Raasveld et al.

Intensive Care Medicine

Intensive Care Medicine Experimental (2022) 10:50
https://doi.org/10.1186/s40635-022-00478-z Experimental

REVIEWS Open Access

Knowledge gaps and research priorities

in adult veno‑arterial extracorporeal membrane
oxygenation: a scoping review
Senta Jorinde Raasveld1*, Carolien Volleman1,8, Alain Combes2,3, Lars Mikael Broman4,5, Fabio Silvio Taccone6,
Elma Peters7, Sanne ten Berg7, Charissa E. van den Brom1,8,11, Holger Thiele9, Roberto Lorusso10,
José P. S. Henriques7 and Alexander P. J. Vlaar1*   

*Correspondence:
[email protected] Abstract
1
Department of Critical Care, Purpose: This scoping review aims to identify and describe knowledge gaps and
Amsterdam University Medical research priorities in veno-arterial extracorporeal membrane oxygenation (VA-ECMO).
Centers, Location Academic
Medical Center, Amsterdam, The Methods: An expert panel was recruited consisting of eight international experts from
Netherlands different backgrounds. First, a list of priority topics was made. Second, the panel devel-
Full list of author information is
available at the end of the article
oped structured questions using population, intervention, comparison and outcomes
(PICO) format. All PICOs were scored and prioritized. For every selected PICO, a struc-
tured literature search was performed.
Results: After an initial list of 49 topics, eight were scored as high-priority. For most
of these selected topics, current literature is limited to observational studies, mainly
consisting of retrospective cohorts. Only for ECPR and anticoagulation, randomized
controlled trials (RCTs) have been performed or are ongoing. Per topic, a summary of
the literature is stated including recommendations for further research.
Conclusions: This scoping review identifies and presents an overview of knowledge
gaps and research priorities in VA-ECMO. Current literature is mostly limited to obser-
vational studies, although with increasing attention for this patient population, more
RCTs are finishing or ongoing. Translational research, from preclinical trials to high-
quality or randomized controlled trials, is important to improve the standard practices
in this critically ill patient population.
Take-home message
This scoping review identifies and presents an overview of research gaps and priorities
in VA-ECMO. Translational research, from preclinical trials to high-quality or randomized
controlled trials, is important to improve the standard practices in this critically ill
patient population.
Keywords: Veno-arterial extracorporeal membrane oxygenation, Extracorporeal
cardiopulmonary resuscitation, Research gaps

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Raasveld et al. Intensive Care Medicine Experimental (2022) 10:50 Page 2 of 17

Introduction
Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a mechani-
cal circulatory support (MCS) used for refractory cardio-circulatory failure, in case
conventional therapies prove insufficient [1]. The past decades, the use and range of
indications for VA-ECMO has been increasing worldwide. In 2021, almost 5000 VA-
ECMO runs were recorded in the ELSO registry, of which 48% survived [2]. Despite
the promising role of VA-ECMO as a cornerstone supportive treatment, complication
rates remain high and should be better evaluated in daily practice. Available guide-
lines are mainly based on expert opinion, resulting in a high variance in local pro-
tocols worldwide. It is important to identify topics which require further attention
in this complex, critically ill patient population. Therefore, the aim of this study is to
identify and describe research gaps in VA-ECMO, and to form recommendations for
future research.

Methods
This scoping review was performed in several steps. Firstly, an expert panel was devel-
oped consisting of eight international experts with research lines and backgrounds in
different medical specialties involved in VA-ECMO practices (Additional file 1 p.2).
Secondly, an initial list of topics was developed by JR, CV and AV. The expert panel
was invited to submit additional topics to this list and give feedback on the topics
stated. Thirdly, per topic, structured questions using population, intervention, com-
parison and outcomes (PICO) format were created. Fourthly, the PICOs were prior-
itized by rating the importance of every PICO on a scale of 0–10 using a cloud-based
survey tool. The eight PICOs with the highest ratings were considered as highest pri-
ority. Fifthly, search strategies were developed for every selected PICO, whereafter
searches in MEDLINE, EMBASE, Web of Science, Google Scholar, and Cochrane
databases were performed up to September 2022, along with trial databases (clinical-
trials.gov, ISRCTN) to identify in-progress trials. Per topic, the search results were
screened by two experts (Additional file 1 p. 9–40).

Results
The initial list of 49 topics can be found in the Additional file 1 (p. 3–8). After rating
the degree of importance, eight topics were selected as depicted in Table 1 and shown
in Fig. 1.

Part I: indication for ECMO

#1 Cardiogenic shock: definition, degree and timing of cardiogenic shock as VA‑ECMO
indication
Timing of ECMO Clinical benefits of VA-ECMO for cardiogenic shock (CS) due to
acute myocardial infarction (AMI) have been demonstrated in observational studies [3].
For defining the degree of severity of cardiogenic shock, different classification systems
are available. Most commonly used classifications include the INTERMACS (Interagency
Registry for Mechanically Assisted Circulatory Support) and Society for Cardiovascu-
lar Angiography and Interventions (SCAI). VA-ECMO may play a role in either INTER-
Table 1 Priority topics and corresponding PICOs
No. Topic Population Intervention Control Outcome Sub-topics

1 Cardiogenic shock: defini- Patients suffering cardiogenic Early in course Refractory cardiogenic shock Shock reversal, in-hospital –
tion, degree and timing of ­shock1 mortality
cardiogenic shock as VA-ECMO
indication
2 Selection criteria for ECPR Patients suffering cardiac arrest ECPR (VA-ECMO) Conventional cardiopulmonary In-hospital mortality, length- Patient age
Raasveld et al. Intensive Care Medicine Experimental

resuscitation of-stay Time-to-ECMO

Location of insertion:
in-hospital/on-site
3 ECMO connecting: percutane- Patients undergoing cannula- Percutaneous cannulation Surgical cannulation Hemorrhage, in-hospital –
ous versus surgical methods tion for VA-ECMO mortality
(2022) 10:50

4 Monitoring: daily therapy goals Patients supported with VA- Daily goals Standard care In-hospital mortality Fluid balance, min/max
ECMO Reducing blood flow
Reducing sedatives
5 Monitoring: optimal balance Patients supported with VA- Accepting a lower MAP Standard MAP (≥ 65 mmHg) In-hospital mortality –
of blood pressure & vasoactive ECMO (< 65 mmHg)
medication
6 Blood transfusion regimen Patients supported with VA- Restrictive regimen (dependent Liberal regimen (dependent of In-hospital mortality Red blood cells
ECMO of blood product) blood product) Platelets
Plasma
7 Anticoagulant therapies Patients supported with VA- Non-heparin anticoagulant Continuous systemic heparin In-hospital mortality LMWH
ECMO therapy Bivalirudin
DTIs
8 Complications: endothelial Patients supported with VA- Monitoring endothelial damage No additional markers/moni- In-hospital mortality ICAM-1
activation and damage ECMO and activation markers toring VCAM
Syndecam-1
DTI direct thrombin inhibitors, ICAM-1 intercellular adhesion molecule 1, MAP mean arterial pressure, ROSC return of spontaneous circulation, VA-ECMO veno-arterial extracorporeal membrane oxygenation, VCAM
vascular cell adhesion molecule
1
Defining early in course and refractory as INTERMACS level 2 (“sliding on inotropes”) and level 1 (“crash and burn”), respectively
Page 3 of 17
Raasveld et al. Intensive Care Medicine Experimental (2022) 10:50 Page 4 of 17

Fig. 1 Priority topics further elaborated in this review. From left to right: a percutaneous versus surgical
methods of cannulation, b anticoagulant therapies, c blood transfusion regimen, d daily therapy goals, e
ECPR selection criteria, f cardiogenic shock, g optimal balance of blood pressure and vasoactive medication,
h endothelial activation and damage. © Myrthe Raasveld

MACS’ level 1 and 2 (1: “crash and burn” vs. 2:“early” phase, “sliding on inotropes”). Ini-
tiation is usually employed for patients refractory to usual resuscitative techniques (i.e.,
inotropes and vasopressors [4]. Guidelines recommend that MCS, including VA-ECMO,
may be considered in patients with either any type of CS (Heart Failure Guidelines [5])
or due to acute coronary syndrome (ACS, European Guidelines [6]). However, there is no
consensus on optimal timing. ‘The sooner the better’ seems likely to assume, but its rela-
tion with the timing of reperfusion, and to the risk benefit of any MCS device remains
unclear.

Before or after percutaneous coronary intervention (PCI) In patients with CS from dif-
ferent etiologies, shorter time from shock onset to ECMO insertion is associated with
lower risk of mortality in observational studies [7]. In selected patients with CS due to
AMI undergoing PCI, early ECMO initiation prior to PCI resulted in better short- and
long-term outcomes, even though this resulted in a longer door-to-balloon time [7–10].
However, respective studies included small numbers of patients, of whom up to 60%
experienced a cardiac arrest. In a single cohort of AMI-CS patients that excluded post-
cardiac arrest patients, no association between time of CS onset to VA-ECMO start
time and 6-month survival was found [11]. Moreover, no conclusion can yet be drawn
regarding which MCS could be most beneficial. Available studies show divergent results,
Raasveld et al. Intensive Care Medicine Experimental (2022) 10:50 Page 5 of 17

whereas crucial variables as timing and severity of disease may be insufficiently corrected
for RCTs on this topic are lacking.

Extracorporeal cardiopulmonary resuscitation (ECPR) In case of refractory cardiac

arrest, ECPR combined with intra-arrest PCI leads to better outcomes in terms of sur-
vival as shown in the highly selected ARREST trial [12]. In the larger PRAGUE-OHCA
trial such a mortality benefit could not be observed, although it does suggest a favorable
neurological outcome in patients receiving ECPR [13]. Contrarily, observational studies
suggest that a delay in the start of ECPR is an independent predictor of poor neurological
outcome and should ideally be minimalized to < 40 min [14].

Future research Timing of VA-ECMO in CS needs further attention. In line with this,
we would recommend to also focus on the simultaneous or consecutive use of alternative
MCS such as Impella (“ECPELLA”).

#2 Patient selection criteria for ECPR

Patient selection for ECPR is a significant challenge for clinicians: on one hand, stringent
selection criteria for ECPR would result in a higher proportion of patients with favora-
ble outcome, however, this would also significantly limit its use in victims of refractory
cardiac arrest [15]. Existing literature on ECPR effectiveness is mainly limited to cohort
studies, with recently first RCTs published (Table 2) [12, 13, 16, 17].

Age and patients’ characteristics Latest ELSO interim guidelines suggest a maximum
age of 70 years for ECPR [18]. However, a large retrospective study found that in case
of a low-flow state < 60 min, ECPR survival rates were independent of age, suggesting
that some elderly patients could be still be considered [19]. At the time of ECPR assess-
ment, patient’s medical history, laboratory values and severity scores are often unknown
or difficult to obtain and can rarely be used into the decisional algorithm. Whether only
patients with an initial shockable rhythm should be treated remains a matter of debate, as
acceptable survival rates have been reported also for non-shockable rhythm, in particular
pulseless activity [20, 21].

Table 2 Selected overview of eligibility criteria in RCTs performed on ECPR

Eligibility criteria ARREST trial Prague-OHCA trial INCEPTION trial
Yannopoulos et al Behlohlavek et al Bol et al

Age ≥ 18 and ≤ 75 years ≥ 18 and ≤ 65 years ≥ 18 and ≤ 70 years

Duration of ongoing resus- No ROSC within the ≥ 5 min of advanced cardiovas- No ROSC ≤ 15 min
citation without obtaining first 3 shocks cular life support without ROSC Expected initiation of
ROSC Estimated transfer cannulation < 60 min. after
time to ED < 30 min arrest
Location of insertion In-hospital In-hospital In-hospital
Initial rhythm VT/VF OHCA with presumed cardiac VT/VF
cause (shockable and non-
shockable rhythms)
ED emergency department, ROSC return of spontaneous circulation, VT ventricular tachycardia, VF ventricular fibrillation
Raasveld et al. Intensive Care Medicine Experimental (2022) 10:50 Page 6 of 17

Time‑to‑ECMO and location of ECMO insertion Time-to-ECMO is associated with

neurological outcome and survival. The ELSO advises early assessment for ECPR and
time from arrest to ECMO (i.e., “low-flow interval”) to be < 60 min [18]. Different cut-
offs of no-flow or low-flow intervals have been evaluated in observational studies, var-
ying from 30 to 60 min. Importantly, the longer the low-flow interval, the higher the
difference in outcome between ECPR and conventional cardiopulmonary resuscitation
(CPR) treated patients, whereas nearly 20% of patients undergoing ECPR with a time-
to-ECMO > 60 min would eventually still experience favorable neurological outcome
[22].
To reduce the low-flow time, which remains of approximately one hour even in
RCTs [12, 13], there are two main strategies: (a) expedited transport to the hospital to
reduce the time to hospital arrival [16]; or (b) pre-hospital ECMO implantation [23].
Currently, a stepped-wedge designed trial comparing on-scene initiation of ECPR and
conventional CPR, is ongoing in the Netherlands (NCT04620070).

Future research As ECPR is also dependent of country-specific logistics and infra-

structure, identifying optimal patient selection criteria is an essential step to further
evaluate the role of ECPR.

Part II: ECMO cannulation

#3 ECMO connecting: percutaneous vs surgical cannulation methods
Multiple cannulation techniques have been widely accepted for VA-ECMO. In case
of post-cardiotomy patients, central placement of the cannulas might be considered,
although recent data showed higher mortality rate as compared to peripheral access
in such a setting [24, 25]. In non-cardiotomy patients, peripheral cannulation, either
via percutaneous or surgical placement, is preferred due to the speed and easy acces-
sibility [1]. Moreover, next to the indication, location (in-hospital or on-scene) can
play a role in choice of cannulation technique. Despite their practical differences, lim-
ited data are available on the impact of placement methods on patients’ outcomes.

Percutaneous vs surgical cannulation A recent analysis of the ELSO Registry includ-

ing 12,592 patients receiving VA-ECMO showed a decreased in-hospital mortality in
favor of percutaneous cannulation when compared to the surgical group [26]. This
finding was supported by a propensity-score matched analysis comparing complica-
tion rates and survival in surgical versus percutaneous peripheral cannulation [27].
This can be explained by a lower degree of cannulation site bleeding and systematic
infection in case of percutaneous cannulation [26]. However, percutaneous cannula-
tion was found to be associated with an increased rate of vascular complications after
decannulation, for which further attention is needed [27].
Both surgical as peripheral cannulation bring the risk of limb ischemia. As a
result, following femoral cannulation, the adequacy of limb perfusion and absence of
ischemia should be carried out by the use of near-infrared spectroscopy (NIRS). If
NIRS is > 50–60% at both legs, a distal perfusion catheter (DPC) might be, theoreti-
cally, not necessary. However, distal limb perfusion is always recommended to avoid
Raasveld et al. Intensive Care Medicine Experimental (2022) 10:50 Page 7 of 17

late intervention in case of leg ischemia, with the occurrence of potential irreversible
injury. Either in case of larger cannulas (19–21 Fr), a NIRS-value < 50–60%, or a dif-
ference over 20% between the arterial and venous cannulated leg, DPCs are recom-
mended [28].

Future research Less invasive percutaneous approach appears to be favorable in terms

of complications and patient outcome. However, this does not take into account the rate
of cannulation failure, which may be higher using percutaneous methods. With the rising
interest of ECPR, complication rates between different locations of cannulation (in-hos-
pital vs. on-scene) should also be taken into account. Also, decannulation differs between
the two methods, leading to different complication profiles. Future studies should focus
on preventing cannulation failure and improving decannulation care, such as removal
techniques, in a prospective setting.

Part III: ECMO support care

#4 Monitoring: daily therapy goals
Reducing blood flow ELSO guidelines state the ideal situation in patients on VA-
ECMO would be to decrease blood flow until the arterial pulse pressure is a minimum
of 10 mmHg or to provide adequate support, according to other parameters of organ
perfusion [1]. As over time the native cardiac function is expected to improve, there is
rationale for evaluating on a daily basis whether blood flow can be reduced. However, few
data have been reported about the course of ECMO blood flow and its manipulation over
time in this setting.

Fluid balance ECMO blood flow and patient’s volume status are intertwined, as on one
hand sufficient intravascular volume is required to ensure adequate blood flow and organ
perfusion, while on the other hand volume overload has to be prevented, despite the high
occurrence rate of blood transfusions and the occurrence of acute kidney injury in these
patients. Retrospective studies in VA-ECMO patients also showed a correlation between
a higher fluid balance and mortality [29–31]. However, no recommendations regarding
optimal fluid balances are described in the latest ELSO guideline, and no high-quality
data on the optimal fluid strategy are available for such patients [32].

Reducing sedatives Factors influencing sedative and analgesic management include

additional treatments, such as the application of targeted temperature management, but
also cannula related discomfort, and a possible change in drug pharmacokinetics due to
the ECMO system (i.e., drug absorption) [33]. For sedation, it is commonly advised to
provide light anesthesia in the first 24 h and then adjust therapy to relieve patient’s anxi-
ety and discomfort, but still allowing a daily repeated neurological examination [1]. For
some indications, such as bridge to lung transplant, awake support is also a possibility.
No hard recommendations can be made based on current literature regarding the use of
paralytics, whereas different factors should be taken into account (i.e., need for controlled
mechanical ventilation, physical therapy). With regard to sedative management, different
observational studies reported comparisons of different anesthetics and analgesics used,
but otherwise literature is scarce.
Raasveld et al. Intensive Care Medicine Experimental (2022) 10:50 Page 8 of 17

Future research In different critically ill patient populations, current studies focus more
and more on how to prevent or treat fluid overload, for example using lung ultrasound.
Prospective studies VA-ECMO patients, focusing on visualizing and evaluating fluid sta-
tus and blood flow, are needed.

#5 Monitoring: optimal balance of blood pressure and vasoactive medication, “less

is more?”
In all-cause shock patients, a target mean arterial pressure (MAP) of above 65 mm Hg is
being aimed for. This is mostly based on settings of sepsis, in which below this threshold
autoregulation fails and tissue perfusion becomes dependent on the MAP’s driving pres-
sure [34]. Current MAP targets in other shock etiologies are based on the same prin-
ciples, despite having a different pathophysiology. In cardiogenic shock, no clear MAP
targets can be set due to limited supporting data [35].
Similarly, in (VA-)ECMO the optimal MAP target remains unknown. ELSO guidelines
lack recommendations, except for when ‘left ventricle overloading’ occurs, in which it is
recommended to reduce the MAP to the lowest acceptable value [36]. In case of ECPR,
ELSO guidelines recommend a MAP between 60 and 80 mmHg [18]. Interestingly, a
recent RCT studying blood pressure targets in comatose OHCA patients found equal
survival and neurological outcomes in the low- (63 mm Hg) versus high-target group
(77 mm Hg) [37]. Theoretically, as the heart has to eject against a continuous blood flow
generated by the ECMO device, a lower MAP seems favorable as it reduces afterload,
and therefore decreases myocardial oxygen demand, possibly optimizing native cardiac
output in the already failing heart [38–40].
Currently, only one study addresses the question of optimal MAP targeting in adult
patients on ECMO. In this retrospective observational study of 116 patients, a higher
average MAP was associated with survival to discharge [38]. Furthermore, in patients
with a lower MAP, a higher incidence of kidney injury was found. However, a lower
MAP might also be the result of other factors contributing to the poor prognosis, rather
than the cause. Due to its retrospective character and small cohort size, no definite con-
clusions can be drawn regarding the optimal MAP for ECMO.
Future research To fill this knowledge gap RCTs are needed. However, in the short
future an RCT will start in the Netherlands, randomizing patients with AMI-CS to either
a standard MAP or to a MAP ≥ 55 mmHg. This will be the first step towards determin-
ing optimal MAP targets in CS patients. Afterwards, the same study design might be
considered to define MAP targets in patients on VA-ECMO.

#6: Adjuvant treatments: blood transfusion regimen

Transfusion guidelines for VA-ECMO patients are limited to expert-opinion statements
in the ELSO guidelines [1]. Advised thresholds are quite liberal, resulting in a high inter-
center variance in thresholds used [41]. Current literature consists mainly of observa-
tional studies.

Red blood cells (RBC) RBC transfusion during VA-ECMO is common: 82–100% of
patients receive RBC transfusion with a mean of 24 RBC units per run [42–45]. The
Raasveld et al. Intensive Care Medicine Experimental (2022) 10:50 Page 9 of 17

hemoglobin (Hb) thresholds described are relatively liberal [46]. One of the hypoth-
eses for these liberal thresholds in VA-ECMO is that patients with cardiac failure can
develop tissue hypoxemia due to reduced cardiac output. The resulting decreased
delivery of oxygen (­DO2) can be compensated by providing a larger Hb buffer. This,
however, does not consider that by the blood flow created by VA-ECMO, a fixed car-
diac output, and thus D ­ O2, can largely be maintained. Evidence to either confirm or
refute this hypothesis is lacking.

Platelets Thrombocytopenia and impaired platelet function are common during VA-
ECMO [47, 48]. ELSO guidelines recommend platelet transfusion to maintain a plate-
let count over 80 × ­109/L [1]. Platelet transfusion occurs in 20–50% of patients, while
reasons for transfusion are not described [42, 49]. Both severity of thrombocytopenia
and platelet transfusion have been associated with mortality [49, 50].

Plasma ELSO guidelines state that indications for plasma transfusion include (i)
(suspicion of ) decreased antithrombin levels; (ii) correction of coagulation distur-
bances or (iii) system priming [1]. One-third of patients receive plasma transfusions;
however, reasons and indications for transfusion are not properly recorded [42, 51].
As the role of plasma in treating hemorrhage is disputable, while increasing the risk
of transfusion-related complications, routine use of plasma should be well considered
[52, 53].

Hemorrhage Hemorrhage is one of the main complications during VA-ECMO, occur-

ring in up 60% of patients [54–56]. Central cannulation increases the risk of a hemorrhagic
event, with an occurrence rate of 52% vs. 33% in peripheral cannulation [57]. Hemorrhage
is associated with all types of transfusion and mortality on ECMO [58]. Therefore, pre-
venting hemorrhage should be a priority in this vulnerable population.

Future research Currently, no prospective studies focusing on transfusion thresholds

have been announced. We recommend that reasons for transfusion of RBC, platelets and
plasma should be further explored. In other non-ECMO patients, using a restrictive Hb
threshold for RBC transfusion has been shown to be safe [59, 60]. As RBC transfusion is
most commonly transfused in patients on ECMO, future research should first focus on
the optimal Hb threshold for RBC transfusion in VA-ECMO.

#7 Adjuvant treatments: anticoagulant therapies

Hemostasis during ECMO is a precarious balance: While (systemic) anticoagulation
is needed to prevent thrombotic complications, hemorrhage remains one of the main
complications during ECMO. Different therapies, targets and monitoring options can be
used, however, this PICO will focus on therapies only.

Unfractionated heparin Unfractionated heparin (UFH) is one of the classic and most
commonly used anticoagulant agents during ECMO [61]. However, it comes along with
a risk of developing heparin-induced thrombocytopenia (HIT), and recommendations
regarding the ideal targets are pending. Several cohort studies have described the safe use
Raasveld et al. Intensive Care Medicine Experimental (2022) 10:50 Page 10 of 17

of lower UFH anticoagulation targets, showing a decrease of hemorrhagic events without

an increase of thrombotic events [62–64].

Low‑molecular weight heparin Low-molecular weight heparin (LMWH) has been

shown to be safe and effective in renal replacement therapy (RRT) [65]. The past years,
a handful of retrospective studies appeared on LMWH in ECMO, showing an equal rate
of hemorrhage and reduced thrombotic event rate in favor of LMWH [66]. Prospective
studies, however, are lacking.

Direct thrombin inhibitors (DTIs) The use of DTIs in ECMO has been increasing, despite
the shortage of prospective studies, mainly indicated in case of suspected HIT. Reports of
the use of argatroban in VA-ECMO are limited to case series [67]. More is known about
bivalirudin, of which observational retrospective studies show the safe use with regard to
hemorrhagic and thrombotic complications [68, 69].

Absent systemic anticoagulation As a result of improved ECMO coating, rationale has

shifted towards lower anticoagulation targets. Some have taken it even further, describing
the safe withhold of anticoagulation in VA-ECMO [70]. However, limitations include a
retrospective design and small sample sizes, thereby limiting generalizability.

Future research One pilot study has been performed comparing UFH targets. Currently,
one RCT is ongoing with expected results early 2024, comparing two systemic heparin
regimes (high and low target) and LMWH (NCT04536272) [71]. Further work is required
to evaluate the best fit anticoagulant therapy and targets in VA-ECMO.

#8 Complications: endothelial activation and damage

ECMO induces a systemic inflammatory response due to among others exposure of the
patient’s blood to the foreign surface of the ECMO circuit. This results in a variety of
coagulative and inflammatory cascades and complex interactions with the endothelium
[72].

Adhesion molecules and selectins Activated endothelium is characterized by overex-

pression of adhesion molecules, such as ICAM1 and VCAM1, and selectins (P-selectin
and E-selectin) that facilitate leukocyte adhesion, rolling, and transmigration of activated
neutrophils. So far, neither adhesion molecules nor selectins have been studied in adult
patients on VA-ECMO.

von Willebrand factor Upon endothelial activation, von Willebrand factor (vWF) is
released from the Weibel–Palade bodies [73]. In VA-ECMO patients, vWF antigen lev-
els were high compared to values in healthy controls and remained high within the first
5 days after initiation of ECMO [74].

Angiopoietin‑2 and VEGF Also released from Weibel–Palade bodies is angiopoietin-2.

Angiopoietin-2 is a growth factor and associated with increased endothelial permeability
and organ dysfunction in patients on cardiopulmonary bypass (CPB) [75, 76]. Although
Raasveld et al. Intensive Care Medicine Experimental (2022) 10:50 Page 11 of 17

angiopoietin-2 levels remained stable within the first three days on VA-ECMO, angi-
opoietin-2 levels were significantly higher in non-survivors compared to survivors [77].
Within the same study, vascular endothelial growth factor (VEGF), a pro-inflammatory
growth factor that enhances endothelial permeability, increased over the first three days
of VA-ECMO support. Interestingly, VEGF was lower in non-survivors compared survi-
vors of VA-ECMO support [77].

Thrombomodulin Thrombomodulin is a thrombin receptor on endothelial cells and

released after injury [78]. In patients on VA-ECMO, no differences were found in soluble
thrombomodulin levels over time nor between survivors and non-survivors [77].

Extracellular vesicles Upon endothelial activation, extracellular vesicles (EVs) are

released, which can mediate intercellular communication. Patients on VA-ECMO had
increased levels of endothelial-derived EVs after ECMO initiation compared to healthy
controls [79]. A follow-up study showed that endothelial-derived EVs did not differ
between survivors and non-survivors [80]. Interestingly, EVs derived from leukocytes
were associated with outcome [80]. These specific EVs are suggested to induce endothe-
lial dysfunction [81].

Future research Activation of the endothelium seems a less well recognized complica-
tion during ECMO, even though it is known from patients on CPB that it is associated
with organ dysfunction [76]. The above-described results show preliminary evidence of
endothelial activation in patients on VA-ECMO. Although inflammation and endothelial
activation might be prices to pay for the benefits of ECMO, we do however recommend
further exploration to possibly counteract the detrimental effects. Lastly, in other criti-
cally ill patient populations, recently successful evaluation of pharmacological interven-
tions in a translational matter have been performed (i.e., protein kinase inhibitors in acute
respiratory distress syndrome). This approach may also be applied to identify and prevent
the negative effects of endothelial activation and damage.

Discussion and conclusion

This scoping review describes a selection of eight high-priority topics in which further
research should be performed in patients receiving VA-ECMO, as identified by an expert
panel. The expert panel primarily identified almost fifty topics for further elucidation,
thereby emphasizing the many current knowledge gaps and research priorities. Available
guidelines specific to patients receiving VA-ECMO are scarce, and in the ones available,
many topics are based on expert-opinion only. This does not come as a surprise, as for
some topics, only one study on the subject could be found. There is a strong need for
further evidence-based research in this critically ill patient population.
For all sub-topics, the majority of studies consisted of an observational design. These
observational studies often had a retrospective design, and were performed in a single-
center setting. This comes along with different disadvantages, including a high risk of
different types of bias (i.e., selection, immortal time), confounding and even methodo-
logical errors. Moreover, the single-center design impedes translation to other centers
or countries, even more when taking into account the lack of evidence-based guidelines.
Raasveld et al. Intensive Care Medicine Experimental (2022) 10:50 Page 12 of 17

For example, in case of ECPR, due to a different hospital occupancy per country, time-
to-ECMO can differ drastically and thereby influence the result either too positive (short
time-to-ECMO, high amount of expert centers and resources) or too negative.
Only a handful of RCTs have been performed on patients receiving ECMO. However,
those are limited to either respiratory support (i.e., venovenous ECMO) or ECPR. Of
these RCTs, stopping early due to meeting the stopping criteria, either for futility or
superiority, is not uncommon [12, 13]. RCTs in VA-ECMO can face multiple important
obstacles. Firstly, due to the wide range of indications, the patient population receiv-
ing VA-ECMO shows a high amount of heterogeneity: for example, ECPR and failure
to wean cardiopulmonary bypass may come with different aspects of clinical attention
and prognoses. Secondly, multicenter cooperation is key for a feasible study, whereas the
number of runs performed by a center can range from a few to high-output. Lastly, ethi-
cal considerations play a large role, as patients are per definition unconscious and thus
informed consent is dependent on by-proxy or deferred consent strategies.
As a result of the lack of studies in patients receiving VA-ECMO, the next best option
consists of the translation and transposition of studies performed in similar patient
populations. Although this may be sufficient in some cases, this does not always apply.
Different research strategies are required to answer the topics as stated in this review.
For example, a translational approach is key in further studying endothelial activation,
wherein an essential step is the forming and testing of hypotheses in in vitro and animal
models. To study the more general topics, such as cannulation method, it may be suffi-
cient to focus primarily on large observational studies or RCTs as it involves all patients
receiving VA-ECMO. Alternative subjects such as choice of anticoagulation on the other
hand are preferred to be performed in a homogenous population, whereas a different
profile of coagulation disturbances and thus bleeding risk may play an important role.
Currently, several RCTs are ongoing and results are expected within the upcoming
years (NCT04620070, NCT04536272). However, with the yearly increasing amount of
ECMO centers, indications for VA-ECMO and thus runs and numbers of patients sup-
ported with VA-ECMO, more research is needed on a shorter notice. Alternative study
designs, such as adaptive platform trials, may be of use in evaluating different adjuvant
treatments in VA-ECMO simultaneously and efficiently, such as combining transfusion
regimen and evaluating microcirculatory disturbances.
In conclusion, this scoping review identifies and presents an overview of research
gaps and priorities in VA-ECMO. Gaining data from translational high-quality research,
ranging from preclinical and animal studies to RCTs is important to improve the stand-
ard practices in this patient population.

Abbreviations
ACS Acute coronary syndrome
AMI Acute myocardial infarction
CPB Cardiopulmonary bypass
CPR Cardiopulmonary resuscitation
CS Cardiogenic shock
DPC Distal perfusion catheter
DTI Direct thrombin inhibitor
ECPR Extracorporeal cardiopulmonary resuscitation
ED Emergency department
ELSO Extracorporeal Life Support Organization
Hb Hemoglobin
Raasveld et al. Intensive Care Medicine Experimental (2022) 10:50 Page 13 of 17

HIT Heparin-induced thrombocytopenia

ICAM-1 Intercellular adhesion molecule-1
INTERMACS Interagency Registry for Mechanically Assisted Circulatory Support
LMWH Low-molecular weight heparin
MAP Mean arterial pressure
MCS Mechanical circulatory support
NIRS Near-infrared spectroscopy
PCI Percutaneous coronary intervention
PICO Patient/population, intervention, comparison and outcomes
RBC Red blood cell
RCT​ Randomized controlled trial
RRT​ Renal replacement therapy
SCAI Society for Cardiovascular Angiography and Interventions
UFH Unfractionated heparin
VA-ECMO Veno-arterial extracorporeal membrane oxygenation
VCAM1 Vascular cell adhesion molecule 1
VEGF Vascular endothelial growth factor
vWF von Willebrand factor

Supplementary Information
The online version contains supplementary material available at https://​doi.​org/​10.​1186/​s40635-​022-​00478-z.

Additional file 1. Supplementary materials.

Acknowledgements
Not applicable.

Author contributions
Concept and design: SJR, APJV. Acquisition, analysis or interpretation of data: all authors. Drafting of the manuscript: all
authors. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: N/A. Supervi-
sion: APJV. All authors read and approved the final manuscript.

Funding
No funding or support was received for this study.
Availability of data and materials
Not applicable.

Declarations
Ethics approval and consent to participate
Not applicable.

Consent for publication

Not applicable.

Competing interests
No competing interests were stated by all authors.

Author details
1
Department of Critical Care, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam,
The Netherlands. 2 Institute of Cardiometabolism and Nutrition, Sorbonne Université, INSERM, UMRS1166-ICAN, Paris,
France. 3 Service de Médicine Intensive‑Réanimation, Institut de Cardiologie, APHP Sorbonne Hospital Pitié-Salpêtrière,
Paris, France. 4 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. 5 Periopera-
tive Medicine and Intensive Care, Karolinska Institutet, Stockholm, Sweden. 6 Department of Intensive Care, Université
Libre de Bruxelles, Hôpital Universitaire de Bruxelles (HUB), Brussels, Belgium. 7 Heart Center, Department of Cardiology,
Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. 8 Labora-
tory of Experimental Intensive Care and Anesthesiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The
Netherlands. 9 Heart Center Leipzig at University of Leipzig and Leipzig Heart Science GmbH, Leipzig, Germany. 10 Depart-
ment of Cardio‑Thoracic Surgery, Heart and Vascular Centre, Maastricht University Medical Centre (MUMC), Cardiovas-
cular Research Institute Maastricht (CARIM), Maastricht, The Netherlands. 11 Department of Anesthesiology, Amsterdam
UMC, VU University, Amsterdam, The Netherlands.

Received: 28 September 2022 Accepted: 14 November 2022

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