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Fig. 21.2 Radial
centrifugal blood pump
(Courtesy Getinge AB,
Rastatt, Germany)
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a polyvinyl chloride tubing, usually coated with unfractionated heparin. The blood
ow is controlled with magnetically actuated centrifugal pumps, replacing formerly
used roller pumps, Fig.21.2 [15, 16]. Due to a potentially developing negative pressure, a cautious approach is needed when inserting or removing indwelling catheters, or performing interventions which include the opening of blood vessels, as this
could lead to aspiration of air by the ECMO system [14, 17].
Gas-exchange devices evolved from the direct air-blood contact systems to the
membrane-based oxygenators, fullling the patient’s need for oxygen supplementation and the carbon dioxide removal. Since the beginning of the twenty-rst century,
polymethylpentene hollow ber membranes are gaining popularity, as gas is conveyed through bundles and the blood circulates around the hollow bers (Fig.21.3)
[14, 18].
The portion of oxygen in the gas mixture is dosed depending on the patient’s
need and may be supplemented up to 100%. Increasing or decreasing of the sweep
gas ow will increase or reduce the carbon dioxide clearance, not altering oxygenation. The gas-blood ow ratio is normally adjusted to maintain normal levels of
carbon dioxide in the blood (normocapnia) [14]. Due to its structure, the oxygenator
presents one of the most common locations for blood clots to form. Therefore, the
regular check of the capacity and integrity of the oxygenator, including the search
for clots, is obligatory in everyday practice.
Finally, the heat exchanger prevents circuit-related heat loss, giving the possibility of targeted temperature management (i.e., rewarming of accidental hypothermia,
treatment of metabolic crisis, therapeutic hypothermia after cardiac arrest, etc.). It
may be a separate component or integrated into the gas-exchange device, commonly
based on hollow ber bundles (nonpermeable) with circulating water (Fig.21.3) [14].
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S. Rajsic et al.
Fig. 21.3 Schematic presentation of a diffusion membrane showing blood ow between the gas
and water-lled network of hollow bers (Courtesy Getinge AB, Rastatt, Germany)
ECMO Indications andCongurations
According to the Extracorporeal Life Support Organization (ELSO), ECMO should
be initiated in selected patients with cardiorespiratory failure when the mortality
risk reaches 80%, and its initiation should be considered in cases with a high mortality risk (more than 50%) [14].
Two main congurations include the venoarterial (VA-ECMO) and venovenous
ECMO (VV-ECMO). The VA-ECMO can be used as a mechanical circulatory support or a combination of both circulatory and pulmonary support. The VA-ECMO
circuit consists of venous drainage to a circuit pump and an oxygenator, with the
return of oxygenated blood to the arterial system. Cannulation can be central (i.e.,
failure to wean from cardiopulmonary bypass) or peripheral (i.e., eCPR). In the case
of central cannulation, access is obtained by direct cannulation of the aorta and the
right atrium. For peripheral cannulation, any large peripheral artery may be used
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with the femoral artery being the most common choice. For the venous drainage, at
least one femoral catheter is advanced into the right atrium [19].
The main indications for VA-ECMO include postcardiotomy cardiac failure,
myocardial infarction, acute-on-chronic heart failure, rewarming after accidental
hypothermia, bridge to heart transplantation, myocarditis, pulmonary embolism,
cardiac arrest, refractory ventricular arrhythmias, cardiac trauma, sepsis, ARDS
with severe cardiac failure, or any other cause of a refractory cardiogenic shock [14].
The VV-ECMO can be used to support an isolated pulmonary failure, without
any need for circulatory support. The circuit consists of venous drainage to a circuit
pump and an oxygenator, with oxygenated blood returning to the venous system.
The main indications include severe ARDS, severe air leak syndromes, resistant
hypercapnia, bridge to lung transplantation, difcult airway management, or any
other cause of acute hypoxemic respiratory failure unresponsive to conventional
therapy [14].
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Extended ECMO Indications andContraindications
Extended ECMO indications present the use of extracorporeal life support in case
of trauma, especially in cases of posttraumatic ARDS or transfusion-associated
acute lung injury, high risk of airway compression (i.e., mediastinal masses), airway
surgery, pulmonary thrombendarterectomy, accidental hypothermia, etc. [19]. Over
the last years, even patients in septic shock could benet from ECMO, if the hemodynamic compromise is mainly related to secondary myocardial dysfunction rather
than distributive vasoplegia [20]. However, this option is reserved only for carefully
selected patients. Another extended indication is rapid rewarming in case of cardiac
instability due of accidental hypothermia. Finally, the use of ECMO in awake
patients awaiting lung transplantation is being described increasingly, reducing the
need for prolonged intubation, mechanical ventilation, and analgosedation.
Given the above, most contraindications for ECMO are rather relative than absolute, as age and size of patient or high risk of systemic bleeding under anticoagulation. Recent or expanding CNS hemorrhage, non-recoverable comorbidity, and
disseminated malignancy remain contraindications for ECMO and have to be carefully weighed against possible benets in terms of outcome [19, 21].
Anticoagulation Strategies During ECMO Support
The exposure of blood to articial surfaces of the extracorporeal circuit and surgical
trauma can initiate and propagate inammatory and coagulation processes, leading
to the need for therapeutic anticoagulation during ECMO support [12–14].
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Systemic anticoagulation is considered the standard of care, crucial in the reduction of thrombosis risk and ECMO circuit components failure. Unfractionated heparin (UFH) is the primary anticoagulant [14, 22]. However, systemic anticoagulation
carries a risk of serious bleeding, with the potential for permanent injury or even
death [23–28]. On the other hand, thromboembolic events may occur as well, thus
requiring careful therapeutic adjustments and follow-up [29–31].
In the case of the heparin-induced thrombocytopenia type II (HIT II) or heparin
resistance, an alternative anticoagulation approach may be employed. When the
HIT II is suspected, heparin should be stopped immediately, and heparin-coated
components need to be removed. Furthermore, anticoagulation using direct thrombin inhibitors (i.e., argatroban, bivalirudin) or factor Xa inhibitors (i.e., rivaroxaban)
should be considered [32]. Failure to continue anticoagulation in patients with HIT
II could lead to a clinically signicant thromboembolism, as this patient population
is prone to thromboembolism [32].
In the last decade, evidence on the so-called anticoagulation-free ECMO support
is emerging, with comparable incidences of thromboembolic events in
anticoagulation- free ECMO patients compared to the standard ones [33]. Due to
inconsistency in reporting, the authors could not draw any denitive conclusion in
regard of hemorrhage [33]. The results of ongoing prospective studies (A-FREE
ECMO-NCT04273607; SAFE-ECMO-NCT04997265; and RATE-NCT04536272)
should help tailor future recommendations regarding anticoagulation.
Moreover, there is extensive research on the methods to reduce the need for systemic anticoagulation, including alternative approaches. Heparin-coated circuits are
considered as the standard of care in many centers worldwide [34, 35]. However, the
optimistic introduction of UFH-coated circuits did not lead to the omission or
reduction of systemic anticoagulation. The use of citrate anticoagulation, as in continuous renal replacement therapy, is limited by the low clearance of citrate, restricting its use to blood ows below 200mL/min, being signicantly below the ow
needed for ECMO.
Despite signicant progress in the research on novel systemic anticoagulation
therapies in the last two decades, the ideal anticoagulatory approach or drug are still
not available. The ideal anticoagulant should have predictable anticoagulant effects
and pharmacokinetics, with both oral and parenteral formulation, wide therapeutic
range, eliminating the need for monitoring, with an available antidote and a rapid
onset and offset of action, and lastly an affordable price [36]. Emerging preclinical
data on novel anticoagulants and the role of antibodies targeting factors XI and XII
showed good safety proles and sufcient efcacy. However, there is still no evidence regarding their safe use in humans [37, 38].
S. Rajsic et al.
Monitoring ofAnticoagulation
Different invitro modalities can aid anticoagulation monitoring and guidance.
The majority of centers employ serial measurements of the activated clotting
time (ACT) and the activated partial thromboplastin time (aPTT), both being fast
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Fig. 21.4 Overview of the most commonly used anticoagulation agents during extracorporeal
membrane oxygenation. aPTT: activated partial thromboplastin time; ACT: activated clotting time
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and affordable methods [39]. Due to intrinsic limitations of both, ACT and aPTT,
alternative methods as measurement of Anti-Xa levels and viscoelastic methods are
being increasingly used (i.e., rotational thromboelastometry—ROTEM®, thromboelastography system-TEG®, viscoelastometry analyzer—ClotPro®, etc.) [13, 40].
An overview of the most commonly used anticoagulants with the mechanism of
action and monitoring methods is presented in Fig.21.4. Unfortunately the discordance between different methods is still common [13].
Complications andMortality
Unfavorable outcomes are not unusual, generating debate about the real value of
ECMO [22, 41–45]. Patient-related complications include acute renal failure,
bleeding, thromboembolic events, sepsis, and pneumonia [22]. The circuit-related
adverse events include formation of circuit clots and thrombi, with potentially devastating consequences. Finally, life-threatening acute mechanical failure, circuit
fractures, or gas embolism are further, rather seldom circuit-related adverse
events [19].
Within the patient-related complications, renal failure (51%) with the need for
renal replacement therapy (44%) and hemorrhage (49%) are the most frequent
adverse events during VA-ECMO support. Other frequently reported complications
include pneumonia (24%), sepsis (18%), and thrombosis (13%) [22]. However, the
approximate rates of complications are heterogeneously reported, making any systematization of the current evidence at least complex. Most of the reports originate
from retrospective studies, with selection bias and potential underestimation as the
main limitations [22].
Acute renal failure is commonly seen as a representation of a multiple organ
failure, caused by a reduction in renal oxygen delivery and/or inammatory kidney
damage, with poor outcomes [46, 47]. Furthermore, bleeding presents one of the
most common and serious ECMO complications, associated with an increased mortality. The identication of risk factors and predictors for adverse events during and
shortly after ECMO support is subjected to intensive research, but strong evidence
on potentially modiable factors is still missing [19, 22, 23, 25, 27, 48, 49].
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Depending on the selected population and bleeding denition, the reported rates
of hemorrhage range from 16% to 46% [22]. Bleeding events occur mostly within
the rst 3days of ECMO initiation, which is the reason why some centers employ a
modied (reduced) anticoagulation protocol in the early ECMO phase. Given the
above, early recognition of complications and their management, including anticoagulation monitoring, are crucial in the rst days of ECMO support.
In regard to thromboembolic events, ECMO patients are at an increased risk
independent of the modality (VA-ECMO vs. VV-ECMO) [31]. Patients receiving
VA-ECMO are frequently postcardiotomy patients, with central cannulation and
sternotomy. Therefore, the risk of bleeding may be increased due to the presence of
surgical wounds. On the other hand, overcautious initiation of the anticoagulatory
protocol may increase the risk of thrombosis. Moreover, patients with respiratory
failure may suffer distinct thromboinammation, a known procoagulant condition
triggered by hyperinammation [12, 50–54]. However, the reported incidence of
thromboembolic events remains low, or underestimated due to unidentied thrombosis in asymptomatic patients. The majority of studies reporting on thrombosis are
limited by their retrospective nature. Therefore, the true incidence of thromboembolic events remains unknown. Finally, the lack of standardized denitions for
thromboembolic events, or outcomes in ECMO patients in general, makes the analysis of the available evidence complicated [31].
S. Rajsic et al.
ECMO Mortality
Based on the data from more than 84,000 adult patients, ELSO reported an inhospital mortality of 55% (VA-ECMO), and 42% (VV-ECMO). The highest rates of
mortality (70%) are reported in case of eCPR [11].
Finally, in the CESAR trial, which compared conventional ventilatory support
against ECMO support for severe ARDS, the survival without severe disability was
signicantly increased in the case of ECMO use [55]. However, a similar trial for
patients suffering refractory cardiac failure is still lacking.
ECMO Weaning
Weaning from ECMO support should be guided by the daily clinical, echocardiographic, and hemodynamic evaluation of the cardiac and lung function recovery.
The initial cause of cardiorespiratory failure should be resolved or at least corrected
before the ECMO weaning trial is initiated.
Ensuing recovery of cardiac function, after at least of 24–48h of VA-ECMO support, a weaning trial may be considered. In this phase, the arterial curve should
show pulsatility, with a mean arterial blood pressure of at least 60mmHg (with or
without inotropic support), and all metabolic disturbances should be corrected
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according to the arterial blood gas measurements [56, 57]. In case of combined
cardiorespiratory failure, before weaning initiation, the lung function should be
evaluated. Otherwise, conversion to VV-ECMO may be considered.
The weaning strategy includes the gradual reduction of pump ow (0.5–1L/min)
over a period of hours, under hemodynamic and echocardiographic control. As the
VA-ECMO circuit ow decreases, the preload will increase with consequent afterload reduction, supporting increase in cardiac ejection. If the cardiac function is
successfully recovered to meet a satisfying organ and limb perfusion, further reduction of pump ow is warranted. However, due to ow reduction in the weaning
phase, the increased risk of thrombosis should be considered [14].
Identication of predictors for successful weaning is still a subject of ongoing
research, and consensus is missing. However, multidisciplinary approach with the
repeated evaluation of cardiac function including the ejection fraction of at least
20%–25% are important factors for ECMO support weaning and decannulation
[14, 57–61].
In case of VV-ECMO support, the recovery of lung function may take more time
compared to cardiac failure. The improvement in patient chest radiography, reduced
airway resistance, increased lung compliance, and improving oxygen saturation
with lower ECMO blood and/or swap gas ows together with reduced venous oxygen saturation may indicate lung recovery.
In these cases ECMO weaning may be considered when a satisfying pulmonary
gas exchange can be guaranteed under a lung protective ventilatory support (i.e.,
fraction of inspired oxygen of 30–60%, positive end expiratory pressure of
5–10 cmH2O, peak inspiratory pressure of 25–30 cmH2O) [14]. The monitoring
during VV-ECMO weaning should include evaluation of respiratory mechanics,
serial arterial blood gas measurements, and hemodynamics. If all criteria for ECMO
weaning are met, pump ow is stopped, and the cannulas are clamped before
decannulation.
Finally, there are diverse ECMO weaning approaches, and each center should
implement a local operating procedure for ECMO weaning until the evidence from
randomized trials is available.
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Future Perspectives
Despite continuous research in this eld, it remains difcult to identify modiable
factors. Hemorrhage or high disease severity scores may be important for timely
intervention to prevent the occurrence of complications, potentially reducing morbidity and mortality.
The adaptation of systemic anticoagulation remains the most approachable factor; however, the ideal anticoagulant or monitoring tool are still lacking. Surface
coating is promising; however, it neither eradicates the need for anticoagulation nor
it reduces the risk of hemorrhage [13, 51, 52].
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The use of aPTT as a main monitoring tool of systemic anticoagulation is increasingly questioned, and alternatives are being introduced. Validation for existing recommendations on the aPTT-guided protocol are still lacking [13, 62, 63].
Anti-factor-Xa for UFH monitoring is based on preliminary evidence [64–67].
The increasing use of ECMO for extended indications, reduction of contraindications, and patient individualized approach will lead to further popularization of
this life support technology. Further adaptations and modications of ECMO circuits and systems may lead to new indications, supporting the evolution of awake
ECMO.Moreover, this will be accompanied by more sophisticated therapies, and
older and sicker patients will be assessed for ECMO support. Therefore, meticulous
weighting of the risks and benets will become even more important in future.
S. Rajsic et al.
Articial Intelligence
Articial intelligence in medicine is becoming an unavoidable tool for patient management, including a growing interest in the use for ECMO support. It can be useful
in providing real-time data, prediction algorithms, and optimization of ECMO support management, with potential to reduce the risk of adverse events and consequently improving patient outcomes.
Algorithms using articial intelligence can be built on large databases containing
patient demographics, basic disease, comorbidities, medical history, and outcomes.
This may be used to identify patterns and predict patients being at higher risk of
poor outcome and thus further adjust the treatment for each patient’s individual
needs. Moreover, it could be used for the monitoring of patient’s vital parameters
(arterial blood pressure, blood oxygen saturation, or carbon dioxide levels), with
algorithms analyzing real-time data. The prediction of worsening of vital parameters may facilitate and accelerate the adjustment of the ECMO support, for example,
in case of constant decrease of the patient’s oxygen saturation, or hypercapnia, such
programs could alert the physician to adjust the ECMO system. This holds especially true in times of strained personal resources.
Finally, articial intelligence has the potential to revolutionize the management
of critically ill patients. Developed algorithms may identify patterns and predict
outcomes, alerting health workers on potential optimization of care. With the constant development in the eld of machine learning, we can expect signicant benets in critical care medicine of the future.
Conclusion
The use of ECMO support is becoming more common, and centers of excellence
with higher volumes will present the safest places to indicate and manage this highrisk life support modality.
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