Discussion
To our knowledge, this is the first systematic review and meta-analysis
of the use of veno venous ECMO in treating severe COVID 19 related ARDS.
We identified 12 independent studies (18-29) that
provided data on the outcome of ECMO in COVID 19 patients. The initial
studies testing the efficacy of ECMO in COVID 19 were small and
pessimistic. A study by Ñamendys-Silva SA (30) looked at
pooled mortality and efficacy from initial Chinese reports (only 17
patients). It included 2 of our included studies (22,25)
and found a mortality of 82.3% (14/17) with no overall benefit of ECMO
(z=0.57, p=0.56). Henry and Lippi (31) shortly followed
by another pooled analysis which included also 2 of our included studies
(22,23) comparing ECMO (total of 17 patients) and
conventional mechanical ventilation and again found no benefit for ECMO
in severe COVID 19 with pooled odds of mortality in the ECMO group
versus the conventional therapy group not significantly different (OR:
2.00, 95%CI: 0.49–8.16) with no observable heterogeneity (I2 = 0%,
Cochran’s Q, p-value = 0.99).
We performed a subgroup single arm meta-analysis for studies including
another arm for invasive mechanical ventilation for severe ARDS due to
COVID 19, but all our ECMO studies had 5 or more patients
(22-25) as per inclusion criteria and again found no
benefit or harm for ECMO in treating severe ARDS in COVID 19. The pooled
odds of mortality in the ECMO group versus the conventional therapy
group were not significantly different (p=0.273, 95%CI: 0.06–1.111).
The mortality was high in both groups (87.5% vs 69.2%). We believe
there are two limitations here, firstly, none of the larger more recent
studies with better outcomes (20,21,26-29) had a control
arm of treating COVID related ARDS with conventional mechanical
ventilation. Secondly, we believe these are two different populations
with patients having variable levels of ARDS severity, with those
receiving ECMO treatment being potentially more critically ill in some
cases, which could have impacted the outcome for mortality rates.
We have shown by our subgroup analysis that heterogeneity was mainly in
the initial Chinese (I2=87%) studies and the following studies showed
homogeneity from the USA (I2=0%, P=0.67) and France (I2=0%, p=0.86)
with lower mortality associated with the use of ECMO for severe COVID 19
patients, although the number of studies was small. The three largest
case series (20,21,27) included in this systematic
review were all outside China and showed more promising results than the
rest of studies with smaller numbers (18,19,22-26,
28,29). A mortality of 29.2% only in these series as compared to a
mortality of 61.1% in the rest of the nine studies (seven Chinese
series). This may reflect the fact that high flow ECMO centres achieve
superior results. Our data thus confirm these results showing the
beneficial effects of ECMO in large tertiary referral centres for the
treatment of COVID 19 ARDS. This is consistent with previous findings of
Barbaro and his colleagues (32) who found lower ECMO
case-mix adjusted mortality in adult patients (adjusted OR, 0.61; 95%
CI, 0.48–0.79) in higher volume ECMO centres. Our definition of high
volume centres is like them as performing more than 30 cases/year.
The role of ECMO in improving outcomes in severely ill COVID 19 patients
seems to be multi factorial. The ARDS observed in COVID 19 patients
mostly fits the Berlin criteria (33) but Gattinoni and
his colleagues (34) have proposed that the classic ARDS
injury is only present in 20-30% of COVID 19 patients with decreased
pulmonary compliance less than 40 ml/cmH2O while the non-ARDS type
(present in 70-80%), the severe hypoxemia is associated with a
respiratory system compliance of more than 50 ml/cmH2O. Hence, severe
hypoxemia is primarily due to ventilation/perfusion (VA/Q) mismatch.
Unlike classic ARDS, high PEEP pressures and prone positioning in this
subgroup of COVID-19 patients do not improve oxygenation through the
classic theory of the recruitment of collapsed areas. Although our meta
regression showed that pre ECMO days of ventilation did not affect
outcome, these patients could benefit from early ECMO to avoid
ventilator-induced lung injury and this was the recommendation from the
only two included studies in our analysis which had zero mortality in
their ECMO patients (18,20)
Secondly, there is an increasing trend to show that COVID 19 infection
is associated with a hypercoagulable and thrombotic state. Yin et al
(35) studied the differences of coagulation features
between severe pneumonia caused by the SARS-CoV-2 (COVID 19) and
non-SARS-CoV-2 viruses and found that platelet count of the COVID19
group was significantly higher than that of non-COVID19 patients. Beyls
and his colleagues (27) suggested that venous-Doppler
ultrasonography of femoral and jugular veins should be performed
routinely for severe COVID-19-related ARDS in preparation in case ECMO
therapy is needed as they found a higher rate of ECMO related line
thrombosis. ECMO circuits eliminate coagulation factors binding them
irreversibly to their surface coating material. Systemic anticoagulation
is usually utilized for ECMO and further aggravates the anti-coagulatory
state on many levels (36). In their current COVID-19
guidelines, the “Extracorporeal life support organisation ELSO”
recommended following existing anti-coagulation guidelines, with
consideration given to an anti-coagulation targeted at the higher end of
normal with vvECMO given the known hyper-coagulable status of COVID-19
patients (37)
In their meta-analysis Munshi and his colleagues (38)
have shown a reduction in 60 day mortality in patients receiving ECMO
for ARDS in comparison to conventional mechanical ventilation with an
associated increased risk of bleeding. The improvement in ARDS outcome
and the anti-thrombotic benefit shown in this meta-analysis is a
hypothesis of the additional benefit in severely ill COVID 19 patients.
Two of our studies (21,23) suggested that higher
mortality related to patients receiving ECMO or conventional mechanical
ventilation for severe ARDS can be related to cytokine production. There
is accumulating evidence suggesting that a sub-group of patients with
severe COVID-19 disease have a cytokine storm syndrome in which a
cascade of activated cytokines leads to harmful auto-amplification of
inflammatory cytokine production leading to end-organ damage and
increasing the risk of mortality. Among COVID-19 patients who have
received ECMO, a strong positive correlation exists between mortality
and high cytokine levels, most notably IL-6 (39).
Ruan et al (23) found that Interleukin-6 concentrations
differed significantly between non survivors and survivors in their
COVID-19 cohort, with non survivors having up to 1.7 times higher
values. We could not study this in our meta-analysis as both studies did
not mention absolute values for cytokines for the ECMO only group.
Our meta-analysis suggests that there is some potential role for ECMO in
appropriately selected patients with severe COVID-19. Although the risk
factors and variables that contribute to the optimal outcome are complex
and reflect individual ECMO center experiences and available resources
during the pandemic, it can be argued that it would be unethical to
withhold ECMO (or consideration for referral to an experienced ECMO
center) in patients who might potentially benefit from this therapy as
suggested by Abrams and colleagues (40) when considering
ECMO for ARDS due to all causes.
The planning and execution of a randomised controlled trial of this
advanced intervention during the current pandemic is difficult. Current
challenges include randomisation of markedly sick patients early with a
higher risk of death, the need for engagement of many centres worldwide,
the lack of the ECMO service in poorer and third world countries and the
inconsistency of managing the control non ECMO group. As a result, a
current study of ECMO in patients with COVID 19 related severe ARDS soon
is unlikely. Thus, our
meta-analysis can provide clinicians with the most comprehensive
synthesis of all the available limited evidence for the outcome of
vvECMO in adult patients with severe ARDS due to COVID-19, although
further data collection and meta-analysis for larger studies are
invited.