The purpose of this report is to describe the international growth, outcomes, complications and technology used in pediatric extracorporeal life support (ECLS) from 2009 to 2015 as reported by participating centers in the Extracorporeal Life Support Organization (ELSO). To date, there are 59,969 children who have received ECLS in the ELSO Registry; among those, 21,907 received ECLS since 2009 with an overall survival to hospital discharge rate of 61%. In 2009, 2,409 ECLS cases were performed at 157 centers. By 2015, that number grew to 2,992 cases in 227 centers, reflecting a 24% increase in patients and 55% growth in centers. ECLS delivered to neonates (0–28 days) for respiratory support was the largest subcategory of ECLS among children <18 years old. Overall, 48% of ECLS was delivered for respiratory support and 52% was for cardiac support or extracorporeal life support to support cardiopulmonary resuscitation (ECPR). During the study period, over half of children were supported on ECLS with centrifugal pumps (51%) and polymethylpentene oxygenators (52%). Adverse events including neurologic events were common during ECLS, a fact that underscores the opportunity and need to promote quality improvement work.

Objective The objective of this study was to determine current practices of anticoagulation in patients on extracorporeal membrane oxygenation (ECMO). Design Internet-based cross-sectional survey distributed between November 2010 – May 2011. Setting Extracorporeal Life Support Organization (ELSO)-registered ECMO centers internationally. Participants ECMO medical directors and coordinators. Interventions None. Measurements and Main Results There were 121 responses from ECMO medical directors and coordinators at 187 ELSO centers with access to the survey. Eight-four of 117 (72%) respondents reported having a written institutional ECMO protocol for both anticoagulation and blood product management at their institution. Sixty-nine of 117 (59%) respondents reported use of tip-to-tip or partially heparin-bonded circuits. Unfractionated heparin was used at all centers; only 8% of respondents indicated use of alternative anticoagulation medications in the 6 months prior to the survey. The preferred method of anticoagulation monitoring was the serial measurement of activated clotting time (ACT), as reported by 97% of respondents. In this survey, 82% of respondents reported antithrombin III (ATIII) testing, 65% reported anti-factor Xa testing, and 43% reported use of thromboelastography during ECMO. Goal ranges for these three tests and interventions triggered by out-of-range values were found to be variable. Conclusions ECMO anticoagulation management policies vary widely by center. The majority of ECMO programs employ ACT as the preferred anticoagulation monitoring tool. The coagulation system is also monitored using more specific markers such as ATIII, anti-factor Xa and thromboelastography by a large number of centers. Future research is needed to elucidate optimal anticoagulation management and improve outcomes.

Extracorporeal life support (ECLS) was developed more than 50 years ago, initially with venoarterial and subsequently with venovenous configurations. As the technique of ECLS significantly improved and newer skills developed, complexity in terminology and advances in cannula design led to some misunderstanding of and inconsistency in definitions, both in clinical practice and in scientific research. This document is a consensus of multispecialty international representatives of the Extracorporeal Life Support Organization, including the North America, Latin America, EuroELSO, South West Asia and Africa, and Asia-Pacific chapters, imparting a global perspective on ECLS. The goal is to provide a consistent and unambiguous nomenclature for ECLS and to overcome the inconsistent use of abbreviations for ECLS cannulation. Secondary benefits are ease of multicenter collaboration in research, improved registry data quality, and clear communication among practitioners and researchers in the field.

The best method to monitor anticoagulation during extracorporeal membrane oxygenation (ECMO) is unknown. We conducted a prospective observational study in a tertiary pediatric intensive care unit. Anti-factor Xa (anti-FXa), antithrombin (AT), and factor VIII activity (FVIII) were measured in blood samples collected at 6, 12, and every 24h of ECMO. We enrolled 34 children who underwent 35 ECMO runs from April 2008–September 2010. ACT and heparin doses were higher, whereas anti-FXa levels were lower in neonates compared to infants/children. Median anti-FXa was 0.4 IU/mL, median AT was 60%, and median FVIII was 67%. Heparin infusion rate, anti-FXa, and AT increased, FVIII was stable, and ACT decreased with each day on ECMO. ACT had poor agreement with anti-FXa (42%). AT was inversely correlated with ACT (r=−0.33), even after adjusting for heparin dose, and positively correlated with anti-FXa (r=0.57). This study emphasizes the age differences as well as the variability over days of coagulation monitoring assays during ECMO. ACT is poorly correlated with anti-FXa and AT modifies the relationship between ACT and heparin dose, indicating that results should be interpreted with caution when managing anticoagulation on ECMO. Additional studies are warranted to determine optimal ECMO anticoagulation monitoring.

CpG island methylation is an epigenetic alteration that contributes to tumorigenesis by transcriptional inactivation of genes. Little is known about the overall levels of CpG island methylation in chronic lymphocytic leukemia (CLL). To provide a baseline estimate of global aberrant methylation and identify target sequences for additional investigation, we performed Restriction Landmark Genomic Scanning on 10 CLL samples. Two methylation-sensitive landmark enzymes were used (NotI and AscI), allowing assessment of over 3000 CpG islands in each sample. Tumorderived Restriction Landmark Genomic Scanning profiles were compared with profiles from CD19-selected B cells from normal volunteers and matched normal neutrophils from 4 CLL patients. We found 2.5-8.1% (mean 4.8%) of the CpG islands in CLL samples were aberrantly methylated compared with controls, and the methylation events had a nonrandom distribution (P < 0.0001). Furthermore, we identified 193 aberrantly methylated sequences, of which 93% have CpG island characteristics and 90% have homology to genes or expressed sequences. One such gene, the G protein-coupled metabotropic glutamate receptor 7 (GRM7), possibly inhibits cyclic AMP signaling in the induction of apoptosis. Bisulfite sequencing of GRM7 confirmed extensive CpG island methylation, and treatment with 5-aza-2-deoxycytidine (decitabine) resulted in up-regulated expression of several genes in vitro with concurrent cellular depletion of DNMT1 protein. Our dual-enzyme global methylation study shows that CLL is characterized by widespread nonrandom CpG island methylation similar to other tumors and provides a panel of novel methylation targets that can be used in larger studies designed to assess impact on disease progression and survival.

Objective To determine if, in children, plasma glial fibrillary acidic protein (GFAP) is associated with brain injury during extracorporeal membrane oxygenation (ECMO) and with mortality. Design Prospective, observational study. Setting Pediatric intensive care unit in an urban tertiary care academic center. Patients Neonatal and pediatric ECMO patients (n=22). Interventions Serial blood sampling for GFAP measurements. Measurements and Main Results Prospective patients age 1 day-18 years who required ECMO from April 2008 to August 2009 were studied. GFAP was measured using an electrochemiluminescent immunoassay developed at Johns Hopkins. Control samples were collected from 99 healthy children (0.5-16 years) and 59 NICU infants without neurologic injury. In controls, the median GFAP concentration was 0.055 ng/mL (IQR: 0-0.092 ng/mL) and the 95th percentile of GFAP was 0.436ng/mL. In ECMO patients, plasma GFAP was measured at 6, 12 and every 24 hours after cannulation. We enrolled 22 children who underwent ECMO. Median age was 7 days (IQR, 2 days-9 years), and primary ECMO indication was: cardiac failure, 6/22 (27.3%), respiratory failure, 12/22 (54.5%), ECPR, 3/22 (13.6%), and sepsis, 1/22 (4.6%). Seven of 22 (32%) patients developed acute neurologic injury (intracranial hemorrhage, brain death or cerebral edema diagnosed by imaging). Fifteen of 22 (68%) survived to hospital discharge. In the ECMO group, peak GFAP levels were higher in children with brain injury than those without (median, 5.9 vs 0.09ng/mL, p=0.04) and in non-survivors compared to survivors to discharge (median, 5.9 vs 0.09ng/mL, p=0.04). The odds ratio (OR) for brain injury for GFAP >0.436ng/mL vs normal was 11.5 (95%CI: 1.3-98.3) and the OR for mortality was 13.6 (95%CI: 1.7-108.5). Conclusions High GFAP during ECMO is significantly associated with acute brain injury and death. Brain injury biomarkers may aid in outcome prediction and neurologic monitoring of ECMO patients to improve outcomes and benchmark new therapies.

The Transfusion and Anemia Expertise Initiative recommendations provide important clinical guidance and applicable tools to avoid unnecessary RBC transfusions. Research recommendations identify areas of focus for future investigation to improve outcomes and safety for RBC transfusion.

Septic shock is a life-threatening condition in which timely treatment substantially reduces mortality. Reliable identification of patients with sepsis who are at elevated risk of developing septic shock therefore has the potential to save lives by opening an early window of intervention. We hypothesize the existence of a novel clinical state of sepsis referred to as the “pre-shock” state, and that patients with sepsis who enter this state are highly likely to develop septic shock at some future time. We apply three different machine learning techniques to the electronic health record data of 15,930 patients in the MIMIC-III database to test this hypothesis. This novel paradigm yields improved performance in identifying patients with sepsis who will progress to septic shock, as defined by Sepsis- 3 criteria, with the best method achieving a 0.93 area under the receiver operating curve, 88% sensitivity, 84% specificity, and median early warning time of 7 hours. Additionally, we introduce the notion of patient-specific positive predictive value, assigning confidence to individual predictions, and achieving values as high as 91%. This study demonstrates that early prediction of impending septic shock, and thus early intervention, is possible many hours in advance.