Extracorporeal life support as bridge to lung transplantation: a systematic review

Study selection and characteristics

The initial search strategy identified 82 potentially eligible studies (Figure 1); 69 studies were excluded for the following reasons: 5 involved pediatric patients,
27 were deemed not relevant and 37 were case series, reviews, letters or congress
proceedings. After a hand search of the bibliographies, 14 articles met the inclusion
criteria and were considered for this systematic review. All were retrospective studies.

Figure 1. Flow chart of the study selection process. Pts, patients.

The main characteristics of patients enrolled are summarized in Table 1. The studies were published in the three years from 2010 to 2013, with 441 patients
enrolled from 1987 to 2012. Eight studies were done in the United States 10],11],20],26],32]–34], three in Italy 35]–37] and one each in Sweden, Germany and France 38]–40]. Ten studies reported a severity score before ECMO bridge: six reported the LAS 10],11],20],32],33],41] and four the SOFA score 26],35],37],39].

Table 1. Characteristics of patients who underwent ECMO bridge to lung transplant and were
enrolled in the selected studies

In all the studies, depending on the clinical conditions, either a veno-venous or
veno-arterial ECMO was used 10],11],20],26],32]–41]. The strategy during ECMO bridging was invasive mechanical ventilation in four studies
33],34],40],41], and spontaneous breathing or invasive ventilation according to clinical needs in
six studies 20],26],32],35]–37]. Unfortunately, four studies provided no information about the ventilation strategy
during ECMO bridging 10],11],38],39].

The time on ECMO bridging before lung transplantation ranged from a median of 3.2 days
34] to 16 days 39] (Table 1). Crotti et al., dividing patients according to whether the waiting time on ECMO was up to 14 days
or longer, observed an ECMO bridging duration of 29.8?±?11.5 days in patients who
received a transplant after waiting more than 14 days on ECMO 35].

Quality of studies

All 14 studies included were retrospective analyses. The sample size ranged from 11
37] to 122 10]. Eight studies were single-center trials. Seven had no control group 20],35]–40]. Only six studies used the LAS system to describe the severity of their pre-bridge
population 10],11],20],32],33],41]. Across all 14 studies there were substantial differences in the inclusion criteria
for patients, ECMO program times, and ECMO support technologies including VV and VA.
Because of this, we cannot exclude a possible confounding role of some important factors
such as diagnosis and comorbidity at the beginning of the bridge. Four studies 10],11],32],37] only examined patients who were successfully bridged to transplantation without mentioning
patients who had died while on the waiting list.

Post-LTx complications differed among studies and were therefore not comparable. For
example, six studies did not report the incidence of primary graft dysfunction. Over
half presented no data on the need for post-LTx mechanical ventilation (Table 2).

Table 2. Outcomes

In addition, a learning-curve bias effect cannot be formally excluded in studies enrolling
patients over a long period. Regional differences among studies in organ allocation
policy, institutional differences in the logistic design and deployment criteria of
extracorporeal circuits and surgeon-specific preferences about organ selection and
operative technique also pose limitations for a reliable comparison. Given the substantial
heterogeneity across studies we did not attempt a meta-analysis because it would not
have yielded clinically meaningful results; data were descriptively summarized.

Survival

The mortality rate of patients on ECMO before lung transplant was reported in ten
studies and ranged between 17% and 50% with multiple organ failure, septic shock,
cardiac failure and bleeding described as the most frequent causes (Table 2). Interestingly, in the study by Weig et al. liver failure developed in up to half the patients who died while awaiting lung
transplant 39].

All 14 studies reported the post-transplant one-year survival rates. In five studies
it ranged from 50% to 70% 10],11],20],39],40], in four 70% to 90% 33],34],36],41] and in two up to 90% 32],38] (Table 2). When patients were stratified according to the ventilation strategy during ECMO
bridge 37] or according to the ECMO bridge duration 35] one-year survival was significantly better in spontaneously breathing patients than
mechanically ventilated ones (85% versus 50%) or when the ECMO bridge duration was
shorter than 14 days (82% versus 29%). Fuehner et al. reported only a six-month survival rate of 80%, for 19 patients on spontaneous breathing
and 7 patients on mechanical ventilation 26]. Similarly, Hoopes et al. found high one-year survival in 26 ECMO bridge transplanted patients, 18 of whom
were ambulatory at transplantation 32].

Bermudez et al. found the survival rate in patients who received ECMO support was similar to a control
group that was mechanically ventilated before transplant (74% versus 78%) 34]. However, they did not report the LAS score comparing the clinical status of the
two groups. Nonetheless, in patients with similar LAS scores (54?±?22 and 54?±?21)
Mason et al. also reported similar survival rates for those bridged with ECMO and those with
mechanical ventilation (50% and 62%). However, this was significantly lower than for
unsupported patients (79%) although this group also had lower LAS scores (40?±?11)
11].

Despite significantly higher LAS scores (87?±?9 versus 44?±?15) Toyoda et al. found comparable survival rates (74% and 83%) in the ECMO group and in patients
who received the transplant without bridge support 33]. Hoopes et al. reported a post-transplant survival rate of ECMO patients comparable to or slightly
higher than that of patients with a LAS score higher than 50 transplanted without
bridge support, from the UNOS database 32]. In contrast, George et al. noted significantly lower survival in ECMO patients and in mechanically ventilated
patients than in unsupported patients with the highest LAS quartile (58%, 68% and
81%) 10]. However, survival of ECMO patients rose significantly, from 30% in 2005 to 75%,
in 2010 10].

Fuehner et al., applying an awake-ECMO strategy avoiding intubation and general anesthesia, found
significantly better survival than with mechanical ventilation (80% versus 50%) 26]. Similarly, Crotti et al. reported a survival rate of 75% in unsupported ECMO patients 35]. Although these two studies suggest that ECMO support as an alternative to invasive
mechanical ventilation seems to achieve better outcomes than when combined with invasive
respiratory assistance, these data come from very experienced centers and may not
be generalizable. Whether ECMO alone is a better bridging strategy to lung transplant
than invasive mechanical ventilation has yet to be investigated more systematically.

George et al., stratifying the data by age and by diagnosis, found that ECMO-bridged patients
younger than 62 years had better one-year survival than older patients (65% versus
38%) as did patients with chronic obstructive pulmonary disease, while patients bridged
to re-lung transplant had the worst outcomes (84% vs 40%) 10].

Length of stay and ECMO-related complications

The ICU and hospital lengths of stay were reported in six 20],26],34],37],38],41] and nine studies 10],11],20],26],32],33],36],37],41] respectively and the medians ranged from 15 to 47 days 20],34] and 22 to 47 days 20] (Table 2). With regard to the ventilation strategy Crotti et al. found that non-invasive ventilation during ECMO bridge was associated with significantly
shorter ICU and hospital stays than invasive mechanical ventilation (31?±?19 versus
84?±?44 days and 52?±?28 versus 119?±?55 days respectively 35]. Similarly, Nosotti et al. found a shorter mean ICU stay after lung transplantation in the awake-ECMO group
than the mechanically ventilated ECMO group, but the difference was not statistically
significant 37].

Postoperative complications in transplanted patients before discharge from hospital
are described in Table 3. The most frequent were the need for tracheostomy (up to 77%) 38], pulmonary graft dysfunction requiring post-lung transplant ECMO (54%) 33], pneumonia (52%) 34], kidney failure treated with renal replacement therapy and critical illness polyneuropathy/myopathy
(up to 70%) 35]. The most frequent causes of death after lung transplantation in ECMO-bridged patients
before discharge were sepsis, multiple organ failure, bleeding and primary graft dysfunction.

Table 3. Complications in patients discharged alive from hospital and causes of death in hospital
after lung transplant