Historical Overview

The development of extracorporeal support technologies is intrinsically linked to the work of 19th century physiologists investigating methods to support isolated limbs and ex vivo organs.^10,11 Experimental physiologists sought to replicate the perfusion and respiratory functions of the heart and lungs. Efforts to achieve extracorporeal ventilation through direct exposure of blood to air led to the bubble oxygenator, in which small bubbles of oxygen were passed through reservoirs of blood, and the film oxygenator, in which blood was conveyed as a thin film over which oxygen was passed to achieve gas exchange.¹² The subsequent discovery of heparin enabled controlled anticoagulation and clinical use of oxygenator methods that relied on direct contact of blood and gas. Concurrent with exploration of extracorporeal ventilation methods was the development of perfusion systems to maintain blood flow to ex vivo organs.¹³ These efforts led to the first clinically used cardiopulmonary bypass circuit consisting of a peristaltic roller pump coupled to a film oxygenator to maintain perfusion and provide gas exchange.¹⁴

Hollow Fiber Membrane Devices andModern Oxygenators

Early oxygenators relying on direct air and blood contact were plagued by complications, such as gas embolization and the propensity to form clots. These difficulties motivated efforts to develop gas exchange devices modeled on the lung, in which blood is separated from inspired air by the alveolar epithelial and capillary endothelial membranes.¹⁵ The first membrane oxygenator consisted of polyethylene tubing wrapped around a central longitudinal axis. This design was adapted from early efforts to produce an artificial kidney and was inspired by the observation that aerated dialysates led to oxygenation of blood pumped through the device.¹⁶ This work prompted the search for the ideal oxygenator biomaterial capable of providing gas transfer, while limiting plasma diffusion across the membrane to maintain device function and operational life. The ability to make silicone into a thin film, coupled with its excellent gas diffusion properties, led to its use in the first membrane oxygenator widely deployed in clinical practice.¹⁷ Improvements in fabrication techniques and device construction led to the widespread adoption of silicone membrane oxygenators in the 1980s.

The advent of poly-4-methyl-1-pentene (PMP) as a biomaterial, with its highly efficient gas transfer properties and limited plasma leakage, led to the development of the modern oxygenator.¹⁸ Newer devices based on PMP are capable of providing prolonged support, often several weeks or longer, before the need for replacement because of reduced performance. An example of a commercially available PMP-based hollow fiber oxygenator is shown in Fig. 28.1. In modern oxygenators, blood is pumped through the device where it comes into contact with sheets of hollow fibers carrying a sweep gas. As carbon dioxide diffuses more rapidly into blood than oxygen because of its higher solubility, oxygenators are designed for blood transiting through the device to have multiple interactions with fiber bundles to achieve adequate oxygenation. Carbon dioxide removal by the device, in turn, is determined by: (1) blood flow rate through the device; (2) sweep gas flow rate; and (3) sweep gas composition.¹⁹

Pump Technology

Early extracorporeal devices relied on peristaltic pumps, widely used in a variety of clinical applications, such as dialysis machines, infusion pumps, and cardiopulmonary bypass machines, to withdraw blood and pass it through the circuit.¹³ Ease of implementation, minimal priming volume, and a set relationship between revolutions per minute (RPMs) and the flow delivered motivated their adoption in early devices. However, these pumps generate flow through physical compression of the tubing, causing trauma to the blood and activation of platelets and leukocytes, while friction of the pump rollers on the tubing creates wear over time, and may lead to tubing rupture and embolization of small pieces of the tubing.²⁰

Centrifugal pumps produce less heating and markedly reduced platelet and leukocyte activation compared with peristaltic pumps, resulting in their rapid integration into modern extracorporeal circuits.²¹ Centrifugal pumps can still induce hemolysis, but this is partially dependent on pump speed, with increased levels of red blood cell destruction observed at extremes of device function.²² Priming of centrifugal pumps is more challenging, and entrained air can be difficult to extract. The high operational speed of centrifugal pumps, typically 2500 to 5000 RPMs, is also a hurdle to the integration of autoregulatory feedback into device operation. An example of a commonly used and commercially available centrifugal pump is shown in Fig. 28.2.

The Modern Extracorporeal Membrane Oxygenation Circuit

Extracorporeal ventilatory support therapies in current clinical practice largely consist of implementations of extracorporeal membrane oxygenation (ECMO) circuits such that the terms can be used interchangeably. However, with the advance of newer, more specialized extracorporeal ventilatory therapies, the terminology of ECMO will likely become associated with a specific device configuration. ECMO itself is a confusing term because it is simultaneously used to refer both to circulatory and ventilatory support implementations of the same device. The specific therapeutic function is dependent on the cannulation strategy used.

The core components of the ECMO circuit consist of: (1) membrane oxygenator; (2) centrifugal pump and pump controller; (3) heater; and (4) vascular cannula and circuit tubing.^23,24 A schematic of the core components of an ECMO circuit is shown in Fig. 28.3. Additional circuit components, such as flow meters and air bubble detectors, can be integrated to provide expanded monitoring capabilities and safeguards to reduce complications. Modern oxygenators also maintain blood at a desired temperature by the passage of heated water through the device housing. An example of a modern ECMO using an integrated pump and oxygenator unit mounted on the controller is shown in Fig. 28.4.

Clinical Adoption of Extracorporeal Membrane Oxygenation Support

The first widely reported successful clinical use of ECMO took place at the California Pacific Medical Center in San Francisco in 1971, in which a 24-year-old man with trauma-related acute respiratory distress syndrome (ARDS) was supported for 75 hours with a modified form of extracorporeal bypass, followed by gradual recovery and hospital discharge.²⁵ Further anecdotal case experience motivated a National Institutes of Health sponsored prospective, randomized, multicenter controlled trial in the early 1970s to compare outcomes for patients with acute respiratory failure supported by conventional medical therapy versus ECMO.²⁶ In the setting of mortality rates of 90% for both groups, the trial was halted prematurely following enrollment of only 90 patients in total. The lack of success of this and subsequent trials dampened enthusiasm for the use of extracorporeal support for adult patients and hampered research and development efforts.

Despite negative trials in adult patients, case experience with ECMO support in neonatal respiratory failure demonstrated marked improvement in mortality compared with predicated outcomes with traditional therapy.⁸ Multiple factors likely contributed to the different outcomes observed in neonates compared with adults, which included prompt initiation of support; different etiology of lung disease in neonates with the primary cause being airway immaturity; and plasticity of the newborn lung. Subsequent clinical trials and accumulating evidence of efficacy led to ECMO becoming the preferred support modality for some forms of neonatal respiratory failure.

Although ECMO gained an increasing presence in pediatric hospitals, it was used on a limited basis as a means of supporting postcardiotomy adult patients unable to wean from cardiopulmonary bypass. By the time of the H1N1 influenza pandemic in 2009, expanding ECMO capability in adult cardiac surgical intensive care units made extracorporeal support an accessible salvage therapy for adult ARDS patients. The pandemic caused a surge in previously healthy patients now critically ill with severe ARDS generating renewed interest in ECMO as a support modality. A large-scale multicenter trial comparing ECMO with traditional ARDS therapy, although flawed by variations in practices and experience level between clinical sites, favored treatment of patients with ARDS at centers capable of providing ECMO support.⁵

Following the H1N1 pandemic, the global number of ECMO centers doubled within seven years.² The increase in ECMO centers coincided with concomitant growth in use of ECMO as support modality. Clinical indications in adult patients are expanding beyond postcardiotomy circulatory failure and salvage therapy in ARDS to providing support for patients as a bridge to transplant and for patients with medical cardiogenic shock.^27–29 Potential indications continue to expand as extracorporeal approaches are being trialed as an alternative to conventional therapies for procedural and operative support.

Cannulation Approaches and Support Modality

ECMO can be categorized as providing two primary forms of support: ventilatory and circulatory. A third possibility consists of a combination of both forms for the patient in circulatory shock with profound concomitant lung failure. The cannulation strategy deployed determines the form of support provided by the ECMO circuit. For this chapter, the following terminology will be used:

• • Venovenous (VV) ECMO: ventilatory support
  
• • Venoarterial (VA) ECMO: circulatory support
  
• • Venoarteriovenous (VAV) ECMO: ventilatory and circulatory support

These terms are used to describe the source of blood entering the circuit (venous) followed by the anatomic site of the blood returned to the patient from the circuit (venous or arterial or a combination of both). VA ECMO can be further described depending on whether the site of cannulation is central VA ECMO, consisting of direct bicaval or right atrial drainage of venous blood and return of oxygenated blood to the aortic arch, or peripheral VA ECMO, in which cannula are inserted into the peripheral vasculature, most commonly the femoral vessels, for drainage and return.^30–32 The differences in anatomic site of cannulation in central and peripheral VA ECMO are shown in Fig. 28.5. In the case of central VA ECMO, the return cannula supplies oxygenated blood to the proximal aortic arch and provides physiologic support for both ventilatory and circulatory failure. As clinical use of ECMO has expanded and initiation of support has extended from the surgical theater to the intensive care unit and emergency department, peripheral cannulation methods relying on the Seldinger technique and serial dilation have become more common to establish vascular access and initiate support.^33–36

For this chapter, the cannula used to remove blood from the patient and direct it to the ECMO circuit is termed the withdrawal cannula, whereas the cannula carrying oxygenated blood from the ECMO circuit to the patient will be referred to as the return cannula. To accommodate high blood flow rates (≥4 L/min), withdrawal cannula typically are large bore (21 or 25 Fr). The withdrawal cannula can be single stage, with a single inlet at the end of the cannula, or multistage, in which small holes are placed at intervals along the length of the cannula to achieve improved drainage.³⁷ Percutaneously placed withdrawal cannula are typically advanced in the inferior vena cava to the level right atrium, with the cannula ranging in length from 50 to 60 cm. Return cannula are frequently shorter, 18 cm is a common length to accommodate placement in the internal jugular vein or femoral artery, depending on the modality of support, and vary in diameter from 15 to 21 Fr. Double lumen cannula, designed for placement in the internal jugular vein with the distal tip residing in the inferior vena cava (IVC) and with holes in the superior vena cava (SVC) to provide for drainage of both upper body and lower body venous blood and an outlet for return of oxygenated blood to the right atrium, are used in VV ECMO to facilitate ambulation.³⁸ The different approaches to cannulation for providing VV ECMO support are shown in Fig. 28.6.

This terminology applies to the most commonly used configurations utilized in clinical practice. Because VV ECMO provides for gas exchange to support lung failure, use of this configuration requires adequate heart function to maintain end-organ perfusion. VA ECMO achieves circulatory support through shunting blood from the systemic venous to the systemic arterial circulation. This configuration profoundly alters systemic hemodynamics with specific effects depending on support titration and the physiologic state of the patient. VAV ECMO is less commonly used and is primarily attempted in patients with combined respiratory and circulatory failure.³⁵

Circuit Operational Parameters

The basic components of the ECMO circuit have few functional parameters for titration of support. ECMO circuit flow is a function of: (1) pump speed; (2) afterload to the pump including circuit resistance and patient vascular resistance; (3) patient volume status and the negative pressure threshold for vascular collapse around the withdrawal cannula; and (4) cardiac function.²⁷ Oxygenator gas exchange is a function of the sweep gas flow rate and composition of the sweep gas. Increasing the sweep gas flow rate increases removal of carbon dioxide whereas increasing the oxygen fraction increases the diffusion gradient to increase delivery to the blood. Support provided by ECMO is a complex integration of device operation and patient physiologic state and anatomy.

Pump speed is the major parameter available to readily adjust circuit flow. The RPM range that constitutes safe operation is specific to a given pump with speeds at either extreme associated with increased risk of hemolysis. High RPMs damage cells from accelerated velocities and increased shear stress, whereas low RPMs result in inefficient propulsion of flow with blood circulating multiple times through a pump before being expelled causing accumulated stress.^39,40 Circuit blood flow is also partially determined by pump afterload. Factors that increase afterload include clot formation within the oxygenator or at connection points in the circuit, kinking or obstruction of the return cannula, and high pressure within the return circulation of the patient. For VV ECMO, in which the return cannula is placed in the venous system, this is less of an issue than for VA ECMO where the pump must work against the pressure of the arterial system. As vascular pressure increases, the amount of flow provided by the ECMO circuit decreases resulting in a reduction in support. Flow is also limited by drain pressure generated by the pump at the withdrawal cannula. As pump RPMs are increased, negative pressure is generated at the drain site within the venous system risking venous collapse around the cannula resulting in a suction event and temporary cessation of flow.

Blood contact with cannulas, tubing, pump, and oxygenator promotes clotting cascade activation increasing the risk of thromboemboli to the patient and circuit failure from thrombosis.⁴¹ Whereas novel antithrombotic coatings and new biomaterials hold promise in reducing clot formation, anticoagulation remains an important consideration.^42–44 This is particularly relevant in circulatory support, in which blood is returned to the systemic arterial circulation where a thromboembolism may cause a stroke or end-organ damage. Anticoagulation is also used in an effort to reduce clot formation within the oxygenator and to extend the operational life of the circuit. Heparin is most commonly used because of its availability, familiarity, and reversibility in the setting of active bleeding. The site of administration, whether delivered systemically or into the circuit, the therapeutic target range, and the laboratory test used to titrate therapy vary between centers all lack definitive evidence to guide a specific approach.

Common ECMO circuit measurements include withdrawal and return pressures and pressures measured across the oxygenator. An increasing pressure drop across the oxygenator can signify clot formation leading to increased flow resistance. Some devices include continuous oxygen saturation measurements of the venous blood, which is a useful marker of recirculation of blood from the return to the withdrawal cannula during VV ECMO support. Additional features include bubble detectors to identify the presence of entrained air in the circuit and flow alarms.

Motivation of Extracorporeal Membrane Oxygenation Use as Bridge to Recovery in Lung Failure

Mechanical ventilation is the mainstay of support for the patient with respiratory failure, but it carries the risk of ventilator-induced lung injury (VILI).^48,49 Animal models of ARDS demonstrate that excessive distending pressures exacerbate underlying injury whereas hyperoxia leads to progressive lung inflammation and eventual death.^50,51 Multicenter clinical studies evaluating ventilation strategies in ARDS demonstrate improved mortality with low tidal volume ventilation (LTVV) approaches while subsequent analysis demonstrating that low lung compliance and high driving pressures are associated with worse patient outcomes.⁵²

In the setting of severe disease, patients may either: (1) not be able to maintain homeostasis with LTVV or (2) may experience ongoing VILI and progressive lung disease despite ventilator optimization. The emergence of ECMO provides an alternative approach to supporting patients unable to be safely maintained with mechanical ventilation alone.⁵³ The motivation for use of ECMO is to maintain physiologic homeostasis while optimizing mechanical ventilation to limit lung injury and facilitate recovery from the underlying disease process. Similar reasoning applies to the use of ECMO for patients with bronchopleural fistulas in which extracorporeal support enables reduced need for positive pressure ventilation to promote lung healing.

The ability of ECMO to achieve its intended therapeutic purpose is dependent on multiple factors: (1) the severity of lung injury and residual gas exchange capacity of the lungs; (2) the specific physiologic impairment; and (3) the fraction of the cardiac output entrained into the ECMO circuit. Increasing severity of lung injury necessitates an increased load on the ECMO circuit to provide physiologic gas exchange. The specific nature of the impairment, whether predominantly hypoxic or hypercapnic, determines the amount of blood flow required to be entrained into the device to achieve its physiologic support goal. The function of the ECMO circuit as a support modality in respiratory failure is intrinsically linked to gas transport in the body. A schematic of the integration of VV ECMO with the systemic venous circulation is shown in Fig. 28.7.

Physiology of Hypoxic and Hypercapnic Respiratory Failure

Approximately 97% of the oxygen content in the arterial circulation is bound to hemoglobin within red blood cells with the residual 3% of oxygen present as dissolved gas.⁵⁴ For ECMO to provide meaningful support to patients with predominantly hypoxic respiratory failure, a large fraction of the total circulating hemoglobin must be entrained into the ECMO circuit to provide adequate oxygen delivery. This reality determines the cannulation strategy and choice of cannula to achieve adequate circuit blood flow.

Unlike oxygen transport, carbon dioxide (CO2) has an additional carrier in the form of bicarbonate ion which acts as a CO2 reservoir in the blood. In arterial blood, approximately 90% of the total CO2 is carried as bicarbonate ion with the remainder present equally as either dissolved gas or bound to hemoglobin.⁵⁵ The enzyme carbonic anhydrase, ubiquitous in red blood cells, reversibly interconverts bicarbonate and CO2 via carbonic acid. The presence of the large reservoir provides additional CO2 that can be ventilated as blood passes through the circuit.

Physiologic differences in oxygen and CO2 transport in the body translate into differing efficacies in extracorporeal support. ECMO is more readily able to support a patient primarily suffering from hypercapnic respiratory failure at a lower blood flow rate in comparison to a patient with predominantly hypoxic failure. The function of the membrane oxygenator also provides for additional titration of gas exchange for CO2 removal not readily available for oxygenation. Increasing the sweep gas rate allows for increased CO2 clearance in comparison with oxygenation in which increasing the fraction of inspired oxygen (FiO2) achieves only modestly increased total levels of oxygen delivery once hemoglobin is fully saturated.^19,56

Cannulation Approaches to Provide Extracorporeal Lung Support

There are three primary VV cannulation approaches for providing ECMO lung support: (1) femoral vein and right internal jugular (RIJ) vein cannulation; (2) dual lumen bicaval cannulation via the RIJ vein; and (3) femoral vein-femoral vein cannulation. The femoral-RIJ approach generally provides for high blood flow levels (>4 liters per minute [LPM]) and is straightforward to manage. Dual lumen bicaval cannula offer upper and lower body venous drainage but typically achieve lower flow rates because of a smaller comparable lumen size in comparison to what can be achieved with a multistage withdrawal cannula. The return outlet of the dual lumen bicaval cannula is also prone to malpositioning and may induce turbulent flow to the right ventricle or cause recirculation within the cannula. An example of the positioning of a dual lumen bicaval cannula as seen on a chest radiograph is shown in Fig. 28.8 with a Doppler ultrasound demonstrating the flow from the return outlet shown in Fig. 28.9. The femoral-femoral vein approach is limited in achievable total flow because the withdrawal cannula must be positioned inferior to the return cannula, which reduces the amount of lower body venous return captured into the circuit. Each cannulation strategy offers specific benefits and drawbacks with a combination of patient anatomic factors, cannulating physician expertise, and physiologic demands of extracorporeal support determining the strategy used.

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