VV ECMO, involving only gas exchange without the use of hemodynamic support, is reserved for refractory hypoxic respiratory failure, with preserved cardiac function. Deoxygenated venous blood is drained into an oxygenator. Subsequently, hyperoxygenated arterialized blood is returned to the venous circulation. Carbon dioxide levels are also controlled in this setting.
Both VA and VV ECMO can be instituted either centrally or peripherally. Central VA ECMO involves cannulation to drain the right atrium and return blood to the ascending aorta. Peripheral VA ECMO drains blood from the femoral or internal jugular vein and returns it through the common femoral artery. Central VV ECMO involves 2 cannulae in the right atrium, and peripheral VV ECMO drains blood from the femoral vein and returns it through the internal jugular vein. Care must be taken with central VV ECMO to separate the cannulae (typically by >2 cm) to avoid redundant recirculation, leading to hypoxia.
The Extracorporeal Life Support Organization is “dedicated to the development and evaluation of novel therapies for support of failing organ systems” and has maintained a multicenter, international ECMO database since 1985. Indications for ECMO are classified as: respiratory failure, heart failure, and cardiopulmonary resuscitation (Table 1).a
There have also been observational and case series studies on patients who experienced cardiac failure from cardiac arrest, failure to wean from CPB, or cardiogenic shock.17–24 The reported survival rate in these studies approached 45%.18–21,23,24 Two studies favored ECMO over cardiopulmonary resuscitation and indicated it was associated with a survival benefit, especially over those who had received cardiopulmonary resuscitation for >10 minutes.17,22
Regardless of the controversy that surrounds ECMO, the past 20 years have seen increased use and the development of new ECMO centers.25 The Extracorporeal Life Support Registry Report from 2012 (recorded internationally from 1991–2011), lists a cumulative sum of 48,437 patients. Approximately, 56% of the 5437 adult patients survived ECMO usage; 45% of all ECMO patients survived until transfer to another facility (Table 3).a More details of morbid complications, however, are required.
Due to the requirement for vascular access, anticoagulation, and blood-surface interfacing, there are multiple complications that can occur to a patient while on ECMO support. These are device related, patient related, or anticoagulation related, as outlined in (Table 4).5,26–28
Nearly 5% of neonatal ECMO runs are complicated by entrainment of air into the venous circuit limb.29 Adults may have a greater tolerance for the same volume of entrained air (especially on VV ECMO), but this remains a feared complication. Treatment options of this complication are similar to the treatment of massive air embolus during CPB, including hypothermic retrograde cerebral perfusion,30 circuit replacement, and hyperbaric oxygen therapy.31
Suction events involve interruption of ECMO flow (with resultant organ hypoperfusion), secondary to venous collapse onto the drainage cannulae from hypovolemia, or from malpositioned cannulae.32 Similarly, obstructed venous drainage can result in venous engorgement, causing the damage of vital organs.
The occurrence of thrombi in the pump or in the oxygenator can be recognized by a visible thrombus, an increasing pressure decrease across the oxygenator, or a low postoxygenator PO2 with a high postoxygenator PCO2.32 Thrombi in the circuit can also be the result of low circuit flow states, such as from malpositioned and kinked tubing or cannulae and from low velocity eddies around connection sites or within the oxygenator. The large contact surface area within the oxygenator is ideal for trapping activated platelets, monocytes, or erythrocytes that promote coagulation either by expressing tissue factor (TF), releasing procoagulant microparticles or both.33–37
Disruption of the red blood cell membrane leads to hemolysis, which is a common complication of patients on ECMO.38 Betrus et al.39 cite implicated causes including thrombus formation in the circuit, shear stress,40,41 mechanical stress from a centrifugal or the roller pump,42 the physical properties of area of turbulence in the ECMO circuit,43 and changes in blood volume.44 Hemolysis can precipitate acute kidney injury (AKI), hematuria,45 and possible neurological sequelae of hyperbilirubinemia. Hemolysis can be measured by decreasing hemoglobin levels, increasing plasma-free hemoglobin levels, and hyperbilirubinemia.46 Furthermore, hemolysis can also cause excess carbon monoxide (CO)38 that has been measured as increased carboxyhemoglobin levels.47 Free heme stimulates heme oxygenase-148 production, converting heme into CO, iron, and biliverdin. CO may act locally as a vasodilator but may also impair tissue oxygenation; it appears that low or excessive heme oxygenase-1 activation, CO generation, and carboxyhemoglobin are associated with adverse outcomes after cardiac surgery.49
Microemboli associated with air emboli generated from central venous lines without air filters have been described by using transcranial Doppler signals in patients on ECMO.50 Air filters have been recommended for use with IV infusions as the membrane oxygenator filter may not arrest such microemboli.
Neurological injury, including cerebrovascular hemorrhage, ischemia, infarction, and general neurological deficit, is the most feared complication52 and is the major cause of death in the infant population.53,54 The incidence and mortality associated with neurological injury is not as extensively described in the adult ECMO population. However, following 28 adult survivors for 5 years after their ECMO treatment of cardiopulmonary failure,55 Risnes et al.55 described normal clinical findings in 43% but impaired neuropsychological performance and pathologic electroencephalograms in 41% of patients, as well as abnormal neuroradiological findings in 52%. The incidence of cerebral infarction and hemorrhage was higher with the use of VA over VV ECMO, but neuropsychological impairment was equally divided.55 Furthermore, of 87 patients treated with ECMO at the Mayo Clinic,56 neurological events occurred in 42 with diagnoses including subarachnoid hemorrhage, ischemic watershed infarctions, hypoxic-ischemic encephalopathy, and brain death. In those who died, 9 of 10 brains studied at autopsy demonstrated hypoxic-ischemic and hemorrhagic lesions of vascular origin. Retrospectively, female gender and thrombocytopenia appeared to be the most important predictors of intracranial hemorrhage, with AKI also contributing. Patients with intracranial hemorrhage had a significantly higher risk of mortality.57 Elucidation of risk factors for other neurological injury would be of value.
AKI also appears to be an independent risk factor for ECMO-associated mortality. In 102 adult ECMO patients, Chen et al.17 identified Acute Kidney Injury Network scores in the categories of age and Glasgow Coma Scale score on the first day of intensive care unit admission as independent risk factors for hospital mortality.58 A smaller study did not confirm these results either due to a reduced sample size or confounding due to reductions in creatinine after hemofiltration performed via the ECMO circuit.59 However, the need for and the duration of renal replacement therapy have both been associated with increased mortality in the setting of ECMO.60 From another perspective, Chang et al.61 demonstrated that low mean arterial blood pressure, decreasing urine output, and a high Sequential Organ Failure Assessment score were independent predictors of in-hospital mortality for patients on ECMO.
Limb ischemia is another serious complication in patients treated with ECMO. Femoral artery cannulation in the pediatric population carries a 50% incidence of limb ischemia, requiring intervention.62 Extrapolation to adult ECMO is unpredictable; larger vessels may lessen ischemic complications, but the need for larger cannulae and comorbid peripheral vascular disease may increase risk. Surprisingly, a comparison of central versus peripheral cannulation63 found similar rates of tissue malperfusion and limb ischemia with both cannulation techniques. Because central cannulation (ascending aorta and right atrium) was associated with a higher incidence of bleeding, higher transfusion rates, a greater need for reoperation and resource utilization, the authors of that article preferred peripheral cannulation. This is confounded by a preponderance of central cannulation in the postoperative setting after sternotomy/cardiac surgery, where the aorta and the right atrium have likely been accessed during the case for the institution of CPB and postoperative coagulopathy-related bleeding complications coexist with ECMO-related bleeding.
Infection is another important complication associated with the use of ECMO. In 2012, Schmidt et al.66 found that there was a significant incidence of ventilator-associated pneumonia, bloodstream infections, cannula infections, and mediastinitis. Independent predictors of death included severe sepsis or septic shock. Risk factors for infectious complications in the pediatric population include increasing age, infection before ECMO institution, and the mode of ECMO.67 In adults, bloodstream infections were the most common finding followed by surgical site, respiratory tract, and urinary tract infections. Independently associated risk factors associated with infectious complications included longer duration of ECMO support, autoimmune disease, and VV mode.68
Anticoagulation-related complications can be due to inadequate (thrombotic) or excessive anticoagulation (hemorrhagic complications). In the setting of ECMO, these complications are inextricably linked to surgical site bleeding, which itself portends considerable morbidity.69 No ideal level of anticoagulation or laboratory target has been determined. A familiar scenario is a physician minimizing heparin for fear of bleeding, while the perfusionist lobbies for more, pointing to fibrin strands in the oxygenator. The ideal most likely lies between these competing perceptions, and deciding on acceptable levels of anticoagulation requires a multidisciplinary discussion considering the following factors.
What is the pre-ECMO coagulation status? The use of antithrombotic or antiplatelet drugs in a premorbid or percutaneous coronary intervention setting, residual heparinization or postoperative coagulopathy after cardiac surgery, hepatic or renal failure complicating cardiogenic shock, inadequately controlled surgical hemorrhage or, conversely, the recent use of prohemostatic drugs (such as recombinant Factor VIIa) all need to be considered when formulating anticoagulation goals.
Which anticoagulants should be used and what are the therapeutic goals? Consideration of reversibility for impending surgery (heparin and protamine), organ dysfunction and drug metabolism (bivalirudin and especially lepirudin are renally cleared, whereas argatroban is hepatically cleared), evidence of existing clot in the circuit, and circuit characteristics that reduce the need for anticoagulation (phosphorylcholine or heparin coating) should be accounted for. If heparin-induced thrombocytopenia is present, then nonheparin anticoagulants are indicated, and (Table 5)70–73 outlines the characteristics of each.
As seen in nonbiological and extracorporeal surfaces such as CPB and ECMO circuits, when blood interacts with nonendothelial surfaces, there is a widespread inflammatory and prothrombotic response. Within minutes of ECMO initiation, there is not only a consumptive coagulopathy but also a dilution of coagulation factors.74,75 Robinson et al.76 and Stallion et al.77 studied platelet activation and transfusion in the early 1990s regarding patients on ECMO. Robinson et al.76 found that platelets adhered to surface fibrinogen, causing activation and platelet aggregation, resulting in thrombocytopenia. Bolliger et al.78 described that both hemodilution and consumption primarily reduce fibrinogen levels.
Despite this initial coagulopathy, anticoagulation is necessary to prevent thrombosis of the cannulae, oxygenator, and circuit tubing.79 Decreased fibrin deposition and microthrombi burden may reduce end-organ damage. Figure 3 depicts the process of thrombin generation occurring during ECMO with the procoagulant stimuli (green background) competing with natural (red background, black border) or pharmacological anticoagulants (red background, white border). These processes of thrombin generation triggered by TF exposure and contact activation occur both within the circuit and the microcirculation. An inflammatory response mediated by the complement system as well as macrophages and cytokines36,80–84 increases TF expression and activates platelets.
In the circuit, platelets and monocytes are deposited in flow eddies and on the oxygenators (likely sites of clot formation) and are capable of expressing TF.33–37 Circulating tissue factor pathway inhibitor and antithrombin III (AT) may be the predominant anticoagulant systems in the circuit. Heparin releases tissue factor pathway inhibitor to the circulation in addition to augmenting AT-dependent inhibition of free Factor Xa and thrombin (and to a lesser extent Factors IXa, XIa, VIIa/TF). Conversely, the site action of direct thrombin inhibitors is limited to thrombin, but they may be better at inhibiting clot-bound thrombin than the large heparin/AT complex. AT has been shown to decrease with the institution of ECMO,85 leading to a procoagulant state86 and decreased heparin responsiveness.87,88 Therefore, monitoring of heparin levels during ECMO, recommended by some,9,86,89–91 may also provide an incomplete picture unless AT levels are also monitored and maintained within a normal range. Supplementation of AT after achieving anticoagulation with higher doses of heparin will lead to a bleeding tendency as the high doses of heparin are no longer necessary after reversal of heparin resistance. This also applies to plasma administration, which acts as a source of AT, and must be considered by the team. Maintaining normal AT levels may avoid this pitfall, but there is no consensus on target levels. However, AT levels below 60% to 70% are associated with venous thrombosis,92 and AT supplementation during CPB reduces subclinical thrombin generation.93
Heparin-coated circuits have been associated with reduced red blood cell trauma and decreased activation of complement and granulocytes94–96 during CPB, but surface leaching of heparin from these circuits may limit this effect during ECMO. Similarly, the thrombogenicity of the circuit may decrease in time due to the Vroman effect, whereby competitive protein exchanges on solid surfaces can occur.97,98 The initial absorption of fibrinogen to the circuit surface encourages a fibrin-mediated procoagulant effect and platelet activation, with replacement by other coagulation-neutral proteins, such as albumin. Thus, the steady state of thrombin binding to fibrin polymers decreases over time, leading to a decrease in fibrinogen consumption and clot activation.
In contrast, the thrombomodulin/proteins C and S system is primarily localized to the endothelium but can be expressed on platelets and monocytes99; its role within the ECMO circuit is unclear, but endothelial expression is downregulated by tumor necrosis factor-α and interleukin-1. Analogous to the acute coagulopathy of trauma,100 ischemic endothelium may shed thrombomodulin into the circulation, leading to protein C consumption, coagulopathy, and hyperfibrinolysis. This, however, remains speculative. Plasmin generation via contact activation and tissue plasminogen activator release leads to fibrinolysis and platelet activation, competing with thrombin-activatable fibrinolysis inhibitor at a local level for the predominating effect. Subsequently, fibrinolysis, platelet dysfunction, and thrombocytopenia may result, leading to a situation resembling disseminated intravascular coagulation,101 although a multicenter, randomized, controlled trial by using the antifibrinolytic ε-aminocaproic acid in infants on ECMO did not show a significant difference in transfusion rates or thrombosis compared with the control group.102 The continuous activation and depletion/consumption of plasma and cellular components that could result in thrombosis or coagulopathy are unpredictable and may coexist in a patient during the course of ECMO support. Close monitoring of coagulation status is therefore necessary.
In contrast to the 400 to 480 second target for CPB, an ACT range of 180 to 220 seconds has been suggested for ECMO.109 However, different ACT platforms and their relationship to measured heparin levels and aPTT are inconsistent, especially in the lower range targeted for ECMO.110–114 Therefore, ACT monitoring alone may not achieve consistent and appropriate anticoagulation monitoring for patients requiring ECMO.
From the early literature on treating venous thromboembolism with unfractionated heparin, it was determined that heparin levels of 0.2 to 0.4 U/mL, or an anti-Factor Xa level of 0.3 to 0.7 U/mL, was equivalent to a 1.5- to 2.5-fold increase form baseline aPTT.115 However, the sensitivity of aPTT to unfractionated heparin is decreased in the setting of inflammation or pregnancy that induce high fibrinogen116 and Factor VIII levels.117 It is increased in Factor XII deficiency, lupus anticoagulant, acquired factor deficiency/hemodilution, liver disease, or disseminated intravascular coagulation, distorting the relationship between heparin levels and aPTT. To complete a hemostatic picture, viscoelastic tests (thromboelastography [TEG®] or rotational thromboelastometry [ROTEM]) can indicate heparin effect (e.g., the “r” time on a TEG®) and, with the use of a heparinase reagent to overcome heparin, can evaluate for an underlying hypo- or hypercoagulable state that may suggest a bleeding or thrombotic tendency, respectively.118 For example, a high fibrinogen and or Factor VIII level can coexist with hepatic disease, presenting a confusing situation of a prolonged prothrombin time (due to reduced Factor VII levels) despite a hypercoagulable state that could be demonstrated on a TEG® or ROTEM (reviewed in detail elsewhere).119 There is no ideal monitor for ECMO, but the above description outlines the need for extensive evaluation in these critically ill patients.
A brief survey of multiple ECMO centers around the nation (Personal communication with high-volume ECMO centers in Pennsylvania, North Carolina, California, and Massachusetts) differs widely on the use of anticoagulation monitoring; some depending only on aPTT, others on ACT, others on a combination of ACT and aPTT, and still others on TEG® only. There is no current national standardized protocol that has been elucidated for the control of anticoagulation for patients on ECMO, and further study is required in this area.
Bleeding may not strictly be secondary to coagulopathy or anticoagulation. Transfusion requirements have been reported120 to average 45 units of packed red blood cells transfused per adult ECMO patient with reexploration rates and massive transfusion of hemostatic blood products 40% to 80% of these patients.
More specifically, as a result of coagulopathy and consumption of clotting factors, adult patients on ECMO may require 2 to 3 packed red blood cells, up to 14 plasma units and cryoprecipitate daily.121–123 Platelet transfusion is also burdensome; counts of 45 to 60,000 count/μL are associated with “mild to moderate” bleeding, but no triggers or target counts have been determined. Larger transfusion volumes are independently associated with an increase in odds of mortality.124 While the prohemostatic effect of recombinant Factor VIIa has been well described and thrombotic complications recognized,125 it must be emphasized that the setting of ECMO predisposes to thrombotic complications,126 especially after coadministration of other factor concentrates.127
Expense regarding coagulopathy and transfusion for patients on ECMO is significant. With an emphasis placed on increasing the quality of patient care at a decreased cost, it is necessary to continue the efforts to study ways of preventing or minimizing blood transfusion in this population, especially as the usage of ECMO increases around the nation.
In summary, additional research is required in the area of adult ECMO, and further steps must be taken to reduce cost internationally. ECMO can be a life-saving modality but requires significant resources and strategies for management including management of numerous complications that may affect patient outcome, especially with respect to anticoagulation and transfusion of blood products. Additional studies are needed to better understand optimal anticoagulation and monitoring, to minimize transfusion, and to describe and minimize morbid complications during ECMO all in an effort to improve quality of care.
Dr. Jerrold Levy is the Section Editor for Hemostasis and Transfusion Medicine for the Journal. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. Levy was not involved in any way with the editorial process or decision.
The authors thank Christopher Edwards and Jay Springfield for their assistance in regard to tables and completed figures.
a ELSO. Extracorporeal Life Support Organization (2009) ELSO patient specific guidelines. Available at http://www.elso.med.umich.edu/WordForms/ELSO%20Pt%20Specific%20Guidelines.pdf 2009. Accessed January 2012.
b ELSO. Extracorporeal Life Support Organization (2009) ELSO patient specific guidelines. Available at http://www.elso.med.umich.edu/WordForms/ELSO%20Pt%20Specific%20Guidelines.pdf 2009. Accessed January 2012.
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