of a DLC to facilitate ambulation and transplant in four patients with cystic fibrosis and hypercapneic respiratory failure. More recently, Lang et al.19 reported their experience with ECMO as a bridge to lung transplantation in 34 patients, and reported the use of a DLC in two patients.
The cannulation strategy is frequently chosen based on the following factors:
1. Facilitate ambulation: DLC via internal jugular vein is the preferred route, although central VA-ECMO and iLATM (PA-LA) can also allow ambulation.
2. Age and medical history of the patient: central cannulation for VA-ECMO is less favored in patients > 65 years of age or history of previous sternotomy
3. Hemodynamic status: central or femoral cannulation for VA-ECMO is often necessary in patients with hemodynamic instability
4. Presence of severe pulmonary hypertension or right heart failure: central or femoral cannulation for VA-ECMO is preferred.
Common cannulation approaches performed for bridging patients to lung transplantation include femoral vein to internal jugular vein (traditional VV), femoral vein to femoral artery (traditional VA), right atrium to aorta (central VA), pulmonary artery to left atrium (PA-LA), and right internal jugular with dual lumen cannula (ambulatory VV).
Figure 4 shows our preferred cannulation strategy for ambulatory ECMO as a bridge to lung transplantation. In this algorithm, all mechanically ventilated patients with hemodynamic instability and respiratory failure undergo open femoral cannulation for VA-ECMO using wire-reinforced arterial (16/18Fr) and long venous cannulas (23–27 Fr) deployed to the right atrium. Vasopressors, paralytics, and sedation are immediately turned off or withdrawn. We deploy an 8 Fr distal femoral arterial flow cannula if clinically indicated to preclude limb ischemia. We do not consider femoral VA-ECMO an appropriate method of long-term support as it precludes ambulatory status. In awake patients who have had a nonfocal neuro exam and adequate end-organ perfusion, the blood path of the VA-ECMO is reversed and the centrifugal pump is excluded from the circuit–AV pumpless extracorporeal lung assist (pECLA). Patients who tolerate femoral pECLA are converted to VV-ECMO with a DLC. Patients with ongoing hemodynamic requirements (right ventricle failure or severe pulmonary hypertension) are converted to central cannulation (RA to PA, PA to LA, and RA to Ao) with off-label use of available ventricular assist device cannulas (Abiomed 32 Fr venous, 10 mm Dacron aortic).
DLC and Atrial Septostomy
Hoopes et al.51 recently reported the use of a DLC in a patient with severe right ventricular failure secondary to pulmonary hypertension associated with pulmonary veno-occlusive disease. In that report, an atrial septostomy was created concomitant to the insertion of the DLC to unload the right heart pressures and to facilitate forward flow (F5Figure 5). The patient was able to ambulate and was successfully bridged to lung transplantation.
Bonacchi et al.52 reported the use of VV-ECMO in 30 patients with severe acute respiratory failure and described their experience with the use of a customized arterial cannula to reduce the amount of blood recirculation fraction (BRF) when high ECMO flows were needed to improve systemic oxygenation. In their χ configuration, a traditional inflow cannula is modified by making a 60° angle in its distal third to allow tip orientation towards the tricuspid valve. In their series, the authors report a significant improvement in oxygenation indices and a reduction of > 20% in the BRF. Importantly, the study showed that the modified cannula can be safely used without mechanical complications.
DLC and Axillary Artery (“walking hybrid”)
Bacchetta et al.53 reported that for patients on VV-ECMO using a DLC, a conversion VA-ECMO can be accomplished by adapting the existing catheter: the two lumens are connected using a Y-connector and the end of the Y-connector is then joined to the venous drainage of the extracorporeal or cardiopulmonary bypass (CPB) circuit. The arterial cannula can then be placed intra-thoracically or peripherally. In their report, the authors described the conversion in one patient bridged to CPB to facilitate lung transplantation (DLC and aortic cannulation) and in another patient was bridged to VA-ECMO (DLC and axillary artery). The authors suggest that using a combined axillary artery cannulation and the DLC venous cannulation could facilitate ambulation while a patient awaited lung transplantation.
The recent success of ECMO as a bridge to lung transplantation is a consequence of both significant advances in technology of the components of the circuit as well as available changes in ECMO configuration that allows the use of ECMO in awake and ambulatory patients. Many centers now advocate the use of a multidisciplinary team in all patients that are treated with ECMO while awaiting lung transplantation. The objectives are to improve the preoperative condition of the patient by enhancing physical strength and cardiovascular fitness and reducing the risk for posttransplant complications.50, 54 Further studies evaluating the long-term effects of ECMO on lung transplant recipients are needed.
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extracorporeal membrane oxygenation (ECMO); transplant; lung; bridge