Anesthesia & Analgesia:
Cardiovascular Anesthesiology: Review Article
Extracorporeal Membrane Oxygenation in the Adult: A Review of Anticoagulation Monitoring and Transfusion
Esper, Stephen A. MD, MBA*; Levy, Jerrold H. MD†; Waters, Jonathan H. MD‡; Welsby, Ian J. MB BS†
From the *Department of Anesthesiology, Cardiovascular and Thoracic Division, University of Pittsburgh, Pittsburgh, Pennsylvania; †Department of Anesthesiology, Cardiothoracic Division, Duke University, Durham, North Carolina; and ‡Departments of Anesthesiology and Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania.
Accepted for publication December 12, 2013.
Conflict of Interest: See Disclosures at the end of the article.
Reprint not be available from the authors.
Address correspondence to Stephen A. Esper, MD, MBA, Department of Anesthesiology, Cardiovascular and Thoracic Division, University of Pittsburgh, Department of Anesthesiology, C-Wing, 200 Lothrop St., Pittsburgh, PA. Address e-mail to email@example.com.
Extracorporeal membrane oxygenation (ECMO) is a method of life support to maintain cardiopulmonary function. Its use as a medical application has increased since its inception to treat multiple conditions including acute respiratory distress syndrome, myocardial ischemia, cardiomyopathy, and septic shock. While complications including neurological and renal injury occur in patients on ECMO, bleeding and coagulopathy are most common. ECMO is associated with an inflammatory response promoting a hypercoagulable state, requiring anticoagulation to avoid thromboembolism originating in the nonendothelial surfaced circuit. However, excessive anticoagulation may result in bleeding complications including intracerebral hemorrhage. Monitoring anticoagulation for ECMO has its origins in cardiopulmonary bypass for cardiac surgery; however, there is no ideal level of anticoagulation, no standardized method to monitor anticoagulation, nor are all centers standardized on what is used for anticoagulation. Multiple blood products are used in an effort to decrease bleeding in the setting of anticoagulation, often in the setting of recent surgery, and this leads to significant increases in cost for patients on ECMO and transfusion-related complications. In this review article, we discuss the evolution of the various modalities of ECMO, indications, contraindications, and complications. Furthermore, we review the different strategies for anticoagulation and treatment of coagulopathy while on ECMO. Finally, we discuss the cost of ECMO and associated blood product transfusion.
Extracorporeal membrane oxygenation (ECMO) maintains cardiopulmonary support, independent of the lungs (veno-venous [VV] ECMO) and/or heart (veno-arterial [VA] ECMO), providing a temporary bridge to recovery, transplantation, or long-term, mechanical circulatory support after acute pulmonary and/or cardiac failure.1
ECMO’s origins were in the 1950s, when, in 1953, Dr. J.H. Gibbon detailed the successful use of a mechanical heart and lung apparatus for cardiac surgery. After this, in 1954 and 1955, Drs. C. Walton Lillehei and John Kirklin2,3 developed and continued to improve on an apparatus to support the human body during open heart surgery. The next decade through the 1970s saw an increase in the use of ECMO to bypass failing lungs and heart in the perioperative setting.4–7 Since that time, systems have been developed for the use in neonates, infants, and adults.
According to data from the Extracorporeal Life Support Organization, member centers have reported the institution of ECMO in 48,000 cumulative patients (neonates, pediatric patients, and adults) since the early 1980s. With ECMO use increasing in both pediatric and adult patients in recent years, it is important to review the management of these patients, including the need for anticoagulation and transfusion. In addition, with increasing health care costs, it has become necessary to evaluate the financial burden associated with the institution and maintenance of ECMO. We will attempt to address the epidemiology of adult patients on ECMO, different types of ECMO, the indications and contraindications, complications, anticoagulation monitoring, transfusion of blood products on ECMO, and the cost of the resources that are currently necessary to maintain a patient on ECMO.
TYPES OF ECMO CIRCUITS
There are 2 types of ECMO that are generally used in the adult population: Veno-arterial (VA) and veno-venous (VV) (Figs. 1 and 2). VA ECMO is instituted for cardiac failure with or without hypoxic respiratory failure, providing both gas exchange and hemodynamic support for a failing cardiac or cardiopulmonary system, restoring both perfusion and oxygenation of end organs. Analogous to cardiopulmonary bypass (CPB), deoxygenated venous blood is drained into an oxygenator. Then, oxygenated arterial blood is returned into the systemic circulation. The ECMO flow rate and residual cardiac function determine whether or not there is a pulmonary circulation, which is desirable to avoid stasis and possible thrombosis. Unrecognized aortic regurgitation may lead to left ventricular dilation, mitral regurgitation, and pulmonary congestion, manifesting as high intracardiac filling pressures and reduced pulmonary compliance and/or pulmonary edema; it must be urgently identified and addressed.
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.
Extracorporeal carbon dioxide removal (ECCO2R) is a variation on the VV ECMO theme.8 Oxygen is provided by the native lungs with the assistance of a ventilator, and carbon dioxide is removed from the extracorporeal circuit. This method has been largely superseded by VV ECMO.
INDICATIONS AND EPIDEMIOLOGY FOR ECMO
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
ECMO indications for respiratory failure include the Murray Score9 to grade acute respiratory distress syndrome (ARDS). A number between 0 (less severe) and 4 (more severe) is assigned to each variable and averaged. For example, a Murray Score of 3 to 4 indicates 80% mortality (Table 2).9 From the 1970s until the early 2000s, multiple studies compared different modalities of ECMO with conventional ventilation in ARDS with outcomes focused on mortality. No difference was reported in the 1970s.10 In the 1980s, Gattinoni et al.11 reported an increased survival (48.8%) with the use of ECCO2R. In a randomized, controlled clinical trial of pressure-controlled inverse ratio ventilation versus ECCO2R, in patients treated with ECCO2R for their lung pathology, while overall survival of ARDS had increased (from approximately 8% in 1979 to 40% in 1986), there was still no significant difference between ECMO and conventional ventilation (42% and 33%).12,13 Recent advances in ECMO circuitry and successes treating primary graft dysfunction after lung transplantation,14 ARDS, and hypoxic respiratory failure during the H1N1 influenza virus epidemic15,16 have renewed interest in VV ECMO. There is controversy surrounding the survival benefit that ECMO provides to ARDS patients because the effect of cointerventions including the use of dialysis, nitric oxide, and permissive hypercapnea used at ECMO centers have not been evaluated or excluded.
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.
Sidebotham et al.32 described multiple examples of device-related hypoxemia, including recirculation of deoxygenated blood secondary to malpostioned cannulae, oxygenator failure, and high metabolic requirements of the patient, exceeding the capabilities of the oxygenator. Repositioning the cannulae, increasing circuit flow, replacing the oxygenator/circuit or adding a second oxygenator, and minimizing hypermetabolism (with neuromuscular blockade or cooling) may reduce morbidity.
Finally, Lewandowski et al.51 described multiple ECMO complications including pump malfunction and tubing rupture, cannulae displacement interrupting ECMO flow and requiring recannulation, heat exchanger malfunction, thrombus in the oxygenator, and major vascular injury during percutaneous or central cannulation.
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.
In a larger series, Bisdas et al.64 evaluated all vascular complications in this population. Ten percent of patients suffered vascular complications, 88% of which occurred with VA ECMO. The only consistent predictor of vascular complications was peripheral arterial disease, although vascular complications were not associated with higher mortality rates at 30 days and at 1 year. It is interesting to note that monitoring near-infrared spectroscopy on the lower limbs and the head has been suggested to guide perfusion strategies (increase in mean arterial blood pressure, oxygen tension, and ECMO flow) that were able to correct malperfusion in 16 of 20 patients.65 Prospective studies in larger populations are necessary to delineate the use of this approach.
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.
COAGULATION AND ANTICOAGULATION CONSIDERATIONS
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.
The activated clotting time (ACT) was first described in 1966,103–105 designed as a crude, whole blood assay that would form a clot within approximately 10 minutes in the setting of high-dose heparin anticoagulation used for CPB, when activated partial thromboplastin time (aPTT) results would be off scale. ACT values are affected by heparin (primarily) but also by thrombocytopenia, platelet dysfunction or inhibition (e.g., GpIIb/IIIa inhibitors), hypothermia, AT level, patient age, hemodilution, hypofibrinogenemia, and oral anticoagulants.106–108
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 AND TRANSFUSION
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
Furthermore, Mishra et al.128 did an analysis of 14 patients undergoing ECMO in Europe and determined that the mean estimated cost for the procedure was $73,122. Total hospital costs were estimated at $213,246. Ten patients experienced bleeding with a mean ECMO duration of 9.5 days.
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.
Name: Stephen A. Esper, MD, MBA.
Contribution: This author is the first and corresponding author of this article, did a literature search, and helped write the article.
Attestation: Stephen Esper attests that this is the approved final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Jerrold H. Levy, MD.
Contribution: This author helped write the article.
Attestation: Jerrold Levy attests that this is the approved final manuscript.
Conflicts of Interest: Steering committee for CSL Behring for aortic surgery and the Medicines Company; research support from ViroPharma; steering committee for Grifols for cardiac surgery.
Name: Jonathan Waters, MD.
Contribution: This author helped to write the article.
Attestation: Jonathan Waters attests that this is the approved final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Ian J. Welsby, MB BS.
Contribution: This author helped to write the article.
Attestation: Ian Welsby attests that this is the approved final manuscript.
Conflicts of Interest: Consultant for CSL Behring, support as PI for an investigator initiated trial from CSL Behring and Terumo BCT. Consultant for T2 biosystems, speaker for Acute Care CME organization.
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. Cited Here...
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.
1. Beurtheret S, Mastroianni C, Pozzi M, D’Alessandro C, Luyt CE, Combes A, Pavie A, Leprince P. Extracorporeal membrane oxygenation for 2009 influenza A (H1N1) acute respiratory distress syndrome: single-centre experience with 1-year follow-up. Eur J Cardiothorac Surg. 2012;41:691–5
2. Donald DE, Harshbarger HG, Kirklin JW. Studies in extracorporeal circulation. II. A method for the recovery and use of blood from the open heart during extracorporeal circulation in man. Ann Surg. 1956;144:223–7
3. Lillehei CW. A personalized history of extracorporeal circulation. Trans Am Soc Artif Intern Organs. 1982;28:5–16
4. Baffes TG, Fridman JL, Bicoff JP, Whitehill JL. Extracorporeal circulation for support of palliative cardiac surgery in infants. Ann Thorac Surg. 1970;10:354–63
5. Bartlett RH, Gazzaniga AB, Jefferies MR, Huxtable RF, Haiduc NJ, Fong SW. Extracorporeal membrane oxygenation (ECMO) cardiopulmonary support in infancy. Trans Am Soc Artif Intern Organs. 1976;22:80–93
6. Dorson W Jr, Baker E, Cohen ML, Meyer B, Molthan M, Trump D, Elgas R. A perfusion system for infants. Trans Am Soc Artif Intern Organs. 1969;15:155–60
7. Rashkind WJ, Freeman A, Klein D, Toft RW. Evaluation of a disposable plastic, low volume, pumpless oxygenator as a lung substitute. J Pediatr. 1965;66:94–102
8. Habashi NM, Borg UR, Reynolds HN. Low blood flow extracorporeal carbon dioxide removal (ECCO2R): a review of the concept and a case report. Intensive Care Med. 1995;21:594–7
9. Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis. 1988;138:720–3
10. Zapol WM, Snider MT, Hill JD, Fallat RJ, Bartlett RH, Edmunds LH, Morris AH, Peirce EC 2nd, Thomas AN, Proctor HJ, Drinker PA, Pratt PC, Bagniewski A, Miller RG Jr. Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA. 1979;242:2193–6
11. Gattinoni L, Pesenti A, Mascheroni D, Marcolin R, Fumagalli R, Rossi F, Iapichino G, Romagnoli G, Uziel L, Agostoni A. Low-frequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respiratory failure. JAMA. 1986;256:881–6
12. Morris AH, Wallace CJ, Menlove RL, Clemmer TP, Orme JF Jr, Weaver LK, Dean NC, Thomas F, East TD, Pace NL, Suchyta MR, Beck E, Bombino M, Sittig DF, Böhm S, Hoffmann B, Becks H, Butler S, Pearl J, Rasmusson B. Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med. 1994;149:295–305
13. Suchyta MR, Clemmer TP, Orme JF Jr, Morris AH, Elliott CG. Increased survival of ARDS patients with severe hypoxemia (ECMO criteria). Chest. 1991;99:951–5
14. Cypel M, Keshavjee S. Extracorporeal life support as a bridge to lung transplantation. Clin Chest Med. 2011;32:245–51
15. Davies A, Jones D, Bailey M, Beca J, Bellomo R, Blackwell N, Forrest P, Gattas D, Granger E, Herkes R, Jackson A, McGuinness S, Nair P, Pellegrino V, Pettilä V, Plunkett B, Pye R, Torzillo P, Webb S, Wilson M, Ziegenfuss MAustralia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators. . Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome. JAMA. 2009;302:1888–95
16. Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, Hibbert CL, Truesdale A, Clemens F, Cooper N, Firmin RK, Elbourne DCESAR trial collaboration. . Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374:1351–63
17. Chen YS, Lin JW, Yu HY, Ko WJ, Jerng JS, Chang WT, Chen WJ, Huang SC, Chi NH, Wang CH, Chen LC, Tsai PR, Wang SS, Hwang JJ, Lin FY. Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis. Lancet. 2008;372:554–61
18. Combes A, Leprince P, Luyt CE, Bonnet N, Trouillet JL, Léger P, Pavie A, Chastre J. Outcomes and long-term quality-of-life of patients supported by extracorporeal membrane oxygenation for refractory cardiogenic shock. Crit Care Med. 2008;36:1404–11
19. Kelly RB, Porter PA, Meier AH, Myers JL, Thomas NJ. Duration of cardiopulmonary resuscitation before extracorporeal rescue: how long is not long enough? ASAIO J. 2005;51:665–7
20. Massetti M, Tasle M, Le Page O, Deredec R, Babatasi G, Buklas D, Thuaudet S, Charbonneau P, Hamon M, Grollier G, Gerard JL, Khayat A. Back from irreversibility: extracorporeal life support for prolonged cardiac arrest. Ann Thorac Surg. 2005;79:178–83 discussion 183–4
21. Pagani FD, Aaronson KD, Swaniker F, Bartlett RH. The use of extracorporeal life support in adult patients with primary cardiac failure as a bridge to implantable left ventricular assist device. Ann Thorac Surg. 2001;71:S77–81 discussion S82–5
22. Shin TG, Choi JH, Jo IJ, Sim MS, Song HG, Jeong YK, Song YB, Hahn JY, Choi SH, Gwon HC, Jeon ES, Sung K, Kim WS, Lee YT. Extracorporeal cardiopulmonary resuscitation in patients with inhospital cardiac arrest: A comparison with conventional cardiopulmonary resuscitation. Crit Care Med. 2011;39:1–7
23. Smedira NG, Blackstone EH. Postcardiotomy mechanical support: risk factors and outcomes. Ann Thorac Surg. 2001;71:S60–6 discussion S82–5
24. Younger JG, Schreiner RJ, Swaniker F, Hirschl RB, Chapman RA, Bartlett RH. Extracorporeal resuscitation of cardiac arrest. Acad Emerg Med. 1999;6:700–7
25. Dela Cruz TV, Stewart DL, Winston SJ, Weatherman KS, Phelps JL, Mendoza JC. Risk factors for intracranial hemorrhage in the extracorporeal membrane oxygenation patient. J Perinatol. 1997;17:18–23
26. Braun JP, Schroeder T, Buehner S, Dohmen P, Moshirzadeh M, Grosse J, Streit F, Schlaefke A, Armstrong VW, Oellerich M, Lochs H, Konertz W, Kox WJ, Spies C. Splanchnic oxygen transport, hepatic function and gastrointestinal barrier after normothermic cardiopulmonary bypass. Acta Anaesthesiol Scand. 2004;48:697–703
27. Conrad SA, Rycus PT, Dalton H. Extracorporeal Life Support Registry Report 2004. ASAIO J. 2005;51:4–10
28. Rossi M, Sganga G, Mazzone M, Valenza V, Guarneri S, Portale G, Carbone L, Gatta L, Pioli C, Sanguinetti M, Montalto M, Glieca F, Fadda G, Schiavello R, Silveri NG. Cardiopulmonary bypass in man: role of the intestine in a self-limiting inflammatory response with demonstrable bacterial translocation. Ann Thorac Surg. 2004;77:612–8
29. Timpa JG, O’Meara C, McILwain RB, Dabal RJ, Alten JA. Massive systemic air embolism during extracorporeal membrane oxygenation support of a neonate with acute respiratory distress syndrome after cardiac surgery. J Extra Corpor Technol. 2011;43:86–8
30. Sahu MK, Ingole PR, Bisoi AK, Venugopal P. Successful management of a case of massive air embolism from cardiopulmonary bypass with retrograde cerebral perfusion in a child. J Cardiothorac Vasc Anesth. 2006;20:80–1
31. Kol S, Ammar R, Weisz G, Melamed Y. Hyperbaric oxygenation for arterial air embolism during cardiopulmonary bypass. Ann Thorac Surg. 1993;55:401–3
32. Sidebotham D, Allen SJ, McGeorge A, Ibbott N, Willcox T. Venovenous extracorporeal membrane oxygenation in adults: practical aspects of circuits, cannulae, and procedures. J Cardiothorac Vasc Anesth. 2012;26:893–909
33. Barstad RM, Ovrum E, Ringdal MA, Oystese R, Hamers MJ, Veiby OP, Rolfsen T, Stephens RW, Sakariassen KS. Induction of monocyte tissue factor procoagulant activity during coronary artery bypass surgery is reduced with heparin-coated extracorporeal circuit. Br J Haematol. 1996;94:517–25
34. Camera M, Frigerio M, Toschi V, Brambilla M, Rossi F, Cottell DC, Maderna P, Parolari A, Bonzi R, De Vincenti O, Tremoli E. Platelet activation induces cell-surface immunoreactive tissue factor expression, which is modulated differently by antiplatelet drugs. Arterioscler Thromb Vasc Biol. 2003;23:1690–6
35. Johnell M, Elgue G, Thelin S, Larsson R, Siegbahn A. Cell adhesion and tissue factor upregulation in oxygenators used during coronary artery bypass grafting are modified by the Corline Heparin Surface. Scand Cardiovasc J. 2002;36:351–7
36. Siddiqui FA, Desai H, Amirkhosravi A, Amaya M, Francis JL. The presence and release of tissue factor from human platelets. Platelets. 2002;13:247–53
37. Van Der Meijden PE, Van Schilfgaarde M, Van Oerle R, Renné T, ten Cate H, Spronk HM. Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost. 2012;10:1355–62
38. Steinhorn RH, Isham-Schopf B, Smith C, Green TP. Hemolysis during long-term extracorporeal membrane oxygenation. J Pediatr. 1989;115:625–30
39. Betrus C, Remenapp R, Charpie J, Kudelka T, Brophy P, Smoyer WE, Lin JJ. Enhanced hemolysis in pediatric patients requiring extracorporeal membrane oxygenation and continuous renal replacement therapy. Ann Thorac Cardiovasc Surg. 2007;13:378–83
40. Nevaril CG, Lynch EC, Alfrey CP Jr, Hellums JD. Erythrocyte damage and destruction induced by shearing stress. J Lab Clin Med. 1968;71:784–90
41. Williams AR. Shear-induced fragmentation of human erythrocytes. Biorheology. 1973;10:303–11
42. Green TP, Kriesmer P, Steinhorn RH, Payne NR, Irmiter RJ, Meyer CL. Comparison of pressure-volume-flow relationships in centrifugal and roller pump extracorporeal membrane oxygenation systems for neonates. ASAIO Trans. 1991;37:572–6
43. Fink SM, Bockman DE, Howell CG, Falls DG, Kanto WP Jr. Bypass circuits as the source of thromboemboli during extracorporeal membrane oxygenation. J Pediatr. 1989;115:621–4
44. Wielogorski JW, Cross DE, Nwadike EV. The effects of subatmospheric pressure on the haemolysis of blood. J Biomech. 1975;8:321–5
45. Zager RA, Gamelin LM. Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure. Am J Physiol. 1989;256:F446–55
46. Walsh-Sukys MC, Cornell DJ, Stork EK. The natural history of direct hyperbilirubinemia associated with extracorporeal membrane oxygenation. Am J Dis Child. 1992;146:1176–80
47. Ziemann-Gimmel P, Schwartz DE. Increased carboxyhemoglobin in a patient with a large retroperitoneal hematoma. Anesth Analg. 2004;99:1800–2
48. Rusca M, Oddo M, Schaller MD, Liaudet L. Carboxyhemoglobin formation as an unexpected side effect of inhaled nitric oxide therapy in severe acute respiratory distress syndrome. Crit Care Med. 2004;32:2537–9
49. Melley DD, Finney SJ, Elia A, Lagan AL, Quinlan GJ, Evans TW. Arterial carboxyhemoglobin level and outcome in critically ill patients. Crit Care Med. 2007;35:1882–7
50. Zanatta P, Forti A, Bosco E, Salvador L, Borsato M, Baldanzi F, Longo C, Sorbara C, Longatti P, Valfrè C. Microembolic signals and strategy to prevent gas embolism during extracorporeal membrane oxygenation. J Cardiothorac Surg. 2010;5:5
51. Lewandowski K, Rossaint R, Pappert D, Gerlach H, Slama KJ, Weidemann H, Frey DJ, Hoffmann O, Keske U, Falke KJ. High survival rate in 122 ARDS patients managed according to a clinical algorithm including extracorporeal membrane oxygenation. Intensive Care Med. 1997;23:819–35
52. Glass P, Miller M, Short B. Morbidity for survivors of extracorporeal membrane oxygenation: neurodevelopmental outcome at 1 year of age. Pediatrics. 1989;83:72–8
53. Bulas DI, Taylor GA, O’Donnell RM, Short BL, Fitz CR, Vezina G. Intracranial abnormalities in infants treated with extracorporeal membrane oxygenation: update on sonographic and CT findings. AJNR Am J Neuroradiol. 1996;17:287–94
54. Horwitz JR, Elerian LF, Sparks JW, Lally KP. Use of extracorporeal membrane oxygenation in the septic neonate. J Pediatr Surg. 1995;30:813–5
55. Risnes I, Wagner K, Nome T, Sundet K, Jensen J, Hynås IA, Ueland T, Pedersen T, Svennevig JL. Cerebral outcome in adult patients treated with extracorporeal membrane oxygenation. Ann Thorac Surg. 2006;81:1401–6
56. Mateen FJ, Muralidharan R, Shinohara RT, Parisi JE, Schears GJ, Wijdicks EF. Neurological injury in adults treated with extracorporeal membrane oxygenation. Arch Neurol. 2011;68:1543–9
57. Kasirajan V, Smedira NG, McCarthy JF, Casselman F, Boparai N, McCarthy PM. Risk factors for intracranial hemorrhage in adults on extracorporeal membrane oxygenation. Eur J Cardiothorac Surg. 1999;15:508–14
58. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin AAcute Kidney Injury Network. . Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11:R31
59. Kim TH, Lim C, Park I, Kim DJ, Jung Y, Park KH. Prognosis in the patients with prolonged extracorporeal membrane oxygenation. Korean J Thorac Cardiovasc Surg. 2012;45:236–41
60. Kielstein JT, Heiden AM, Beutel G, Gottlieb J, Wiesner O, Hafer C, Hadem J, Reising A, Haverich A, Kühn C, Fischer S. Renal function and survival in 200 patients undergoing ECMO therapy. Nephrol Dial Transplant. 2013;28:86–90
61. Chang WW, Tsai FC, Tsai TY, Chang CH, Jenq CC, Chang MY, Tian YC, Hung CC, Fang JT, Yang CW, Chen YC. Predictors of mortality in patients successfully weaned from extracorporeal membrane oxygenation. PLoS One. 2012;7:e42687
62. Gander JW, Fisher JC, Reichstein AR, Gross ER, Aspelund G, Middlesworth W, Stolar CJ. Limb ischemia after common femoral artery cannulation for venoarterial extracorporeal membrane oxygenation: an unresolved problem. J Pediatr Surg. 2010;45:2136–40
63. Kanji HD, Schulze CJ, Oreopoulos A, Lehr EJ, Wang W, MacArthur RM. Peripheral versus central cannulation for extracorporeal membrane oxygenation: a comparison of limb ischemia and transfusion requirements. Thorac Cardiovasc Surg. 2010;58:459–62
64. Bisdas T, Beutel G, Warnecke G, Hoeper MM, Kuehn C, Haverich A, Teebken OE. Vascular complications in patients undergoing femoral cannulation for extracorporeal membrane oxygenation support. Ann Thorac Surg. 2011;92:626–31
65. Wong JK, Smith TN, Pitcher HT, Hirose H, Cavarocchi NC. Cerebral and lower limb near-infrared spectroscopy in adults on extracorporeal membrane oxygenation. Artif Organs. 2012;36:659–67
66. Schmidt M, Bréchot N, Hariri S, Guiguet M, Luyt CE, Makri R, Leprince P, Trouillet JL, Pavie A, Chastre J, Combes A. Nosocomial infections in adult cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation. Clin Infect Dis. 2012;55:1633–41
67. Vogel AM, Lew DF, Kao LS, Lally KP. Defining risk for infectious complications on extracorporeal life support. J Pediatr Surg. 2011;46:2260–4
68. Sun HY, Ko WJ, Tsai PR, Sun CC, Chang YY, Lee CW, Chen YC. Infections occurring during extracorporeal membrane oxygenation use in adult patients. J Thorac Cardiovasc Surg. 2010;140:1125–32.e2
69. Karkouti K, Wijeysundera DN, Yau TM, Beattie WS, Abdelnaem E, McCluskey SA, Ghannam M, Yeo E, Djaiani G, Karski J. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion. 2004;44:1453–62
70. . Argatroban [package insert]. Research Triangle Park, NC: Exela Pharma Sciences L; 2012
71. . Heparin Sodium [package insert]. Schaumburg, IL: Fresenius Kabi USA L; 2013
72. . Antithrombin III (Human), Thrombate III [package insert]. Research Triangle Park, NC: Talecris Biotherapeutics I; 2012
73. . Angiomax(R) (bivalirudin) [package insert]. Parsippany, NJ: Bivalirudin: The Medicines Compnay; 2000
74. Oliver WC. Anticoagulation and coagulation management for ECMO. Semin Cardiothorac Vasc Anesth. 2009;13:154–75
75. Plötz FB, van Oeveren W, Bartlett RH, Wildevuur CR. Blood activation during neonatal extracorporeal life support. J Thorac Cardiovasc Surg. 1993;105:823–32
76. Robinson TM, Kickler TS, Walker LK, Ness P, Bell W. Effect of extracorporeal membrane oxygenation on platelets in newborns. Crit Care Med. 1993;21:1029–34
77. Stallion A, Cofer BR, Rafferty JA, Ziegler MM, Ryckman FC. The significant relationship between platelet count and haemorrhagic complications on ECMO. Perfusion. 1994;9:265–9
78. Bolliger D, Szlam F, Molinaro RJ, Rahe-Meyer N, Levy JH, Tanaka KA. Finding the optimal concentration range for fibrinogen replacement after severe haemodilution: an in vitro
model. Br J Anaesth. 2009;102:793–9
79. Marasco SF, Lukas G, McDonald M, McMillan J, Ihle B. Review of ECMO (extra corporeal membrane oxygenation) support in critically ill adult patients. Heart Lung Circ. 2008;17(Suppl 4):S41–7
80. Celi A, Pellegrini G, Lorenzet R, De Blasi A, Ready N, Furie BC, Furie B. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci U S A. 1994;91:8767–71
81. Esmon CT. The protein C pathway. Chest. 2003;124:26S–32S
82. Esmon CT. The impact of the inflammatory response on coagulation. Thromb Res. 2004;114:321–7
83. Gear AR, Camerini D. Platelet chemokines and chemokine receptors: linking hemostasis, inflammation, and host defense. Microcirculation. 2003;10:335–50
84. Mann KG, Butenas S, Brummel K. The dynamics of thrombin formation. Arterioscler Thromb Vasc Biol. 2003;23:17–25
85. Niebler RA, Christensen M, Berens R, Wellner H, Mikhailov T, Tweddell JS. Antithrombin replacement during extracorporeal membrane oxygenation. Artif Organs. 2011;35:1024–8
86. Urlesberger B, Zobel G, Zenz W, Kuttnig-Haim M, Maurer U, Reiterer F, Riccabona M, Dacar D, Gallisti S, Leschnik B, Muntean W. Activation of the clotting system during extracorporeal membrane oxygenation in term newborn infants. J Pediatr. 1996;129:264–8
87. Avidan MS, Levy JH, Scholz J, Delphin E, Rosseel PM, Howie MB, Gratz I, Bush CR, Skubas N, Aldea GS, Licina M, Bonfiglio LJ, Kajdasz DK, Ott E, Despotis GJ. A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass. Anesthesiology. 2005;102:276–84
88. Avidan MS, Levy JH, van Aken H, Feneck RO, Latimer RD, Ott E, Martin E, Birnbaum DE, Bonfiglio LJ, Kajdasz DK, Despotis GJ. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2005;130:107–13
89. Green TP, Isham-Schopf B, Irmiter RJ, Smith C, Uden DL, Steinhorn RH. Inactivation of heparin during extracorporeal circulation in infants. Clin Pharmacol Ther. 1990;48:148–54
90. Green TP, Isham-Schopf B, Steinhorn RH, Smith C, Irmiter RJ. Whole blood activated clotting time in infants during extracorporeal membrane oxygenation. Crit Care Med. 1990;18:494–8
91. Khaja WA, Bilen O, Lukner RB, Edwards R, Teruya J. Evaluation of heparin assay for coagulation management in newborns undergoing ECMO. Am J Clin Pathol. 2010;134:950–4
92. Francis CW, Pellegrini VD Jr, Harris CM, Stulberg B, Gabriel KR, Marder VJ. Prophylaxis of venous thrombosis following total hip and total knee replacement using antithrombin III and heparin. Semin Hematol. 1991;28:39–45
93. Hashimoto K, Yamagishi M, Sasaki T, Nakano M, Kurosawa H. Heparin and antithrombin III levels during cardiopulmonary bypass: correlation with subclinical plasma coagulation. Ann Thorac Surg. 1994;58:799–804 discussion 804–5
94. Thelin S, Bagge L, Hultman J, Borowiec J, Nilsson L, Thorelius J. Heparin-coated cardiopulmonary bypass circuits reduce blood cell trauma. Experiments in the pig. Eur J Cardiothorac Surg. 1991;5:486–91
95. Videm V, Svennevig JL, Fosse E, Semb G, Osterud A, Mollnes TE. Reduced complement activation with heparin-coated oxygenator and tubings in coronary bypass operations. J Thorac Cardiovasc Surg. 1992;103:806–13
96. Borowiec J, Thelin S, Bagge L, Nilsson L, Venge P, Hansson HE. Heparin-coated circuits reduce activation of granulocytes during cardiopulmonary bypass. A clinical study. J Thorac Cardiovasc Surg. 1992;104:642–7
97. Vroman L, Adams AL. Findings with recording ellipsometer suggesting rapid exchange of specific plasma proteins at liquid/solid interfaces. Surface Science. 1969;16:438–6
98. Hirsh SL, McKenzie DR, Nosworthy NJ, Denman JA, Sezerman OU, Bilek MM. The Vroman effect: competitive protein exchange with dynamic multilayer protein aggregates. Colloids Surf B Biointerfaces. 2013;103:395–404
99. Esmon CT. The protein C anticoagulant pathway. Arterioscler Thromb. 1992;12:135–45
100. Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, Pittet JF. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma. 2008;64:1211–7
101. Muntean W. Coagulation and anticoagulation in extracorporeal membrane oxygenation. Artif Organs. 1999;23:979–83
102. Horwitz JR, Cofer BR, Warner BW, Cheu HW, Lally KP. A multicenter trial of 6-aminocaproic acid (Amicar) in the prevention of bleeding in infants on ECMO. J Pediatr Surg. 1998;33:1610–3
103. Hattersley PG. The treatment of classical hemophilia with cryoprecipitates. Laboratory control with readily available tests. JAMA. 1966;198:243–7
104. Hattersley PG. Activated coagulation time of whole blood. JAMA. 1966;196:436–40
105. Hattersley PG. Activated coagulation time as screening test. JAMA. 1972;222:583–4
106. Chan AK, Leaker M, Burrows FA, Williams WG, Gruenwald CE, Whyte L, Adams M, Brooker LA, Adams H, Mitchell L, Andrew M. Coagulation and fibrinolytic profile of paediatric patients undergoing cardiopulmonary bypass. Thromb Haemost. 1997;77:270–7
107. Baird CW, Zurakowski D, Robinson B, Gandhi S, Burdis-Koch L, Tamblyn J, Munoz R, Fortich K, Pigula FA. Anticoagulation and pediatric extracorporeal membrane oxygenation: impact of activated clotting time and heparin dose on survival. Ann Thorac Surg. 2007;83:912–9 discussion 919–20
108. Martindale SJ, Shayevitz JR, D’Errico C. The activated coagulation time: suitability for monitoring heparin effect and neutralization during pediatric cardiac surgery. J Cardiothorac Vasc Anesth. 1996;10:458–63
109. Lawson DS, Walczak R, Lawson AF, Shearer IR, Ing R, Schulman S, Kern F, Jaggers J. North American neonatal extracorporeal membrane oxygenation (ECMO) devices: 2002 survey results. J Extra Corpor Technol. 2004;36:16–21
110. Colby CE, Sheehan A, Benitz W, Van Meurs K, Halamek LP, Moss RL. Maintaining adequate anticoagulation on extracorporeal membrane oxygenation therapy: Hemochron Junior Low Range versus Hemochron 400. J Extra Corpor Technol. 2003;35:35–8
111. Despotis GJ, Summerfield AL, Joist JH, Goodnough LT, Santoro SA, Spitznagel E, Cox JL, Lappas DG. Comparison of activated coagulation time and whole blood heparin measurements with laboratory plasma anti-Xa heparin concentration in patients having cardiac operations. J Thorac Cardiovasc Surg. 1994;108:1076–82
112. Reiner JS, Coyne KS, Lundergan CF, Ross AM. Bedside monitoring of heparin therapy: comparison of activated clotting time to activated partial thromboplastin time. Cathet Cardiovasc Diagn. 1994;32:49–52
113. Nankervis CA, Preston TJ, Dysart KC, Wilkinson WD, Chicoine LG, Welty SE, Nelin LD. Assessing heparin dosing in neonates on venoarterial extracorporeal membrane oxygenation. ASAIO J. 2007;53:111–4
114. O’Neill AI, McAllister C, Corke CF, Parkin JD. A comparison of five devices for the bedside monitoring of heparin therapy. Anaesth Intensive Care. 1991;19:592–6
115. Hirsh J, Anand SS, Halperin JL, Fuster V. Mechanism of action and pharmacology of unfractionated heparin. Arterioscler Thromb Vasc Biol. 2001;21:1094–6
116. Kaptoge S, Di Angelantonio E, Pennells L, Wood AM, White IR, Gao P, Walker M, Thompson A, Sarwar N, Caslake M, Butterworth AS, Amouyel P, Assmann G, Bakker SJ, Barr EL, Barrett-Connor E, Benjamin EJ, Björkelund C, Brenner H, Brunner E, Clarke R, Cooper JA, Cremer P, Cushman M, Dagenais GR, D’Agostino RB Sr, Dankner R, Davey-Smith G, Deeg D, Dekker JM, Engström G, Folsom AR, Fowkes FG, Gallacher J, Gaziano JM, Giampaoli S, Gillum RF, Hofman A, Howard BV, Ingelsson E, Iso H, Jørgensen T, Kiechl S, Kitamura A, Kiyohara Y, Koenig W, Kromhout D, Kuller LH, Lawlor DA, Meade TW, Nissinen A, Nordestgaard BG, Onat A, Panagiotakos DB, Psaty BM, Rodriguez B, Rosengren A, Salomaa V, Kauhanen J, Salonen JT, Shaffer JA, Shea S, Ford I, Stehouwer CD, Strandberg TE, Tipping RW, Tosetto A, Wassertheil-Smoller S, Wennberg P, Westendorp RG, Whincup PH, Wilhelmsen L, Woodward M, Lowe GD, Wareham NJ, Khaw KT, Sattar N, Packard CJ, Gudnason V, Ridker PM, Pepys MB, Thompson SG, Danesh JEmerging Risk Factors Collaboration. . C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med. 2012;367:1310–20
117. Conlan MG, Folsom AR, Finch A, Davis CE, Sorlie P, Marcucci G, Wu KK. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost. 1993;70:380–5
118. Agati S, Ciccarello G, Salvo D, Turla G, Undar A, Mignosa C. Use of a novel anticoagulation strategy during ECMO in a pediatric population: single-center experience. ASAIO J. 2006;52:513–6
119. Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg. 2008;106:1366–75
120. Rastan AJ, Lachmann N, Walther T, Doll N, Gradistanac T, Gommert JF, Lehmann S, Wittekind C, Mohr FW. Autopsy findings in patients on postcardiotomy extracorporeal membrane oxygenation (ECMO). Int J Artif Organs. 2006;29:1121–31
121. Ang AL, Teo D, Lim CH, Leou KK, Tien SL, Koh MB. Blood transfusion requirements and independent predictors of increased transfusion requirements among adult patients on extracorporeal membrane oxygenation – a single centre experience. Vox Sang. 2009;96:34–43
122. . Ang AL: Predictors of increased transfusion requirements and optimizing transfusional support in patients on extracorporeal membrane oxygenation (ECMO). ISBT Science Series. 2012;7:89–91
123. Butch SH, Knafl P, Oberman HA, Bartlett RH. Blood utilization in adult patients undergoing extracorporeal membrane oxygenated therapy. Transfusion. 1996;36:61–3
124. Smith A, Hardison D, Bridges B, Pietsch J. Red blood cell transfusion volume and mortality among patients receiving extracorporeal membrane oxygenation. Perfusion. 2013;28:54–60
125. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363:1791–800
126. Swaminathan M, Shaw AD, Greenfield RA, Grichnik KP. Fatal Thrombosis After Factor VII Administration During Extracorporeal Membrane Oxygenation. J Cardiothorac Vasc Anesth. 2008;22:259–60
127. Bui JD, Despotis GD, Trulock EP, Patterson GA, Goodnough LT. Fatal thrombosis after administration of activated prothrombin complex concentrates in a patient supported by extracorporeal membrane oxygenation who had received activated recombinant factor VII. J Thorac Cardiovasc Surg. 2002;124:852–4
128. Mishra V, Svennevig JL, Bugge JF, Andresen S, Mathisen A, Karlsen H, Khushi I, Hagen TP. Cost of extracorporeal membrane oxygenation: evidence from the Rikshospitalet University Hospital, Oslo, Norway. Eur J Cardiothorac Surg. 2010;37:339–42
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