Extracorporeal membrane oxygenation (ECMO), a type of extracorporeal life support (ECLS), was first utilized in the pediatric population in the 1970s.1–3 What began as a largely untested treatment modality of last resort in moribund patients has become an established, increasingly applied intervention in the management of respiratory and/or cardiac failure. According to the Pediatric Extracorporeal Life Support Organization (ELSO) Registry’s latest international report, there was a 24% increase in the number of reported pediatric ECMO cases and a 55% increase in the number of participating centers between 2009 and 2015.4 Although neonates with respiratory failure remain the largest cumulative group in the ELSO registry, their proportion of new cases reported has dropped off significantly since the early 1990s because of advances in neonatal ventilation and broadening indications for ECMO use.4,5 Unconventional uses, such as elective or semielective ECMO cannulation for hemodynamic support during high-risk procedures, have been reported in both adults and children and are likely to become more commonplace as the technology advances and the risk-benefit profiles of such strategies are better understood.6–8
Given the increasing utilization and evolving epidemiology of ECMO support, pediatric anesthesiologists practicing at medical centers with ECMO capability should have a thorough working understanding of this support modality.
Indications and Contraindications
ECMO, as an adjunct to optimal conventional management, is indicated to temporarily support heart and/or lung function during cardiopulmonary failure with a high risk of mortality. In this setting, it is used as a bridge to recovery, implementation of a further bridging strategy (eg, ventricular assist device, lung assist device), transplantation, or further decision-making. Support may be partial or full, and ranges from days to months in duration. Absolute criteria for ECMO implementation have not been definitely established, but suggested age-specific and indication-specific criteria have been put forth in the ELSO Guidelines.9 ECMO is increasingly being utilized during cardiac arrest in the neonatal and pediatric patient populations as part of extracorporeal cardiopulmonary resuscitation and has shown to confer a survival advantage.4,10 It may also be indicated on an elective or a semielective basis in situations where an anticipated period of cardiopulmonary insufficiency could lead to morbidity such as during high-risk diagnostic, interventional, or surgical procedures.6,7
“Absolute” contraindications to ECMO use vary by age group, but generally include lethal chromosomal disorder or congenital anomalies, irreversible brain damage, high-grade intracranial hemorrhage, uncontrolled bleeding, and recent surgical (especially neurosurgical) procedures or trauma.9 ECMO is relatively contraindicated in patients with prolonged pre-ECMO ventilation, those with irreversible end-organ damage, and in cases of futility.9 In the neonatal population, age younger than 34 weeks postconceptual age and weight <2 kg are also relative contraindications because of the increased risk of major intracranial hemorrhage and mortality.11,12
Circuitry, Modes, and Cannulation Strategy
The basic ECMO circuit (Fig. 1) consists of access cannulas (venous, arterial, double-lumen venous), circuit tubing, a mechanical pump (roller or centrifugal), a gas exchange device (oxygenator), and a heat exchanger. More complex circuits also incorporate integrated flow and pressure monitors, infusion and blood sampling ports, continuous oxyhemoglobin monitoring, and a veno-arterial bridge to allow for weaning and/or temporary disconnection of the patient from the circuit.13 An in-depth review of the evolution and the relative benefits of the various circuitry options is beyond the scope of this primer and has been well examined elsewhere.13 ECMO system selection and customization remains patient size- and institution-dependent; however, over the last decade, there has been an overall trend toward centrifugal pumps and nonsilicone oxygenators.4 ECMO circuits can be primed with a clear (crystalloid) or blood (packed red blood cells, fresh frozen plasma, albumin, platelets) prime depending on the urgency of cannulation and the size of the patient. Clear-primed circuits are considered usable for up to 30 days, although system sterility may be maintained beyond this period.14–16
Venous-Venous (VV) ECMO
VV ECMO is utilized in cases of respiratory failure with preserved cardiac function. Blood is drained from a major vein, pumped through the ECMO circuit, and returned to the patient through a vein, either through a separate venous cannula or through the more proximally located orifice of a double-lumen venous cannula (Fig. 2). Double-lumen venous catheters are available as small as 8 Fr and are placed with transesophageal or fluoroscopic guidance to optimize positioning of the distal cannula to direct flow into the right atrium and thereby minimize mixing of oxygenated and deoxygenated blood. Irrespective of optimal cannula placement, there will always be some degree of venous mixing and arterial desaturation (80% to 90%) with this mode of ECMO. Adequate oxygenation is dependent on adequate cardiac output, hemoglobin concentration, membrane gas exchange properties, and ECMO flow. VV ECMO flow rates should allow for adequate oxygen delivery (6 to 7 mL/kg/min in neonates, 4 to 5 mL/kg/min in children, 3 mL/kg/min in adults) to compensate for normal consumption.9 Target VV ECMO flow is typically 120% of target venous-arterial (VA) ECMO flow, for example, 120 mL/kg/min in neonates. If VV ECMO is instituted solely for carbon dioxide (CO2) removal, the required flow rate is much less (∼10% cardiac output), with CO2 removal dependent on the sweep gas flow rate and the membrane gas exchange properties.
Venous-Arterial (VA) ECMO
VA ECMO can be used for mechanical support in cases of respiratory, cardiac, or combined cardiorespiratory failure. Blood is drained from the venous system and returned to the arterial system through peripherally (carotid or femoral) or centrally inserted cannulas (Fig. 3). The circuit should be sized to be capable of supporting a normal cardiac index (3 L/m2/min). Similar to VV ECMO, adequate oxygenation is dependent on adequate ECMO flow (ie, systemic perfusion), hemoglobin concentration, and membrane gas exchange properties. Typical flow rates for infants, children, and adults are 100, 75, and 50 mL/kg/min, respectively, with a target mixed venous saturation of >70%.9 CO2 removal is dependent on the sweep gas flow rate and the membrane gas exchange properties.
VA ECMO exposes the patient to the risks of systemic embolism (air, thrombus), ischemia distal to the arterial cannulation site, and in the case of femoral cannulation in the setting of preserved cardiac output, differential hypoxemia. In the pediatric patient, the choice of arterial cannulation site is dependent on patient size, history of past cannulations, and institutional preference.17,18 Distal arterial perfusion, vessel-sparing arterial cannulation, and carotid artery repair have been proffered as potential solutions to mitigate the long-term ischemic complications of arterial cannulation; however, they have not been decisively proven to improve outcomes.19–21 Patients cannulated to VA ECMO may require the percutaneous or surgical placement of an additional cannula to completely unload the left ventricle and prevent left ventricle distention and its downstream effects (cardiogenic edema, intracardiac thrombus formation, subendocardial ischemia).22,23
Arterio-venous ECMO is used very rarely for isolated CO2 removal. This type of ECMO is flow limited and capable of providing limited respiratory support. Arterial inflow forces blood across a membrane gas exchanger and blood is then returned to the patient through a venous cannula.
Patients supported with ECMO require intensive monitoring. This is accomplished by a combination of invasive monitoring lines, laboratory tests (blood gases, hematocrit, coagulation parameters), and monitoring devices that are integrated into the ECMO circuit itself. During VV ECMO, central venous and arterial pressure monitoring are accurate and reflective of the patient’s underlying cardiac function. Perturbations in these values should be addressed just as they would be in a patient without ECMO support. During VA ECMO, systemic perfusion is a function of both native cardiac output (20% to 40%) and ECMO flow (60% to 80%). The arterial pressure waveform is dampened in patients supported with VA ECMO, with the degree of pulsatility present dependent on the patient’s myocardial function and native cardiac output. An increase in pulsatility may indicate myocardial recovery, whereas a decrease may indicate worsening myocardial dysfunction, excessive afterload, hypovolemia, or dysrhythmia. When siting an arterial line, it is important to consider the location of the arterial cannula so that the arterial blood gas sample drawn from this line is representative of the body as a whole. With carotid artery cannulation, an artery other than the ipsilateral radial or the ulnar artery should be used to avoid erroneously sampling the highly oxygenated arterial cannula outflow. With femoral artery cannulation, the right radial artery is the preferred site (and sites distal to the cannula are avoided), so that differential oxygenation (North-South syndrome, ECMO Harlequin syndrome) can be better detected and monitored as cardiac function improves. Any site may be used when a central cannulation strategy is used. Unlike in VV ECMO, measured central venous pressures (CVP) are inaccurate because of venous drainage through the ECMO circuit; however, the trend can be informative, and should be monitored closely. Acute increases in CVP may be indicative of venous cannula obstruction, tension pneumothorax, tamponade, or abdominal compartment syndrome. Decreases in CVP are seen with hypovolemia and can lead to intermittent venous cannula obstruction (line “chatter”) and resultant hemolysis.
Modern ECMO circuits incorporate several important in-line monitors that detect bubbles and measure flow, inlet (premembrane) and outlet (postmembrane) line pressures, and premembrane and postmembrane oxyhemoglobin concentration. Excessively low (more negative) inlet pressures or high outlet pressures indicate cannula obstruction, whereas an increasing transmembrane gradient (>50 mm Hg) may indicate clotting within the oxygenator. Circuits with servo pressure regulation will adjust pump flow to prevent excessive extremes in these pressures.
The hemodynamic goal of VA ECMO is to optimize systemic perfusion, and hence oxygen delivery, in the setting of cardiorespiratory failure. ECMO flow is titrated to ensure an age-appropriate mean arterial pressure, and the adequacy of perfusion is confirmed with measurements of mixed venous oxygenation (MVO2, goal >70%), serum lactate, and urine output. Although VA ECMO volume off-loads the right heart, it increases left ventricular afterload and can thus further compromise myocardial function.24 Inotropic support and/or afterload-reducing agents may be required to maintain normal left-sided pressures, wall tension, and adequate forward flow through the heart. In cases where systemic vascular resistance is low, a pure vasopressor may be needed to maintain a normal mean arterial pressure.
Fluid management of the patient on ECMO targets euvolemia with a normal body weight. Once stable hemodynamics have been achieved, diuretics are administered to achieve a slightly negative daily fluid balance. Continuous hemofiltration may be added when the response to diuretics is inadequate.9
Bleeding occurs in up to 38% to 89.6% of pediatric patients supported with ECMO and is associated with increased mortality.25–27 A cardiac (or extracorporeal cardiopulmonary resuscitation) indication for cannulation, recent cardiac surgery, VA ECMO strategy, age older than 1 year, and longer duration of ECMO support have all been shown to be risk factors for bleeding.25–27 Consumptive coagulopathy, platelet dysfunction, hyperfibrinolysis, acquired von Willebrand syndrome, and the effects of administered anticoagulants all are known to play a role.28 ECMO blood transfusion protocols are institution-specific and based on limited evidence. Transfusions to maintain a hematocrit of 35% to 40%, international normalized ratio <2, fibrinogen >100 to 150 mg/dL, and a platelet count >80 to 100,000 are generally accepted, with much lower platelet counts accepted in older patients without bleeding or risk of bleeding.29 Careful consideration should be made as to the risks and benefits associated with both intensive monitoring and transfusion. Phlebotomy directly contributes to the transfusion requirement in pediatric ECMO patients whereas it has been shown that red blood cell transfusion is often not effective in improving tissue oxygenation and is associated with increased mortality in a dose-response fashion.25,30,31 Antifibrinolytic therapy is a safe and effective adjunct in the management of the bleeding ECMO patient.32,33 Recombinant activated factor VII has shown limited efficacy in this clinical setting.34,35
Patients supported with ECMO are commonly managed with protective ventilatory strategies to prevent and manage ventilator-associated lung injury. Limited peak inspiratory pressures (18 to 20 mm Hg H2O), limited size-appropriate tidal volumes (6 to 8 mL/kg), a low rate (∼10 breaths/min), and a generous positive end-expiratory pressure can be applied as a starting point for most patients. Patient-specific factors such as underlying lung pathology or congenital heart disease may require alternate, more customized, management strategies, especially during the weaning process. When ECMO is instituted for a respiratory indication, it is generally preferable to increase ECMO rather than ventilatory support in the event of inadequate gas exchange. Patients supported with peripheral ECMO as a bridge to lung transplant may be extubated to minimize deconditioning.
ECMO management requires careful monitoring and modulation of the coagulation system. When ECMO is initiated, a patient’s blood is exposed to a large surface area of foreign material, initiating an immediate, continuous procoagulant, proinflammatory response. Serum proteins are deposited on the exposed circuitry components, leading to a process of platelet activation, coagulation (contact/intrinsic and extrinsic) pathway activation, and fibrinolysis.36 Thrombosis is a common complication of ECMO, with an increased risk found in pediatric patients with a nonrespiratory indication for support, VA ECMO strategy, and in those with hemolysis.25 Although thrombosis may not be associated with an increased risk of mortality, the continuous nature of this process can lead to a consumptive coagulopathy and bleeding, which is associated with increased mortality.25–27
Anticoagulation management in the neonatal and pediatric ECMO population is less straightforward than in adults because of maturational changes in the coagulation system that alter both the therapeutic response to anticoagulants and the reliability of the available monitoring studies.37–43 The most common anticoagulant used during ECMO support is unfractionated heparin because of its wide availability, familiarity of use, rapid onset, and reversibility with protamine.44 A bolus dose of 50 to 100 U/kg is administered immediately before cannulation, followed by a continuous infusion of 20 to 50 U/kg/h once the activated clotting time is <300s. The infusion is titrated to a goal activated clotting time of 180 to 220 seconds (1.5 times normal) measured every 30 minutes to 2 hours depending on the clinical situation. In neonates, who are most at risk for intraventricular hemorrhage, the bolus dose is often limited to 50 U/kg. There are currently no evidence-based guidelines for the management of anticoagulation during neonatal and pediatric ECMO. Monitoring practices vary widely by institution but are increasingly incorporating several laboratory parameters including activated partial thromboplastin time, thromboelastography, fibrinogen, antithrombin III, and anti-factor Xa.44 It has yet to be definitively proven that monitoring protocols incorporating multiple parameters lead to an improvement in outcomes or that such an improvement is transferrable across programs.45–47
Bivalirudin, a parenteral direct thrombin inhibitor, has been used safely for pediatric ECMO patients with a contraindication to heparin therapy.48 Bivalirudin has a number of theoretical advantages compared with heparin—it binds to both free and clot-bound thrombin, has a short half-life, is nonrenally metabolized, and lacks both required cofactors (ie, antithrombin III) and feedback inhibitors. It does not, however, have a reversal agent or inhibit the contact pathway. Bivalirudin is administered as a bolus dose of 0.05 to 0.5 mg/kg, followed by an infusion of 0.03 to 0.1 mg/kg/h, titrated to an activated partial thromboplastin time of 1.5 to 2× normal.
The initiation of ECMO support drastically alters the pharmacokinetics of drugs administered to the patient because of an increase in volume of distribution, altered clearance, and sequestration of drugs in the ECMO circuitry components. Lipophilic and protein-bound drugs such as fentanyl are more prone to sequestration, as has been demonstrated in multiple small ex vivo and in vivo pharmacokinetic studies.49–53 With the exception of morphine, the initiation of ECMO support requires the careful, but significant up-titration of most sedative and analgesic agents to obtain and maintain the desired therapeutic effect.
In conclusion, improvements in ECMO equipment and the care of patients supported with ECMO led to an increased utilization of this technology. Hence, the pediatric anesthesiologist is increasingly faced with managing patients during ECMO cannulation, decannulation, cardiac, and noncardiac surgical procedures in the operating room or at the bedside in the intensive care unit. A better understanding of the cannulation strategies, hemodynamics, pharmacokinetics, and pharmacodynamics of the patient on ECMO is a must to safely manage these children.
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