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Review

Subtypes and Mechanistic Advances of Extracorporeal Membrane Oxygenation-Related Acute Brain Injury

by
Bixin Deng
1,
Junjie Ying
2 and
Dezhi Mu
1,2,*
1
Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
2
Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu 610041, China
*
Author to whom correspondence should be addressed.
Brain Sci. 2023, 13(8), 1165; https://doi.org/10.3390/brainsci13081165
Submission received: 10 July 2023 / Revised: 31 July 2023 / Accepted: 3 August 2023 / Published: 4 August 2023
(This article belongs to the Topic Advances in Neurocritical Care)
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Abstract

:
Extracorporeal membrane oxygenation (ECMO) is a frequently used mechanical cardiopulmonary support for rescuing critically ill patients for whom conventional medical therapies have failed. However, ECMO is associated with several complications, such as acute kidney injury, hemorrhage, thromboembolism, and acute brain injury (ABI). Among these, ABI, particularly intracranial hemorrhage (ICH) and infarction, is recognized as the primary cause of mortality during ECMO support. Furthermore, survivors often suffer significant long-term morbidities, including neurocognitive impairments, motor disturbances, and behavioral problems. This review provides a comprehensive overview of the different subtypes of ECMO-related ABI and the updated advance mechanisms, which could be helpful for the early diagnosis and potential neuromonitoring of ECMO-related ABI.

1. Introduction

Extracorporeal membrane oxygenation (ECMO), a life-saving modality first proposed in 1960s [1], has been widely used in neonates to adults, especially those with severe disease who are unresponsive to conventional therapies or those requiring organ transplantation. The cannulation method divides ECMO into two modes: venovenous (VV) and venoarterial (VA)-ECMO. In VV-ECMO, blood is drained from a large vein, circulated through a centrifugal pump and semi-permeable membrane for gas exchange, and returned via a vein, supporting pulmonary function in patients with refractory hypoxemia. VA-ECMO is similar, including a centrifugal pump and oxygenator; however, oxygenated blood is returned via an artery, providing heart and lung support for patients lacking regular heart functions [2]. Central VA-ECMO canulation was conducted via direct venous penetration into the right atrium or direct arterial cannulation into the ascending aorta. On the other hand, peripheral VA-ECMO, referring to femoro-femoral cannulation, femoro-axillary cannulation, jugular-axillary cannulation, and jugular-carotid cannulation [3].
Despite the potential benefits of ECMO, this life-saving technology may be associated with serios complications, including acute brain injury (ABI) [4]. Acute brain injury encompasses several clinical neurologic events, including intracranial hemorrhage (ICH), ischemic stroke, hypoxic–ischemic brain injury (HIBI), cerebral edema, seizure, and brain death. Studies based on the Extracorporeal Life Support Organization Registry (ELSO) have reported ABI in 11–20% of adult patients undergoing VA-ECMO [5,6], and the most recent meta-analysis excluding data from ELSO up to 12.5% [7]. However, the actual incidence may be higher due to a lack of standardized neuromonitoring, limited use of computed tomography (CT) and/or magnetic resonance imaging (MRI) during ECMO, and challenges in the neuroimaging of patients supported by ECMO [8,9]. Previous research indicates that patients undergoing VA-ECMO for cardiac support have a higher ABI rate than those undergoing VV-ECMO for respiratory failure [10,11], with neonates [12] and preterm infants [13] being particularly susceptible. Notably, autopsy studies have reported a significantly higher occurrence of ECMO-related ABI, ranging from 68% to 81% [2,14,15].
Cerebral injuries significantly impact hospital mortality, with rates up to 95% and 100% in patients with two or three or more central nervous system (CNS) complications, respectively [5]. According to a study using the international ECMO registry data, the survival rates for adult VA-ECMO-treated patients with radiographically confirmed infarction or hemorrhage were 17.4% and 10.5%, respectively, compared to 57% in those without cerebral lesions [16]. Survivors also have a relatively high probability of subsequent disability [4]. This review provides an overview of the patterns, possible mechanisms, and monitoring methods of ECMO-induced ABI.

2. Patterns of ECMO-Related ABI

The characteristics of each subtypes of cerebral injuries in patients with ECMO are not well described. In studies reporting brain autopsy data, ECMO-related ABI was found in 68% of adult patients and 79% of infants, with HIBI reported as the most common ABI in both populations, followed by intracranial hemorrhage and ischemic infarction [14,15].

2.1. Intracranial Hemorrhage

ICH (including micro- and macro-hemorrhages) was diagnosed in 22/43 (51%) of decedents during autopsy [2], while, in retrospective studies, the prevalence of ICH was similar between VV- and VA-ECMO patients (2–18% vs. 4–19%, respectively) [5,10,17,18,19,20]. Pathologically, ICH occurs more frequently in the frontal neocortex, basal ganglia, cerebellum, and pons [2]. As reported, the most common type of intracranial hemorrhage is subarachnoid hemorrhage (SAH), followed by petechial intraparenchymal hemorrhage [14,19]. However, the ICH timing is not yet well characterized. In one study, 85% of ICH presented on a CT scan shortly after cannulation [19], while, in another study, the median time for ICH detection was 7 days after ECMO initiation (see Table 1) [18].
Moreover, the mechanisms underlying ICH are not well understood. A previous study reported that two steps are involved. First, the integrity of endothelial cells and the blood–brain barrier is altered, following the extravasation of plasma and erythrocytes, impairing hemostasis [21]. In addition, bloodstream infection is correlated with ICH in patients using a left ventricular assistive device; therefore, it may also play a role in ECMO patients [22,23]. Furthermore, a previous study found that, although the hemorrhagic group had the highest average blood pressure, it had the lowest cerebral tissue oxygenation saturation, suggesting that elevated vascular resistance may lead to poor cerebral perfusion [24]. The risk factors related to ICH include use of anticoagulants and antiplatelet therapy [22], female sex [25], higher pre-cannulation PaCO2 [26], thrombocytopenia, high transfusion requirements [18], a large dual-lumen venovenous cannula [20], ECMO duration [17], bloodstream infections [22], renal failure, and dialysis [27]. Finally, ICH patients are known to have high mortality and morbidity [18].

2.2. Ischemic Stroke

In a mixed VA- and VV-ECMO study, ischemic stroke was observed in 4.1% of patients across all age groups [28]. Although ischemic stroke is more common in VA ECMO (3.6–5.3%), it also occurs in VV ECMO patients (1.7–2%) [5,10,25,27,28]. However, one study reported that the true prevalence is also underestimated, and a rate of 11% was reported recently [29]. The pathology of ischemic stroke, occurring in the frontal neocortex, basal ganglia, anterior hypophysis, and cerebellum [2], is territorial, such that embolism may be the underlying mechanism [30,31]. Moreover, one study claimed that ischemic stroke events during ECMO are located in the left hemisphere in 70% of cases [32].
Although poorly described, cerebral venous sinus thrombosis and emboli from the circuit through the patent foramen ovale are possible etiologies of ischemic stroke [33]. In addition, researchers reported that it tends to occur 1 week after ECMO cannulation, with the only risk factor being platelets >350 giga/L at ECMO initiation [25]. However, other studies have concluded that multiple factors likely contribute to ischemic stroke, including a low brain perfusion state, a dual-lumen venovenous catheter [25,34], hemolysis [35], internal jugular vein cannulation [33], and acute infection or sepsis [36,37], which can lead to thromboembolization. Additionally, in an animal study, hyperthermia was shown to be associated with ischemic cerebral injury in the hemisphere ipsilateral to ligation, leading to elevated cerebral metabolism [38].

2.3. Seizures

Seizures are abnormal, paroxysmal electroencephalography (EEG) events that vary from background activity [39]. Due to the use of sedative drugs and a lack of EEG monitoring, seizure incidence may also be underestimated at 2–6% in patients undergoing VA ECMO [5,26] and 1.3% in VV ECMO adult patients [40]. Previous studies have claimed that younger pediatric patients have higher occurrence of seizures than older patients [41,42]. Other studies using continuous EEG and regular sedation reported a much higher seizure rate in patients [43,44,45]. Seizure activity can be subsequently detected in patients with ICH, embolic infarcts, or global cerebral hypoxia/anoxia [46]. However, most ECMO-related seizures are related to neurologic insults, occurring around the time of cannulation [45]. It is noteworthy that, in children and adults under ECMO, severe background abnormalities (burst suppressions, severe slowing or unresponsiveness, or electrographic seizures) result in CT- or MRI-defined brain injury and poor outcomes, including lower IQ and neurodevelopmental delays [47,48,49,50]. Importantly, severely abnormal background activity in the first 24 h after ECMO initiation is associated with death and seizure lateralization related to arterial cannulation position, including the middle cerebral artery (MCA) territory. However, in patients presented with seizures, mostly implicating brain injury, only one-third of patients with ABI had monitored seizures [39]. Moreover, cerebral gas embolism (CGE) may result in the rapid onset of epileptic seizures [51], and cerebral edema is another known risk factor for seizures [52].

2.4. Hypoxic–Ischemic Brain Injury (HIBI)

As the most common type of ABI in patients who received ECMO at autopsy [14,15], HIBI is reported to have a higher incidence in patients with VA-ECMO over VV-ECMO (13% vs. 1%, p < 0.001) [53]. Pathologically, HIBI demonstrates the most diffuse damage in multiple anatomic locations [2], involving the cortex, cerebellum, brain stem, and basal ganglia, with a preponderance in the cerebral cortices (82%) and cerebellum (55%) [14]. Hypoxia from refractory respiratory failure is a possible cause, while CO2 dysregulation, cerebral vasoconstriction, and North–South syndrome, resulting from hemodynamic changes specific to VA-ECMO, can lead to cerebral ischemia [33]. When it comes to risk factors, HIBI is most likely to occur in patients with hypertension, hyperlactatemia, and low pH (acidosis), and signs of inadequate perfusion. It often presents during the peri-ECMO cannulation period (24 h) before and after ECMO cannulation [14], because ECMO provides adequate perfusion of the brain after successful cannulation.

2.5. Brain Death

The occurrence of brain death is reportedly different in the two modes of ECMO. Approximately 2% in patients with VV-ECMO and 7.9–13.1% in patients with VA-ECMO [5,7,54]. Contrary to the prevalence of ABI in different populations, the incidence of brain death in pediatric patients increases with age, from 1.3% in those aged 0–30 days, to 4.0% in those aged 31 days to less than 1 year, and finally to 8.4% in those aged 1 year to less than 16 years [55]. Additionally, severe post-anoxic swelling, extensive infarction, or hemorrhage may lead to brain death [5,36]. Traditionally, brain death was defined as irreversible functional loss of the entire brain, including the brainstem [56]. Clinical assessments of brain death include hemodynamic stability (systolic arterial pressure >90 mmHg), adequate core temperature (>36 °C), and without circulating analgesics, sedatives, muscle blocking agents, or severe electrolyte or glucose disturbances [57]. Unfortunately, in the presence of ECMO support, brain death determination is challenging and there are no guidelines for the determination of brain death in ECMO [46]. Moreover, novel monitoring methods such as EEG, plasma biomarker glial fibrillary acidic protein (GFAP), and cerebral angiography may be useful; however, they still require further investigation [58,59,60].

3. Possible Mechanisms of ABI in ECMO

3.1. Common Mechanisms

3.1.1. Altered Hemostasis

As blood components come into contact with the extracorporeal surface, they inevitably activate the coagulation system (Figure 1), which may lead to endothelial injury and disrupted microcirculation; thus, anticoagulation and antiplatelet drugs are often used in this condition [61]. The intrinsic coagulation pathway is initiated by factor XII, combined with factor XI, high-molecular-weight kininogen (HMWK), and pre-kallikrein, which are components of the contact system. Factor XII is cleaved into factor XIIa and factor XIIf. Factor XIIa, achieving maximal levels within 10 min of ECMO initiation, not only triggers the following steps in the coagulation cascade but also converts HMWK and pre-kallikrein into bradykinin and kallikrein, respectively. Both promote XII and XI activations [62,63]. On the other hand, the extrinsic pathway is thought to be less important for this process. However, regardless of the ex- or intrinsic pathway, they share one activator, FXa, which converts prothrombin to thrombin to form clots [64].
Unfractionated heparin (UFH), the gold standard and frequently used anticoagulant during ECMO, downregulates thrombin and activated factor X (factor Xa) by enhancing the antithrombin activity. Meanwhile, activated partial thromboplastin time (APTT), activated clotting time (ACT), anti-factor Xa activity levels (anti-Xa), blood drug concentration, and viscoelastic tests are used as anticoagulation monitoring methods [65]. Of these, a range of 1.5 to 2.5 times the patient’s baseline APTT (40–80 s) or a goal of 180–220 s for ACT is mostly used in cases of thromboembolism or bleeding risk [66,67]. However, the most appropriate anticoagulation monitoring tests is still missing, and recently, it was reported that the levels of APTT did not show any association with bleeding or thrombosis [29,68]. In addition, low-molecular-weight heparin (LMWH) is widely used to prevent and treat venous thromboembolism. Although it targets factor Xa, it also activates antithrombin, exerting an anticoagulant effect [65].
Platelets promote hemostasis and accelerate clotting. It is noteworthy that, in one study, the platelet count dropped to 150 g/L on day 5 from 221 g/L prior to ECMO initiation [69], A previous study reported that platelet loss during ECLS is mainly caused by platelet activation and blood draw for diagnostic phlebotomy, while approximately one-third of the cause of platelet loss remains unknown [70]. Moreover, platelets have been shown to be dysfunctional in ECMO-supported critically ill neonates despite platelet transfusion [71].
Because the ECMO circuit provides a large surface of area of blood interface and its composition, thrombi from it are noteworthy. A previous study showed that ECMO-associated venous thromboembolism rates ranging from 18 to 85% in different centers [72]. These thrombi were seen in oxygenator membrane surface, arterial tubing venous tubing, and connector thrombi [73], and when the thrombi returned to the body they caused damage to multiple organs.
However, inadequate systemic anticoagulation increases the risk of bleeding in cases of overdosing or thrombosis in case of underdosing. Therefore, it is essential to monitor anticoagulation and balance procoagulant and anticoagulant factors [74,75]. Viscoelastic hemostatic assays (VHA) and whole blood point-of-care coagulation assays are used to measure the viscoelastic properties of the clot. Of these, thromboelastography (TEG) and thromboelastometry (ROTEM) are the only two VHAs validated for clinical use, both are equipped with multiple assays, allowing extrinsic and intrinsic clot activation, the assessment of the contribution of fibrinogen formation and heparinase assays. Although VHA has only been validated as a guideline for therapeutic administrations, the hypercoagulable state demonstrated by TEG and ROTEM has also predicted a high risk of thrombotic complications in several studies [76,77]. In addition to underlying disease and anticoagulant therapy, different configurations of ECMO may also alter hemostasis. Compared to VV-ECMO, patients on VA-ECMO have significantly decreased platelet counts, fibrinogen, antithrombin, and clot strength with higher D-dimer levels, which are in parallel with consumptive coagulopathy. The rate of thrombosis is approximately 40% in VA-ECMO, while in VV-ECMO, it is doubled [78].

3.1.2. Immune System Activation

Although patients receiving ECMO support have severe disorders that can lead to immune system activation, exposure to the artificial surface of the ECMO circuit and disrupted cerebral autoregulation can also alter the immune system, inducing the expression of various immune cells and cytokines [79]. Consequently, systemic inflammatory response syndrome (SIRS) can be induced following a series of fatal complications, including bleeding, thrombosis, and capillary leakage syndrome [64].
The components of the contact system also drive inflammation and directly activate neutrophils [62]. Moreover, thrombin, a vital product of the coagulation system activated by the contact system during ECMO, is the main activator of platelets, which secrete several soluble mediators and bind to leukocytes [64]. The complement system, at the forefront of the innate immune response, is activated following ECMO initiation. Moreover, among the three activation pathways (the classical pathway (CP), alternative pathway (AP), and lectin pathway (LP)), the AP has been shown to be the prominent mechanism of complement activation [80], responsible for the production of proinflammatory anaphylatoxins C3a, C5a, and the membrane attack complex. This, in turn, leads to increased vascular permeability, smooth muscle contraction, leukocyte recruitment, and the production/release of other inflammatory cytokines [81].
Although phagocytes are also activated during ECMO, they do not accumulate in the extracorporeal circuits or release humoral factors [82]. In a porcine ECMO model of induced SIRS, mast cells in the intestinal mucosa are thought to be responsible for a rapid increase in TNF-α and IL-8 immediately after ECMO initiation, as evidenced by higher sensitivity in detecting inflammation during ECMO compared to blood leukocyte and C-reactive protein counts [83].
In addition, neutrophils are also activated in ECMO, with the activators shown to be kallikrein [62], Xa, TNF-α, thrombin [64], and C5a [84], resulting in the attracting and priming of neutrophils and adherence to the endothelium [84]. Widespread microvascular injury and multiorgan dysfunction are possible by adhering to the capillary/venular endothelium and producing cytokines, arachidonic acid metabolites, and reactive oxygen species [85,86]. Another study, using ex vivo models of ECMO, showed that neutrophils are activated within the first 30 min of ECMO initiation; however, leukocytes do not adhere to the extracorporeal circuit [82]. Although the autoreactivity of B and cytotoxic T cells to CNS-specific antigens was detected, parallel to ECMO treatment [79], their function in ECMO-related brain damage remains unknown.
Elevated IL-8 can act as a powerful trigger to induce the adhesion of monocytes to the vascular endothelium [87]. Another cytokine, IL-6, which acts as both a pro- and anti-inflammatory cytokine, is also elevated in adult and pediatric ECMO patients [64]. However, studies have suggested that increased IL-6 levels are associated with lung injury [88] and poor survival rate [89].
Although activated neutrophils levels are significantly increased, the high number of immature neutrophils responsible for immunosuppression is higher in ECMO patients, resulting in a high risk of infection. In addition, both mature and immature neutrophils express low levels of the C5a receptor [90], which is related to their ability to kill gram-positive cocci [91]. In addition to abnormal neutrophils, monocyte dysfunction, T-cell dysfunction, and the expansion of myeloid-derived suppressor cells (MDSC) are also observed under these conditions, with powerful immunosuppression [92,93] or immunoparalysis. Notably, a recent study suggests that it may be associated with worse outcomes in patients receiving ECMO (Figure 2) [94].

3.2. Mechanism of ABI Specific to VA-ECMO

3.2.1. Hemodynamics in ECMO

There are multiple choices of cannulation artery, with the right common carotid artery being the most commonly used in infants [95]. While peripheral ECMO is more common in the elderly, the blood flow from the oxygenator to the vessels is not in accordance with intrinsic cardiac flow, such that the blood flow from the two points of circulation will meet. This “mixing cloud” is determined by the amount of ECMO support provided and the degree of left ventricular ejection (Figure 3) [96]. Thus, in the presence of pulmonary dysfunction, the blood ejected from the left ventricle is not well oxygenated. This differential [97] can lead to hypoxia in organs perfused by the proximal aortic branches, including the coronary and innominate arteries. For example, if the mixing cloud is located between the brachiocephalic trunk and the left common carotid artery, then the two cerebral hemispheres will be perfused by blood with different levels of oxygen, velocity, pressure, and pulsatility [98,99].

3.2.2. Cannulation Method

In adult, central ECMO (blood returned to the body via an ascending aortic cannula) is associated with left hemisphere lesions, while peripheral ECMO (blood returned to the body via a right common carotid artery cannula pointing toward the arch of the aorta) is related to right hemisphere lesions; predominantly located in the MCA territory [39]. Other researchers have found significantly increased diastolic and mean cerebral blood flow (CBF) velocities in the internal carotid artery contralateral to the cannulation side compared with the pre-ECMO level and in the control group [100]. A similar result is seen in animal experiments, where CBF [38] showed a significant decrease in the hemisphere ipsilateral to the cannulation side. One study [101] reported that neurologic injury in central ECMO patients, including ICH, increased intracranial pressure, and ischemic injury, is detectable just after higher CBF velocity is monitored. In addition, two other asymmetrical distributions of blood flow, significantly higher blood flow velocity in the right rather than left posterior cerebral artery (PCA), and higher systolic flow in the left MCA after ECMO cannulation rather than in the right MCA are reported in support of the fact that hemorrhagic and ischemic injuries tend to, respectively, occur in the left and right hemispheres [95].

3.2.3. Changes in Cerebral Autoregulation

A healthy brain has the ability, known as cerebral autoregulation, to maintain a relatively stable blood flow [102], which may be measured through the cerebral oximetry index (COx). A changing correlation between artery blood pressure (ABP) and cerebral oximetry approaches +1 when pressure autoregulation is lost, and cerebral tissue oxygen saturation becomes passive to changes in ABP. In the presence of intact pressure autoregulation, tissue oxygen saturation is no longer passive to ABP, and COx fluctuates around zero [103]. The impairment of cerebral autoregulation during ECMO has been shown to be correlated with neuroimaging abnormalities [104]. Studies measuring COx in ECMO patients found that ischemic patients had elevated COx values and low ABP associated with impaired autoregulation [24,105]. However, cerebral autoregulation can be altered by several factors such as acid-base status, blood carbon dioxide levels, oxygen saturation, pulsatile flow patterns, and blood pressure [24], some of which may occur before ECMO cannulation.

3.2.4. Changes in Pulse Pressure

Pulse pressure, a dynamic sign of cardiovascular function, is often disturbed in patients receiving VA-ECMO. Specifically, low pulse pressure, defined as <20 mmHg throughout the first 12 h after ECMO initiation, is associated with ABI in patients supported by VA-ECMO [106]. The blood flow in patients supported by VA-ECMO is non-pulsatile, which is inferior to pulsatile perfusion in preserving microcirculation, resulting in collapsed capillaries, activation of inflammation, elevated lactate, and microvascular shunting from decreased hemodynamic energy [107,108]. In addition, increased leukocyte adherence and reduced endothelial-derived nitric oxide from decreased/irregular shear forces [107,109] have been observed. Reduced nitric oxide results in vasoconstriction, neutrophil activation, and expression of cellular adhesion molecules [107]. Other studies have indicated that reduced pulsatility correlates with endothelial cell dysfunction and integrality, presented by increased tight junction biomarkers ZO-1 and Occludin [110], resulting in capillary leakage and vascular permeability breakdown [111]. This kind of dysfunction can be reversed by the restoration of pulsatility [112].

3.3. Mechanisms of ABI Specific to VV-ECMO

There are different mechanisms in the pathophysiology of brain injury between patients receiving VV-ECMO and VA-ECMO. Due to different cannulation methods, the hemodynamic changes are less pronounced in VV-ECMO than in VA-ECMO. Furthermore, a previous study has confirmed that it is the blood flow, not the cannula position, that has a major impact on VV-ECMO efficacy [113]. Moreover, abrupt O2 and CO2 changes at ECMO initiation is specific to VV-ECMO. Because of the ability of cerebral blood flow regulation that CO2 possesses, a sudden change in PaCO2 at ECMO onset would influence the blood flow, which could precipitate brain damage [114], as the ICH and HIBI occurred shortly after ECMO cannulation or during the peri-cannulation period.

3.4. Damage Caused by Underlying Disease

Patients who require ECMO support suffer from critical illness, such as cardiac shock, cardiac arrest, or respiratory failure. Consequently, there is no doubt that these severe disorders can also lead to brain damage. Thus, cerebral lesions diagnosed with during or after ECMO support could precede ECMO, with the ECMO circulation aggravating brain damage.
For example, hypoxia can also be caused by underlying diseases. Normally, almost a third of cardiac output is received by the central nervous system, which means the brain is sensitive to anoxia. As one of the major indications for VA-ECMO, CA itself can also cause brain injury through following steps: a “no-flow period”, which represents the stop of cerebral blood flow right after the onset of CA; a “partial-flow period”, representing the phase when the cerebral blood returns to 25–40% of baseline; and a “reperfusion injury”, resulting from the return of spontaneous circulation [115]. In respiratory failure or ARDS, patients also experienced hypoxia, hypercapnia, and respiratory acidosis, which are involved in the onset of brain injury. Moreover, in patients with ARDS, right ventricular dysfunction occurred in over 20% patients [116]. The cardiac output was severely affected, which caused hemodynamic compromise, resulting systemic malperfusion and multi-organ failure [117].
Apart from hypoxia, other conditions such as inflammation, infection, acidosis, and electrolyte disturbances, are also involved in this process [27].

3.5. Neuromonitoring Based on the Possible Mechanisms

In the presence of ECMO support, traditional neuromonitoring methods are limited. Patients on ECMO with intracranial lesions may not exhibit neurological symptoms prior to diagnosis [118,119]. Moreover, patients with normal CT neuroimaging exhibit a 67% rate of abnormalities [2]. Therefore, it is critical to implement accurate neuromonitoring methods. However, understanding the mechanisms of ECMO-related ABI would be helpful for the early detection and intervention of ABI, which can improve the prognosis.
Several neuromonitoring methods has been tested in studies. For example, transcranial doppler ultrasound (TCD) can detect micro embolic signals (MES) in intracranial arteries [120] and monitor CBF velocity [101]. Continuous electroencephalography (cEEG) continuously monitors brain activity [39]. Near-infrared spectroscopy (NIRS) can be used to monitor brain perfusion, regional cerebral oxygen saturation (rScO2), and hemodynamic stability [121]. Furthermore, brain injury biomarkers, S100B [118], neuron-specific enolase (NSE) [122], GFAP [59], and tau protein [123] are proven to have an elevated level in ECMO patients with intracranial lesions. Notably, the diagnostic accuracy of combined monitoring modalities, such as EEG plus neuroimaging, plasma brain injury biomarkers plus Doppler ultrasound, and cerebral oximetry plus Doppler ultrasound, is higher than that of cEEG, NIRS, TCD, or plasma biomarkers alone [124].

4. Future Perspectives and Development

4.1. Anticoagulants Monitoring

Patients receiving ECMO with bleeding or thrombotic complications are associated with increased morbidity and mortality [125,126]; thus, adequate anticoagulation strategies and monitoring methods are crucial in avoiding these complications. Individualized anticoagulation therapy, the development of extracorporeal circuit materials, and multicenter studies may improve the effectiveness of anticoagulation therapy. Additionally, due to the shortages (which can be affected by other factors, such as high variability, etc.) of APTT and ACT in the monitoring of anticoagulant, novel methods, such as an anti-Xa assay, and the VHA has been used in many clinical laboratories [76]. For example, it is reported that the application of the anti-Xa assay for heparin monitoring in cardiac indicated, neonate [127], and pediatric [128] patients receiving ECMO was associated with a decreased bleeding rate, while another study has reported that patients in the TEG group tended to have fewer bleed complications; moreover, the heparin dosing was lower in the TEG group, and thrombotic complications did not increase compare to the APTT group [129].

4.2. Therapeutic Hypothermia

Therapeutic hypothermia is proven to be associated with improved survival and better neurological outcomes in neonates with moderate-to-severe hypoxic–ischemic encephalopathy [130], and it has been used in ECMO patients to reduce cerebral complications. Researchers claimed that early mild hypothermia exerted a positive effect on neurological outcomes in both children and adult ECMO patients [131,132]. On the other hand, mild hypothermia in neonates treated by ECMO did not improve the outcomes. This opposing outcome may be due to different populations and studies [133].

4.3. Hemoadsorption in ECMO

In the context of critical illness and ECMO support, patients often develop sepsis and a state of hyperinflammation, which are thought to be associated with poor prognosis, including brain damage [134,135]. Therefore, clinical interventions targeting inflammation are required. Hemoadsorption, which can remove cytokines, bilirubin, myoglobin, and certain medications, seems a promising novel therapeutic principle [136]. And it has been confirmed that VA-ECMO-integrated hemoadsorption treatment is associated with accelerated recovery from multiorgan and microcirculatory dysfunction, reduced inflammatory response, fewer hemorrhagic complications, and a lower risk of early mortality [137].

5. Conclusions

In conclusion, this study reviewed the characteristics of different subtypes and possible underlying mechanisms of ECMO-related ABI, including VA- and VV-ECMO, and VA- or VV-ECMO-specific mechanisms. The early detection of ECMO-related ABI is possible using combined neuromonitoring methods.

Author Contributions

Conceptualization: B.D. and J.Y.; writing—original draft preparation, B.D.; writing—review and editing, D.M.; figure preparation, B.D.; supervision, J.Y. and D.M.; funding acquisition, D.M. and J.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Key R&D Program of China (2021YFC2701700, 2021YFC2701704), the National Natural Science Foundation of China (81971433, 82271749, 82201905), and grants from the Science and Technology Bureau of Sichuan Province (2022NSFSC1498) and the Fundamental Research Funds for the Central University (SCU2023D006).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing not applicable. No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Kennedy, J.H. The role of assisted circulation in cardiac resuscitation. JAMA 1966, 197, 615–618. [Google Scholar] [CrossRef] [PubMed]
  2. Khan, I.R.; Gu, Y.; George, B.P.; Malone, L.; Conway, K.S.; Francois, F.; Donlon, J.; Quazi, N.; Reddi, A.; Ho, C.Y.; et al. Brain Histopathology of Adult Decedents After Extracorporeal Membrane Oxygenation. Neurology 2021, 96, e1278–e1289. [Google Scholar] [CrossRef] [PubMed]
  3. Gajkowski, E.F.; Herrera, G.; Hatton, L.; Velia Antonini, M.; Vercaemst, L.; Cooley, E. ELSO Guidelines for Adult and Pediatric Extracorporeal Membrane Oxygenation Circuits. ASAIO J. 2022, 68, 133–152. [Google Scholar] [CrossRef] [PubMed]
  4. Khan, I.R.; Saulle, M.; Oldham, M.A.; Weber, M.T.; Schifitto, G.; Lee, H.B. Cognitive, Psychiatric, and Quality of Life Outcomes in Adult Survivors of Extracorporeal Membrane Oxygenation Therapy: A Scoping Review of the Literature. Crit. Care Med. 2020, 48, e959–e970. [Google Scholar] [CrossRef] [PubMed]
  5. Lorusso, R.; Barili, F.; Mauro, M.D.; Gelsomino, S.; Parise, O.; Rycus, P.T.; Maessen, J.; Mueller, T.; Muellenbach, R.; Belohlavek, J.; et al. In-Hospital Neurologic Complications in Adult Patients Undergoing Venoarterial Extracorporeal Membrane Oxygenation: Results From the Extracorporeal Life Support Organization Registry. Crit. Care Med. 2016, 44, e964–e972. [Google Scholar] [CrossRef]
  6. Cho, S.M.; Canner, J.; Chiarini, G.; Calligy, K.; Caturegli, G.; Rycus, P.; Barbaro, R.P.; Tonna, J.; Lorusso, R.; Kilic, A.; et al. Modifiable Risk Factors and Mortality From Ischemic and Hemorrhagic Strokes in Patients Receiving Venoarterial Extracorporeal Membrane Oxygenation: Results From the Extracorporeal Life Support Organization Registry. Crit. Care Med. 2020, 48, e897–e905. [Google Scholar] [CrossRef]
  7. Rajsic, S.; Treml, B.; Jadzic, D.; Breitkopf, R.; Oberleitner, C.; Popovic Krneta, M.; Bukumiric, Z. Extracorporeal membrane oxygenation for cardiogenic shock: A meta-analysis of mortality and complications. Ann. Intensive Care 2022, 12, 93. [Google Scholar] [CrossRef]
  8. Jeong, S.C.; Kim, H.J.; Shin, Y.S.; Han, J.W.; Lim, J.Y.; Son, H.S. Influence of cannula positioning on brain injury during extracorporeal membrane oxygenation. J. Thorac. Dis. 2018, 10, 6184–6191. [Google Scholar] [CrossRef]
  9. Caturegli, G.; Kapoor, S.; Ponomarev, V.; Kim, B.S.; Whitman, G.J.R.; Ziai, W.; Cho, S.M. Transcranial Doppler microemboli and acute brain injury in extracorporeal membrane oxygenation: A prospective observational study. JTCVS Tech. 2022, 15, 111–122. [Google Scholar] [CrossRef]
  10. Lorusso, R.; Gelsomino, S.; Parise, O.; Di Mauro, M.; Barili, F.; Geskes, G.; Vizzardi, E.; Rycus, P.T.; Muellenbach, R.; Mueller, T.; et al. Neurologic Injury in Adults Supported With Veno-Venous Extracorporeal Membrane Oxygenation for Respiratory Failure: Findings From the Extracorporeal Life Support Organization Database. Crit. Care Med. 2017, 45, 1389–1397. [Google Scholar] [CrossRef] [PubMed]
  11. Rastan, A.J.; Dege, A.; Mohr, M.; Doll, N.; Falk, V.; Walther, T.; Mohr, F.W. Early and late outcomes of 517 consecutive adult patients treated with extracorporeal membrane oxygenation for refractory postcardiotomy cardiogenic shock. J. Thorac. Cardiovasc. Surg. 2010, 139, 302–311.e1. [Google Scholar] [CrossRef] [Green Version]
  12. Makdisi, G.; Wang, I.W. Extra Corporeal Membrane Oxygenation (ECMO) review of a lifesaving technology. J. Thorac. Dis. 2015, 7, E166–E176. [Google Scholar] [CrossRef] [Green Version]
  13. Raets, M.M.; Dudink, J.; Ijsselstijn, H.; van Heijst, A.F.; Lequin, M.H.; Houmes, R.J.; Wildschut, E.D.; Reiss, I.K.; Govaert, P.; Tibboel, D. Brain injury associated with neonatal extracorporeal membrane oxygenation in the Netherlands: A nationwide evaluation spanning two decades. Pediatr. Crit. Care Med. 2013, 14, 884–892. [Google Scholar] [CrossRef]
  14. Cho, S.M.; Geocadin, R.G.; Caturegli, G.; Chan, V.; White, B.; Dodd, O.J.; Kim, B.S.; Sussman, M.; Choi, C.W.; Whitman, G.; et al. Understanding Characteristics of Acute Brain Injury in Adult Extracorporeal Membrane Oxygenation: An Autopsy Study. Crit. Care Med. 2020, 48, e532–e536. [Google Scholar] [CrossRef]
  15. Caturegli, G.; Cho, S.M.; White, B.; Chen, L.L. Acute Brain Injury in Infant Venoarterial Extracorporeal Membrane Oxygenation: An Autopsy Study. Pediatr. Crit. Care Med. 2021, 22, 297–302. [Google Scholar] [CrossRef]
  16. Khan, I.; Rehan, M.; Parikh, G.; Zammit, C.; Badjatia, N.; Herr, D.; Kon, Z.; Hogue, C.; Mazzeffi, M. Regional Cerebral Oximetry as an Indicator of Acute Brain Injury in Adults Undergoing Veno-Arterial Extracorporeal Membrane Oxygenation-A Prospective Pilot Study. Front. Neurol. 2018, 9, 993. [Google Scholar] [CrossRef] [Green Version]
  17. Omar, H.R.; Mirsaeidi, M.; Mangar, D.; Camporesi, E.M. Duration of ECMO Is an Independent Predictor of Intracranial Hemorrhage Occurring During ECMO Support. ASAIO J. 2016, 62, 634–636. [Google Scholar] [CrossRef] [PubMed]
  18. Fletcher-Sandersjöö, A.; Bartek, J., Jr.; Thelin, E.P.; Eriksson, A.; Elmi-Terander, A.; Broman, M.; Bellander, B.M. Predictors of intracranial hemorrhage in adult patients on extracorporeal membrane oxygenation: An observational cohort study. J. Intensive Care 2017, 5, 27. [Google Scholar] [CrossRef]
  19. Lockie, C.J.A.; Gillon, S.A.; Barrett, N.A.; Taylor, D.; Mazumder, A.; Paramesh, K.; Rowland, K.; Daly, K.; Camporota, L.; Meadows, C.I.S.; et al. Severe Respiratory Failure, Extracorporeal Membrane Oxygenation, and Intracranial Hemorrhage. Crit. Care Med. 2017, 45, 1642–1649. [Google Scholar] [CrossRef] [PubMed]
  20. Mazzeffi, M.; Kon, Z.; Menaker, J.; Johnson, D.M.; Parise, O.; Gelsomino, S.; Lorusso, R.; Herr, D. Large Dual-Lumen Extracorporeal Membrane Oxygenation Cannulas Are Associated with More Intracranial Hemorrhage. ASAIO J. 2019, 65, 674–677. [Google Scholar] [CrossRef] [PubMed]
  21. Mazzeffi, M.; Kon, Z.; Sanchez, P.; Herr, D. Impact of acute liver failure on mortality during adult ECLS. Intensive Care Med. 2016, 42, 299–300. [Google Scholar] [CrossRef]
  22. Cho, S.M.; Lee, T.; Starling, R.C.; Thompson, N.R.; Uchino, K. The Impact of Infection and Elevated INR in LVAD-Associated Intracranial Hemorrhage: A Case-Crossover Study. ASAIO J. 2019, 65, 545–549. [Google Scholar] [CrossRef] [PubMed]
  23. Lee, T.; Buletko, A.B.; Matthew, J.; Cho, S.M. Bloodstream infection is associated with subarachnoid hemorrhage and infectious intracranial aneurysm in left ventricular assist device. Perfusion 2020, 35, 117–120. [Google Scholar] [CrossRef] [PubMed]
  24. Tian, F.; Farhat, A.; Morriss, M.C.; Tweed, J.; Li, X.; Huet, B.; Thiagarajan, R.R.; Raman, L. Cerebral Hemodynamic Profile in Ischemic and Hemorrhagic Brain Injury Acquired During Pediatric Extracorporeal Membrane Oxygenation. Pediatr. Crit. Care Med. 2020, 21, 879–885. [Google Scholar] [CrossRef]
  25. Le Guennec, L.; Cholet, C.; Huang, F.; Schmidt, M.; Bréchot, N.; Hékimian, G.; Besset, S.; Lebreton, G.; Nieszkowska, A.; Leprince, P.; et al. Ischemic and hemorrhagic brain injury during venoarterial–extracorporeal membrane oxygenation. Ann. Intensive Care 2018, 8, 129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Shou, B.L.; Ong, C.S.; Zhou, A.L.; Al-Kawaz, M.N.; Etchill, E.; Giuliano, K.; Dong, J.; Bush, E.; Kim, B.S.; Choi, C.W.; et al. Arterial Carbon Dioxide and Acute Brain Injury in Venoarterial Extracorporeal Membrane Oxygenation. ASAIO J. 2022, 68, 1501. [Google Scholar] [CrossRef]
  27. Luyt, C.E.; Bréchot, N.; Demondion, P.; Jovanovic, T.; Hékimian, G.; Lebreton, G.; Nieszkowska, A.; Schmidt, M.; Trouillet, J.L.; Leprince, P.; et al. Brain injury during venovenous extracorporeal membrane oxygenation. Intensive Care Med. 2016, 42, 897–907. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Nasr, D.M.; Rabinstein, A.A. Neurologic Complications of Extracorporeal Membrane Oxygenation. J. Clin. Neurol. 2015, 11, 383–389. [Google Scholar] [CrossRef] [Green Version]
  29. Rajsic, S.; Breitkopf, R.; Treml, B.; Jadzic, D.; Oberleitner, C.; Oezpeker, U.C.; Innerhofer, N.; Bukumiric, Z. Association of aPTT-Guided Anticoagulation Monitoring with Thromboembolic Events in Patients Receiving V-A ECMO Support: A Systematic Review and Meta-Analysis. J. Clin. Med. 2023, 12, 3224. [Google Scholar] [CrossRef]
  30. He, Y.; Ying, J.; Tang, J.; Zhou, R.; Qu, H.; Qu, Y.; Mu, D. Neonatal Arterial Ischaemic Stroke: Advances in Pathologic Neural Death, Diagnosis, Treatment, and Prognosis. Curr. Neuropharmacol. 2022, 20, 2248–2266. [Google Scholar] [CrossRef]
  31. Lee, K.J.; Jung, K.H.; Byun, J.I.; Kim, J.M.; Roh, J.K. Infarct pattern and clinical outcome in acute ischemic stroke following middle cerebral artery occlusion. Cerebrovasc. Dis. 2014, 38, 31–38. [Google Scholar] [CrossRef]
  32. Clair, M.P.; Rambaud, J.; Flahault, A.; Guedj, R.; Guilbert, J.; Guellec, I.; Durandy, A.; Demoulin, M.; Jean, S.; Mitanchez, D.; et al. Prognostic value of cerebral tissue oxygen saturation during neonatal extracorporeal membrane oxygenation. PLoS ONE 2017, 12, e0172991. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Cho, S.M.; Farrokh, S.; Whitman, G.; Bleck, T.P.; Geocadin, R.G. Neurocritical Care for Extracorporeal Membrane Oxygenation Patients. Crit. Care Med. 2019, 47, 1773–1781. [Google Scholar] [CrossRef] [PubMed]
  34. de Waha, S.; Schoene, K.; Fuernau, G.; Desch, S.; Eitel, I.; Pöss, J.; Meyer-Saraei, R.; Eitel, C.; Tilz, R.; Schuler, G.; et al. Prognostic impact of atrial fibrillation in cardiogenic shock complicating acute myocardial infarction: A substudy of the IABP-SHOCK II trial. Clin. Res. Cardiol. 2018, 107, 233–240. [Google Scholar] [CrossRef] [PubMed]
  35. Omar, H.R.; Mirsaeidi, M.; Socias, S.; Sprenker, C.; Caldeira, C.; Camporesi, E.M.; Mangar, D. Plasma Free Hemoglobin Is an Independent Predictor of Mortality among Patients on Extracorporeal Membrane Oxygenation Support. PLoS ONE 2015, 10, e0124034. [Google Scholar] [CrossRef]
  36. Chiarini, G.; Cho, S.M.; Whitman, G.; Rasulo, F.; Lorusso, R. Brain Injury in Extracorporeal Membrane Oxygenation: A Multidisciplinary Approach. Semin. Neurol. 2021, 41, 422–436. [Google Scholar] [CrossRef]
  37. Johnson, T.P.; Nath, A. Neurological syndromes driven by postinfectious processes or unrecognized persistent infections. Curr. Opin. Neurol. 2018, 31, 318–324. [Google Scholar] [CrossRef]
  38. Slinko, S.; Caspersen, C.; Ratner, V.; Kim, J.J.; Alexandrov, P.; Polin, R.; Ten, V.S. Systemic hyperthermia induces ischemic brain injury in neonatal mice with ligated carotid artery and jugular vein. Pediatr. Res. 2007, 62, 65–70. [Google Scholar] [CrossRef] [Green Version]
  39. Sansevere, A.J.; DiBacco, M.L.; Akhondi-Asl, A.; LaRovere, K.; Loddenkemper, T.; Rivkin, M.J.; Thiagarajan, R.R.; Pearl, P.L.; Libenson, M.H.; Tasker, R.C. EEG features of brain injury during extracorporeal membrane oxygenation in children. Neurology 2020, 95, e1372–e1380. [Google Scholar] [CrossRef]
  40. Lorusso, R.; Belliato, M.; Mazzeffi, M.; Di Mauro, M.; Taccone, F.S.; Parise, O.; Albanawi, A.; Nandwani, V.; McCarthy, P.; Kon, Z.; et al. Neurological complications during veno-venous extracorporeal membrane oxygenation: Does the configuration matter? A retrospective analysis of the ELSO database. Crit. Care 2021, 25, 107. [Google Scholar] [CrossRef]
  41. Abend, N.S.; Arndt, D.H.; Carpenter, J.L.; Chapman, K.E.; Cornett, K.M.; Gallentine, W.B.; Giza, C.C.; Goldstein, J.L.; Hahn, C.D.; Lerner, J.T.; et al. Electrographic seizures in pediatric ICU patients: Cohort study of risk factors and mortality. Neurology 2013, 81, 383–391. [Google Scholar] [CrossRef] [PubMed]
  42. Payne, E.T.; Zhao, X.Y.; Frndova, H.; McBain, K.; Sharma, R.; Hutchison, J.S.; Hahn, C.D. Seizure burden is independently associated with short term outcome in critically ill children. Brain 2014, 137, 1429–1438. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Cho, S.M.; Ziai, W.; Mayasi, Y.; Gusdon, A.M.; Creed, J.; Sharrock, M.; Stephens, R.S.; Choi, C.W.; Ritzl, E.K.; Suarez, J.; et al. Noninvasive Neurological Monitoring in Extracorporeal Membrane Oxygenation. ASAIO J. 2020, 66, 388–393. [Google Scholar] [CrossRef]
  44. Lin, J.J.; Banwell, B.L.; Berg, R.A.; Dlugos, D.J.; Ichord, R.N.; Kilbaugh, T.J.; Kirsch, R.E.; Kirschen, M.P.; Licht, D.J.; Massey, S.L.; et al. Electrographic Seizures in Children and Neonates Undergoing Extracorporeal Membrane Oxygenation. Pediatr. Crit. Care Med. 2017, 18, 249–257. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Piantino, J.A.; Wainwright, M.S.; Grimason, M.; Smith, C.M.; Hussain, E.; Byron, D.; Chin, A.; Backer, C.; Reynolds, M.; Goldstein, J. Nonconvulsive seizures are common in children treated with extracorporeal cardiac life support. Pediatr. Crit. Care Med. 2013, 14, 601–609. [Google Scholar] [CrossRef] [PubMed]
  46. Illum, B.; Odish, M.; Minokadeh, A.; Yi, C.; Owens, R.L.; Pollema, T.; LaBuzetta, J.N. Evaluation, Treatment, and Impact of Neurologic Injury in Adult Patients on Extracorporeal Membrane Oxygenation: A Review. Curr. Treat. Options Neurol. 2021, 23, 15. [Google Scholar] [CrossRef] [PubMed]
  47. Bauer Huang, S.L.; Said, A.S.; Smyser, C.D.; Lin, J.C.; Guilliams, K.P.; Guerriero, R.M. Seizures Are Associated With Brain Injury in Infants Undergoing Extracorporeal Membrane Oxygenation. J. Child. Neurol. 2021, 36, 230–236. [Google Scholar] [CrossRef]
  48. Cook, R.J.; Rau, S.M.; Lester-Pelham, S.G.; Vesper, T.; Peterson, Y.; Adamowski, T.; Sturza, J.; Silverstein, F.S.; Shellhaas, R.A. Electrographic Seizures and Brain Injury in Children Requiring Extracorporeal Membrane Oxygenation. Pediatr. Neurol. 2020, 108, 77–85. [Google Scholar] [CrossRef]
  49. Sinnah, F.; Dalloz, M.A.; Magalhaes, E.; Wanono, R.; Neuville, M.; Smonig, R.; Radjou, A.; Mourvillier, B.; Bouadma, L.; Timsit, J.F.; et al. Early Electroencephalography Findings in Cardiogenic Shock Patients Treated by Venoarterial Extracorporeal Membrane Oxygenation. Crit. Care Med. 2018, 46, e389–e394. [Google Scholar] [CrossRef]
  50. Patel, A.K.; Biagas, K.V.; Clark, E.C.; Traube, C. Delirium in the Pediatric Cardiac Extracorporeal Membrane Oxygenation Patient Population: A Case Series. Pediatr. Crit. Care Med. 2017, 18, e621–e624. [Google Scholar] [CrossRef]
  51. Pinho, J.; Amorim, J.M.; Araújo, J.M.; Vilaça, H.; Ribeiro, M.; Pereira, J.; Ferreira, C. Cerebral gas embolism associated with central venous catheter: Systematic review. J. Neurol. Sci. 2016, 362, 160–164. [Google Scholar] [CrossRef] [PubMed]
  52. Yuliati, A.; Federman, M.; Rao, L.M.; Chen, L.; Sim, M.S.; Matsumoto, J.H. Prevalence of Seizures and Risk Factors for Mortality in a Continuous Cohort of Pediatric Extracorporeal Membrane Oxygenation Patients. Pediatr. Crit. Care Med. 2020, 21, 949–958. [Google Scholar] [CrossRef] [PubMed]
  53. Shoskes, A.; Migdady, I.; Rice, C.; Hassett, C.; Deshpande, A.; Price, C.; Hernandez, A.V.; Cho, S.M. Brain Injury Is More Common in Venoarterial Extracorporeal Membrane Oxygenation Than Venovenous Extracorporeal Membrane Oxygenation: A Systematic Review and Meta-Analysis. Crit. Care Med. 2020, 48, 1799–1808. [Google Scholar] [CrossRef] [PubMed]
  54. Mateen, F.J.; Muralidharan, R.; Shinohara, R.T.; Parisi, J.E.; Schears, G.J.; Wijdicks, E.F. Neurological injury in adults treated with extracorporeal membrane oxygenation. Arch. Neurol. 2011, 68, 1543–1549. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Haines, N.M.; Rycus, P.T.; Zwischenberger, J.B.; Bartlett, R.H.; Undar, A. Extracorporeal Life Support Registry Report 2008: Neonatal and pediatric cardiac cases. ASAIO J. 2009, 55, 111–116. [Google Scholar] [CrossRef]
  56. Russell, J.A.; Epstein, L.G.; Greer, D.M.; Kirschen, M.; Rubin, M.A.; Lewis, A. Brain death, the determination of brain death, and member guidance for brain death accommodation requests: AAN position statement. Neurology 2019, 92, 228–232. [Google Scholar] [CrossRef] [Green Version]
  57. Bein, T.; Müller, T.; Citerio, G. Determination of brain death under extracorporeal life support. Intensive Care Med. 2019, 45, 364–366. [Google Scholar] [CrossRef]
  58. Thomas, E.O.; Manara, A.; Dineen, R.A.; Mortimer, A.; Aziz, O.; Dean, P.; Elliott, P.; Summers, D.M.; Whitfield, P.C.; Hutchinson, P.J.; et al. The use of cerebral computed tomographic angiography as an ancillary investigation to support a clinical diagnosis of death using neurological criteria: A consensus guideline. Anaesthesia 2023, 78, 330–336. [Google Scholar] [CrossRef]
  59. Bembea, M.M.; Savage, W.; Strouse, J.J.; Schwartz, J.M.; Graham, E.; Thompson, C.B.; Everett, A. Glial fibrillary acidic protein as a brain injury biomarker in children undergoing extracorporeal membrane oxygenation. Pediatr. Crit. Care Med. 2011, 12, 572–579. [Google Scholar] [CrossRef]
  60. Lie, S.A.; Hwang, N.C. Challenges of Brain Death and Apnea Testing in Adult Patients on Extracorporeal Membrane Oxygenation-A Review. J. Cardiothorac. Vasc. Anesth. 2019, 33, 2266–2272. [Google Scholar] [CrossRef]
  61. Rajsic, S.; Breitkopf, R.; Oezpeker, U.C.; Bukumirić, Z.; Dobesberger, M.; Treml, B. The Role of Excessive Anticoagulation and Missing Hyperinflammation in ECMO-Associated Bleeding. J. Clin. Med. 2022, 11, 2314. [Google Scholar] [CrossRef]
  62. Datzmann, T.; Träger, K. Extracorporeal membrane oxygenation and cytokine adsorption. J. Thorac. Dis. 2018, 10, S653–S660. [Google Scholar] [CrossRef]
  63. Wendel, H.P.; Scheule, A.M.; Eckstein, F.S.; Ziemer, G. Haemocompatibility of paediatric membrane oxygenators with heparin-coated surfaces. Perfusion 1999, 14, 21–28. [Google Scholar] [CrossRef] [PubMed]
  64. Millar, J.E.; Fanning, J.P.; McDonald, C.I.; McAuley, D.F.; Fraser, J.F. The inflammatory response to extracorporeal membrane oxygenation (ECMO): A review of the pathophysiology. Crit. Care 2016, 20, 387. [Google Scholar] [CrossRef] [Green Version]
  65. Rajsic, S.; Breitkopf, R.; Jadzic, D.; Popovic Krneta, M.; Tauber, H.; Treml, B. Anticoagulation Strategies during Extracorporeal Membrane Oxygenation: A Narrative Review. J. Clin. Med. 2022, 11, 5147. [Google Scholar] [CrossRef]
  66. Esper, S.A.; Welsby, I.J.; Subramaniam, K.; John Wallisch, W.; Levy, J.H.; Waters, J.H.; Triulzi, D.J.; Hayanga, J.W.A.; Schears, G.J. Adult extracorporeal membrane oxygenation: An international survey of transfusion and anticoagulation techniques. Vox Sang. 2017, 112, 443–452. [Google Scholar] [CrossRef] [PubMed]
  67. Levi, M.; Hunt, B.J. A critical appraisal of point-of-care coagulation testing in critically ill patients. J. Thromb. Haemost. 2015, 13, 1960–1967. [Google Scholar] [CrossRef] [PubMed]
  68. Rajsic, S.; Treml, B.; Jadzic, D.; Breitkopf, R.; Oberleitner, C.; Bachler, M.; Bösch, J.; Bukumiric, Z. aPTT-guided anticoagulation monitoring during ECMO support: A systematic review and meta-analysis. J. Crit. Care 2023, 77, 154332. [Google Scholar] [CrossRef]
  69. Malfertheiner, M.V.; Philipp, A.; Lubnow, M.; Zeman, F.; Enger, T.B.; Bein, T.; Lunz, D.; Schmid, C.; Müller, T.; Lehle, K. Hemostatic Changes During Extracorporeal Membrane Oxygenation: A Prospective Randomized Clinical Trial Comparing Three Different Extracorporeal Membrane Oxygenation Systems. Crit. Care Med. 2016, 44, 747–754. [Google Scholar] [CrossRef] [PubMed]
  70. Atchison, C.; Widdershins, A.; Chandler, W.L. Causes of platelet loss during extracorporeal life support. Artif. Organs 2023, 47, 160–167. [Google Scholar] [CrossRef]
  71. Cheung, P.Y.; Sawicki, G.; Salas, E.; Etches, P.C.; Schulz, R.; Radomski, M.W. The mechanisms of platelet dysfunction during extracorporeal membrane oxygenation in critically ill neonates. Crit. Care Med. 2000, 28, 2584–2590. [Google Scholar] [CrossRef]
  72. Fisser, C.; Reichenbächer, C.; Müller, T.; Schneckenpointner, R.; Malfertheiner, M.V.; Philipp, A.; Foltan, M.; Lunz, D.; Zeman, F.; Lubnow, M. Incidence and Risk Factors for Cannula-Related Venous Thrombosis After Venovenous Extracorporeal Membrane Oxygenation in Adult Patients With Acute Respiratory Failure. Crit. Care Med. 2019, 47, e332–e339. [Google Scholar] [CrossRef] [PubMed]
  73. Figueroa Villalba, C.A.; McMullan, D.M.; Reed, R.C.; Chandler, W.L. Thrombosis in Extracorporeal Membrane Oxygenation (ECMO) Circuits. ASAIO J. 2022, 68, 1083–1092. [Google Scholar] [CrossRef] [PubMed]
  74. Levy, J.H.; Staudinger, T.; Steiner, M.E. How to manage anticoagulation during extracorporeal membrane oxygenation. Intensive Care Med. 2022, 48, 1076–1079. [Google Scholar] [CrossRef] [PubMed]
  75. Abruzzo, A.; Gorantla, V.; Thomas, S.E. Venous thromboembolic events in the setting of extracorporeal membrane oxygenation support in adults: A systematic review. Thromb. Res. 2022, 212, 58–71. [Google Scholar] [CrossRef]
  76. McMichael, A.B.V.; Ryerson, L.M.; Ratano, D.; Fan, E.; Faraoni, D.; Annich, G.M. 2021 ELSO Adult and Pediatric Anticoagulation Guidelines. ASAIO J. 2022, 68, 303–310. [Google Scholar] [CrossRef]
  77. Henderson, N.; Sullivan, J.E.; Myers, J.; Wells, T.; Calhoun, A.; Berkenbosch, J.; Tzanetos, D.T. Use of Thromboelastography to Predict Thrombotic Complications in Pediatric and Neonatal Extracorporeal Membranous Oxygenation. J. Extra Corpor. Technol. 2018, 50, 149–154. [Google Scholar] [CrossRef]
  78. Cartwright, B.; Bruce, H.M.; Kershaw, G.; Cai, N.; Othman, J.; Gattas, D.; Robson, J.L.; Hayes, S.; Alicajic, H.; Hines, A.; et al. Hemostasis, coagulation and thrombin in venoarterial and venovenous extracorporeal membrane oxygenation: The HECTIC study. Sci. Rep. 2021, 11, 7975. [Google Scholar] [CrossRef]
  79. Ortega, S.B.; Pandiyan, P.; Windsor, J.; Torres, V.O.; Selvaraj, U.M.; Lee, A.; Morriss, M.; Tian, F.; Raman, L.; Stowe, A.M. A Pilot Study Identifying Brain-Targeting Adaptive Immunity in Pediatric Extracorporeal Membrane Oxygenation Patients With Acquired Brain Injury. Crit. Care Med. 2019, 47, e206–e213. [Google Scholar] [CrossRef]
  80. Nilsson, B.; Ekdahl, K.N.; Mollnes, T.E.; Lambris, J.D. The role of complement in biomaterial-induced inflammation. Mol. Immunol. 2007, 44, 82–94. [Google Scholar] [CrossRef]
  81. Dunkelberger, J.R.; Song, W.C. Complement and its role in innate and adaptive immune responses. Cell Res. 2010, 20, 34–50. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Graulich, J.; Walzog, B.; Marcinkowski, M.; Bauer, K.; Kössel, H.; Fuhrmann, G.; Bührer, C.; Gaehtgens, P.; Versmold, H.T. Leukocyte and endothelial activation in a laboratory model of extracorporeal membrane oxygenation (ECMO). Pediatr. Res. 2000, 48, 679–684. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Mc, I.R.B.; Timpa, J.G.; Kurundkar, A.R.; Holt, D.W.; Kelly, D.R.; Hartman, Y.E.; Neel, M.L.; Karnatak, R.K.; Schelonka, R.L.; Anantharamaiah, G.M.; et al. Plasma concentrations of inflammatory cytokines rise rapidly during ECMO-related SIRS due to the release of preformed stores in the intestine. Lab. Investig. 2010, 90, 128–139. [Google Scholar] [CrossRef] [Green Version]
  84. Ricklin, D.; Lambris, J.D. Complement in immune and inflammatory disorders: Pathophysiological mechanisms. J. Immunol. 2013, 190, 3831–3838. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. DePuydt, L.E.; Schuit, K.E.; Smith, S.D. Effect of extracorporeal membrane oxygenation on neutrophil function in neonates. Crit. Care Med. 1993, 21, 1324–1327. [Google Scholar] [CrossRef] [PubMed]
  86. Fortenberry, J.D.; Bhardwaj, V.; Niemer, P.; Cornish, J.D.; Wright, J.A.; Bland, L. Neutrophil and cytokine activation with neonatal extracorporeal membrane oxygenation. J. Pediatr. 1996, 128, 670–678. [Google Scholar] [CrossRef]
  87. Gerszten, R.E.; Garcia-Zepeda, E.A.; Lim, Y.C.; Yoshida, M.; Ding, H.A.; Gimbrone, M.A., Jr.; Luster, A.D.; Luscinskas, F.W.; Rosenzweig, A. MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 1999, 398, 718–723. [Google Scholar] [CrossRef]
  88. Shi, J.; Chen, Q.; Yu, W.; Shen, J.; Gong, J.; He, C.; Hu, Y.; Zhang, J.; Gao, T.; Xi, F.; et al. Continuous renal replacement therapy reduces the systemic and pulmonary inflammation induced by venovenous extracorporeal membrane oxygenation in a porcine model. Artif. Organs 2014, 38, 215–223. [Google Scholar] [CrossRef]
  89. Risnes, I.; Wagner, K.; Ueland, T.; Mollnes, T.; Aukrust, P.; Svennevig, J. Interleukin-6 may predict survival in extracorporeal membrane oxygenation treatment. Perfusion 2008, 23, 173–178. [Google Scholar] [CrossRef]
  90. Frerou, A.; Lesouhaitier, M.; Gregoire, M.; Uhel, F.; Gacouin, A.; Reizine, F.; Moreau, C.; Loirat, A.; Maamar, A.; Nesseler, N.; et al. Venoarterial extracorporeal membrane oxygenation induces early immune alterations. Crit. Care 2021, 25, 9. [Google Scholar] [CrossRef]
  91. Spaan, A.N.; Surewaard, B.G.; Nijland, R.; van Strijp, J.A. Neutrophils versus Staphylococcus aureus: A biological tug of war. Annu. Rev. Microbiol. 2013, 67, 629–650. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Uhel, F.; Azzaoui, I.; Grégoire, M.; Pangault, C.; Dulong, J.; Tadié, J.M.; Gacouin, A.; Camus, C.; Cynober, L.; Fest, T.; et al. Early Expansion of Circulating Granulocytic Myeloid-derived Suppressor Cells Predicts Development of Nosocomial Infections in Patients with Sepsis. Am. J. Respir. Crit. Care Med. 2017, 196, 315–327. [Google Scholar] [CrossRef] [PubMed]
  93. Siegel, P.M.; Orlean, L.; Bojti, I.; Kaier, K.; Witsch, T.; Esser, J.S.; Trummer, G.; Moser, M.; Peter, K.; Bode, C.; et al. Monocyte Dysfunction Detected by the Designed Ankyrin Repeat Protein F7 Predicts Mortality in Patients Receiving Veno-Arterial Extracorporeal Membrane Oxygenation. Front. Cardiovasc. Med. 2021, 8, 689218. [Google Scholar] [CrossRef] [PubMed]
  94. Combes, A.; Brodie, D.; Chen, Y.S.; Fan, E.; Henriques, J.P.S.; Hodgson, C.; Lepper, P.M.; Leprince, P.; Maekawa, K.; Muller, T.; et al. The ICM research agenda on extracorporeal life support. Intensive Care Med. 2017, 43, 1306–1318. [Google Scholar] [CrossRef]
  95. Yu, S.H.; Mao, D.H.; Ju, R.; Fu, Y.Y.; Zhang, L.B.; Yue, G. ECMO in neonates: The association between cerebral hemodynamics with neurological function. Front. Pediatr. 2022, 10, 908861. [Google Scholar] [CrossRef]
  96. Alwardt, C.M.; Patel, B.M.; Lowell, A.; Dobberpuhl, J.; Riley, J.B.; DeValeria, P.A. Regional perfusion during venoarterial extracorporeal membrane oxygenation: A case report and educational modules on the concept of dual circulations. J. Extra Corpor. Technol. 2013, 45, 187–194. [Google Scholar] [CrossRef]
  97. Cove, M.E. Disrupting differential hypoxia in peripheral veno-arterial extracorporeal membrane oxygenation. Crit. Care 2015, 19, 280. [Google Scholar] [CrossRef] [Green Version]
  98. Stevens, M.C.; Callaghan, F.M.; Forrest, P.; Bannon, P.G.; Grieve, S.M. Flow mixing during peripheral veno-arterial extra corporeal membrane oxygenation—A simulation study. J. Biomech. 2017, 55, 64–70. [Google Scholar] [CrossRef]
  99. Nezami, F.R.; Khodaee, F.; Edelman, E.R.; Keller, S.P. A Computational Fluid Dynamics Study of the Extracorporeal Membrane Oxygenation-Failing Heart Circulation. ASAIO J. 2021, 67, 276–283. [Google Scholar] [CrossRef]
  100. Lohrer, R.M.; Bejar, R.F.; Simko, A.J.; Moulton, S.L.; Cornish, J.D. Internal carotid artery blood flow velocities before, during, and after extracorporeal membrane oxygenation. Am. J. Dis. Child. 1992, 146, 201–207. [Google Scholar] [CrossRef]
  101. O’Brien, N.F.; Hall, M.W. Extracorporeal membrane oxygenation and cerebral blood flow velocity in children. Pediatr. Crit. Care Med. 2013, 14, e126–e134. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Paulson, O.B.; Strandgaard, S.; Edvinsson, L. Cerebral autoregulation. Cerebrovasc. Brain Metab. Rev. 1990, 2, 161–192. [Google Scholar] [PubMed]
  103. Brady, K.M.; Mytar, J.O.; Lee, J.K.; Cameron, D.E.; Vricella, L.A.; Thompson, W.R.; Hogue, C.W.; Easley, R.B. Monitoring cerebral blood flow pressure autoregulation in pediatric patients during cardiac surgery. Stroke 2010, 41, 1957–1962. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Tian, F.; Morriss, M.C.; Chalak, L.; Venkataraman, R.; Ahn, C.; Liu, H.; Raman, L. Impairment of cerebral autoregulation in pediatric extracorporeal membrane oxygenation associated with neuroimaging abnormalities. Neurophotonics 2017, 4, 041410. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Gilmore, M.M.; Stone, B.S.; Shepard, J.A.; Czosnyka, M.; Easley, R.B.; Brady, K.M. Relationship between cerebrovascular dysautoregulation and arterial blood pressure in the premature infant. J. Perinatol. 2011, 31, 722–729. [Google Scholar] [CrossRef] [Green Version]
  106. Shou, B.L.; Wilcox, C.; Florissi, I.; Kalra, A.; Caturegli, G.; Zhang, L.Q.; Bush, E.; Kim, B.; Keller, S.P.; Whitman, G.J.R.; et al. Early Low Pulse Pressure in VA–eCMO Is Associated with Acute Brain Injury. Neurocrit. Care 2022, 38, 612–621. [Google Scholar] [CrossRef]
  107. O’Neil, M.P.; Fleming, J.C.; Badhwar, A.; Guo, L.R. Pulsatile versus nonpulsatile flow during cardiopulmonary bypass: Microcirculatory and systemic effects. Ann. Thorac. Surg. 2012, 94, 2046–2053. [Google Scholar] [CrossRef]
  108. Wang, S.; Force, M.; Moroi, M.K.; Patel, S.; Kunselman, A.R.; Ündar, A. Effects of Pulsatile Control Algorithms for Diagonal Pump on Hemodynamic Performance and Hemolysis. Artif. Organs 2019, 43, 60–75. [Google Scholar] [CrossRef]
  109. Chiu, J.J.; Chien, S. Effects of disturbed flow on vascular endothelium: Pathophysiological basis and clinical perspectives. Physiol. Rev. 2011, 91, 327–387. [Google Scholar] [CrossRef] [Green Version]
  110. Li, G.; Zhu, S.; Zeng, J.; Yu, Z.; Meng, F.; Tang, Z.; Zhu, P. Arterial Pulsatility Augments Microcirculatory Perfusion and Maintains the Endothelial Integrity during Extracorporeal Membrane Oxygenation via hsa_circ_0007367 Upregulation in a Canine Model with Cardiac Arrest. Oxid. Med. Cell Longev. 2022, 2022, 1630918. [Google Scholar] [CrossRef]
  111. Wollborn, J.; Siemering, S.; Steiger, C.; Buerkle, H.; Goebel, U.; Schick, M.A. Phosphodiesterase-4 inhibition reduces ECLS-induced vascular permeability and improves microcirculation in a rodent model of extracorporeal resuscitation. Am. J. Physiol. Heart Circ. Physiol. 2019, 316, H751–H761. [Google Scholar] [CrossRef] [PubMed]
  112. Purohit, S.N.; Cornwell, W.K., 3rd; Pal, J.D.; Lindenfeld, J.; Ambardekar, A.V. Living Without a Pulse: The Vascular Implications of Continuous-Flow Left Ventricular Assist Devices. Circ. Heart Fail. 2018, 11, e004670. [Google Scholar] [CrossRef] [PubMed]
  113. Leoni, M.; Szasz, J.; Meier, J.; Gerardo-Giorda, L. Blood flow but not cannula positioning influences the efficacy of Veno-Venous ECMO therapy. Sci. Rep. 2022, 12, 20950. [Google Scholar] [CrossRef]
  114. Cavayas, Y.A.; Munshi, L.; Del Sorbo, L.; Fan, E. The Early Change in PaCO2 after Extracorporeal Membrane Oxygenation Initiation Is Associated with Neurological Complications. Am. J. Respir. Crit. Care Med. 2020, 201, 1525–1535. [Google Scholar] [CrossRef]
  115. Tahsili-Fahadan, P.; Farrokh, S.; Geocadin, R.G. Hypothermia and brain inflammation after cardiac arrest. Brain Circ. 2018, 4, 1–13. [Google Scholar] [CrossRef]
  116. Levy, D.; Desnos, C.; Lebreton, G.; Théry, G.; Pineton de Chambrun, M.; Leprince, P.; Hammoudi, N.; Schmidt, M.; Combes, A.; Hékimian, G. Early Reversal of Right Ventricular Dysfunction after Venovenous Extracorporeal Membrane Oxygenation in Patients with COVID-19 Pneumonia. Am. J. Respir. Crit. Care Med. 2023, 207, 784–787. [Google Scholar] [CrossRef]
  117. Rao, P.; Ali, H.; Hypes, C.; Natt, B.; Kazui, T.; Khalpey, Z.; Cairns, C.; Mosier, J. Right Ventricular Dysfunction in Acute Respiratory Distress Syndrome. Crit. Care Med. 2018, 46, 67. [Google Scholar] [CrossRef]
  118. Fletcher-Sandersjöö, A.; Lindblad, C.; Thelin, E.P.; Bartek, J., Jr.; Sallisalmi, M.; Elmi-Terander, A.; Svensson, M.; Bellander, B.M.; Broman, L.M. Serial S100B Sampling Detects Intracranial Lesion Development in Patients on Extracorporeal Membrane Oxygenation. Front. Neurol. 2019, 10, 512. [Google Scholar] [CrossRef] [Green Version]
  119. Lidegran, M.K.; Mosskin, M.; Ringertz, H.G.; Frenckner, B.P.; Lindén, V.B. Cranial CT for diagnosis of intracranial complications in adult and pediatric patients during ECMO: Clinical benefits in diagnosis and treatment. Acad. Radiol. 2007, 14, 62–71. [Google Scholar] [CrossRef]
  120. Marinoni, M.; Migliaccio, M.L.; Trapani, S.; Bonizzoli, M.; Gucci, L.; Cianchi, G.; Gallerini, A.; Tadini Buoninsegni, L.; Cramaro, A.; Valente, S.; et al. Cerebral microemboli detected by transcranial doppler in patients treated with extracorporeal membrane oxygenation. Acta Anaesthesiol. Scand. 2016, 60, 934–944. [Google Scholar] [CrossRef] [PubMed]
  121. Zhang, M.; Yang, Y.; Chen, X.; Song, Y.; Zhu, L.; Gong, X.; Zhang, H.; Xu, Z. Application of Near-Infrared Spectroscopy to Monitor Perfusion During Extracorporeal Membrane Oxygenation After Pediatric Heart Surgery. Front. Med. 2021, 8, 762731. [Google Scholar] [CrossRef] [PubMed]
  122. Reuter, J.; Peoc’h, K.; Bouadma, L.; Ruckly, S.; Chicha-Cattoir, V.; Faille, D.; Bourrienne, M.C.; Dupuis, C.; Magalhaes, E.; Tanaka, S.; et al. Neuron-Specific Enolase Levels in Adults Under Venoarterial Extracorporeal Membrane Oxygenation. Crit. Care Explor. 2020, 2, e0239. [Google Scholar] [CrossRef] [PubMed]
  123. Lee, A.E.; Pandiyan, P.; Liu, M.M.; Williams, M.A.; Everett, A.D.; Mueller, G.P.; Morriss, M.C.; Raman, L.; Carlson, D.; Gatson, J.W. Tau Is Elevated in Pediatric Patients on Extracorporeal Membrane Oxygenation. ASAIO J. 2020, 66, 91–96. [Google Scholar] [CrossRef]
  124. Bembea, M.M.; Felling, R.; Anton, B.; Salorio, C.F.; Johnston, M.V. Neuromonitoring During Extracorporeal Membrane Oxygenation: A Systematic Review of the Literature. Pediatr. Crit. Care Med. 2015, 16, 558–564. [Google Scholar] [CrossRef]
  125. Werho, D.K.; Pasquali, S.K.; Yu, S.; Donohue, J.; Annich, G.M.; Thiagarajan, R.R.; Hirsch-Romano, J.C.; Gaies, M.G. Hemorrhagic complications in pediatric cardiac patients on extracorporeal membrane oxygenation: An analysis of the Extracorporeal Life Support Organization Registry. Pediatr. Crit. Care Med. 2015, 16, 276–288. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Dalton, H.J.; Garcia-Filion, P.; Holubkov, R.; Moler, F.W.; Shanley, T.; Heidemann, S.; Meert, K.; Berg, R.A.; Berger, J.; Carcillo, J.; et al. Association of bleeding and thrombosis with outcome in extracorporeal life support. Pediatr. Crit. Care Med. 2015, 16, 167–174. [Google Scholar] [CrossRef]
  127. Meshulami, N.; Green, R.; Kaushik, S. Anti-Xa testing for pediatric and neonatal patients on extracorporeal membrane oxygenation. Perfusion 2023. ahead of print. [Google Scholar] [CrossRef]
  128. Figueroa Villalba, C.A.; Brogan, T.V.; McMullan, D.M.; Yalon, L.; Jordan, D.I.; Chandler, W.L. Conversion From Activated Clotting Time to Anti-Xa Heparin Activity Assay for Heparin Monitoring During Extracorporeal Membrane Oxygenation. Crit. Care Med. 2020, 48, e1179–e1184. [Google Scholar] [CrossRef]
  129. Panigada, M.; E Iapichino, G.; Brioni, M.; Panarello, G.; Protti, A.; Grasselli, G.; Occhipinti, G.; Novembrino, C.; Consonni, D.; Arcadipane, A.; et al. Thromboelastography-based anticoagulation management during extracorporeal membrane oxygenation: A safety and feasibility pilot study. Ann. Intensive Care 2018, 8, 7. [Google Scholar] [CrossRef] [Green Version]
  130. Tagin, M.A.; Woolcott, C.G.; Vincer, M.J.; Whyte, R.K.; Stinson, D.A. Hypothermia for neonatal hypoxic ischemic encephalopathy: An updated systematic review and meta-analysis. Arch. Pediatr. Adolesc. Med. 2012, 166, 558–566. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  131. Lou, S.; MacLaren, G.; Clark, J.; Paul, E.; Best, D.; Delzoppo, C.; d’Udekem, Y.; Butt, W. Safety of therapeutic hypothermia in children on veno-arterial extracorporeal membrane oxygenation after cardiac surgery. Cardiol. Young 2015, 25, 1367–1373. [Google Scholar] [CrossRef] [PubMed]
  132. Al-Kawaz, M.; Shou, B.; Prokupets, R.; Whitman, G.; Geocadin, R.; Cho, S.M. Mild hypothermia and neurologic outcomes in patients undergoing venoarterial extracorporeal membrane oxygenation. J. Card. Surg. 2022, 37, 825–830. [Google Scholar] [CrossRef] [PubMed]
  133. Cashen, K.; Reeder, R.W.; Shanti, C.; Dalton, H.J.; Dean, J.M.; Meert, K.L. Is therapeutic hypothermia during neonatal extracorporeal membrane oxygenation associated with intracranial hemorrhage? Perfusion 2018, 33, 354–362. [Google Scholar] [CrossRef] [PubMed]
  134. Zhou, R.; Ying, J.; Qiu, X.; Yu, L.; Yue, Y.; Liu, Q.; Shi, J.; Li, X.; Qu, Y.; Mu, D. A new cell death program regulated by toll-like receptor 9 through p38 mitogen-activated protein kinase signaling pathway in a neonatal rat model with sepsis associated encephalopathy. Chin. Med. J. 2022, 135, 1474–1485. [Google Scholar] [CrossRef] [PubMed]
  135. Schlapbach, L.J.; Chatfield, M.D.; Rycus, P.; MacLaren, G. Extracorporeal Membrane Oxygenation for Group B Streptococcal Sepsis in Neonates: A Retrospective Study of the Extracorporeal Life Support Organization Registry. Pediatr. Crit. Care Med. 2020, 21, E505–E512. [Google Scholar] [CrossRef]
  136. Napp, L.C.; Ziegeler, S.; Kindgen-Milles, D. Rationale of Hemoadsorption during Extracorporeal Membrane Oxygenation Support. Blood Purif. 2019, 48, 203–214. [Google Scholar] [CrossRef]
  137. Soltesz, A.; Molnar, Z.A.; Szakal-Toth, Z.; Tamaska, E.; Katona, H.; Fabry, S.; Csikos, G.; Berzsenyi, V.; Tamas, C.; Edes, I.F.; et al. Influence of Venoarterial Extracorporeal Membrane Oxygenation Integrated Hemoadsorption on the Early Reversal of Multiorgan and Microcirculatory Dysfunction and Outcome of Refractory Cardiogenic Shock. J. Clin. Med. 2022, 11, 6517. [Google Scholar] [CrossRef]
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Figure 1. Coagulation activation in patients supported by extracorporeal membrane oxygenation (ECMO). When blood comes into contact with the artificial surface of the ECMO system, the intrinsic coagulation pathway is activated. The products of this contact system, kallikrein and bradykinin, exert a self-amplification function. Additionally, the extrinsic pathway, starting with the tissue factor released from endothelial cells and expressed on monocytes, plays a role in thrombus formation. HMWK: high-molecular-weight kininogen; TF: tissue factor; PLT: platelet.
Figure 1. Coagulation activation in patients supported by extracorporeal membrane oxygenation (ECMO). When blood comes into contact with the artificial surface of the ECMO system, the intrinsic coagulation pathway is activated. The products of this contact system, kallikrein and bradykinin, exert a self-amplification function. Additionally, the extrinsic pathway, starting with the tissue factor released from endothelial cells and expressed on monocytes, plays a role in thrombus formation. HMWK: high-molecular-weight kininogen; TF: tissue factor; PLT: platelet.
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Figure 2. (a) Immune activation in patients supported by extracorporeal membrane oxygenation (ECMO). In addition to the underlying disorders, contact between the blood and the biomaterial of ECMO inevitably alters the immune system. The complement system is first activated; the alternative pathway (AP) is the main activation pathway, and C3 and C5 are cleaved into C3a, C3b, C5a, and C5b. Both C3a and C5a are anaphylatoxins that can increase leukocyte recruitment, vascular permeability, smooth muscle contraction, and the release of inflammatory mediators. Moreover, various immune cells, such as monocytes, mast cells, phagocytes, and neutrophils, are involved and exert vital effects. (b) The interaction between immune and coagulation systems in patients supported by ECMO. Neutrophil, activated by several factors, such as FXa, thrombin in the coagulation system, kallikrein in the contact system, and C5a and TNF-α in the immune system, is thought to play a vital role in organ damage by releasing stores of cytotoxic enzymes, cytokines, arachidonic acid metabolites, and reactive oxygen species. Additionally, when activated by thrombin, PLT conjugates with leukocytes, especially neutrophils, and monocytes. Thus, there is an interaction between the immune and coagulation systems. LP: lectin pathway; CP: classical pathway.
Figure 2. (a) Immune activation in patients supported by extracorporeal membrane oxygenation (ECMO). In addition to the underlying disorders, contact between the blood and the biomaterial of ECMO inevitably alters the immune system. The complement system is first activated; the alternative pathway (AP) is the main activation pathway, and C3 and C5 are cleaved into C3a, C3b, C5a, and C5b. Both C3a and C5a are anaphylatoxins that can increase leukocyte recruitment, vascular permeability, smooth muscle contraction, and the release of inflammatory mediators. Moreover, various immune cells, such as monocytes, mast cells, phagocytes, and neutrophils, are involved and exert vital effects. (b) The interaction between immune and coagulation systems in patients supported by ECMO. Neutrophil, activated by several factors, such as FXa, thrombin in the coagulation system, kallikrein in the contact system, and C5a and TNF-α in the immune system, is thought to play a vital role in organ damage by releasing stores of cytotoxic enzymes, cytokines, arachidonic acid metabolites, and reactive oxygen species. Additionally, when activated by thrombin, PLT conjugates with leukocytes, especially neutrophils, and monocytes. Thus, there is an interaction between the immune and coagulation systems. LP: lectin pathway; CP: classical pathway.
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Figure 3. Peripheral extracorporeal membrane oxygenation (p ECMO). Blood returns to the body via the femoral artery with unnatural blood flow dynamics. In the presence of heart function, the two circulations meet at a point known as the mixing cloud; the location of the mixing cloud determines whether the organs are perfused by natural or ECMO blood flow.
Figure 3. Peripheral extracorporeal membrane oxygenation (p ECMO). Blood returns to the body via the femoral artery with unnatural blood flow dynamics. In the presence of heart function, the two circulations meet at a point known as the mixing cloud; the location of the mixing cloud determines whether the organs are perfused by natural or ECMO blood flow.
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Table 1. Characteristic of each pattern of ECMO-related ABIs.
Table 1. Characteristic of each pattern of ECMO-related ABIs.
Patterns Of ABIIncidenceIntracranial LocationTiming
ICHVV: 2–18%,
VA: 4–19%		frontal neocortex,
basal ganglia, cerebellum, pons		shortly after cannulation to 7 days cannulation
Ischemic StrokeVV: 1.7–2%
VA: 3.6–5.3%		frontal neocortex, basal ganglia
anterior hypophysis cerebellum		second week of ECMO support
SeizuresVA: 2–6%
VV: 1.3%		MCA territory3.2 h of the initiation of cEEG monitoring
HIBIVV: 1%
VA: 13%		cerebral cortex, cerebellum
brain stem, basal ganglia		peri-ECMO cannulation period
Brain DeathVV: 2%
VA: 7.9%		NANA
ECMO: extracorporeal membrane oxygenation; ABI: acute brain injury; VV: venovenous; VA: venoarterial; ICH: intracranial hemorrhage; HIBI: hypoxic–ischemic brain injury; cEEG: continuous electroencephalogram; MCA: middle cerebral artery.
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Deng, B.; Ying, J.; Mu, D. Subtypes and Mechanistic Advances of Extracorporeal Membrane Oxygenation-Related Acute Brain Injury. Brain Sci. 2023, 13, 1165. https://doi.org/10.3390/brainsci13081165

AMA Style

Deng B, Ying J, Mu D. Subtypes and Mechanistic Advances of Extracorporeal Membrane Oxygenation-Related Acute Brain Injury. Brain Sciences. 2023; 13(8):1165. https://doi.org/10.3390/brainsci13081165

Chicago/Turabian Style

Deng, Bixin, Junjie Ying, and Dezhi Mu. 2023. "Subtypes and Mechanistic Advances of Extracorporeal Membrane Oxygenation-Related Acute Brain Injury" Brain Sciences 13, no. 8: 1165. https://doi.org/10.3390/brainsci13081165

APA Style

Deng, B., Ying, J., & Mu, D. (2023). Subtypes and Mechanistic Advances of Extracorporeal Membrane Oxygenation-Related Acute Brain Injury. Brain Sciences, 13(8), 1165. https://doi.org/10.3390/brainsci13081165

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