Evolving Therapies and Technologies in Extracorporeal Membrane Oxygenation

Abstract

Since its inception, Extracorporeal Membrane Oxygenation (ECMO) and its application have significantly evolved in the face of numerous challenges and clinical needs. Here, we trace the historical evolution, challenges, and recent advancements in Extracorporeal Membrane Oxygenation (ECMO), highlighting milestones, like the “Bubble Oxygenator” and the standardization efforts by the Extracorporeal Life Support Organization (ELSO). Technological innovations, including miniaturization and enhanced oxygenators, have rendered ECMO more portable and efficient. Global applications, like managing epidemics and supporting developing countries, are discussed, along with the transformative impact of telemedicine on ECMO care. In summary, this chapter illuminates ECMO’s journey from its historical origins to its transformative modern role. It underscores its adaptability and pivotal position in the field of medical science and patient care.

1. Introduction

Extracorporeal Membrane Oxygenation (ECMO) is a life-saving medical technique employed in critical cases of respiratory or cardiac failure when conventional methods are insufficient. ECMO has revolutionized cardiothoracic surgery and critical care. John H. Gibbon’s ground-breaking work on the heart-lung machine in the 1930s laid the foundation for extracorporeal circulation. ECMO was initially mostly used for experimental and research purposes. However, Donald Hill reported the first successful use of ECMO in an adult with respiratory using a Bramson-type membrane oxygenator in 1972 [1]. The adoption of ECMO, thereafter, has faced numerous challenges like limited patient selection criteria, technical limitations, and high complication rates. Over the years, advances in clinical care, guidelines, drug discovery, and technology have reduced the risks associated with ECMO, thus widening its scope with the hopes of continued improved patient outcomes. Though primarily used to temporarily support cardiopulmonary function in various situations, there are many nonconventional applications of ECMO in clinical practice.

2. The extracorporeal membrane oxygenation circuit

The ECMO system comprises a blood pump, oxygenator, tubing, and cannulas. The cannulas serve as vascular access. Typically, there is a drainage cannula(s) through which deoxygenated venous blood is removed from the patient and pumped through the oxygenator where the blood is oxygenated, and carbon dioxide (CO2) is removed, then it passes through the heat exchanger before being infused into the patient via the return cannula(s) (Figure 1). The tubing connects the patient to the ECMO circuit, facilitating the continuous flow of blood. The common drainage cannula placement sites include the internal jugular, subclavian, and femoral veins as well as the vena cavae and right atrium. The return cannula can be placed in the aorta, innominate, carotid, axillary, and femoral arteries (arterial return cannula) or the internal jugular, subclavian, and femoral veins (venous return cannula). When the drainage cannula is in a venous structure and the return cannula is in an arterial structure, it is venoarterial ECMO (VA-ECMO) configuration. If both drainage and return cannulas are in a venous structure, it is called a venovenous ECMO (VV-ECMO) configuration. VV-ECMO primarily supports the respiratory system and give the patient time to recover or improve respiratory function or secure a transplant. VA-ECMO provides both cardiac and respiratory support, and is a bridge to recovery, durable mechanical circulatory support or transplant. The specific clinical scenario and the desired level of support dictates the cannulation strategy.

Figure 1.

Veno-venous and veno-arterial ECMO configuration [2].

3. Advancements in ECMO technology

As the healthcare needs of patients have evolved over the years, ECMO technology and the indications for its use have also evolved to suit the growing clinical needs. These technological advances have contributed to a reduction in adverse events, improvements in the efficiency of ECMO technologies and better clinical outcomes. Some of such advances in ECMO technology are discussed here.

3.1 Miniaturization of ECMO equipment

Historically, ECMO machines were cumbersome and required dedicated spaces within well-equipped hospitals. However, the development of miniaturized ECMO equipment has ushered in a new era of ECMO therapy characterized by enhanced portability and versatility. The creation of compact, lightweight systems, with handles and wheels, enhances the portability of ECMO, enabling rapid deployment to the patient’s bedside, particularly in emergency scenarios such as cardiac arrest. These smaller and shorter circuits make ECMO mobile, permitting easy ECMO transfer and use in the field, within and between hospitals. It also plays a critical role in mass casualty and disaster response by swiftly providing life-saving support to multiple critically ill patients. Thus, extending ECMO’s applicability to diverse clinical settings beyond the traditional confines of the intensive care unit.

Today, many miniaturized ECMO systems exist. For instance, the Cardiohelp device is a compact and portable ECMO device that offers both ECMO and ventricular assist device (VAD) support and ease of transport within hospitals and between facilities. The Novalung system, which has highly miniaturized and specialized for neonates, infants, and children, offers precise flow control and oxygenation that is crucial for neonatal care [3, 4].

3.2 Improved oxygenators

Membrane oxygenators are critical components of ECMO systems as they facilitate efficient oxygenation of blood and removal of carbon dioxide across a microporous membrane surface (Figures 2 and 3). Advancements in oxygenator design and materials have played a crucial role in revolutionizing the technology and clinical use of ECMO. Newer oxygenators offer enhanced gas exchange efficiency, reducing the risk of complications associated with inadequate oxygenation or excessive carbon dioxide levels. One notable improvement is the reduction in surface area, which minimizes the contact between blood and artificial surfaces. This design alteration has been instrumental in decreasing oxygenator thrombosis and hemolysis and associated complications. Examples of successful oxygenator designs include the DeWall bubble oxygenator, the Kolobow silicone membrane oxygenator, and the hollow-fiber oxygenator, are effective, clinically proven, and relatively inexpensive to manufacture. Non-microporous oxygenators, which combine operational efficiency and longevity, may dominate future applications (Figure 4).

Figure 2.

Cardiohelp™ portable life support system by Getinge AB (Göteborg, Sweden) [5].

Figure 3.

Novalung® heart and lung therapy system by Fresenius medical care (Massachusetts, USA) [6].

Figure 4.

Richard DeWall and the “bubble oxygenator” heart-lung machine (1956) [7].

In patients awaiting lung transplantation, avoiding mechanical ventilation is desirable and such percutaneous carbon dioxide removal devices or extracorporeal respiratory support are appealing solutions [3, 8]. The Hemolung, a ‘respiratory dialysis’ device, is an extracorporeal carbon dioxide removal device with an integrated pump/oxygenator in a veno-venous configuration, has been described and used to avoid the need for conventional ventilator use [9]. Potential benefits include averting prolonged intubation and tracheostomy, ventilator-induced lung injury and infections, and/or high sedation requirements. Early studies are promising, but definitive data are still lacking as to the true benefit of this strategy [3, 8].

3.3 Cannulas

Cannulas are vital to initiating ECMO support and there are various types of cannulas. They are categorized based on size, shape (straight or curved), number of lumens (single or dual lumen), the materials they are made of (polyurethane, polyvinylchloride, or silicone), or the patient population they are used for (i.e. neonatal, pediatric, and adult) etc. They can also be classified as single-stage or multistage. Single stage cannulas have side holes near the tip of the cannula, while multi-stage cannulas have additional further away from the tip.

Arterial cannulas, such as straight and curved varieties, provide avenues for oxygenated blood to be returned to the patient, supporting both oxygenation and hemodynamic stability. Venous cannulas, which may be single-lumen or double-lumen, facilitate efficient blood withdrawal and reinfusion. Double lumen Cannulas (DLCs) are used in VV-ECMO and offer the advantage of single venous access site. Thus limiting the incisions, bleeding risk, and concern for carotid artery ligation without a significant hemodynamic trade off [10]. The DLCs available in the US at present are (1) the Maquet Avalon Elite dual-lumen cannula (Wayne, New Jersey), (2) the Maquet dual-lumen cannula (Wayne, New Jersey), (3) MC3 Crescent® (Medtronic International Trading Sàrl, Tolochenaz, Switzerland) (4) the OriGen (Austin, Texas), (5) the Covidien ECMO (Mansfield, Massachusetts), and (6) Protek-Duo (CardiacAssist Inc., LivaNova, Pittsburgh, PA) [10, 11].

Protek-Duo is a special type of double-lumen cannula which courses the superior vena cava, right atrium, right ventricle, crossing the pulmonary valve to terminate in the main pulmonary artery. It drains the right atrium and empties the blood into the main pulmonary artery, thus helping offload the right ventricle. Thus, when used in combination with ECMO, the Protek-Duo- ECMO circuit serves as a right ventricular assist device with the added function of an oxygenator [11].

4. Advances in clinical applications and indications for ECMO use

Since the clinical adoption in neonatal acute respiratory distress syndrome treatment, the clinical application of ECMO has continued to expand (Figure 5). Landmark clinical trials, like the CESAR (Conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure) [13] and the EOLIA (Extracorporeal Membrane Oxygenation to Rescue Acute Lung Injury in Severe Acute Respiratory Distress Syndrome) [14] trials provided a better understanding the role and benefits of ECMO in adults with ARDS. Some of these novel clinical applications of ECMO are discussed below.

Figure 5.

Examples of commercially available single and dual lumen ECMO cannulas [12].

4.1 ECMO in infectious epidemics and pandemics

ECMO has played a vital role in infectious epidemics across the globe like the 2009 H1N1 influenza epidemic where the use of ECMO showed a 71% survival advantage in patients who failed conventional therapy [3, 15]. It also proved beneficial in the Middle East respiratory syndrome corona virus (MERSCoV) [15]. The significance of ECMO was further underscored by the global COVID-19 pandemic. The COVID-19 virus causes acute respiratory distress syndrome (ARDS) and severe complications that pushed hospitals to their limits. In the face of COVID-related ARDS, ECMO emerged as a vital tool to support patients with severe respiratory distress, especially in cases where conventional ventilatory support fell short. Globally, hospitals began to rely on ECMO to save lives, leading to a substantial increase in its utilization. ECMO proved to be a lifeline in managing severe hypoxemic respiratory failure and its complications, reduced mortality rates, and offered a bridge to lung recovery making it an indispensable tool in the COVID-19 pandemic response [14, 16].

4.2 ECMO in cardiopulmonary resuscitation (CPR)

Refractory cardiac arrest is described as failure to achieve return of spontaneous circulation (ROSC) despite adequate CPR. ECMO-cardiopulmonary resuscitation (ECPR) is the application of extracorporeal circulation in a patient who suffers unexpected circulatory arrest or pulselessness due to cardiac mechanical failure [17, 18, 19]. ECPR is a valuable evidence-based tool especially in refractory cardiac arrest. The ARREST (Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation) trial (2020) and INCEPTION (Early Extracorporeal CPR for Refractory Out-Of-Hospital Cardiac Arrest) trial (2023) showed that early use of ECPR was associated with significantly higher rates of ROSC, better neurological outcomes, substantial increase in survival and hospital discharge compared to conventional CPR [20, 21]. Early initiation of ECMO during resuscitation efforts plays a pivotal role in augmenting cardiac output, ensuring oxygenation, and providing continuous circulatory support, ultimately increasing the chances of achieving ROSC and survival. Adding ECMO to the resuscitation also affords the medical providers more time to conduct their resuscitative effort, thereby expanding the “resuscitation window”.

Although neurologic complications like stroke, hypoxic–ischemic brain injury, and seizures are known complications of ECMO use, early use of ECPR confers a neuroprotective effect to cardiac arrest patients [22]. Yannopoulos et al. (2020) demonstrated that ECPR preserves neurologic function and improves long term neurologic functional status scores among survivors, relative to conventional CPR [23]. This provides further impetus to adopt ECPR in prehospital and hospital settings.

4.3 Intraoperative ECMO support for lung surgery

The use of ECMO as an intraoperative adjunct during lung transplantation offers several benefits. It temporarily offers respiratory and mechanical support, if needed, and allows the surgical team to work in a bloodless field. This reduces the risk of bleeding complications and ensures that the surgery can proceed with meticulous precision. Furthermore, enables surgeons to work more precisely and with an extended time frame, which is often crucial for the success of lung transplantation. Successful ECMO support has expanded the pool of eligible lung transplant recipients, allowing for transplantation in patients who might not have been candidates due to their critical condition. It allows the surgical team to pause native lung ventilation, and switch between single and double lung ventilation and vice-versa. It is particularly helpful in patients with significant pulmonary hypertension.

4.4 ECMO in liver transplant patient management

ECMO has a key role to play in liver transplant patient management [24]. It can be used before, during and after liver transplantation surgery and its indications for use continue to expand in this patient population. It provides cardiopulmonary support in before during and after transplantation. It may be considered for transplant patients with perioperative severe, acute, and reversible causes of respiratory and/or cardiovascular collapse with high likelihood of mortality [25]. Intraoperatively, the use of ECMO may also confer some technical benefit.

4.5 ECMO as destination therapy in end stage cardiopulmonary disease

Prolonged ECMO use was associated with complications, mostly related to haemolysis, thrombosis, and systemic inflammation and consequent end organ damage. Hence, the use of ECMO in has often been as a bridge to short term recovery or another form of mechanical circulatory support or transplantation. However, recent advancements are changing this landscape. Miniaturized circuits and the use of biocompatible materials have made prolonged ECMO support safer and reduced the risk of circuit-related complications. Newer oxygenators provide more efficient gas exchange while minimizing trauma to blood components, making prolonged support more sustainable. Further, advanced anticoagulation strategies, such as heparin-coated circuits and personalized management, strike a balance between preventing clot formation and minimizing bleeding risks.

Today, prolonged ECMO support is no longer solely a bridge to transplantation but also can serve as a destination therapy for individuals who are not transplant candidates, offering a renewed chance at life and improved quality of life [26, 27]. This paradigm shift has broadened the therapeutic window for patients facing severe cardiac or respiratory failure. This was made feasible advances in technology, medication, improved clinical care and other factors like enhanced patient management protocols encompassing nutrition, infection control, and sedation strategies are integral to mitigating complications and supporting recovery.

4.6 Nonconventional indications for ECMO use

ECMO has remarkable adaptability across diverse medical contexts, expanding its utility beyond conventional cardiorespiratory failure. Extracorporeal CO2 Removal (ECCO2R) is a treatment option that demonstrates ECMO’s versatility by addressing hypercapnia with targeted respiratory support and the PrismaLung is a novel commercially available device that can be used for this purpose [28, 29]. In patients suffering from accidental hypothermia, which is refractory to conventional therapy, ECMO has been shown to confer a survival benefit, especially in those with hypothermic cardiac arrest [30]. In cases of toxic ingestions or poisoning, ECMO serves a dual-purpose intervention by providing circulatory and respiratory assistance, facilitating the removal of toxic substances. In scenarios such as intractable seizures, ECMO proves valuable for neuroprotection, showcasing its broader role in life support. In organ transplantation, ECMO maintains stability for patients awaiting organs. Lastly, there is a role for ECMO use in conditions like status asthmaticus that have failed conventional therapy.

5. ECMO and international health

5.1 Extracorporeal life support organization (ELSO) and ELSO guidelines

Established in 1989, the Extracorporeal Life Support Organization (ELSO) has played a crucial role in providing comprehensive guidelines and has become a cornerstone of enhanced patient care, safety, and the promotion of evidence-based practices globally. ELSO guidelines have helped standardize protocols for ECMO initiation and management, serving as a valuable resource for healthcare professionals. With well-defined recommendations for patient selection, anticoagulation strategies, and infection control, ELSO guidelines ensure the uniform and secure application of ECMO across various healthcare settings globally. Further, ELSO’s global reach and collaboration have fostered the standardization of ECMO practices globally. By fostering a collaborative community of experts and stakeholders, ELSO guidelines draw from diverse perspectives and global experiences.

ELSO has also contributed significantly to ECM research, policies, and protocols and the ELSO guidelines have evolved to become the bedrock of ECMO care. By emphasizing advances in patient care, a commitment to research and evidence-based practice, and the promotion of international collaboration and standardization, ELSO guidelines have profoundly impacted the field. They serve as a trusted guide for healthcare professionals, promoting standardized, evidence-based care that ultimately benefits critically ill patients in need of lifesaving ECMO therapy.

5.2 ECMO and global health

While ECMO is considered a life-saving therapy, its widespread adoption in resource-limited settings is hampered by factors such as cost, infrastructure, and trained personnel. Attempts to adopt ECMO in developing countries would require a multifaceted and innovative approach, including the development of cost-effective systems, training and capacity building, integration with telemedicine, and a robust framework for humanitarian aid and disaster relief. Addressing this gap involves the development of cost-effective ECMO systems, support for local manufacturing, and collaborations with international organizations to expand access to this critical technology.

The success of ECMO therapy is intrinsically linked to the knowledge and skills of the healthcare providers. Training programs, both on a national and international scale, are pivotal in building capacity and expertise in ECMO in developing countries. Through a combination of didactic, simulation-based training, and clinical apprenticeships, healthcare professionals can gain the competencies needed to provide ECMO care safely and effectively. Telemedicine can be leveraged to provide ECMO support in developing settings. This may include remote consultation, real-time decision-making, troubleshooting, and guidance for healthcare providers in remote or underserved areas. This could enhance the quality of care and patient outcomes by providing expert oversight in select situations where ECMO specialists are scarce, thus improving ECMO access.

6. Future directions in ECMO

As the scope and practice of extracorporeal membrane oxygenation continues to advance, several exciting directions are emerging, promising to redefine the landscape of critical care, cardiovascular surgery, and life support. Some particularly promising avenues of exploration are ambulatory ECMO, the integration of Artificial Intelligence (AI) in ECMO management, regenerative medicine, and the development of bioartificial lungs.

6.1 Ambulatory ECMO

Ambulatory ECMO represents a paradigm shift in ECMO therapy, envisioning a future where patients with severe cardiopulmonary compromise can regain mobility and a degree of normalcy very early during treatment. Traditional ECMO systems are tethered to bulky bedside machinery and stiff cannulas, limiting patients’ mobility and quality of life. Ambulatory ECMO seeks to overcome these limitations by developing portable ECMO systems that allow patients to move about, even outside the hospital. With ambulatory ECMO, patients are able to begin physical therapy and attain independence sooner [11]. The introduction of dual lumen single cannulas, for V-V ECMO offers the benefit of easier ambulation with a single cannulation site, but it’s adoption is not yet widespread [31, 32].

Compact and lightweight ECMO equipment may empower patients with severe heart or lung conditions to regain some independence while receiving life-saving support. These systems will be designed with a focus on patient comfort and ease of use, ensuring that patients can engage in physical therapy, engage in social interactions, and possibly even return to some of their daily activities. Additionally, telemedicine and remote monitoring will play a crucial role in ambulatory ECMO, allowing healthcare providers to closely follow patients’ progress and adjust as needed.

From a hospital perspective, ambulatory ECMO is cost saving [11]. Compared to non-ambulatory ECMO subjects, ambulatory ECMO patients had 73% lower postoperative intensive care unit cost, 22% lower hospitalization cost, and 11% lower overall cost [33]. However, the implementation of ambulatory ECMO brings its own set of challenges, including the need for precise management of anticoagulation, circuit safety, and comprehensive training for patients and caregivers. In the future, research and innovation in ambulatory ECMO aim to address these challenges, with the goal of improving the quality of life and outcomes for patients facing severe cardiopulmonary conditions.

6.2 Bioartificial lungs and biocompatible ECMO systems

Bioartificial lungs represents technologies that seed natural or synthetic scaffolds with progenitor cells or biocompatible cells. They aim to emulate the functions of the human lung while facilitating the repair and regeneration of damaged lung tissue. These artificial lungs are designed to promote cellular growth and regeneration, potentially enabling patients with severe lung injury to regain lung function over time. Bioartificial lungs are not only expected to support gas exchange but also contribute to reducing inflammation and modulating the immune response. Alabdullh et al. (2023), described the “biohybrid lung”, which they developed as a lung-assist device with identical technical principles as ECMO, but to address the problem of hemocompatibility, they endothelialized all blood-contacting surfaces including the membrane oxygenator [34]. Innovative technological advances like these offer a glimpse into a future where ECMO therapy goes beyond life support, striving for the restoration of organ function and overall patient health. This innovative approach could reduce the duration of ECMO support, minimize complications, and improve long-term outcomes for patients.

6.3 ECMO, regenerative medicine and extracorporeal organ support

The convergence of ECMO and regenerative medicine holds the promise of not only sustaining life but also promoting organ preservation, recovery, and regeneration. In the context of regenerative medicine, ECMO can serve as a platform for delivering stem cells, growth factors, and other regenerative agents directly to the injured or failing organs. For instance, ECMO can be utilized to provide mechanical support to patients with acute lung injury, while concurrently delivering regenerative factors to stimulate lung tissue repair. This approach seeks to harness the innate regenerative potential of the body, enhancing the chances of organ recovery. While still in the early stages of exploration, this innovative combination of ECMO and regenerative medicine is poised to revolutionize critical care by offering a pathway to restore not only life but also organ function, ultimately leading to better patient outcomes and quality of life.

Additionally, ECMO principles can be leveraged to assist not only the heart and lungs but also other vital organs. This approach recognizes the interconnectedness of organ systems within the human body and aims to address multi-organ failure and severe dysfunction. This concept of extracorporeal organ support extends to applications where ECMO technologies are adapted to help remove waste products, maintain electrolyte balance, and facilitate organ rest. A good example is extracorporeal hepatic support, where ECMO-like systems can provide partial or full hepatic support by eliminating toxins and metabolites from the bloodstream, mitigating liver failure, and allowing time for the liver to recover [35]. These emerging therapies emphasize the versatility of ECMO, beyond cardiopulmonary support, as a life-saving technology that improves patient outcomes and quality of life.

6.4 Artificial intelligence (AI) in ECMO

Artificial Intelligence (AI) represents the present and future frontier of healthcare advancement. The integration of AI into ECMO technology and patient management holds tremendous potential to enhance patient care, optimize therapy, and improve outcomes. AI can assist healthcare providers in making real-time decisions by analyzing vast amounts of data, detecting and even predicting complications, and providing personalized treatment strategies. AI algorithms can monitor and interpret data from various sensors and monitors connected to the ECMO circuit, as well as data from the patient’s electronic health record. By continuously assessing these inputs, AI can provide early warnings of potential issues, such as clot formation in the circuit, hemodynamic instability, or signs of infection. This proactive approach allows healthcare providers to intervene promptly, preventing complications and improving patient safety. AI-driven decision support can also assist in optimizing parameters, such as pump speed and ventilator settings, to ensure that the patient receives the most effective therapy.

7. Conclusion

The historical evolution of Extracorporeal Membrane Oxygenation (ECMO) has led to substantial progress in various domains of critical care and cardiovascular surgery. Notable advancements include the miniaturization of ECMO equipment, making it more portable and versatile, as well as improved oxygenators that enhance gas exchange while reducing complications. ECMO has emerged as a valuable tool in cardiopulmonary resuscitation, significantly improving survival rates and long-term neurological outcomes. Prolonged ECMO support is now safer, thanks to miniaturized circuits and advanced anticoagulation strategies. The Extracorporeal Life Support Organization (ELSO) has played a pivotal role in standardizing ECMO protocols and expanding its use globally. Future directions in ECMO encompass ambulatory ECMO, integration of Artificial Intelligence (AI), bioartificial lungs, regenerative medicine, and extracorporeal organ support. In developing countries, capacity building and telemedicine integration are vital for expanding ECMO’s accessibility. This journey from historical origins to cutting-edge innovations underscores ECMO’s adaptability and its pivotal role in the ever-evolving landscape of medical science and patient care.