ECMO for Respiratory Failure in the Patient with Advance Lung Disease: A Bridge to Recovery or Decision

Abstract

Extracorporeal membrane oxygenation (ECMO) has clear benefits in patients with acute cardiopulmonary failure. However, selecting patients who will benefit from extracorporeal membrane oxygenation can be a challenge and remains a hurdle for clinicians today. An increased concern when considering ECMO therapy is whether the patient will recover enough function and be able to be weaned from ECMO support and survive to discharge or undergo lung transplantation and specially on whether to extend extracorporeal membrane oxygenation as a bridge to recovery in those with concerns of a meaningful recovery or as a bridge-to-decision (BTD) for patients whose criteria for lung transplantation are unknown. In addition, ECMO is a resource-intensive form of lung support that requires significant institutional commitment and a well-trained team to ensure good outcomes. The critical factors in the decision-making process when there are concerns regarding the initiation, continuation, or withdrawal of ECMO include early transfer to a specialized lung transplant center and a multidisciplinary consensus among lung transplant pulmonologists, lung transplant surgeons, and ECMO critical care intensivists to expedited transplant evaluation and to clearly defined the goals of care and selecting the appropriate candidates who will benefit from ECMO as a BTD for patients not listed yet for lung transplantation.

1. Introduction

Since the 1950s, extracorporeal lung support has experienced continuous advancements in technology and a better understanding of ECMO physiology, which has led to less morbidity and more liberal use of this technology in acute respiratory failure (ARF). Experiences in selecting and managing patients with acute cardiac and respiratory failure treated with ECMO continue to grow. ECMO is a resource-intense form of lung support that requires significant institutional commitments and a well-trained team to ensure good outcomes.

There are clear benefits of ECMO in patients with acute respiratory failure such as acute respiratory distress syndrome (ARDS), hypercapneic respiratory failure related to infections or flare of their underlying disease, and pulmonary arterial hypertension (PAH) patients with decompensated right heart failure as a bridge-to-recovery (BTR), and as a bridge-to-decision (BTD) for lung transplant candidates, who have not completed the lung transplant evaluation, and as a bridge-to-transplant (BTT) for decompensated lung transplant candidates, hoping to avoid mechanical ventilation, sedation, and the use of neuromuscular blocking agents for conditioning, preservation of lung transplant candidacy, and ultimately better long-term outcomes. However, the decision to support patients with acute or acute-on-chronic respiratory failure with ECMO is challenging. No single guideline exists to aid decision-making, and the clinical management decisions are highly center-specific.

Based on the organ procurement and transplantation network (OPTN)/and the scientific registry of transplant recipient database (SRTR) 2020 report, lung transplant candidates hospitalized in the intensive care unit (ICU) comprised 13.8% of transplant recipients; 9.2% were hospitalized but not in the ICU. Also, candidates continued to be bridged-to-transplant; 3.6% on mechanical ventilation and ECMO, 1.8% on mechanical ventilation only, and 3.1% ECMO only [1].

This chapter will review the ECMO support as a BTR and as a BTD in patients with advanced lung disease and respiratory failure not listed for a lung transplant, including the limited data and the lack of good guidelines on candidate selection and the need for advance care planning, early palliative care involvement, and the need to involve patient and family on the implications of ECMO withdrawn when not a candidate for lung transplantation before deciding to accept ECMO as a bridge-to-decision.

2. ECMO as a bridge to recovery for acute respiratory failure in patients with advance lung disease

Treating patients with interstitial lung disease (ILD) and acute respiratory failure (ARF) is challenging. Lung transplantation is the only definitive therapy for patients with severe and meaningful recovery. Unfortunately, acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an often deadly complication of idiopathic pulmonary fibrosis (IPF).

Mechanical ventilation is a significant problem in advanced interstitial lung disease patients as the lung parenchyma is susceptible to ventilator-induced lung injury and oxygen toxicity [2, 3]. This likely triggers further disease progression [4]. Also, these patients often have secondary pulmonary hypertension and right ventricular dysfunction, increasing ventilation strategies’ challenges [5]. Patients with advanced lung disease who developed respiratory failure and required mechanical ventilation have high mortality (70–90%) [6]. On the other hand, ECMO support might prevent ventilator-induced lung injury and worsening right ventricular dysfunction. However, the value of ECMO in patients with acute respiratory failure due to underlying lung fibrosis has not yet been well studied.

Kreuter et al. [7] published an international survey from 66 countries and 509 pulmonologists to assess the global variability in the prevention, diagnostic, and treatment of AE-IPF and reported that in case of respiratory failure, invasive ventilation was offered only to 45% to patients suitable for lung transplantation (LTx), as a BTT or in very selected other cases. Extracorporeal membrane oxygenation was offered to 44% of patients suitable for LTx as a bridge-to-transplant, mainly in Europe (57%) and the fewest in Oceania (24%). Palliative care was considered by 65% of the pulmonologist. The differences in these approaches were again significant between continents. Some of the differences in approaches might be related to center protocols, ICU resources, and ECMO expertise team experiences. Technology and resources also vary among countries.

2.1 ECMO for acute respiratory distress syndrome

Several landmark trials of venovenous (VV)—ECMO for acute respiratory distress syndrome (ARDS) are often referenced when discussing the potential benefits of ECMO for respiratory failure. Key studies supporting the efficacy of ECMO include the Australian and New Zealand study on H1N1-induced ARDS patients treated with ECMO having greater than 70% survival [8]. Around this time, major improvements were made to the ECMO devices, including more efficient oxygenators, fewer thrombotic centrifugal pumps, and improved percutaneous vascular access cannulas.

Peek et al. [9] conducted a multicenter randomized control trial based in the UK called the CESAR trial, where patients with ARDS were randomized to conventional therapy or ECMO, showing that patients with ARDS who were referred to an ECMO center had significantly improved survival 6 months from discharge than those who were not referred and treated with medical management alone. Severe ARDS was defined as a Murray score above three or an arterial pH below 7.20. Essential exclusion criteria were prolonged high oxygen requirement or high-pressure mechanical ventilation for more than 7 days before considering enrollment. The results of the CESAR trial showed improved survival without severe disability in the patients considered for ECMO. 63% of the ECMO consideration group was alive at 6 months, whereas only 47% of the conventional therapy group survived that timeframe. Most deaths in the ECMO group were from multi-system organ failure, whereas 60% of the standard therapy patients died of respiratory failure. The release of the data from the CESAR trial and the treatment successes from the 2009 Influenza pandemic has propagated ECMO use in various clinical settings.

The REVA study group published their results using ECMO for H1N1-associated ARDS and identified at 1-year post-ICU discharge that 83% of patients treated with ECMO had returned to work vs. 64% of non-ECMO treated patients [10].

The ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) clinical trial randomized patients to VV ECMO based on blood gas and ventilator criteria similar to CESAR [11]. However, its results further clouded the data regarding the benefits of ECMO for refractory ARDS. In total, 249 patients were randomized in the study, and there were no significant differences between the two groups. At the primary endpoint of 60 days, 35% of the ECMO group had died, whereas 46% of the control group was dead. The highest sub-group mortality was those patients who crossed over from the control group to ECMO, as 57% of them were dead by 60-days. They concluded that among patients with very severe ARDS, 60-day mortality was not significantly lower with ECMO than with a strategy of conventional mechanical ventilation that included ECMO as rescue therapy. Despite what appears to be trending toward better survival with earlier ECMO, the data did not reach statistical significance.

2.2 ECMO for hypercapnic respiratory failure

The treatment of acute exacerbations of chronic obstructive lung disease (COPD) resulting in hypercapnic respiratory failure refractory to medical treatment has been invasive mechanical ventilation (IMV). In the most severe cases, these may be refractory to conventional therapies and mechanical ventilation, becoming life-threatening. Invasive mechanical ventilation develops a considerable reduction in respiratory muscle strength, having a higher risk of prolonged weaning and failure to wean compared to other causes of acute hypercapnic respiratory failure and a more increased need for early tracheostomy. These patients also have a higher risk of developing complications such as ventilator-associated pneumonia (VAP), ventilator-induced lung injury (VILI), ventilator-associated diaphragmatic dysfunction (VIDD), and critical illness myopathy and neuropathy associated with steroids and neuromuscular blockade agents often used during their critical ICU admission [12]. Extracorporeal carbon dioxide removal (ECCO2R) represents an attractive approach in this setting for carbon dioxide removal options to avoid and possibly prevent worsening respiratory failure and respiratory acidosis and shorten the duration of IMV.

In 2009, Dr. Zwischenberger’s group successfully used venovenous-ECMO for carbon dioxide removal (ECCO2R) in a hypercarbic patient with COPD. They successfully reduced PaCO2, minute ventilation, and ventilator pressures [13]. In 2013, the Columbia University group used ECCO2R to facilitate extubation in five patients with COPD, all of whom had failed to wean from the ventilator. These patients were extubated in a median time of 4 h and most were ambulatory within 24 h of venovenous ECMO initiation. Once extubated, patients were rehabilitated while on ECCO2R, with a mean time to ambulation of 19.4 ± 12.6 hours after ECCO2R. Moreover, all patients survived hospital discharge [14]. Since that time, multiple reports have supported the efficacy of venovenous ECMO in treating hypercapnic respiratory failure in COPD and reducing intubation time or preventing it all together [15, 16]. In the ÉCLAIR study, Braune et al. [16] showed that IMV was avoided in 56% of cases treated with ECCO2R but was associated with a higher incidence of complications.

Although ECCO2R seems effective in improving or mitigating hypercapnic acidosis and possibly reducing the rate of endotracheal intubation, its use is associated with a range of vascular, hematological, and other complications. Thrombocytopenia and heparin-induced thrombocytopenia are also commonly observed. Other serious complications associated with arterial cannulation include distal limb ischemia, compartment syndrome of the lower limb requiring fasciotomy, or limb amputation [17]. Bleeding is the most common complication of ECCO2R. The need for anticoagulation increases the risk of significant bleeding, including cerebral, gastrointestinal, and nasopharyngeal bleeds. The published incidence of substantial bleeding complications is between 2 and 50% [18].

2.3 ECMO for pulmonary arterial hypertension

Patients with group 1 pulmonary arterial hypertension (PAH) and decompensated right ventricular failure (RHF) were not previously considered for ECMO as a BTT or BTR because options were limited by the idea that PAH patients would not be able to weaned from ECMO as a BTR from an acute decompensation and by long transplantation wait times and perceived inability to weaned from ECMO. Rosenzweig et al. [19] published a retrospective review of ECMO as a BTR for PAH. A total of six patients (age 32 ± 11 years) underwent ECMO bridging. Two patients who were considered good candidates for lung transplantation underwent successful ECMO-BTT. Four patients who were not regarded as promising candidates for lung transplantation experienced ECMO-BTR with the escalation of targeted medical therapies before weaning off ECMO. Three of four ECMO-BTR patients survived ECMO decannulation (duration 7–23 days). This single-institution experience demonstrated the beneficial use of upper body configuration ECMO strategy without mechanical support in PAH patients as a BTR or BTT when they failed to respond to medical therapy. In addition, this strategy facilitates mobility with physical therapy, thereby optimizing transplant candidacy.

Chicotka et al. [20] published a retrospective review of 50 patients with interstitial lung disease and pulmonary hypertension treated initially with either VV or venoarterial (VA) ECMO as a bridge-to-transplant. They found that patients with early VA ECMO initiation had significantly better survival to transplantation than those with early VV ECMO (p = 0.03). In addition, there was a 59% reduction in risk of death for VA compared with VV ECMO (HR 0.41, 95% confidence interval: 0.18 to 0.92, p = 0.03) shown by cox proportional hazards modeling. Also, there was an 80% reduction in the risk of death when ambulating on ECMO before lung transplant (HR 20, 95% confidence interval: 0.08 to 0.48, p < 0.01). In this single-institution experience, they found that combined ECMO with targeted PAH therapies was successfully used as BTT or BTR for acute right heart failure in group 1 PAH patients leading to significant improvement in gas exchange and end-organ function. Unfortunately, only 10 patients in this series of 50 were IPAH and 5 Eisenmenger. This approach needs further assessment, and as experience grows, we may anticipate earlier instituting ECMO in suitable group 1 PAH patients.

3. ECMO as a bridge-to-decision or bridge-to-transplant in patients with advance lung disease

The most significant issue with lung transplantation is often long wait times. This problem seems more prominent in the Eurotransplant area than in the United Network for Organ Sharing area. Based on the OPTN/SRTR 2022 report, lung transplant candidates continued to be bridged-to-transplant; 3.6% on mechanical ventilation and ECMO, 1.8% on mechanical ventilation only, and 3.1% ECMO only and ECMO-BTT patients who survive to LTx have a post-transplant survival rate comparable to those who did not receive ECMO pre-transplant [1].

Traditionally, the concept of ECMO use in respiratory failure was to initiate it in conjunction with invasive mechanical ventilation and later by discontinuing ECMO support before ventilator weaning. However, with the ability of ECMO to take over the function of the gas exchange of the ventilator, this pattern is changing, and it will continue to evolve as further technological improvements are made. Some centers have reported successfully starting ECMO instead of invasive mechanical ventilation, bypassing the ventilator entirely [21, 22]. Abrams et al. [21] described an evolving paradigm of extracorporeal membrane oxygenation (ECMO) in respiratory failure as a temporary adjunct to invasive mechanical ventilation in severe respiratory failure and using ECMO to facilitate removal or avoidance of IMV while bridge-to-recovery or bridge-to-transplant, at their institution. The paradigm of bridge-to-transplant or bridge-to-decision from IMV and ECMO remains a consideration. However, it remains to be defined who are the specific patient populations for whom these strategies are most appropriate, including those with hypercapnic respiratory failure or awaiting lung transplantation.

Salna and Bacchetta [23] described a clinical decision-making algorithm used at their institution to optimize ECMO configurations and cannulation strategies based on patients’ pathophysiology using a multidisciplinary ECMO team approach for BTT. Factors to decide whether patients will benefit from BTT were age, functional status on admission, underlying disease, infection or other organ system dysfunction, and anticipated waitlist time. The primary goal of using ECMO as a BTT was to optimize transplant candidates before transplantation to improve lung transplant outcomes. Their goal was to help ambulation, which depends on optimal cannulation configurations and early physiotherapy, with patients being mobilized as early as ECMO day 1 [24]. They also aim to cannulate patients without intubation or general anesthesia whenever possible for accelerated recovery or optimization for transplantation.

Trudzinski et al. [25] published a retrospective analysis of patients with ILD and ARF treated with or without ECMO from March 2012 to August 2015. Forty patients with interstitial lung disease referred to their intensive care unit for acute respiratory failure were included in the analysis. Twenty-one were treated with ECMO. ECMO was initiated regardless of whether they could be a lung transplant candidate. From the total of 13 patients who were evaluated, eight were found adequate candidates for ECMO as a BTT. Six patients underwent lung transplantation, and 14 of the 15 patients who did not undergo lung transplantation (93.3%) died after 40.3 ± 27.8 days on ECMO. 83.3% of the patients who had a lung transplant were able to be discharged from the hospital. Their important finding was that those patients with ILD on ECMO who were not lung transplant candidates had a high mortality rate, comparable with the mortality rate of patients mechanically ventilated. Also, they demonstrated that ECMO had no value as a transplant-independent outcome improvement in ILD. On the other hand, patients who are candidates for lung transplantation benefit from ECMO therapy. The biggest reason for this benefit is the time gained on ECMO. They concluded that ECMO is a lifesaving option for patients with ILD and ARF provided they are candidates for lung transplantation. Unfortunately, ECMO cannot reverse the poor prognosis in patients who do not qualify for lung transplantation.

Decision supporting patients with acute or acute-on-chronic respiratory failure with ECMO is challenging, and there is no single guideline to help in decision-making. Even so, several high-volume lung transplants and ECMO centers have published their experience with ECMO as a bridge to transplant [22, 26, 27]. A typical decision tree of ECMO as a bridge-to-transplant algorithmic implementation, used only for those listed patients, as shown in Figure 1 (adapted from Biscotti et al. [26]).

Figure 1.

Bridge to transplantation decision algorithm. ^*Pulmonary hypertension (PH). ^†Atrial septal defect (ASD). (ECLS = extracorporeal life support). Adapted from Biscotti et al. [26].

The timing of ECMO implementation is crucial. Therefore, they attempted to select patients in whom post-ECMO rehabilitation is likely, as best predicted by patients’ pre-ECMO physical therapy performance. The aim was to liberate all patients from mechanical ventilation by using strategies such as early tracheostomy. The criteria for initiating physical therapy included hemodynamic stability, secure cannulas without active bleeding, and patient willingness to cooperate. Ambulation was implemented once the patients demonstrated physiologically adequate ECMO support is demonstrated during initial bedside physical therapy. Seventy-two patients received ECMO as a bridge to LTx. Of the 72 patients, 55.6% underwent the transplantation procedure, 92.5% survived to discharge, and 84% survived for 2 years. Patients with cystic fibrosis were more likely to have a BTT than patients with other lung diseases. Daily participation in physical therapy was achieved in 69.4% of patients. This study demonstrated favorable survival in patients receiving ECMO as a BTT, attaining high rates of physical therapy, and avoiding mechanical ventilation in patients awaiting lung transplantation. With more than half of these patients successfully BTT, we gained insight into the factors influencing patients’ outcomes, including patient selection, the timing of ECMO, and patient management. However, clinical management decisions are highly center-specific, and these treatment algorithms must be adapted to fit the clinical setting appropriately.

The cannulation strategy was based on the patient’s underlying disease, respiratory and hemodynamic status, and anticipated worsening of hypoxemia or progressive secondary pulmonary hypertension (PH). They also attempt to select patients in whom post-ECMO rehabilitation is likely, as best predicted by patients’ pre-ECMO physical therapy performance. The form of ‘awake ECMO’ with spontaneously breathing patients is a safe and effective approach to BTT [26, 27, 28, 29]. Several high-volume centers have shown that BTT has comparable outcomes with patients not requiring support [26, 27, 30, 31, 32].

Another meaningful discussion is the outcomes in the unique subset of patients requiring prolonged use of ECMO support before lung transplantation. In a 2016 review of the Extracorporeal Life Support Organization international multi-institutional registry, of 974 patients who required prolonged (>14 days) ECMO support, 46% of these patients did not experience native lung recovery; among these, 40 patients (4.1%) underwent LTx with a 50% postoperative in-hospital mortality [33]. The longest reported successful bridge to transplant required ECMO support of 155 days [34]. Another case report describes a patient remaining on ECMO for as long as 403 days while waiting for a lung transplant. The authors conclude that it is at least technically feasible to maintain patients awaiting lung transplantation on ECMO for extended periods, albeit maintaining for more than 1-year may be difficult [35]. ECMO cannot reverse the poor prognosis in patients that do not qualify for lung transplantation. ARF in ILD is devastating in patients without the option of a lung transplant, despite ECMO.

The current biggest challenges for clinicians are when to consider ECMO as a BTD in patients with end-stage lung disease not yet listed for lung transplantation. The decision is less about using ECMO-BTT and more about whether to extend ECMO-BTD to patients whose lung transplant candidate status is unknown and whether the patient clinically deteriorates while completing their lung transplant evaluation. Also, what if ECMO is needed to facilitate a remaining component of the transplant workup if a previously healthy patient has failed all interventions following an acute, irreversible pulmonary disease. Hoopes and colleagues [22] described a salvage transplant as a feasible approach in this cohort. Although the precise relationship between providing ECMO to patients before active listing and survival to transplant is unknown, their study examined 31 patients who successfully had ECMO-BTT, including seven patients not yet listed for transplant prior to ECMO initiation. The 1-year outcomes of the patients transplanted from an ECMO-BTT was greater than 90% [22]. In this context, rescue therapy denotes lung transplantation in patients not listed before ARF. In particular, salvage transplantation opens a window for clinically sick patients who are not yet listed for lung transplantation, allowing them to be transferred on ECMO to a facility and have an expedited evaluation for potential lung transplantation.

Patients with ILD that survived mechanical ventilation to discharge had a very limited prognosis without lung transplantation; 1-year survival rates were only 4% [36]. In some situations, such as acute exacerbation of ILD, it may be preferable to initiate ECMO-BTD, avoid intubation and mechanical ventilation, the use of sedation helping being awake, maintenance in the nutrition status, mobilization avoiding frailty, and provide emotional support for the patient and the family, and allowing patients who are otherwise considered good candidates to be able to complete the lung transplant evaluation.

Ideally, the bridge-to-decision patients have been already evaluated for a lung transplant and are hospitalized at an expertise lung transplant and ECMO center with adequate ICU resources to support these complex patients with the potential for long-term care, and the patient has completed part of the key initial lung transplant evaluation so that the remaining of the completed evaluation can be expedited, and that the patient does not have any obvious contraindications to be a candidate for lung transplantation.

In general, bridge-to-decision patients should have minimal or absent characteristics that have been associated with worse bridge-to-transplant survival. A multidisciplinary consensus among the lung transplant physicians, critical care intensivists, and ECMO team is essential for a successful transition from ECMO-BTD to ECMO-BTT. in addition, daily multidisciplinary rounds, including advanced care planning and early palliative care involvement are important. The patient and their family should be encouraged to reflect on these implications before deciding to accept ECMO bridge-to-decision. The decision to provide ECMO to patients with advanced lung disease not yet listed for lung transplant should apply existing data and expert opinion to the clinical circumstance. With tempered judgment and expert care, ECMO can provide a pathway to life for patients with end-stage lung disease who are not listed for a lung transplant at the time of their critical admission.

Another concern is when patients, who have started ECMO support, are not candidates for LTx. This situation is ethically challenging and emotionally charged, referred to as a ‘bridge to nowhere“, with obvious implications for the patient, their family, the caregivers, the hospital, and the healthcare system” [37]. Therefore, it is important to minimize this risk as much as possible through meticulous patient selection. Other concerns for decisions on considering patients who are candidates for ECMO BTD are those patients who are highly sensitized and have a higher risk for worsening sensitization due to ECMO-related needs for blood transfusion and concerns for increased waiting times, infections risk, and vascular complications. Other concerns for decisions on considering patients who are candidates for ECMO BTD are those patients who are highly sensitized and have higher risk for worsening sensitization due to ECMO related need for blood transfusion and concerns for increase waiting times, infections risk and vascular complications.

Even though ECMO as a BTD can benefit patients and families by giving them more time to share with each other and for discussions on collaborative decision-making. Courtwright et al. states the most common ethical issues involving disagreements among and between healthcare teams, patients, family, and other surrogates, particularly when confronted with decisions about the continuation or withdrawal of ECMO [38].

4. Conclusions

ECMO is a lifesaving option for patients with advanced lung disease, and ARF provided they are suitable candidates for lung transplantation. Salvage transplantation opens a door for clinically sick patients who are not yet listed for lung transplantation, allowing them to be transferred on ECMO to a facility and have an expedited evaluation for potential lung transplantation. There is limited data and a lack of good guidelines on candidate selection.

The question regarding using ECMO as a BTD in patients with end-stage lung disease not yet listed for lung transplantation and if the patient clinically deteriorates while nearing completion of their transplant evaluation, or if ECMO support is needed to facilitate completing the lung transplant evaluation, is more challenged than whether using ECMO-BTT.

Daily interdisciplinary rounds, advanced care planning, and early palliative care involvement are essential. The patient and family should be encouraged to reflect on these implications before deciding to accept ECMO-BTD. It is important to have a protocol for ECMO withdrawal when not a candidate for LTx. Consensus guidelines on ECMO-BTD for patients, not jet listed for LTx as risk stratification to better assess those patients who will benefit the most and have the best outcomes post-transplant.