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.

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.

Extracorporeal cardiopulmonary resuscitation outcomes for children with out-of-hospital and emergency department cardiac arrest.

OBJECTIVE: Data suggest extracorporeal cardiopulmonary resuscitation (ECPR) improves survival in adult patients with refractory cardiac arrest; however, ECPR outcomes in pediatric patients with out-of-hospital cardiac arrest (OHCA) is lacking. The primary aim of this study was to characterize pediatric patients who experience OHCA or cardiac arrest in the ED (EDCA). The secondary aim was to examine associations of cardiac arrest and location of ECPR cannulation with mortality. METHODS: We performed a retrospective analysis of the Extracorporeal Life Support Organization registry. We included pediatric patients (age > 28 days to <18 years) who received ECPR for refractory OHCA or EDCA between 2010 and 2019. Patient, cardiac arrest, and ECPR cannulation characteristics were summarized. We examined associations of location of cardiac arrest and ECPR cannulation with in-hospital mortality using multivariable logistic regression. RESULTS: We analyzed data from 140 pediatric patients. 66 patients (47%) experienced OHCA and 74 patients (53%) experienced EDCA. Overall survival to hospital discharge was 31% (20% OHCA survival vs. 41% EDCA survival, p = 0.008). In adjusted analyses, OHCA was associated with 3.9 times greater odds of mortality (95% confidence interval [CI] 1.61, 9.81) when compared to compared to EDCA. The location of ECPR cannulation was not associated with mortality (odds ratio 1.8, 95% CI 0.75, 4.3). CONCLUSIONS: The use of ECPR for pediatric patients with refractory OHCA is associated with poor survival compared to patients with EDCA. Location of ECPR cannulation does not appear to be associated with mortality.

Fetal exome sequencing for isolated increased nuchal translucency: should we be doing it?

OBJECTIVE: To evaluate the utility of prenatal exome sequencing (ES) for isolated increased nuchal translucency (NT) and to investigate factors that increase diagnostic yield. DESIGN: Retrospective analysis of data from two prospective cohort studies. SETTING: Fetal medicine centres in the UK and USA. POPULATION: Fetuses with increased NT ≥3.5 mm at 11-14 weeks of gestation recruited to the Prenatal Assessment of Genomes and Exomes (PAGE) and Columbia fetal whole exome sequencing studies (n = 213). METHODS: We grouped cases based on (1) the presence of additional structural abnormalities at presentation in the first trimester or later in pregnancy, and (2) NT measurement at presentation. We compared diagnostic rates between groups using Fisher exact test. MAIN OUTCOME MEASURES: Detection of diagnostic genetic variants considered to have caused the observed fetal structural anomaly. RESULTS: Diagnostic variants were detected in 12 (22.2%) of 54 fetuses presenting with non-isolated increased NT, 12 (32.4%) of 37 fetuses with isolated increased NT in the first trimester and additional abnormalities later in pregnancy, and 2 (1.8%) of 111 fetuses with isolated increased NT in the first trimester and no other abnormalities on subsequent scans. Diagnostic rate also increased with increasing size of NT. CONCLUSIONS: The diagnostic yield of prenatal ES is low for fetuses with isolated increased NT but significantly higher where there are additional structural anomalies. Prenatal ES may not be appropriate for truly isolated increased NT but timely, careful ultrasound scanning to identify other anomalies emerging later can direct testing to focus where there is a higher likelihood of diagnosis.

Evolving fetal phenotypes and clinical impact of progressive prenatal exome sequencing pathways: cohort study.

OBJECTIVES: To determine (1) the diagnostic yield and turnaround time (TAT) of two consecutive prenatal exome sequencing (ES) pathways, (2) the evolution of the fetal phenotype and (3) the clinical impact of detecting causative pathogenic variants and incidental findings. METHODS: This was a retrospective cohort analysis of prospectively collected fetal cases that underwent trio ES in the presence of a structural anomaly and normal chromosomal microarray testing in the West Midlands Regional Genetics Laboratory, Birmingham, UK. The study included two phases: (1) between July 2018 and October 2020, the clinical pathway from the Prenatal Assessment of Genomes and Exomes (PAGE) study was adopted and involved prenatal trio ES based on a panel of 1542 development disorder genes and case selection by a multidisciplinary team; (2) between October 2020 and July 2021, prenatal trio ES investigation was based on the National Health Service (NHS) England R21 pathway, with definitive inclusion criteria and a panel of 1205 prenatally relevant genes. Deep phenotyping was performed throughout pregnancy and postnatally. RESULTS: A total of 54 cases were included. The diagnostic yield before vs after R21 pathway implementation was 28.0% (7/25) and 55.2% (16/29), respectively (P = 0.04). The respective values for mean TAT were 54.0 days (range, 14-213 days) and 14.2 days (range, 3-29 days). In cases in which a causative pathogenic variant was identified and in which the pregnancy reached the third trimester, additional anomalies were detected between the second and third trimesters in 73.3% (11/15) of cases, predominantly secondary to progressive hydropic features (3/11 (27.3%)), arthrogryposis (3/11 (27.3%)) or brain anomaly (2/11 (18.2%)). In three cases, a variant of uncertain significance was reclassified to likely pathogenic based on postnatal information. Detection of a causative pathogenic variant had a significant clinical impact in 78.3% (18/23) of cases, most frequently affecting decision-making regarding the course of the pregnancy and neonatal management (7/18 (38.9%)). CONCLUSIONS: Prenatal ES using the NHS England R21 pathway showed great promise when applied to this cohort, allowing a genetic diagnosis to be made in over half of preselected cases with a fetal structural anomaly on ultrasound. Monitoring and real-time updating of fetal phenotype and reclassification of variants based on postnatal findings is vital to increase the clinical impact that is already evident from this emerging genomic technology. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Waitlist and posttransplant outcomes of critically ill infants awaiting heart transplantation managed without ventricular assist device support.

BACKGROUND: Infants listed for heart transplant are at high risk for waitlist mortality. While waitlist mortality for children has decreased in the current era of increased ventricular assist device use, outcomes for small infants supported by ventricular assist device remain suboptimal. We evaluated morbidity and survival in critically ill infants listed for heart transplant and managed without ventricular assist device support. METHODS: Critically ill infants (requiring ≥1 inotrope and mechanical ventilation or ≥2 inotropes without mechanical ventilation) listed between 2008 and 2019 were included. During the study period, infants were managed primarily medically. Mechanical circulatory support, specifically extracorporeal membrane oxygenation, was utilized as "rescue therapy" for decompensating patients. RESULTS: Thirty-two infants were listed 1A, 66% with congenital heart disease. Median age and weight at listing were 2.2 months and 4.4 kg, with 69% weighing <5 kg. At listing, 97% were mechanically ventilated, 41% on ≥2 inotropes, and 25% under neuromuscular blockade. Five patients were supported by ECMO after listing. A favorable outcome (transplant or recovery) was observed in 84%. One-year posttransplant survival was 92%. Infection was the most common waitlist complication occurring in 75%. Stroke was rare, occurring in one patient who was supported on ECMO. Renal function improved from listing to transplant, death, or recovery (eGFR 70 vs 87 ml/min/1.73m2 , p = .001). CONCLUSION: A strategy incorporating a high threshold for mechanical circulatory support and acceptance of prolonged mechanical ventilation and neuromuscular blockade can achieve good survival and morbidity outcomes for critically ill infants listed for heart transplant.

Evidence to Support the Clinical Utility of Prenatal Exome Sequencing in Evaluation of the Fetus with Congenital Anomalies: Scientific Impact Paper No. 64 [February] 2021.

Structural differences (congenital anomalies) in the makeup of the baby's heart, brain and other organs are found on antenatal ultrasound scans in up to 3% of pregnancies. These often have a genetic cause, arising because of changes in the chromosomes (which store our genetic material) or the DNA code that make up the genes. The more differences a baby has the more likely the risk of underlying genetic disease. If a structural difference is found, parents are usually offered a genetic test, which may be carried out on cells taken either from the placenta (chorionic villous sampling) or the fluid surrounding the baby (amniocentesis). At the moment, these cells are only tested for changes in the chromosomes and are only able to reveal the underlying cause in about 40% of unborn babies. Prenatal exome sequencing (ES) is a new genetic test, which, when combined with testing the DNA of both parents can find changes in the baby's genetic code. If a DNA change is found that can explain the structural changes seen on ultrasound, specific information about the underlying diagnosis can be given to the parents. Having this information can help parents make important decisions about their ongoing pregnancy, as well as help doctors to care for the mother and baby. Finding a genetic change can also help to understand how the condition has arisen and whether it might happen again in another pregnancy. It may also be possible to test for the genetic condition in future pregnancies. Although prenatal ES is an exciting new way to improve diagnosis rates for structural differences, it has some challenges. While the test is very detailed, it may not always find a genetic explanation and sometimes the results are difficult to interpret. For example, genetic changes can be found where their significance for the pregnancy is unclear. More recently, two studies have now shown that prenatal ES can find a genetic diagnosis in at least 10% of pregnancies with structural differences where standard chromosome testing has been negative. This paper reviews these studies, along with earlier evidence on ES and provides clinicians with guidance for future practice.

COngenital heart disease and the Diagnostic yield with Exome sequencing (CODE) study: prospective cohort study and systematic review.

OBJECTIVE: To determine the incremental yield of antenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) or conventional karyotyping in prenatally diagnosed congenital heart disease (CHD). METHODS: A prospective cohort study of 197 trios undergoing ES following CMA or karyotyping owing to CHD identified prenatally and a systematic review of the literature were performed. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov (January 2000 to October 2019) databases were searched electronically for studies reporting on the diagnostic yield of ES in prenatally diagnosed CHD. Selected studies included those with more than three cases, with initiation of testing based upon prenatal phenotype only and that included cases in which CMA or karyotyping was negative. The incremental diagnostic yield of ES was assessed in: (1) all cases of CHD; (2) isolated CHD; (3) CHD associated with extracardiac anomaly (ECA); and (4) CHD according to phenotypic subgroup. RESULTS: In our cohort, ES had an additional diagnostic yield in all CHD, isolated CHD and CHD associated with ECA of 12.7% (25/197), 11.5% (14/122) and 14.7% (11/75), respectively (P = 0.81). The corresponding pooled incremental yields from 18 studies (encompassing 636 CHD cases) included in the systematic review were 21% (95% CI, 15-27%), 11% (95% CI, 7-15%) and 37% (95% CI, 18-56%), respectively. The results did not differ significantly when subanalysis was limited to studies including more than 20 cases, except for CHD associated with ECA, in which the incremental yield was greater (49% (95% CI, 17-80%)). In cases of CHD associated with ECA in the primary analysis, the most common extracardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system (23/52 (44.2%)). The greatest incremental yield was in cardiac shunt lesions (41% (95% CI, 19-63%)), followed by right-sided lesions (26% (95% CI, 9-43%)). In the majority (68/96 (70.8%)) of instances, pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes. The most common (19/96 (19.8%)) monogenic syndrome identified was Kabuki syndrome. CONCLUSIONS: There is an apparent incremental yield of prenatal ES in CHD. While the greatest yield is in CHD associated with ECA, consideration could also be given to performing ES in the presence of an isolated cardiac abnormality. A policy of routine application of ES would require the adoption of robust bioinformatic, clinical and ethical pathways. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Fetal hydrops and the Incremental yield of Next-generation sequencing over standard prenatal Diagnostic testing (FIND) study: prospective cohort study and meta-analysis.

OBJECTIVE: To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non-immune hydrops fetalis (NIHF). METHODS: A prospective cohort study (comprising an extended group of the Prenatal Assessment of Genomes and Exomes (PAGE) study) was performed which included 28 cases of prenatally diagnosed NIHF undergoing trio ES following negative CMA or karyotyping. These cases were combined with data from a systematic review of the literature. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched electronically (January 2000 to October 2020) for studies reporting on the incremental yield of ES over CMA or karyotyping in fetuses with prenatally detected NIHF. Inclusion criteria for the systematic review were: (i) at least two cases of NIHF undergoing sequencing; (ii) testing initiated based on prenatal ultrasound-based phenotype; and (iii) negative CMA or karyotyping result. The incremental diagnostic yield of ES was assessed in: (i) all cases of NIHF; (ii) isolated NIHF; (iii) NIHF associated with an additional fetal structural anomaly; and (iv) NIHF according to severity (i.e. two vs three or more cavities affected). RESULTS: In the extended PAGE study cohort, the additional diagnostic yield of ES over CMA or karyotyping was 25.0% (7/28) in all NIHF cases, 21.4% (3/14) in those with isolated NIHF and 28.6% (4/14) in those with non-isolated NIHF. In the meta-analysis, the pooled incremental yield based on 21 studies (306 cases) was 29% (95% CI, 24-34%; P < 0.00001; I2 = 0%) in all NIHF, 21% (95% CI, 13-30%; P < 0.00001; I2 = 0%) in isolated NIHF and 39% (95% CI, 30-49%; P < 0.00001; I2 = 1%) in NIHF associated with an additional fetal structural anomaly. In the latter group, congenital limb contractures were the most prevalent additional structural anomaly associated with a causative pathogenic variant, occurring in 17.3% (19/110) of cases. The incremental yield did not differ significantly according to hydrops severity. The most common genetic disorders identified were RASopathies, occurring in 30.3% (27/89) of cases with a causative pathogenic variant, most frequently due to a PTPN11 variant (44.4%; 12/27). The predominant inheritance pattern in causative pathogenic variants was autosomal dominant in monoallelic disease genes (57.3%; 51/89), with most being de novo (86.3%; 44/51). CONCLUSIONS: Use of prenatal next-generation sequencing in both isolated and non-isolated NIHF should be considered in the development of clinical pathways. Given the wide range of potential syndromic diagnoses and heterogeneity in the prenatal phenotype of NIHF, exome or whole-genome sequencing may prove to be a more appropriate testing approach than a targeted gene panel testing strategy. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Conversion From Activated Clotting Time to Anti-Xa Heparin Activity Assay for Heparin Monitoring During Extracorporeal Membrane Oxygenation.

OBJECTIVES: Anticoagulation with unfractionated heparin remains the most common therapy used to prevent circuit thrombosis during extracorporeal membrane oxygenation, but no consensus exists on the optimal method or targets for heparin monitoring. From 2015 to 2018, we switched from monitoring heparin during extracorporeal membrane oxygenation using activated clotting times to anti-Xa heparin activity assays. This study describes the transition from activated clotting time to anti-Xa heparin activity assay monitoring and the associated clinical changes. DESIGN: Retrospective analysis at single institution. SETTING: Referral Children's Hospital. PATIENTS: A total of 145 pediatric patients over 152 extracorporeal membrane oxygenation runs using 206 extracorporeal membrane oxygenation circuits. INTERVENTIONS: Anticoagulation protocol quality improvement. MEASUREMENTS AND MAIN RESULTS: From 2015 to 2018, heparin monitoring during extracorporeal membrane oxygenation changed from hourly activated clotting time to anti-Xa heparin activity assay every 6 hours with an associated 75% reduction in the circuit changes per extracorporeal membrane oxygenation day. Over the 4 years, patients with an average anti-Xa heparin activity assay of at least 0.25 U/mL showed a 59% reduction in circuit changes per extracorporeal membrane oxygenation day compared with less than 0.15 U/mL. In addition to its association with reduced circuit changes, anti-Xa heparin activity assay monitoring was also associated with reduced heparin dose changes per day from 11 ± 4 to 2 ± 1 (p < 0.001), smaller heparin dose changes (less variation in dose), and reduced diagnostic phlebotomy volumes from 41 ± 6 to 25 ± 11 mL/day (p < 0.001). The number of patients with reported bleeding decreased from 69% using activated clotting time to 51% (p = 0.03). Transfusion rates did not change. CONCLUSIONS: Over 4 years, we replaced the activated clotting time assay with the anti-Xa heparin activity assay for heparin monitoring during extracorporeal membrane oxygenation. Minimum anti-Xa heparin activity assay levels of 0.25 U/mL were associated with reduced circuit changes. Further studies are needed to determine the optimum anti-Xa heparin activity assay therapeutic range during extracorporeal membrane oxygenation.

Outcomes After In-Hospital Pediatric Recurrent Cardiac Arrests.

OBJECTIVES: The objective of this study is to determine outcomes of recurrent cardiac arrest events in the general pediatric inpatient population. DESIGN: Retrospective cohort study of inpatients in a single institution. SETTING: A tertiary care free-standing children's hospital. PATIENTS: All patients less than 18 years old at Seattle Children's Hospital with recurrent cardiac arrest events occurring from January 1, 2010, to March 1, 2018, were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Overall survival to hospital discharge was 50% and all survivors had a good neurologic outcome, defined as Pediatric Cerebral Performance Category of 3 or less, or unchanged from baseline. Survival among patients who received extracorporeal life support was 43% and among those who received extracorporeal cardiopulmonary resuscitation, 33%. Initial arrest factors associated with survival included initial rhythm of ventricular tachycardia or ventricular fibrillation, shorter duration of cardiopulmonary resuscitation, and absence of multiple organ dysfunction. Additionally, nonsurvivors had more severe metabolic acidosis in the prearrest and postarrest period. CONCLUSIONS: Survival after pediatric in-hospital recurrent cardiac arrest is higher than previously reported. There is also evidence that initial rhythm other than ventricular tachycardia/ventricular fibrillation and longer duration of cardiopulmonary resuscitation as well as multiple organ dysfunction and more severe lactic acidosis in the peri-arrest period are associated with poor outcomes.

The use of extracorporeal membrane oxygenation in human immunodeficiency virus-positive patients: a review of a multicenter database.

AIM: We chose to evaluate the survival of extracorporeal membrane oxygenation among patients with human immunodeficiency virus in a multicenter registry. METHODS: Retrospective case review of the Extracorporeal Life Support Organization Registry respiratory failure of all patients with human immunodeficiency virus supported with extracorporeal membrane oxygenation. RESULTS: A total of 126 patients were included. Survival to discharge was 36%. Eight infants were supported with extracorporeal membrane oxygenation and three (37.5%) survived to discharge. Respiratory extracorporeal membrane oxygenation was the primary indication (78%) with a 39% survival, while cardiac and extracorporeal cardiopulmonary resuscitation indications accounted for 16% and 6% of patients with survivals of 30% and 12.5%, respectively. These differences did not reach significance. There were no significant differences between survivors and non-survivors in demographic data, but non-survivors had significantly more non-human immunodeficiency virus pre-extracorporeal membrane oxygenation infections than survivors. There were no differences in other pre-extracorporeal membrane oxygenation supportive therapies, mechanical ventilator settings, or arterial blood gas results between survivors and non-survivors. The median duration of mechanical ventilation prior to cannulation was 52 (interquartile range: 13-140) hours, while the median duration of the extracorporeal membrane oxygenation exposure was 237 (interquartile range: 125-622) hours. Ventilator settings were significantly lower after 24 hours compared to pre-extracorporeal membrane oxygenation settings. Complications during extracorporeal membrane oxygenation exposure including receipt of renal replacement therapy, inotropic infusions, and cardiopulmonary resuscitation were more common among non-survivors compared to survivors. Central nervous system complications were rare. CONCLUSION: Survival among patients with human immunodeficiency virus infection who receive extracorporeal membrane oxygenation was less than 40%. Infections before extracorporeal membrane oxygenation cannulation occurred more often in non-survivors. The receipt of renal replacement therapy, inotropic infusions, or cardiopulmonary resuscitation during extracorporeal membrane oxygenation was associated with worse outcome.

The Extracorporeal Life Support Organization Maastricht Treaty for Nomenclature in Extracorporeal Life Support. A Position Paper of the Extracorporeal Life Support Organization.

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.

Assessment of muscle oxygenation in children with congenital heart disease.

BACKGROUND: Adaptive responses to congenital heart disease result in altered muscle perfusion and muscle metabolism. Such changes may be detectable using noninvasive spectroscopic monitors. AIMS: In this study we aimed to determine if resting muscle oxygen saturation (MOx) is lower in children with acyanotic or cyanotic congenital heart disease than in healthy children and to identify differences in muscle oxygen consumption in children with cyanotic and acyanotic congenital heart disease. METHODS: Using a custom fiber optic spectrometer system, optical measurements were obtained from the calf or forearm of 49 patients (17 with acyanotic congenital heart disease, 18 with cyanotic congenital heart disease, and 14 control). Twenty additional control patients were used to develop the analytic model. Spectra were used to determine MOx at baseline, during arterial occlusion, and during reperfusion. The rate of muscle desaturation during arterial occlusion was also evaluated. Two-sample t-tests were used to compare each heart disease group with the controls. RESULTS: Patients with acyanotic and cyanotic congenital heart disease had lower baseline MOx than controls. Baseline MOx was 91.3% (CI 85.9%, 96.7%) for acyanotic patients, 91.1% (CI 86.3%, 95.9%) for cyanotic patients, and 98.9% (CI 96.7%, 101.1%) for controls. Similarly, MOx was lower in the acyanotic and cyanotic groups than the controls after reperfusion (84.6% [CI 74.1%, 95.1%] and 82.1% [CI 74.5%, 89.7%] vs 98.9% [96.5%, 101.3%]). The rate of decline in oxygenation was significantly greater in cyanotic patients versus controls (0.46%/s (CI 0.30%, 0.62%/s) vs 0.17%/s (0.13%, 0.21%/s)). CONCLUSION: This study demonstrates that muscle oxygenation is abnormal in children with both cyanotic and acyanotic congenital heart disease. This suggests that noninvasive monitoring of muscle oxygenation may provide valuable information in situations where children with congenital heart disease may be at risk of hemodynamic compromise.

The clinical utility of genetic testing of tissues from pregnancy losses.

OBJECTIVE: To map the current testing being undertaken following pregnancy loss across the UK and to examine the clinical utility in terms of identifying a cause for the loss and in identifying couples at risk of an unbalanced liveborn child. DESIGN: Retrospective audit. SETTING: UK, for the year 2014. POPULATION: An audit of 6465 referrals for genetic testing of tissue samples following pregnancy loss. METHODS: Data were obtained by questionnaire from 15 UK regional genetics laboratories. MAIN OUTCOME MEASURES: Data were analysed with respect to gestational age, the presence of identified fetal anomalies, methodologies used, abnormality rates and the presence of a parental balanced rearrangement. RESULTS: Of 6465 referrals a genetic cause was identified in 22% of cases (before 12 weeks' gestation, in 47%; at 12-24 weeks, in 14%; after 24 weeks, in 6%). In 0.4% of cases a balanced parental rearrangement was identified where there was a risk of an affected liveborn child in a future pregnancy. Eighty percent of genetic imbalances identified were aneuploidy or triploidy and could be identified by quantitative fluorescence polymerase chain reaction alone. There was significant variation across the UK in acceptance criteria, testing strategies and thus level of resolution of testing. CONCLUSIONS: Genetic testing of tissues following pregnancy loss identifies a probable cause of fetal demise in 22% of cases, but it is of low clinical utility in identifying couples at risk of a future unbalanced liveborn child. A comprehensive multidisciplinary review is needed to develop proposals for an affordable and equitable service. TWEETABLE ABSTRACT: UK audit of genetic testing of fetal loss shows variation in access to and resolution of analysis.

Comparison of Transplant Waitlist Outcomes for Pediatric Candidates Supported by Ventricular Assist Devices Versus Medical Therapy.

OBJECTIVES: Ventricular assist devices have gained popularity in the management of refractory heart failure in children listed for heart transplantation. Our primary aim was to compare the composite endpoint of all-cause pretransplant mortality and loss of transplant eligibility in children who were treated with a ventricular assist device versus a medically managed cohort. DESIGN: This was a retrospective cohort analysis. SETTINGS: Data were obtained from the Scientific Registry of Transplant Recipients. PATIENTS: The at-risk population (n = 1,380) was less than 18 years old, either on a ventricular assist device (605 cases) or an equivalent-severity, intensively medically treated group (referred to as MED, 775 cases). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The impact of ventricular assist devices was estimated via Cox proportional hazards regression (hazard ratio), dichotomizing 1-year outcomes to "poor" (22%: 193 deaths, 114 too sick) versus all others (940 successful transplants, 41 too healthy, 90 censored), while adjusting for conventional risk factors. Among children 0-12 months old, ventricular assist device was associated with a higher risk of poor outcomes (hazard ratio, 2.1; 95% CI, 1.5-3.0; p < 0.001). By contrast, ventricular assist device was associated with improved outcomes for ages 12-18 (hazard ratio, 0.3; 95% CI, 0.1-0.7; p = 0.003). For candidates 1-5 and 6-11 years old, there were no differences in outcomes between the ventricular assist device and MED groups (hazard ratio, 0.8 and 1.0, p = 0.43 and 0.9). The interaction between ventricular assist devices and age group was strongly significant (p < 0.001). CONCLUSIONS: This is a comparative study of ventricular assist devices versus medical therapy in children. Age is a significant modulator of waitlist outcomes for children with end-stage heart failure supported by ventricular assist device, with the impact of ventricular assist devices being more beneficial in adolescents.

Venovenous extracorporeal life support in patients with HIV infection and Pneumocystis jirovecii pneumonia.

AIM: As experience with extracorporeal life support (ECLS) increases, indications for its use have expanded to diverse patient populations, including those with HIV infection. Pneumocystis jirovecii pneumonia (PJP) is a particularly devastating complication of HIV infections. The objective of this study was to review ECLS use in HIV-positive patients, with particular emphasis on those with concomitant PJP infection. METHODS: All patients were treated by the same ECLS team, consisting of an ECLS specialist intensivist, cardiothoracic surgeon and allied medical professionals at three healthcare institutions. The same ECLS protocol was utilized for all patients during the study period. A retrospective review was performed for all HIV-positive patients placed on ECLS from May 2011 to October 2014. Demographic, clinical, ECLS and complication data were reviewed to identify risk factors for death. RESULTS: A total of 22 HIV-positive patients received ECLS therapy during the study period. All patients were supported with venovenous ECLS and overall survival to hospital discharge was 68%. Survival amongst the PJP positive cohort was 60%. Non-survivors were more likely to require inotropic medications on ECLS (100% non-survivors vs. 46.7% survivors, p=0.022) and had a longer total duration of ECLS (13 days non-survivors vs. 7 days survivors, p=0.011). No difference was observed between PJP-positive and PJP-negative patients with regard to demographic data, complication rates or survival. CONCLUSION: ECLS is a viable treatment option in carefully selected HIV-positive patients, including those with severe disease as manifested by PJP infection.

Identification and functional characterisation of genetic variants in OLFM2 in children with developmental eye disorders.

Anophthalmia, microphthalmia, and coloboma are a genetically heterogeneous spectrum of developmental eye disorders and affect around 30 per 100,000 live births. OLFM2 encodes a secreted glycoprotein belonging to the noelin family of olfactomedin domain-containing proteins that modulate the timing of neuronal differentiation during development. OLFM2 SNPs have been associated with open angle glaucoma in a case-control study, and knockdown of Olfm2 in zebrafish results in reduced eye size. From a cohort of 258 individuals with developmental eye anomalies, we identified two with heterozygous variants in OLFM2: an individual with bilateral microphthalmia carrying a de novo 19p13.2 microdeletion involving OLFM2 and a second individual with unilateral microphthalmia and contralateral coloboma who had a novel single base change in the 5' untranslated region. Dual luciferase assays demonstrated that the latter variant causes a significant decrease in expression of OLFM2. Furthermore, RNA in situ hybridisation experiments using human developmental tissue revealed expression in relevant structures, including the lens vesicle and optic cup. Our study indicates that OLFM2 is likely to be important in mammalian eye development and disease and should be considered as a gene for human ocular anomalies.

Shifting Risks and Conflicting Outcomes-ECMO for Neonates with Congenital Diaphragmatic Hernia in the Modern Era.

OBJECTIVES: To update previously described trends for neonates with congenital diaphragmatic hernia (CDH) receiving ECMO with changes in recommendations for care, and to determine how recent advancements in respiratory care have affected this patient population. STUDY DESIGN: This study is a retrospective review of more than 2500 neonates with CDH who received ECMO listed in the Extracorporeal Life Support Organization (ELSO) registry. Cochran-Armitage and multivariate regression analyses were used to analyze changes in the patient population over time and in mortality-related risk factors. RESULTS: Almost one-half (48.1%) of the term neonates survived to discharge, representing a 13.8% decline in survival over the past 25 years (P < .0001). Over the past 10 years, the prevalence of respiratory acidosis more than doubled (P < .0001) and the prevalence of major complications increased (P < .001). During the same period, the number of ECMO courses longer than 1 week increased (P < .001), whereas the prevalence of multiple complications (>4) decreased (P < .0001). Surgeries performed on ECMO were associated with worse outcomes than those performed off ECMO. ECMO duration no longer represents a mortality-related risk factor. CONCLUSIONS: Survival rates for neonates with CDH receiving ECMO have continued to drop in the modern era. Although the safety of ECMO has improved over the last decade, the number of patients experiencing significant respiratory acidosis has more than doubled-increasing the risk of intracranial hemorrhage and overall mortality. The evidence for permissive hypercapnia remains mixed; nonetheless, we believe that the risks outweigh the rewards in this patient population.