Executive Summary: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE (PEACE) Consensus Conference.

OBJECTIVES: To present recommendations and consensus statements with supporting literature for the clinical management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus conference. DATA SOURCES: Systematic review was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial meetings of international, interprofessional experts in the management ECMO for critically ill children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill children. DATA EXTRACTION: Within each of eight subgroup, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: A systematic review was conducted using MEDLINE, Embase, and Cochrane Library databases, from January 1988 to May 2021. Each panel developed evidence-based and, when evidence was insufficient, expert-based statements for the clinical management of anticoagulation for children supported with ECMO. These statements were reviewed and ratified by 48 PEACE experts. Consensus was obtained using the Research and Development/UCLA Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed 23 recommendations, 52 expert consensus statements, and 16 good practice statements covering the management of ECMO anticoagulation in three broad categories: general care and monitoring; perioperative care; and nonprocedural bleeding or thrombosis. Gaps in knowledge and research priorities were identified, along with three research focused good practice statements. CONCLUSIONS: The 91 statements focused on clinical care will form the basis for standardization and future clinical trials.

The Influence of the Extracorporeal Membrane Oxygenation Circuit and Components on Anticoagulation Management: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding the influence of extracorporeal membrane oxygenation (ECMO) circuit components on anticoagulation practices for pediatric ECMO for the Pediatric ECMO Anticoagulation CollaborativE. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: Management of ECMO anticoagulation in the setting of different ECMO circuit components. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Twenty-nine references were used for data extraction and informed recommendations, evidence-based consensus statements, and good practice statements. Evidence tables were constructed using a standardized data extraction form. DATA SYNTHESIS: Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements or good practice statements for the influence of ECMO circuit and components on anticoagulation management. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. One good practice statement, 2 weak recommendations, and 2 consensus statements are presented. CONCLUSIONS: The incorporation of new component technologies into clinical practice has outpaced clinical investigations of anticoagulation strategies for pediatric ECMO. Future investigations should leverage academic and industrial collaborations, translational platforms, and modern biostatistical methods to improve patient outcomes.

2021 ELSO Adult and Pediatric Anticoagulation Guidelines.

DISCLAIMER: These guidelines for adult and pediatric anticoagulation for extracorporeal membrane oxygenation are intended for educational use to build the knowledge of physicians and other health professionals in assessing the conditions and managing the treatment of patients undergoing ECLS / ECMO and describe what are believed to be useful and safe practice for extracorporeal life support (ECLS, ECMO) but these are not necessarily consensus recommendations. The aim of clinical guidelines are to help clinicians to make informed decisions about their patients. However, adherence to a guideline does not guarantee a successful outcome. Ultimately, healthcare professionals must make their own treatment decisions about care on a case-by-case basis, after consultation with their patients, using their clinical judgment, knowledge and expertise. These guidelines do not take the place of physicians' and other health professionals' judgment in diagnosing and treatment of particular patients. These guidelines are not intended to and should not be interpreted as setting a standard of care or be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment must be made by the physician and other health professionals and the patient in light of all the circumstances presented by the individual patient, and the known variability and biological behavior of the clinical condition. These guidelines reflect the data at the time the guidelines were prepared; the results of subsequent studies or other information may cause revisions to the recommendations in these guidelines to be prudent to reflect new data, but ELSO is under no obligation to provide updates. In no event will ELSO be liable for any decision made or action taken in reliance upon the information provided through these guidelines.

Extracorporeal Life Support Organization (ELSO): 2020 Pediatric Respiratory ELSO Guideline.

DISCLAIMER: This guideline describes prolonged extracorporeal life support (ECLS) and extracorporeal membrane oxygenation (ECMO), applicable to Pediatric respiratory failure. These guidelines describe useful and safe practice, prepared by ELSO and based on extensive experience and are considered consensus guidelines. These guidelines are not intended to define standard of care and are revised at regular intervals as new information, devices, medications, and techniques become available.

Hematologic concerns in extracorporeal membrane oxygenation.

This ISTH "State of the Art" review aims to critically evaluate the hematologic considerations and complications in extracorporeal membrane oxygenation (ECMO). ECMO is experiencing a rapid increase in clinical use, but many questions remain unanswered. The existing literature does not address or explicitly state many pertinent details that may influence hematologic complications and, ultimately, patient outcomes. This review aims to broadly introduce modern ECMO practices, circuit designs, circuit materials, hematologic complications, transfusion-related considerations, age- and size-related differences, and considerations for choosing outcome measures. Relevant studies from the 2019 ISTH Congress in Melbourne, which further advanced our understanding of these processes, will also be highlighted.

Evaluating Mortality Risk Adjustment Among Children Receiving Extracorporeal Support for Respiratory Failure.

This study evaluates whether three commonly used pediatric intensive care unit (PICU) severity of illness scores, pediatric risk of mortality score (PRISM) III, pediatric index of mortality (PIM) 2, and pediatric logistic organ dysfunction (PELOD), are the appropriate tools to discriminate mortality risk in children receiving extracorporeal membrane oxygenation (ECMO) support for respiratory failure. This study also evaluates the ability of the Pediatric Risk Estimate Score for Children Using Extracorporeal Respiratory Support (Ped-RESCUERS) to discriminate mortality risk in the same population, and whether Ped-RESCUERS' discrimination of mortality is improved by additional clinical and laboratory measures of renal, hepatic, neurologic, and hematologic dysfunction. A multi-institutional retrospective cohort study was conducted on children aged 29 days to 17 years with respiratory failure requiring respiratory ECMO support. Discrimination of mortality was evaluated with the area under the receiver operating curve (AUC); model calibration was measured by the Hosmer-Lemeshow goodness of fit test and Brier score. Admission PRISM-III, PIM-2, and PELOD were found to have poor ability to discriminate mortality with an AUC of 0.56 [0.46-0.66], 0.53 [0.43-0.62], and 0.57 [0.47-0.67], respectively. Alternatively, Ped-RESCUERS performed better with an AUC of 0.68 [0.59-0.77]. Higher alanine aminotransferase, ratio of the arterial partial pressure of oxygen the fraction of inspired oxygen, and lactic acidosis were independently associated with mortality and, when added to Ped-RESCUERS, resulted in an AUC of 0.75 [0.66-0.82]. Admission PRISM-III, PIM-2, and PELOD should not be used for pre-ECMO risk adjustment because they do not discriminate death. Extracorporeal membrane oxygenation population-derived scores should be used to risk adjust ECMO populations as opposed to general PICU population-derived scores.

Novel Surfaces in Extracorporeal Membrane Oxygenation Circuits.

The balance between systemic anticoagulation and clotting is challenging. In normal hemostasis, the endothelium regulates the balance between anticoagulant and prothrombotic systems. It becomes particularly more challenging to maintain this physiologic hemostasis when we are faced with extracorporeal life support therapies, where blood is continuously in contact with a foreign extracorporeal circuit surface predisposing a prothrombotic state. The blood-surface interaction during extracorporeal life support therapies requires the use of systemic anticoagulation to decrease the risk of clotting. Unfractionated heparin is the most common anticoagulant agent widely used in this setting. New trends include the use of direct thrombin inhibitor agents for systemic anticoagulation; and surface modifications that aim to overcome the blood-biomaterial surface interaction by modifying the hydrophilicity or hydrophobicity of the polymer surface; and coating the circuit with substances that will mimic the endothelium or anti-thrombotic agents. To improve hemocompatibility in an extracorporeal circuit, replication of the anti-thrombotic and anti-inflammatory properties of the endothelium is ideal. Surface modifications can be classified into three major groups: biomimetic surfaces (heparin, nitric oxide, and direct thrombin inhibitors); biopassive surfaces [phosphorylcholine, albumin, and poly- 2-methoxyethylacrylate]; and endothelialization of blood contacting surface. The focus of this paper will be to review both present and future novel surface modifications that can obviate the need for systemic anticoagulation during extracorporeal life support therapies.

VV extracorporeal life support for the Third Millennium: will we need anticoagulation?

Since the late 1600's medicine and science have entertained the idea of extracorporeal circulation. With this technology to allow for cardiac and pulmonary support came the development of anticoagulation. Although this advanced the technology and capabilities of extracorporeal life support, it was not without complications and risks. The most common complications in extracorporeal life support (ECLS) present day are related to hemorrhage and thrombus due to the need for systemic anticoagulation and the challenges associated with it. This review focuses on present day techniques for anticoagulation for ECLS and what future surface modifications may do to obviate the use of systemic anticoagulation entirely.

Acetaminophen clearance during ex vivo continuous renal replacement therapies.

Intravenous acetaminophen is an adjuvant to opioid use in critically ill and surgical patients requiring continuous renal replacement therapy (CRRT). The objective of this study was to determine the ex vivo transmembrane clearance of intravenous acetaminophen during continuous hemofiltration and hemodialysis. Transmembrane clearance was assessed using a validated ex vivo bovine blood model for CRRT using an F8 or HF1400 hemodiafilter. Ultrafiltrate and dialysate flow rates were 1, 2, and 3 L/h. Urea and acetaminophen clearances were calculated and compared. Acetaminophen was readily cleared by continuous hemofiltration with both hemodiafilters. Acetaminophen clearance rates were 92-98% of ultrafiltrate production rates. Similarly, dialytic acetaminophen clearances approximated dialysate flow rates for both hemodiafilters. Acetaminophen is readily cleared by CRRT. Patients receiving CRRT and acetaminophen may require increased doses for adequate pain control.

Prospective Side by Side Comparison of Outcomes and Complications With a Simple Versus Intensive Anticoagulation Monitoring Strategy in Pediatric Extracorporeal Life Support Patients.

OBJECTIVES: A continuous infusion of unfractionated heparin is the most common anticoagulant used for pediatric patients on extracorporeal life support. The objective of this study was to compare extracorporeal life support complications and outcomes between two large-volume pediatric extracorporeal life support centers that use different anticoagulation strategies. DESIGN: Prospective, observational cohort study. SETTING: The University of Michigan used simple anticoagulation monitoring, whereas the University of Alberta used an intensive anticoagulation monitoring strategy. PATIENTS: Pediatric patients on extracorporeal life support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was major bleeding per extracorporeal life support run defined as bleeding that was retroperitoneal, pulmonary, or involved the CNS; bleeding greater than 20 mL/kg over 24 hours; or bleeding that required surgical intervention. Secondary outcomes measured were patient thrombosis per run, circuit thrombosis per run, and survival to hospital discharge per patient. Eighty-eight patients (95 runs) less than 18 years old were enrolled at the two centers over 2 years. The two centers enrolled different extracorporeal life support populations; University of Alberta enrolled more postcardiac surgical patients (74% vs 47%; p = 0.005). The indication for extracorporeal life support support also varied by center (p = 0.04). The two centers used similar proportions of VA extracorporeal life support (p = 0.3). Median (interquartile range) unfractionated heparin doses were similar between University of Michigan and University of Alberta, 30 (21-34) U/kg/hr and 26 (22-31) U/kg/hr, p value equals to 0.3, respectively. Median (interquartile range) antifactor Xa was lower in the University of Michigan cohort (0.23 [0.19-0.28] vs 0.41 [0.36-0.46] U/mL; p < 0.001). There was no significant difference in major bleeding (15% University of Michigan vs 21% University of Alberta; p = 0.6) or in patient thromboses (18% University of Michigan vs 13% University of Alberta; p = 0.5). There was no significant difference in survival to hospital discharge (University of Michigan 63% vs University of Alberta 73%; p = 0.1). CONCLUSIONS: Although this prospective cohort study compared different pediatric extracorporeal life support populations, the results did not identify a significant difference in outcomes between simple and intensive anticoagulation monitoring strategies.

Thromboprophylaxis in Extracorporeal Circuits: Current Pharmacological Strategies and Future Directions.

The development of extracorporeal devices for organ support has been a part of medical history and progression since the late 1900s. These types of technology are primarily used and developed in the field of critical care medicine. Unfractionated heparin, discovered in 1916, has really been the only consistent form of thromboprophylaxis for attenuating or even preventing the blood-biomaterial reaction that occurs when such technologies are initiated. The advent of regional anticoagulation for procedures such as continuous renal replacement therapy and plasmapheresis have certainly removed the risks of systemic heparinization and heparin effect, but the challenges of the blood-biomaterial reaction and downstream effects remain. In addition, regional anticoagulation cannot realistically be applied in a system such as extracorporeal membrane oxygenation because of the high blood flow rates needed to support the patient. More recently, advances in the technology itself have resulted in smaller, more compact extracorporeal life support (ECLS) systems that can-at certain times and in certain patients-run without any form of anticoagulation. However, the majority of patients on ECLS systems require some type of systemic anticoagulation; therefore, the risks of bleeding and thrombosis persist, the most devastating of which is intracranial hemorrhage. We provide a concise overview of the primary and alternate agents and monitoring used for thromboprophylaxis during use of ECLS. In addition, we explore the potential for further biomaterial and technologic developments and what they could provide when applied in the clinical arena.

Development and validation of the pediatric risk estimate score for children using extracorporeal respiratory support (Ped-RESCUERS).

PURPOSE: To develop and validate the Pediatric Risk Estimation Score for Children Using Extracorporeal Respiratory Support (Ped-RESCUERS). Ped-RESCUERS is designed to estimate the in-hospital mortality risk for children prior to receiving respiratory extracorporeal membrane oxygenation (ECMO) support. METHODS: This study used data from an international registry of patients aged 29 days to less than 18 years who received ECMO support from 2009 to 2014. We divided the registry into development and validation datasets by calendar date. Candidate variables were selected for model inclusion if the variable independently changed the mortality risk by at least 2 % in a Bayesian logistic regression model with in-hospital mortality as the outcome. We characterized the model's ability to discriminate mortality with the area under curve (AUC) of the receiver operating characteristic. RESULTS: From 2009 to 2014, 2458 non-neonatal children received ECMO for respiratory support, with a mortality rate of 39.8 %. The development dataset contained 1611 children receiving ECMO support from 2009 to 2012. The model included the following variables: pre-ECMO pH, pre-ECMO arterial partial pressure of carbon dioxide, hours of intubation prior to ECMO support, hours of admission at ECMO center prior to ECMO support, ventilator type, mean airway pressure, pre-ECMO use of milrinone, and a diagnosis of pertussis, asthma, bronchiolitis, or malignancy. The validation dataset included 438 children receiving ECMO support from 2013 to 2014. The Ped-RESCUERS model from the development dataset had an AUC of 0.690, and the validation dataset had an AUC of 0.634. CONCLUSIONS: Ped-RESCUERS provides a novel measure of pre-ECMO mortality risk. Future studies should seek external validation and improved discrimination of this mortality prediction tool.

Development and Validation of the Neonatal Risk Estimate Score for Children Using Extracorporeal Respiratory Support.

OBJECTIVE: To develop and validate the Neonatal Risk Estimate Score for Children Using Extracorporeal Respiratory Support, which estimates the risk of in-hospital death for neonates prior to receiving respiratory extracorporeal membrane oxygenation (ECMO) support. STUDY DESIGN: We used an international ECMO registry (2008-2013); neonates receiving ECMO for respiratory support were included. We divided the registry into a derivation sample and internal validation sample, by calendar date. We chose candidate variables a priori based on published evidence of association with mortality; variables independently associated with mortality in logistic regression were included in this parsimonious model of risk adjustment. We evaluated model discrimination with the area under the receiver operating characteristic curve (AUC), and we evaluated calibration with the Hosmer-Lemeshow goodness-of-fit test. RESULTS: During 2008-2013, 4592 neonates received ECMO respiratory support with mortality of 31%. The development dataset contained 3139 patients treated in 2008-2011. The Neo-RESCUERS measure had an AUC of 0.78 (95% CI 0.76-0.79). The validation cohort had an AUC = 0.77 (0.75-0.80). Patients in the lowest risk decile had an observed mortality of 7.0% and a predicted mortality of 4.4%, and those in the highest risk decile had an observed mortality of 65.6% and a predicted mortality of 67.5%. CONCLUSIONS: Neonatal Risk Estimate Score for Children Using Extracorporeal Respiratory Support offers severity-of-illness adjustment for neonatal patients with respiratory failure receiving ECMO. This score may be used to adjust patient survival to assess hospital-level performance in ECMO-based care.

Epidemiology of Stroke in Pediatric Cardiac Surgical Patients Supported With Extracorporeal Membrane Oxygenation.

BACKGROUND: Stroke is a common complication of extracorporeal membrane oxygenation (ECMO), and pediatric cardiac surgical patients may be at higher risk. Epidemiology and risk factors for stroke in these patients are not well characterized. METHODS: We analyzed pediatric (<18 years) cardiac ECMO cases in the Extracorporeal Life Support Organization Registry from 2002 to 2013. Cardiac surgical patients were identified, and procedures were stratified according to The Society of Thoracic Surgeons morbidity categories. The primary outcome was any stroke (hemorrhagic or infarction) identified by neuroimaging. Risk factors were identified through multivariable logistic regression. RESULTS: We analyzed 3,517 cardiac surgical patients; 81% with cyanotic disease, and 57% in high-risk categories from The Society of Thoracic Surgeons (categories 4 and 5). Overall, 12% experienced stroke while receiving ECMO, and those with stroke had greater in-hospital mortality (72% versus 51%; p < 0.0001). In multivariable analysis, neonatal status (adjusted odds ratio, 1.8; 95% confidence interval, 1.3 to 2.4), lower weight-for-age z score (adjusted odds ratio, 1.1 for each 1-point decrease; 95% confidence interval, 1.04 to 1.25), and longer ECMO duration (upper quartile [≥ 167 hours] adjusted odds ratio, 1.4; 95% confidence interval, 1.1 to 1.8) were independently associated with increased stroke risk, whereas cyanotic disease, The Society of Thoracic Surgeons category, and bypass time were not. CONCLUSIONS: This multicenter analysis demonstrates that pediatric cardiac surgical patients on ECMO are at high risk of stroke; younger or underweight patients and those with longer ECMO duration are at greatest risk, independent of procedural complexity. Future study is necessary to determine how anticoagulation or other clinical practices can be modified to reduce stroke incidence.