3.2 Characteristics of Included SRs
3.2.1 Annual Trends in Publications
The correlation between the number of studies and the year of publication was plotted to visualize the trend of ECMO treatment studies published over time. SRs on ECMO first appeared in 2010, although our search began with databases construction. Nonetheless, there has been a worldwide increase in ECMO literature, with a peak in 2020. Figure 3 depicts the trend in publication of research studies.
3.2.2 Geographical Distribution
SRs exhibited variation in their country of origin, with the greatest frequency being observed for Canada [24, 27, 28, 31, 34] (n = 5). Other nations represented were the United States [22, 33, 35, 38] (n = 4), Italy [23, 37] (n = 2), China [36] (n = 1), Brazil [30] (n = 1), France [32] (n = 1), Korea [25] (n = 1), Netherlands [26] (n = 1), and United Kingdom [29] (n = 1).
3.2.3 Primary studies and participants
The number of studies included for ECMO ranged from 2 to 75, with an average of 14. Ten SRs contained fewer than 10 ECMO-related primary studies, five SRs included 10 to 25 primary studies, and two SRs contained more than 25 primary studies. Three SRs only included the type of randomized controlled trial (RCT), seven SRs included RCT and other study types, and seven SRs were limited to study categories other than RCT. The range of participants included in SRs was 429 to 38160, averaging 5168. The majority of SRs (n = 12) included more than 1000 participants. There was a wide variety of clinical topics in the included SRs, including acute respiratory distress syndrome (ARDS) [31] (n = 1), dependent ARDS [38] (n = 1), severe ARDS [27, 30, 32, 36] (n = 4), acute respiratory failure (ARF) [24] (n = 1), ARF due to H1N1 influenza pandemic [22] (n = 1), acute lung injury (ALI) due to H1N1 influenza infection [23] (n = 1), acute liver failure (ALF) or acute on chronic liver failure (ACLF) [34] (n = 1), cardiac arrest [26, 28, 29, 33, 35, 37] (n = 6), and cardiac arrest of cardiac origin [25] (n = 1). The numbers of primary studies and participants are shown in Table 1.
Table 1
Summary of the included SRs of ECMO treatment
First author, publication year | Disease | Design of primary studies | No. of primary studies | No. of participants | Outcome | Conclusion | Overall Confidence |
Munshi L, 2019 [31] | ARDS | RCT, observational study | 5 | 899 | 60-day mortality, treatment failure, mortality at longest available follow-up | probably beneficial | ⨁⨁⨁◯ moderate |
Shrestha D B, 2022 [38] | dependent ARDS | RCT, retrospective study, prospective observational study, cohort study | 12 | 1208 | 30-day mortality, 90-day mortality, in-hospital mortality, ICU mortality, length of hospital stays, average ICU length of stay | inconclusive | ⨁◯◯◯ very low |
Tillmann B W, 2017 [27] | severe ARDS | RCT, cohort study | 27 | 1674 | survival, adverse events | inconclusive | ⨁⨁◯◯ low |
Mendes Pedro Vitale, 2019 [30] | severe ARDS | RCT | 2 | 429 | mortality, treatment failure, need for renal replacement therapy, ICU lengths of stay, hospital lengths of stay | probably beneficial | ⨁⨁⨁◯ moderate |
Alain Combes, 2020 [32] | severe ARDS | RCT | 2 | 429 | 90-day mortality, 90-day treatment failure, 28-day mortality, 60-day mortality, ICU-free days, hospital-free days, ventilation-free days, vasopressor-free days, RRT-free days, neurological failure-free days | beneficial | ⨁⨁⨁⨁ high |
Zhu Y, 2021 [36] | severe ARDS | RCT, retrospective or prospective cohort study | 7 | 867 | 90-day mortality, 30-day mortality, 60-day mortality, hospital mortality, mortality at the longest duration of follow-up, device-related adverse events (pneumothorax, massive bleeding, intracranial bleeding, cardiac arrest, massive stroke and death due to mechanical ventilation or ECMO) | beneficial | ⨁⨁⨁◯ moderate |
Munshi L, 2014 [24] | ARF | RCT, observational study | 10 | 1248 | in-hospital mortality, ICU length of stay, adverse events (bleeding, barotrauma, and sepsis) | inconclusive | ⨁◯◯◯ very low |
Mitchell M D, 2010 [22] | ARF due to H1N1 influenza pandemic | RCT, cohort study | 6 | 827 | mortality | inconclusive | ⨁◯◯◯ very low |
Alberto Zangrillo, 2013 [23] | ALI due to H1N1 influenza infection | observational study | 8 | 1357 | mortality | beneficial | ⨁⨁◯◯ low |
Alshamsi Fayez, 2020 [34] | ALF or ACLF | RCT | 25 | 1796 | mortality, hepatic encephalopathy outcome, adverse events (hypotension, bleeding, thrombocytopenia, line infections) | probably beneficial | ⨁⨁⨁◯ moderate |
Ouweneel Dagmar M, 2016 [26] | cardiac arrest | cohort study | 10 | 3127 | 30-day survival rate, 30-day favorable neurological outcome | beneficial | ⨁⨁◯◯ low |
Beyea M M, 2018 [28] | cardiac arrest | case series, cohort study | 75 | 5570 | neurologic status at hospital discharge, survival | inconclusive | ⨁◯◯◯ very low |
Twohig C J, 2019 [29] | cardiac arrest | retrospective or prospective observational study | 9 | 26030 | survival at hospital discharge or 30 days, neurological function | probably beneficial | ⨁⨁◯◯ low |
Miraglia D, 2020 [33] | cardiac arrest | cohort study | 6 | 1108 | 30-day and long-term favorable neurological outcome, 30-day and long-term survival | probably beneficial | ⨁⨁⨁◯ moderate |
Miraglia D, 2020 [35] | cardiac arrest | cohort study, case-control study | 6 | 1750 | long-term neurological intact survival | probably beneficial | ⨁◯◯◯ very low |
Scquizzato T, 2022 [37] | cardiac arrest | RCT, observational study | 6 | 1177 | survival with favorable neurological outcome at the longest follow-up available, survival at the longest follow-up available/hospital discharge/30 days, rate of neurological impairments | beneficial | ⨁⨁◯◯ low |
Ahn Chiwon, 2016 [25] | cardiac arrest of cardiac origin | retrospective or prospective cohort study | 11 | 38160 | survival, overall neurologic outcome | probably beneficial | ⨁◯◯◯ very low |
3.3 Methodological Quality of Included SRs
In terms of methodological quality, the overall confidence was rated as “Moderate” for six [23, 27, 28, 35–37], seven SRs scored “Low” [25, 26, 29, 31–34], four SRs scored “Critically Low” [22, 24, 30, 38], and “High” for none SRs according to AMSTAR-2 criteria. The most frequent flaws were as follows: lack of a reasonable explanation for the selection of study design type for inclusion, the absence of a report on sources of funding for included studies, a lack of a statement regarding potential sources of conflict of interest, and the absence of a protocol. Figure 4 depicts the methodological quality of the 17 SRs included in the analysis.
3.4 Evidence Mapping
For diseases that overlap, the overall evidence quality was considered. Individual SRs reflected the conclusions, which were confirmed by an internal review. The evidence mapping on ECMO for adults is presented in Fig. 5.
3.4.1 Evidence of “beneficial” effect
The effects of ECMO, as indicated by statistically significant pooled treatment effects in SRs, were determined based on a substantial number of research studies that included findings on severe ARDS and ALI due to H1N1 influenza infection.
Four SRs [27, 30, 32, 36] evaluated the effects of ECMO on severe ARDS relative to conventional therapy. Among them, one SR [30] with moderate evidence quality was selected as “probably beneficial” on this mapping, suggestive of the probable efficacy of ECMO in severe ARDS; the efficacy of ECMO and severe ARDS in this study was likely linked to reducing mortality, treatment failure, and the need for renal replacement therapy, but longer ICU and hospital lengths of stay. Two SRs [32, 36], including 2 RCTs with moderate or high evidence quality, were selected as “beneficial” on this mapping, suggesting positive support for ECMO in severe ARDS based on 90-day and 30-day mortality outcomes; additionally, there was no difference in device-related adverse events compared to conventional therapy. The remaining SR [27], with low evidence quality, showed an “inconclusive” conclusion in survival to hospital discharge, indicative of weak confidence to support the effectiveness of ECMO. In general, 75% of SRs (comprising 6 RCTs) were classified under the categories of “beneficial” or “probably beneficial”. The overlapping severe ARDS of four SRs was eventually classified as a “beneficial” conclusion considering the overall evidence quality.
A single SR [23] consisting of eight observational studies, which were of low evidence quality, evaluated the impact of ECMO on ALI due to H1N1 influenza infection compared to conventional therapy. Results indicated that ECMO was feasible and effective in patients with ALI due to H1N1 infection; however, subjects with severe comorbidities or multiorgan failure remained at high risk of in-hospital death if prolonged support (more than one week) was required in the majority of cases, which ended in a “beneficial” conclusion.
3.4.2 Evidence of “probably beneficial” effect
A considerable number of research studies on clinical topics such as ARDS, ALF or ACLF, and cardiac arrest were used to determine the promising effects of ECMO, as evidenced by statistically significant pooled treatment effects in SRs.
One SR [31], with moderate evidence quality, compared the effects of ECMO on ARDS to conventional therapy, finding that venovenous ECMO in ARDS adults was associated with lower 60-day mortality (relative risk [RR] = 0.73, 95% confidence interval [CI]: 0.58–0.92, P = 0.008, I²=0%), but also a moderate risk of bleeding.
One SR [34] with moderate evidence quality comparing extracorporeal life support (ECLS) to usual care found that ECLS might decrease mortality (RR = 0.84, [95% CI: 0.74–0.96], moderate certainty) and improve hepatic encephalopathy (RR = 0.71, [95% CI: 0.60–0.84], low certainty) in patients with ALF or ACLF. The impact of ECLS on hypotension (RR = 1.46, [95% CI: 0.98–2.2], low certainty), bleeding (RR = 1.21, [95% CI: 0.88–1.66], moderate certainty), thrombocytopenia (RR = 1.62, [95% CI: 1.0-2.64], very low certainty) and line infection (RR = 1.92, [95% CI: 0.11–33.44], low certainty) was uncertain.
Six SRs on cardiac arrest produced controversial results [26, 28, 29, 33, 35, 37]. Among them, two SRs [26, 37], both low evidence quality, were selected as “beneficial” on this mapping, suggestive of positive support for ECMO in cardiac arrest based on a 30-day survival rate ([95% CI: 6–20%], P < 0.001), 30-day favorable neurological outcome ([95% CI: 7–20%, P < 0.0001), survival with the favorable neurological outcome at the longest follow-up available (OR = 2.11, [95% CI: 1.41–3.15], P < 0.001), survival at the longest follow-up available (OR = 1.40, [95% CI: 1.05–1.87], P = 0.02). Three SRs [29, 33, 35] with very low, low, or moderate evidence quality showed a “probably beneficial” conclusion on this mapping, suggesting the probable efficacy of ECMO in cardiac arrest; the efficacy of ECMO and cardiac arrest in these studies was likely associated with improved survival, 30-day and long-term favorable neurological outcome, and long-term neurologically intact survival. The remaining SR [28] of 63 case series and 12 cohort studies concerning out-of-hospital cardiac arrest (OHCA), with very low evidence quality, demonstrated that although a trend toward improved survival with good neurologic outcome was reported in controlled, low-risk of bias cohort studies, a preponderance of low-quality evidence may ascribe an optimistic effect size of extracorporeal cardiopulmonary resuscitation (ECPR) on survival among OHCA patients, rated as “inconclusive” conclusion. On the whole, 83.3% of SRs were classified into “beneficial” or “probably beneficial” categories. For the overlapping cardiac arrest of six SRs, we ultimately rated it as “probably beneficial” conclusion after considering the overall quality of the evidence.
3.4.3 Evidence of “inconclusive” effect
This mapping contained several SRs that provided evidence of the potential inconclusive effect of ECMO in treating clinical topics, including dependent ARDS, ARF, ARF due to the H1N1 influenza pandemic, and cardiac arrest of cardiac origin.
According to one SR [38] with very low evidence quality, 30-day mortality (OR = 0.56, [95% CI: 0.37–0.84]) and 90-day mortality (OR = 0.59, [95% CI: 0.41–0.85]) were reduced in dependent ARDS patients managed with ECMO. However, ECMO management was associated with a 7.28-day increase in ICU duration of stay (MD = 7.28, [95% CI: 2.55–12.02]). In addition, there was no statistically significant difference between ECMO and conventional therapy in terms of in-hospital mortality (OR = 0.75, [95% CI: 0.40–1.41]), ICU mortality (OR = 1.00, [95% CI: 0.36–2.79]), or hospital duration of stay (MD = 3.92, [95% CI: -6.26-14.79]).
One SR [24] with very low evidence quality indicated that ECLS was not associated with a mortality benefit in ARF patients (RR = 1.02, [95% CI: 0.79–1.33], I2 = 77%) and was associated with an increased risk of bleeding (RR = 11.44, [95% CI: 3.11–42.06], I2 = 0%). However, a significant mortality benefit was observed in venovenous ECLS studies of higher quality (RR = 0.62, [95% CI: 0.45–0.8], I2 = 25%).
One SR [22] with very low evidence quality demonstrated that there was insufficient evidence to recommend for the use of ECMO among patients with ARF due to the H1N1 influenza pandemic.
One SR [25] with very low evidence quality indicated that ECPR yielded comparable survival (OR = 2.26, [95% CI: 0.45–11.20]) and neurologic outcomes (OR = 3.14, [95% CI: 0.66–14.85]) to CCPR in the out-of-hospital cardiac arrest of cardiac origin patients. However, in cases of in-hospital cardiac arrest of cardiac origin patients, ECPR demonstrated a significantly higher survival rate (OR = 2.40, [95% CI: 1.44–3.98]) and improved neurologic outcomes (OR = 2.63, [95% CI: 1.38–5.02]) compared to CCPR.
3.4.4 Evidence of “no effect”
No SR clearly declared that ECMO was harmful to clinical topics.
3.4.5 Evidence of “harmful” effect
No SR clearly declared that ECMO was harmful to clinical topics.