Introduction
Lung transplant is considered an established treatment for patients with end-stage chronic respiratory failure [
1]. Since the first successful report in 1983 by Cooper and colleagues [
2], more than 30,000 lung transplants have been done worldwide [
3]. The significantly larger number of candidates than available organs explains the long waiting times and high risk of perioperative morbidity and mortality [
1,
4‐
6]. Contributing to this high mortality rate is also the lack of efficacious and safe means of artificial respiratory support for patients awaiting the transplant once they develop acute respiratory failure with refractory hypoxemia and hypercapnia [
4,
7]. Mechanical ventilation
per se can aggravate acute respiratory failure and hemodynamic instability, increasing the risk of ventilator-associated pneumonia and ventilator-induced lung injury [
7‐
10]. Mechanically ventilated pre-transplant patients have been reported to have significantly higher post-transplant mortality rates than non-ventilated patients [
11,
12].
More than three decades ago, extracorporeal membrane oxygenation (ECMO) was introduced to manage patients on the lung transplant waiting list who were dying of acute respiratory failure refractory to mechanical ventilation [
4,
13]. The first report of ECMO as a feasible bridging strategy to transplantation goes back to 1975: the patient survived transplantation but died shortly after from complications of infection [
14]. After a randomized trial that suggested that ECMO was associated with a worse outcome than mechanical ventilation in patients with acute respiratory failure [
15], ECMO as a bridge to lung transplant fell into disuse [
4].
More recently, however, thanks to improvements in technology, safety profile and manageability of extracorporeal life support strategies [
16,
17], ECMO has been reintroduced in some centers as an option for patients with severe respiratory failure awaiting lung transplant [
4,
10,
13,
18‐
22]. The number of lung transplant candidates who could benefit from ECMO is now significantly larger [
13,
19,
20,
22]. A report by the United Network of Organ Sharing (UNOS) showed that, despite its complexity and side effects, the use of ECMO as a bridge to lung transplant has risen by 150% in the two last years compared to the previous decades (1970 to 2010) [
4]. However, given the small numbers of transplantable lungs, bridging lung-transplant candidates on ECMO has raised ethical concerns about the risk of potentially selecting for transplantation, very severely ill patients with the risk of poor post-transplant outcome. Instead, according to the lung allocation score (LAS) system, organs should be allocated to patients who have the greatest need, such as those on ECMO, but who are also likely to benefit most from the transplant [
5,
6,
23,
24].
In this perspective, new advances have demonstrated the potential of ECMO as an alternative to mechanical ventilation in awake, spontaneously breathing patients. With awake-ECMO patients preserve their muscle tone, with greater possibility of early mobilization and participation in intensive physical therapy, thus improving their condition before a lung transplant and making for a better post-transplant outcome [
20,
25‐
29].
Given the lack of definitive data on the efficacy of ECMO as bridge to lung transplantation, and the consequent lack of a clear consensus on this strategy [
6], we conducted a systematic review to assess the current evidence on the use of ECMO in patients with advanced respiratory failure awaiting lung transplant.
Materials and methods
Search strategy and selection of studies
Our search used the statement - preferred reporting items for systematic reviews and meta-analyses (PRISMA) - as a guide [
30]. We made a computerized search of MEDLINE/PubMED and EMBASE databases from January 2000 to June 2014. Our search was limited to studies on humans and adults. We limited the selection to studies written in English, French, German or Spanish. We used the following search keywords and terms: “preoperative extracorporeal membrane oxygenation” OR “preoperative ECMO” AND “lung transplantation”, “extracorporeal membrane oxygenation” OR “ECMO” AND “bridge to lung transplantation”, “ambulatory extracorporeal membrane oxygenation” OR “ambulatory ECMO” AND “lung transplantation”.
Three reviewers (DC, SC and SF) independently screened citation titles and abstracts. We looked through the references of all articles retrieved and reviewed the articles to identify additional potentially eligible studies. In case of disagreement the authors reviewed the article in question together until they reached a consensus. We deleted duplicate papers. All potentially eligible papers were retrieved in full and assessed to confirm eligibility.
We screened studies for relevance that enrolled patients awaiting lung transplant who were admitted to ICU to receive ECMO support as a bridging procedure, including veno-venous approach and veno-arterial support. We excluded studies that enrolled patients treated with pump-free extracorporeal interventional lung-assist devices. We included studies enrolling at least ten patients on ECMO bridging. Data were abstracted in duplicate by two reviewers (SC and SF) and any discrepancies were solved by discussion.
The following information was collected in a datasheet: publication (first author’s name, year, journal), study design, number of enrolled patients on ECMO bridge, number of patients who died while awaiting transplant, type of ECMO support, timing of ECMO bridge, outcomes, survival after lung transplant.
Assessment of methodological quality
Two authors (SC and SF) independently assessed the methodological quality of the studies. They employed critical appraisal skills program (CASP) tools using the CASP checklist for case-control studies [
31].
Discussion
This systematic review suggests that the use of ECMO support as a bridge strategy for patients awaiting lung transplant is associated with high perioperative morbidity and mortality but achieves acceptable one-year survival, very similar to that of mechanically ventilated patients. The initial goal of this systematic review was to verify the feasibility of meta-analysis of the retrieved data. However, in view of the wide heterogeneity of the selected studies we decided to make only a qualitative summary of the selected literature. The 14 studies included are not randomized trials, but retrospective analyses of case series in which the selection of patients and ECMO treatment were discretional to the center and not homogeneous, thus possibly affecting the efficacy of the treatment and certainly preventing the results being evaluated in a meta-analysis.
Lung transplantation is the only option for patients with end-stage lung failure. However, organ supply is grossly inadequate compared to the large numbers of patients awaiting transplant, so mortality in the waiting list is still very high [
11]. In this setting, mechanical ventilation and ECMO are the only supportive strategies available to prolong these patients’ lives, increasing their chances of receiving suitable organs.
Although the main benefit of mechanical ventilation is to improve gas exchange [
12], it can in fact open the way to pulmonary infection, sepsis and muscle atrophy, prolonging weaning after lung transplant and making it difficult [
11,
42,
43]. ECMO, on the other hand, could potentially provide adequate respiratory and hemodynamic support, with fewer of the side effects of mechanical ventilation in patients awaiting lung transplant, offering an alternative bridging strategy [
7,
13,
19,
20,
22,
44]. However, many transplant centers still consider ECMO a contraindication to lung transplant given the mixed outcomes in patients transplanted from ECMO [
6]. This systematic review found that ECMO-bridged patients had satisfactory post-transplant survival, similar to patients bridged with mechanical ventilation. ECMO has helped to save numerous high-risk transplant candidates with otherwise acutely lethal conditions.
Proper patient selection for ECMO is clearly essential for a good long-term outcome. In the studies reviewed here, ECMO was not considered suitable for patients with sepsis, neurologic impairment, profound malnutrition [
41] or severe graft dysfunction after lung transplantation [
33], whereas advanced age (>50 years) was not a contraindication [
41]. The clinical conditions of patients supported with pre-transplant ECMO are usually more critical than those of the population awaiting lung transplant and this may have a negative influence on their overall outcome [
16]. However, this systematic review found that at least in selected reports the post-transplant outcome of ECMO-bridged patients was comparable to recipients who did not receive pre-transplant support. Any excessive reduction of the post-transplant survival rate of ECMO-bridged recipients would obviously defeat the principle of allocating transplantable lungs on the basis not only of the severity of their clinical condition, but also the potential long-term benefit. The definition of clinical parameters predicting survival for ECMO-bridged patients would certainly help clarify this problematic question [
22,
45].
In most of the studies reviewed patients bridged with ECMO were also supported with mechanical ventilation, thus combining two invasive means of respiratory support, each with potentially harmful side effects. Recent reports do suggest that invasive mechanical ventilation may still be considered an effective bridge. Mason
et al. showed that the unadjusted post-transplant survival at one year was 62% for recipients bridged with mechanical ventilation, 50% for those bridged with ECMO, and 79% for unsupported patients [
11]. Vermeijden
et al. compared the outcomes of 13 lung transplant recipients bridged with invasive mechanical ventilation with 70 controls who received no pre-transplant support [
46]. Interestingly, the two groups had similar post-transplant survival and incidence of primary graft dysfunction.
To further improve the outcome for ECMO-bridged patients, therefore, it has been proposed that non-invasive ventilation should be used rather than invasive mechanical ventilation. This could minimize the muscular deconditioning and ventilator-associated morbidity [
42,
47‐
49]. Furthermore, the possibility of keeping patients awake could avoid the hemodynamic consequences of general anesthesia and positive-pressure ventilation, especially in those with pulmonary hypertension. The study that enrolled patients bridged to transplant with ECMO as an alternative to invasive mechanical ventilation did in fact find significantly better six-month survival with ECMO than with mechanical ventilation (62% versus 35%) [
26]; this suggests that preserving spontaneous breathing may keep patients in a better condition, with fewer of the drawbacks of mechanical ventilation.
Among the factors that can affect post-transplant outcome in patients bridged with ECMO, the most frequent are the duration of the bridge and the timing of the lung transplant [
6]. Although patients can tolerate ECMO for long periods [
34,
50,
51], any extra waiting time may significantly increase mortality [
35]. Crotti
et al. showed that patients who received a lung transplant after waiting more than 14 days had significantly higher rates of mortality and morbidity. ECMO-bridged patients should therefore be routinely re-assessed to make sure there are no exclusion criteria for lung transplantation, in order to optimize outcomes and avoid futile transplants [
16].
The incidence of complications in ECMO patients awaiting lung transplant was similar to those previously reported in patients receiving ECMO for acute respiratory or cardiogenic shock [
52]. It was not possible to compare the ICU and hospital lengths of stay for ECMO and non-ECMO patients because most of the studies gave no figures for the control group. Only two studies reported a shorter hospital stay for patients receiving awake-ECMO than for those given mechanical ventilation [
26,
35].
These observations suggest that ECMO might make it easier to optimize the clinical conditions of transplant candidates, mainly for more active participation in the activities of daily living, including ambulation, despite their critical respiratory illness. However, the length of stay depends on many factors, such as hospital mortality, which are not necessarily directly linked to support with ECMO or mechanical ventilation.
Limitations
The present systematic review has several limitations. First, the studies included are not controlled or randomized trials but retrospective analyses of case series, with broad heterogeneity. Clearly, observational studies rarely provide sufficiently robust evidence to recommend changes to clinical practice or health policy decision-making. However, they are the only ones that provide any useful evidence for certain topics [
31].
Second, the ventilatory strategy of the patients on ECMO bridging is not described (in terms of end-expiratory positive pressure, tidal volume, inspiratory pressure). Third, indications, type and duration of ECMO bridging differed among studies and some patients may have been described twice because they were reported in different studies [
10,
11,
33,
34,
41]. Fourth, although we confined our literature search to the year 2000 onward because subsequent important advances were made in the technology for ECMO devices and mechanical ventilation recommendations that could have mixed up the results, three studies [
11,
34,
36] enrolled patients before this period. Fifth, other extracorporeal life support strategies, potentially more easily manageable than ECMO, such as the artero-venous low flow extracorporeal carbon dioxide removal [
53], the pulmonary artery-left atrium para-corporeal circuit configuration [
54], and the minimally invasive low blood flow carbon dioxide removal systems [
55], have been used as bridge to lung transplantation, but were excluded from this systematic review. The continuous technological advancement in the field of extracorporeal life support provides progressively more innovative devices, with the purpose to better suit specific patient populations. However, the notable difference of these newer strategies from ECMO in terms of management, complexity, and contribution to gas exchange, suggest they should be considered as a separate issue.
Conclusions
Since its first application as a bridge to lung transplantation in patients with decompensating acute respiratory failure, ECMO support has gradually been used more frequently not only as salvage therapy, but also as a very promising alternative bridging strategy to mechanical ventilation, allowing more physiological respiratory assistance. However, given the quality and the wide heterogeneity among studies in this complex field, current clinical evidence does not permit any firm conclusions on the efficacy of ECMO as a bridge to lung transplantation in addition, or as an alternative to mechanical ventilation, and further prospective, more systematic multicenter trials are awaited. Future studies should ideally consider ECMO as part of a global algorithm of care for patients with end-stage lung disease, aiming at keeping them eligible for transplant despite refractoriness to maximal medical therapy, rather than just as an isolated means of respiratory support.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
All the authors conceived and designed the systematic review. DC, SC, SF screened citation titles and abstracts to identify potentially eligible papers. SC, SF abstracted data in duplicate from the articles retrieved. AC collected the information from the articles retrieved in a datasheet. DC, SC, SF, LD wrote the paper. All authors read and approved the final manuscript.