Authors

• Gordana Bačić — University Hospital Centre Rijeka, Rijeka, Croatia — ORCID: 0000-0002-9050-5314
• Vjekoslav Tomulić — University Hospital Centre Rijeka, Rijeka, Croatia — ORCID: 0000-0002-3749-5559
• Igor Medved — University Hospital Centre Rijeka, Rijeka, Croatia — ORCID: 0000-0002-2029-200X
• Luka Zaputović — University Hospital Centre Rijeka, Rijeka, Croatia — ORCID: 0000-0001-9415-9618
• Teodora Zaninović — University Hospital Centre Rijeka, Rijeka, Croatia
• Jurjević — University Hospital Centre Rijeka, Rijeka, Croatia — ORCID: 0000-0001-8359-3910
• David Gobić — University Hospital Centre Rijeka, Rijeka, Croatia — ORCID: 0000-0001-9406-1127

Abstract

Extracorporeal membrane oxygenation (ECMO) is a procedure that provides extracorporeal mechanical circulatory or respiratory support and is used primarily in patients with life-threatening forms of heart or respiratory failure. There are two basic types of ECMO support: veno-venous (VV) and veno-arterial (VA) ECMO. VV ECMO ensures blood gas exchange and is applied in cases of severe reversible respiratory insufficiency. VA ECMO supports the function of the heart and lungs; other than in reversible forms of damaged heart function, it can also be used in irreversible forms of heart failure as a bridge to heart transplantation or to the implantation of mechanical circulatory support device. ECMO is an invasive and technically complex procedure that is performed in critically ill patients and thus has a high risk of complications. Results of ECMO treatment vary depending on the indications for the procedure itself. Patients in whom ECMO was applied for respiratory support show better outcomes compared with those with cardiogenic shock or cardiac arrest. Despite a lack of evidence based on large randomized studies to support its application, in clinical practice ECMO represents a life-saving method of treatment in well-selected critical patients.

Keywords

KLJUČNE RIJEČI: izvantjelesna membranska oksigenacija, kardiogeni šok, respiracijska insuficijencija, extracorporeal membrane oxygenation, cardiogenic shock, respiratory insufficiency

DOI

Full Text

## Introduction Extracorporeal membrane oxygenation (ECMO) is a procedure that provides extracorporeal mechanical circulatory or respiratory support in which a special device is used to extract venous blood from the organism, oxygenate it, and then return it to the organism. The basic goal of ECMO is achieving satisfactory oxygen supply to the body and removal of carbon dioxide in patients with severe forms of heart or respiratory failure, when they are refractory to conventional treatment (1). The procedure of extracorporeal membrane oxygenation was used for the first time in 1971 (2). Over the following decades, it became an universally accepted method in the treatment of severe forms of heart and respiratory failure in childhood; only in recent years has it become a common treatment modality in adult critical patients (3-5).Thanks to the technical developments and growing experience, the results of ECMO treatment have been increasingly improving, and the indications were gradually extended (6-10). Consequently, the number of patients treated with ECMO has been growing significantly every year. According to the ELSO (Extracorporeal Life Support Organisation) registry, by January 2017 ECMO had been applied in 86 287 patients all over the world, of whom 26 813 (31%) were adult patients (11). In order to make the results of ECMO treatment as favorable as possible, timely recognition of patients who require extracorporeal circulatory or respiratory support is important, as well as determining whether any contraindications are present and choosing the appropriate form of treatment. Thus, the goal of this review is to present the basic principles of ECMO treatment in the adult population, the indications and contraindications based on current guidelines, and the possible complications from this procedure. ## The procedure and basic forms of ECMO support The basic parts of the ECMO system are a pump that allows blood flow, an oxygenator, and cannulae (**Figure 1**). Deoxygenated venous blood is led outside the organism using an “access” cannula placed in the venous part of the circulation using the negative pressure created by the pump. The pump then pushes blood towards the oxygenator, where it is enriched with oxygen while carbon dioxide is simultaneously removed. If it is necessary to keep the blood and body temperatures at a specific level, the blood saturated with oxygen is directed to a heat exchanger where it is heated or cooled, after which the blood is returned to the arterial or venous part of the circulation via the “return” cannula. The choice between these two return approaches is what differentiates the two types of ECMO support, veno-venous (VV) and veno-arterial (VA) ECMO (**Figure 2**). Which modality will be applied in a particular patient depends on heart function. Figure 1. Extracorporeal membrane oxygenation circuit configuration. Figure 2. Veno-venous and peripheral veno-arterial extracorporeal membrane oxygenation. ## Veno-Venous ECMO When applying VV ECMO, venous blood is extracted through the “access” cannula, usually placed in the femoral vein; the oxygenated blood is returned to the venous system through the “return” cannula in the internal jugular vein. In this way, VV ECMO ensures oxygenation and the removal of carbon dioxide from the venous blood, while at the same time reducing the necessary level of mechanical ventilation support and thus minimizing the risk of ventilator-induced lung injury (12). Since the oxygenated blood returns to the venous part of the circulation, VV ECMO does not ensure hemodynamic support and is used in patients with no significant damage to heart function who only need respiratory support. As opposed to VA ECMO, it allows physiological hemodynamics to take place with a minimal risk of systemic thromboembolism and without artery cannulation being necessary. Thus the incidence of complications during VV ECMO is significantly lower (13). ## Veno-arterial ECMO In VA ECMO, the oxygenated blood is returned to the organism via a “return” cannula placed in one of the great arteries. In this way, as in standard cardiopulmonary bypasses, VA ECMO circumvents the heart and lungs and takes over or supports the circulatory function of the heart and can simultaneously take over or support the function of gas exchange in the blood. Systemic arterial flow is a result of the flow in the circulatory system and left ventricular ejection. It can be used for left-sided and right-sided heart failure (14). There are two forms of VA ECMO: central and peripheral. In central VA ECMO, the cannulae are placed in the central structures (the right atrium and ascending aorta) by using an open surgical approach; this is used after cardiac surgery procedures in cases of inability to wean the patient from an external blood flow device or in cases of severe cardiorespiratory failure when there is high flow needed to achieve sufficient tissue perfusion (15). In peripheral VA ECMO, the great peripheral blood vessels (usually in the femoral region) are cannulated using either a percutaneous approach or surgical preparation. This modality ensures predominantly circulatory support and is not used in patients with respiratory insufficiency (16). Peripheral VA ECMO with small cannulae placed with a percutaneous approach, the so-called low-flow veno-arterial ECMO, allows very rapid initiation of hemodynamic support for patients in cardiorespiratory arrest (17). ## Indications for the application of ECMO Since the very beginning, ECMO has been most commonly used in patients with potentially reversible, life-threatening forms of heart or respiratory failure refractory to conventional treatment. However, today the indications for ECMO support are much broader and encompass certain patients with irreversible damage to target organs, cardiac arrest, and also patients undergoing high-risk procedures in interventional cardiology (1). ## Indication for VA ECMO VA ECMO is most commonly applied after cardiac surgery procedures, in cases of inability to wean the patient from the external blood flow device. The next most important indication is cardiogenic shock of any etiology that persists despite appropriate supplementation of intravascular volume, high doses of inotropic medications, and application of an intra-aortic balloon pump (18-20). Cardiogenic shock is defined as a heart index 2 and persistent hypotension (systolic pressure 10 min) | | Periprocedural support for high-risk percutaneous coronary interventions | ## Indications for VV ECMO According to ELSO guidelines, the application of VV ECMO should be considered in patients with potentially reversible hypoxic respiratory insufficiency of any etiology when the risk of death is equal to or greater than 50%, and it is indicated in cases where risk of death is equal to or greater than 80% (**Table 2**) (30). The risk of death is assessed based on the value of the Pa02/Fi02 (partial arterial pressure of oxygen/fraction of inspired oxygen) ratio or the Murray score: ### Table 2: Indications for veno-venous extracorporeal membrane oxygenation. | Hypoxic respiratory failure with PaO2/FiO2 90% and/or Murray score 3-4 despite optimal care for >6 hours | | --- | | CO2 retention on mechanical ventilation despite high plato pressure (>30 cm H2O) | | Severe air leak syndromes | | Need for intubation in a patient on lung transplant list | | Immediate cardiac or respiratory collapse (pulmonary embolism, blocked airway unresponsive to optimal care) | - 50% risk of death combined with Pa02/Fi02 2 >0.9 and/or Murray score 2-3; - 80% risk of death combined with Pa02/Fi02 2 >0.9 and/or Murray score 4-6 during 6 hours and longer. The Murray score is a scoring system based on four parameters (Pa02/Fi02 ratio, PEEP (Positive End Expiratory Pressure), dynamic pulmonary compliance, the number of pulmonary quadrants with alveolar infiltration on chest x-ray) and indicates the severity of respiratory insufficiency (31). When assessing whether the damage to lung function is reversible, the etiology of the primary disease, age, previous state of the patient, and the duration of mechanical ventilation should be taken into consideration. ECMO treatment has shown very good results in some conditions such as aspiration pneumonia, drowning, or asthma. Mechanical ventilation lasting for more than seven days and advanced age are associated with a high risk of adverse outcomes despite ECMO application and are thus considered relative contraindications (32). ## Contraindications for ECMO Since ECMO is a high-risk and costly procedure, it is crucial to individually assess the risk and benefit of the procedure before deciding to commence the treatment. According to current guidelines, there are very few absolute contraindications for ECMO applications, and most conditions represent only relative contraindications (1, 33). Absolute contraindications for ECMO are: - Patients with irreversible damage to target organs who are not suitable for heart or lung transplantation or other forms of support, since continued quality life after recovery is not likely (e.g. terminal malignant disease, unwitnessed cardiorespiratory arrest, severe damage to the central nervous system) - Noncompliant patients (1) The most common relative contraindications are related to the application of anticoagulation therapy, manifest bleeding, and advanced age. When the application of unfractioned heparin (UFH) is not possible, for instance due to heparin-induced thrombocytopenia (HIT), other anticoagulants such as bivalirudin or argatroban can be used. Thanks to the system of cannulae and parts of the device coated in an anticoagulant agent, short-term ECMO application is possible even without systemic anticoagulation therapy, which allows its use in patients with manifest bleeding that cannot be stopped with the appropriate procedures (33). The age limit after which application of ECMO is not recommended has not been clearly defined, but the risk of adverse outcomes grows proportionately to the age of the patient (32). Particular ECMO types have specific contraindications. Peripheral VA ECMO is contraindicated in severe peripheral vascular disease and in cases of aneurysm of the abdominal aorta with thrombotic masses. VV ECMO should not be applied in severe right-sided or left-sided heart failure and in severe pulmonary hypertension (mean pressure in the pulmonary artery >50 mmHg) (33). ## Complications in ECMO procedures ECMO is an invasive and technically very complex procedure that compromises the integrity of the blood vessel walls and interferes with numerous physiological processes. Patients in which it is indicated already have a high predicted mortality rate due to their primary illness (2). Consequently, the complications associated with ECMO are still common and significantly increase the morbidity and mortality (5, 34-39). According to currently completed studies, VV ECMO has fewer complications in comparison with VA ECMO. Children have a lower total number of complications in comparison with adults, but have a higher incidence of neurological complications (32, 40). Complications due to ECMO treatment can be divided into two main categories: - Complications related to the ECMO circuit (mechanical) - Complications related to the patient (medical) ## Complications related to the ECMO circuit Mechanical complications associated with the ECMO system itself include thrombosis, air embolism, dysfunction of individual parts of the circuit, and loss or reduction of circuit flow. The presence of small blood clots (1-5 mm in size) within the system is a common occurrence and usually does not require intervention but just continuous monitoring. If the clots are larger or growing, it is necessary to replace some or all parts of the circuit since the clots can cause a disturbance in the function of the pump or oxygenator, systemic thromboembolism, or the development of disseminated intravascular coagulopathy. Air entrainment into the circuit is a rare, but life-threatening complication that requires immediate clamping of the cannulae and stopping the flow (31). ## Complications related to the patient The most common complication related to the patient is bleeding which is present in 10-30% of cases (32, 41). In addition to systemic heparinization, the factors that contribute to the increased risk of bleeding are thrombocytopenia, thrombocyte function disorder, and relative lack of clotting factors as a consequence of blood contacting the artificial material within the circuit. Treatment of clinically significant bleeding is based on reducing target activated clotting time (ACT) values or temporary stoppage of heparin and, if necessary, blood transfusion, reconstitution of thrombocytes, and clotting factors (42). Due to systemic UFH application, the appearance of heparin-induced thrombocytopenia with concomitant predisposition to thrombosis is a possibility. In such cases, UFH must be replaced by different anticoagulant medication such as direct thrombin inhibitors bivalirudin or argatroban (43). After bleeding, infections are the next most significant group of complications. The risk of infection rises with the duration of ECMO support due to the presence of intravascular cannulae, and the critical condition of patients who most commonly need long-term support further exacerbates this risk (38). The incidence of neurological complications varies between 4-37% depending on the age of the patient (44). According to data from the ELSO registry, complications are most common in newborns in the form of intracranial bleeding (11%), epileptic seizures (7%), and ischemic stroke (3.5%). Ischemic stroke is more common in adulthood (4%), followed by epileptic seizures and intracranial bleeding, both with comparable incidence (2%) (45). Neurological complications in all age groups increase the rate of hospital mortality (44). ## VA ECMO-specific complications Specific complications are possible during the application of VA ECMO. Cannulation can lead to injury to the artery (perforation or dissection), ischemia of the extremities distally from the cannula, or to development of pseudoaneurysm at the insertion site. In addition, cases of thrombus formation in heart cavities have been reported, caused by blood stasis in cases of low ventricular output (2). ## Treatment results According to the annual report from the ELSO registry, ECMO was applied in 86 287 patients by January 2017. Among the 26 813 adult patients, 15 875 (59.2%) were successfully weaned from ECMO, and 12 616 (47.1%) survived until discharge or transfer to another institution. Treatment results differ in individual groups of patients depending on the indications for the procedure. Survival until discharge or transfer for patients in whom ECMO was applied for respiratory support was 57%, 40% for patients with cardiogenic shock, and 28% with ECPR (11). The first randomized studies undertaken on adult patients with severe respiratory insufficiency did not demonstrate the advantage of ECMO in comparison with conventional methods of treatment (46). It was only in 2009 that the publication of the results of the CESAR study (Conventional ventilatory support versus ECMO for Severe Adult Respiratory failure) as well as treatment results during the H1N1 viral pneumonia epidemic in Australia and New Zealand once again sparked interest for the application of ECMO in adult patients. This multicentric study demonstrated better survival and lower disability after six months in patients with ARDS referred to an ECMO center in comparison with the conventional approach (5, 47). In the meantime, the majority of mostly observational and controlled studies also showed better outcomes in patients with respiratory insufficiency treated with ECMO in comparison with conventional treatment (31, 35, 36, 48-55). There have been no randomized studies conducted on patients with indications for circulatory support, and outcome data are mostly based on observational studies and case series. The survival rates of patients treated with VA ECMO due to cardiogenic shock, cardiac arrest, or inability to wean from an external blood flow device after surgical procedures in these studies were 24-53% (56-63). When fulminant myocarditis was the indication for ECMO, the survival rate was as high as 71-80% (64). Poorer treatment outcomes in the patient group with cardiogenic shock in comparison with patients with respiratory insufficiency were a consequence of the primary disease, but also of the higher incidence of complications during VA ECMO application. The patient group with cardiac arrest had the worst treatment outcomes, as expected (65, 66). ## Conclusion ECMO is a form of extracorporeal mechanical circulatory or respiratory support that is primarily used in patients with severe forms of heart and respiratory failure with high predicted mortality. Although evidence based on large randomized studies is lacking, in clinical practice ECMO represents a life-saving method of treatment in well-selected adult patients.

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