Pharmacokinetics of Human Plasma-Derived Antithrombin in Pediatric Patients Supported on Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) support of critically ill pediatric patients is associated with increased risk of thromboembolic events, and unfractionated heparin is used commonly for anticoagulation. Given reports of acquired antithrombin (AT) deficiency in this patient population and associated concern for heparin resistance, AT activity measurement and off-label AT replacement have become common in pediatric ECMO centers despite limited optimal dosing regimens. We conducted a retrospective cohort study of pediatric ECMO patients (0 to <18 years) at a single academic center to characterize the pharmacokinetics (PK) of human plasma-derived AT. We demonstrated that a two-compartment turnover model appropriately described the PK of AT, and the parameter estimates for clearance, central volume, intercompartmental clearance, peripheral volume, and basal AT input under non-ECMO conditions were 0.338 dL/h/70 kg, 38.5 dL/70 kg, 1.16 dL/h/70 kg, 40.0 dL/70 kg, and 30.4 units/h/70 kg, respectively. Also, ECMO could reduce bioavailable AT by 50% resulting in 2-fold increase of clearance and volume of distribution. To prevent AT activity from falling below predetermined thresholds of 50% activity in neonates and 80% activity in older infants and children, we proposed potential replacement regimens for each age group, accompanied by therapeutic drug monitoring.

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.

Priorities for Clinical Research in Pediatric Extracorporeal Membrane Oxygenation Anticoagulation From the Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To identify and prioritize research questions for anticoagulation and hemostasis management of neonates and children supported with extracorporeal membrane oxygenation (ECMO) from the Pediatric ECMO Anticoagulation CollaborativE (PEACE) consensus. DATA SOURCES: Systematic review was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021, followed by serial consensus conferences of international, interprofessional experts in the management of ECMO for critically ill neonates and children. STUDY SELECTION: The management of ECMO anticoagulation for critically ill neonates and children. DATA EXTRACTION: Within each of the eight subgroups, two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. DATA SYNTHESIS: Following the systematic review of MEDLINE, EMBASE, and Cochrane Library databases from January 1988 to May 2021, and the consensus process for clinical recommendations and consensus statements, PEACE panel experts constructed research priorities using the Child Health and Nutrition Research Initiative methodology. Twenty research topics were prioritized, falling within five domains (definitions and outcomes, therapeutics, anticoagulant monitoring, protocolized management, and impact of the ECMO circuit and its components on hemostasis). CONCLUSIONS: We present the research priorities identified by the PEACE expert panel after a systematic review of existing evidence informing clinical care of neonates and children managed with ECMO. More research is required within the five identified domains to ultimately inform and improve the care of this vulnerable population.

Management of Bleeding and Thrombotic Complications During Pediatric Extracorporeal Membrane Oxygenation: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

OBJECTIVES: To derive systematic-review informed, modified Delphi consensus regarding the management of bleeding and thrombotic complications during pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE Consensus Conference. DATA SOURCES: A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021. STUDY SELECTION: The management of bleeding and thrombotic complications of ECMO. DATA EXTRACTION: Two authors reviewed all citations independently, with a third independent reviewer resolving conflicts. Twelve references were used for data extraction and informed recommendations. 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 for the management of bleeding and thrombotic complications in pediatric ECMO patients. 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. Two good practice statements, 5 weak recommendations, and 18 consensus statements are presented. CONCLUSIONS: Although bleeding and thrombotic complications during pediatric ECMO remain common, limited definitive data exist to support an evidence-based approach to treating these complications. Research is needed to improve hemostatic management of children supported with ECMO.

Exploratory factor analysis yields grouping of brain injury biomarkers significantly associated with outcomes in neonatal and pediatric ECMO.

In this two-center prospective cohort study of children on ECMO, we assessed a panel of plasma brain injury biomarkers using exploratory factor analysis (EFA) to evaluate their interplay and association with outcomes. Biomarker concentrations were measured daily for the first 3 days of ECMO support in 95 participants. Unfavorable composite outcome was defined as in-hospital mortality or discharge Pediatric Cerebral Performance Category > 2 with decline ≥ 1 point from baseline. EFA grouped 11 biomarkers into three factors. Factor 1 comprised markers of cellular brain injury (NSE, BDNF, GFAP, S100ß, MCP1, VILIP-1, neurogranin); Factor 2 comprised markers related to vascular processes (vWF, PDGFRß, NPTX1); and Factor 3 comprised the BDNF/MMP-9 cellular pathway. Multivariable logistic models demonstrated that higher Factor 1 and 2 scores were associated with higher odds of unfavorable outcome (adjusted OR 2.88 [1.61, 5.66] and 1.89 [1.12, 3.43], respectively). Conversely, higher Factor 3 scores were associated with lower odds of unfavorable outcome (adjusted OR 0.54 [0.31, 0.88]), which is biologically plausible given the role of BDNF in neuroplasticity. Application of EFA on plasma brain injury biomarkers in children on ECMO yielded grouping of biomarkers into three factors that were significantly associated with unfavorable outcome, suggesting future potential as prognostic instruments.

Higher levels of brain injury biomarker tau are associated with unfavorable outcomes in patients supported with ECMO following cardiac arrest.

Aim: We sought to determine if higher plasma levels of brain injury biomarkers neurofilament light (NfL), phosphorylated tau 181 (pT181), tau, and ubiquitin C-terminal hydrolase L1 (UCHL1) were associated with unfavorable outcomes in children supported on extracorporeal membrane oxygenation (ECMO) with and without preceding cardiac arrest. Methods: We conducted a secondary analysis of a two-center prospective observational study of ECMO patients 0-<18 years. Plasma concentrations of NfL, pT181, tau, and UCHL1 were measured on ECMO days 1, 2 and 3. Unfavorable outcome was defined as in-hospital mortality or discharge Pediatric Cerebral Performance Category (PCPC) >2 with decline from baseline PCPC among survivors. Results: Among 88 children on ECMO, mean tau levels were significantly higher on each of the first three ECMO days in children who underwent extracorporeal cardiopulmonary resuscitation (ECPR) compared to those with non-ECPR cardiac arrest or with no cardiac arrest preceding ECMO. Higher ECMO day 1 tau levels were significantly associated with increased hazard of unfavorable outcome in unadjusted (HR, 1.35, 95% CI 1.09-1.66) and adjusted (HR, 1.42; 95% CI 1.13-1.79) models. Higher levels of NfL or pT181 were not associated with increased hazard for unfavorable outcome in multivariable models. UCHL1 values were outside of detectable limits and thus deferred from analysis. Conclusions: Levels of tau were significantly associated with increased hazard of death or unfavorable neurologic outcome in unadjusted and adjusted models. Biomarkers of brain injury, particularly tau, may aid in detection of neurologic injury and neuroprognostication in patients on ECMO with and without preceding cardiac arrest.

Pre-existing Immunocompromising Conditions and Outcomes of Acute COVID-19 Patients Admitted for Pediatric Intensive Care.

BACKGROUND: We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. METHODS: 55 hospitals in 30 U.S. states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted March 12, 2020-December 30, 2021 to the pediatric intensive care unit (PICU) or high acuity unit for acute COVID-19 were included. RESULTS: Of 1,274 patients, 105 (8.2%) had an ICC including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid organ transplantation, 16 (15.2%) solid tumors and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs. 4.6%, p = 0.005) and hospitalization was longer (p = 0.01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, p = 0.40). In patients with ICC, bacterial co-infection was more common in those with life-threatening COVID-19. CONCLUSIONS: In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities.

First documented rhythm and clinical outcome in children who undergo extracorporeal cardiopulmonary resuscitation for in-hospital cardiac arrest: A report from the american heart association get with the guidelines® - resuscitation registry (GWTG-R).

INTRODUCTION: Outcomes of conventional cardiopulmonary resuscitation are improved when the initial rhythm is shockable (ventricular fibrillation or pulseless ventricular tachycardia). In children, the first documented rhythm is typically asystole or pulseless electrical activity. We evaluate the role the initial rhythm plays in outcomes for children undergoing extracorporeal cardiopulmonary resuscitation (ECPR) for in-hospital cardiac arrest. METHODS: Consecutive patients < 18 years with in-hospital ECPR events ≥ 10 minutes reported to the American Heart Association Get With The Guidelines® - Resuscitation registry from 2014 to 2019 were included. Primary outcome was survival to hospital discharge. Logistic regression modeling was used to compute propensity score matching based on patient, cardiac arrest event and hospital characteristics; patients with initial shockable rhythm were matched to patients with initial non-shockable rhythm. RESULTS: The final cohort included 466 patients, of which 82 (18%) had a shockable, and 384 (82%) had a non-shockable initial rhythm. After propensity score matching of 287 (62%) patients, there was no difference in survival to hospital discharge (risk ratio [RR] 1.2, 95% CI, 0.95-1.53, p = 0.13) or favorable neurologic outcome, defined as Pediatric Cerebral Performance Category (PCPC) of 1 or 2, or no decline from baseline (RR 1.28, 95% CI, 0.84-1.96, p = 0.25) between patients with and without shockable initial rhythm. CONCLUSIONS: In children with in-hospital cardiac arrest undergoing ECPR, there was no significant difference in survival or favorable neurologic outcome between those with initial shockable rhythm compared to non-shockable rhythm. Further investigation to evaluate ECPR patient characteristics and outcomes is warranted to help guide eligibility and ECMO deployment practices.

Continuous Electroencephalography (EEG) Protocol Improves Seizure Detection in Children on Extracorporeal Membrane Oxygenation.

BACKGROUND / OBJECTIVE: Seizures are a complication for pediatric patients requiring extracorporeal membrane oxygenation (ECMO). There are no standardized guidelines regarding continuous electroencephalography (EEG) monitoring to detect seizures in these patients, and the impact of protocolized monitoring has not been evaluated. Here we examined the effects of continuous EEG protocol implementation in our pediatric ECMO population. METHODS: Retrospective chart reviews were conducted on 57 patients who underwent extracorporeal membrane oxygenation and concurrent continuous EEG out of 165 patients supported on extracorporeal membrane oxygenation. Timing of continuous EEG initiation and seizures detected by continuous EEG was determined for 5 years prior to and 15 months after protocol implementation. RESULTS: Protocol implementation was associated with increased ECMO-supported patients who were concurrently monitored by continuous EEG. Time from ECMO cannulation to continuous EEG initiation was shorter (median 7 hours after versus 16.2 hours before; P < .001). Patients who had ongoing seizures at the start of continuous EEG recording decreased from 64% preprotocol to 0% postprotocol (P < .001), and there was an associated earlier time to break in status epilepticus postprotocol. Seizures were detected past 48 hours after cannulation in 50% of patients in the postprotocol group. CONCLUSIONS: Protocol implementation resulted in earlier continuous EEG initiation and more EEGs initiated before seizure onset with evidence of altered seizure dynamics. Although current recommendations suggest that continuous EEG duration of 24-48 hours results in seizure detection for >90% of critically ill adults, longer monitoring may be needed to reliably detect seizures in children supported with ECMO, particularly if monitoring is initiated earlier in the post-cannulation period.

Infants Admitted to US Intensive Care Units for RSV Infection During the 2022 Seasonal Peak.

Importance: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections (LRTIs) and infant hospitalization worldwide. Objective: To evaluate the characteristics and outcomes of RSV-related critical illness in US infants during peak 2022 RSV transmission. Design, Setting, and Participants: This cross-sectional study used a public health prospective surveillance registry in 39 pediatric hospitals across 27 US states. Participants were infants admitted for 24 or more hours between October 17 and December 16, 2022, to a unit providing intensive care due to laboratory-confirmed RSV infection. Exposure: Respiratory syncytial virus. Main Outcomes and Measures: Data were captured on demographics, clinical characteristics, signs and symptoms, laboratory values, severity measures, and clinical outcomes, including receipt of noninvasive respiratory support, invasive mechanical ventilation, vasopressors or extracorporeal membrane oxygenation, and death. Mixed-effects multivariable log-binomial regression models were used to assess associations between intubation status and demographic factors, gestational age, and underlying conditions, including hospital as a random effect to account for between-site heterogeneity. Results: The first 15 to 20 consecutive eligible infants from each site were included for a target sample size of 600. Among the 600 infants, the median (IQR) age was 2.6 (1.4-6.0) months; 361 (60.2%) were male, 169 (28.9%) were born prematurely, and 487 (81.2%) had no underlying medical conditions. Primary reasons for admission included LRTI (594 infants [99.0%]) and apnea or bradycardia (77 infants [12.8%]). Overall, 143 infants (23.8%) received invasive mechanical ventilation (median [IQR], 6.0 [4.0-10.0] days). The highest level of respiratory support for nonintubated infants was high-flow nasal cannula (243 infants [40.5%]), followed by bilevel positive airway pressure (150 infants [25.0%]) and continuous positive airway pressure (52 infants [8.7%]). Infants younger than 3 months, those born prematurely (gestational age <37 weeks), or those publicly insured were at higher risk for intubation. Four infants (0.7%) received extracorporeal membrane oxygenation, and 2 died. The median (IQR) length of hospitalization for survivors was 5 (4-10) days. Conclusions and Relevance: In this cross-sectional study, most US infants who required intensive care for RSV LRTIs were young, healthy, and born at term. These findings highlight the need for RSV preventive interventions targeting all infants to reduce the burden of severe RSV illness.

Effect of Red Blood Cell Transfusion on Regional Tissue Oxygenation in Pediatric Cardiac Surgery Patients.

BACKGROUND: Red blood cell (RBC) transfusions are used frequently in pediatric patients admitted to the intensive care unit (ICU) after cardiac surgery. To improve data-driven transfusion decision-making in the ICU, we conducted a retrospective analysis to assess the effect of RBC transfusion on cerebral and somatic regional oxygenation (rSO2). METHODS: We evaluated post- versus pre-RBC transfusion cerebral rSO2 and somatic rSO2 in all consecutive pediatric patients (age >28 days to <18 years) who underwent biventricular cardiac surgery at a single center between July 2016 and April 2020. RESULTS: The final data set included 263 RBC postoperative transfusion events in 75 patients who underwent 83 surgeries. The median pretransfusion hemoglobin was 10.6 g/dL (25th-75th percentile, 9.3-11.6). The median pretransfusion cerebral and somatic rSO2 were 63% (54-71) and 69% (55-80), which increased by a median of 3 percentage points (-2 to 6) and 2 percentage points (-3 to 6), respectively, after transfusion. After adjusting for pretransfusion hemoglobin, change in hemoglobin posttransfusion versus pretransfusion, and potential confounders (age, sex, and STAT surgical mortality risk score), the posttransfusion versus pretransfusion change in cerebral or somatic rSO2 was not statistically significant. Pretransfusion cerebral rSO2 (crSO2) was ≤50%, a previously described threshold for increased risk for unfavorable neurological outcome, for 22 of 138 (16%) transfusion events with complete pre- and post-crSO2 data. Sixteen of these 22 (73%) transfusions resulted in a posttransfusion crSO2 >50%. When restricting analysis to the first (index) transfusion after arrival to the ICU from the operating room (administered at a median of 1.15 postoperative days [25th-75th percentile, 0.84-1.93]), between-patient pretransfusion hemoglobin was not associated with pretransfusion crSO2 but within-patient posttransfusion versus pretransfusion hemoglobin difference was significantly associated with posttransfusion versus pretransfusion crSO2 difference (mean posttransfusion versus pretransfusion crSO2 difference, 2.54; 95% confidence interval, 0.50-4.48). CONCLUSIONS: In this study, neither cerebral nor somatic rSO2 increased significantly post- versus pre-RBC transfusion in pediatric cardiac surgery patients admitted to the ICU after biventricular repairs. However, almost three-quarters of transfusions administered when pretransfusion crSO2 was below the critical threshold of 50% resulted in a posttransfusion crSO2 >50%. In addition, the significant within-patient change in crSO2 in relation to the change in posttransfusion versus pretransfusion hemoglobin in the immediate postoperative period suggests that a personalized approach to transfusion following within-patient trends of crSO2 rather than absolute between-patient values may be an important focus for future research.

Extracorporeal Membrane Oxygenation Characteristics and Outcomes in Children and Adolescents With COVID-19 or Multisystem Inflammatory Syndrome Admitted to U.S. ICUs.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) has been used successfully to support adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related cardiac or respiratory failure refractory to conventional therapies. Comprehensive reports of children and adolescents with SARS-CoV-2-related ECMO support for conditions, including multisystem inflammatory syndrome in children (MIS-C) and acute COVID-19, are needed. DESIGN: Case series of patients from the Overcoming COVID-19 public health surveillance registry. SETTING: Sixty-three hospitals in 32 U.S. states reporting to the registry between March 15, 2020, and December 31, 2021. PATIENTS: Patients less than 21 years admitted to the ICU meeting Centers for Disease Control criteria for MIS-C or acute COVID-19. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The final cohort included 2,733 patients with MIS-C ( n = 1,530; 37 [2.4%] requiring ECMO) or acute COVID-19 ( n = 1,203; 71 [5.9%] requiring ECMO). ECMO patients in both groups were older than those without ECMO support (MIS-C median 15.4 vs 9.9 yr; acute COVID-19 median 15.3 vs 13.6 yr). The body mass index percentile was similar in the MIS-C ECMO versus no ECMO groups (89.9 vs 85.8; p = 0.22) but higher in the COVID-19 ECMO versus no ECMO groups (98.3 vs 96.5; p = 0.03). Patients on ECMO with MIS-C versus COVID-19 were supported more often with venoarterial ECMO (92% vs 41%) for primary cardiac indications (87% vs 23%), had ECMO initiated earlier (median 1 vs 5 d from hospitalization), shorter ECMO courses (median 3.9 vs 14 d), shorter hospital length of stay (median 20 vs 52 d), lower in-hospital mortality (27% vs 37%), and less major morbidity at discharge in survivors (new tracheostomy, oxygen or mechanical ventilation need or neurologic deficit; 0% vs 11%, 0% vs 20%, and 8% vs 15%, respectively). Most patients with MIS-C requiring ECMO support (87%) were admitted during the pre-Delta (variant B.1.617.2) period, while most patients with acute COVID-19 requiring ECMO support (70%) were admitted during the Delta variant period. CONCLUSIONS: ECMO support for SARS-CoV-2-related critical illness was uncommon, but type, initiation, and duration of ECMO use in MIS-C and acute COVID-19 were markedly different. Like pre-pandemic pediatric ECMO cohorts, most patients survived to hospital discharge.

Impact of red blood cell transfusion on regional cerebral oxygen saturation during pediatric ECMO.

BACKGROUND: Low cerebral regional tissue oxygenation (crSO2) is associated with unfavorable neurological outcomes in children requiring extracorporeal membrane oxygenation (ECMO) support. Red blood cell (RBC) transfusion can improve brain oxygenation and crSO2 has been proposed as a noninvasive monitoring tool that could aid in RBC transfusion decision-making. However, how crSO2 responds to RBC transfusion is largely unknown. STUDY DESIGN AND METHODS: This was a retrospective, observational cohort study of all patients <21 years supported on ECMO at a single institution from 2011 to 2018. Transfusion events were grouped by pre-transfusion hemoglobin concentration (<10, 10- < 12, and ≥ 12 g/dL). Post- versus pre-transfusion crSO2 changes were analyzed using linear mixed-effects models. RESULTS: The final cohort included 830 transfusion events in 111 patients. Hemoglobin increased significantly post- versus pre-RBC transfusion (estimated mean increase of 0.47 g/dL [95% CI, 0.35-0.58], p < .001), as did crSO2 (estimated mean increase of 1.82 percentage points [95% CI, 1.23-2.40], p < .001). Larger improvements in crSO2 were associated with lower pre-transfusion crSO2 values (p < .001). There was no difference in mean change in crSO2 across the three hemoglobin groups in unadjusted analysis (p = .5) or after adjusting for age, diagnostic category, and pre-transfusion rSO2 (p = .15). Pre-transfusion crSO2 was <50% for 112 of 830 (13.5%) transfusion events, with only 30 (26.8%) crSO2 measurements noted to increase ≥50% post-transfusion. DISCUSSION: Among neonatal and pediatric patients on ECMO support, there was a statistically significant increase in crSO2 following RBC transfusion, although clinical significance needs to be investigated further. The effect was strongest among patients with lower crSO2 pre-transfusion.

Evaluation of acquired antithrombin deficiency in paediatric patients supported on extracorporeal membrane oxygenation.

AIMS: There remains a paucity of literature regarding best practice for antithrombin (AT) monitoring, dosing and dose-response in paediatric extracorporeal membrane oxygenation (ECMO) patients. METHODS: We conducted a retrospective cohort study at a quaternary care paediatric intensive care unit in all patients <18 years of age supported on ECMO from 1 June 2011 to 30 April 2020. Adverse events and outcomes were characterized for all ECMO runs. AT activity and replacement were characterized and compared between two clinical protocols. AT activities measured post- vs. pre-AT replacement were compared in order to characterize a dose-response relationship. RESULTS: The final cohort included 191 patients with 201 ECMO runs and 2028 AT activity measurements. The median AT activity was 65% (interquartile range [IQR], 51-82) and 879 (43.3%) measurements met the criteria of deficient. The overall median AT dose and increase in AT activity were 50.6 units/kg/dose (IQR, 39.5-67.2) and 23.5% (IQR, 9.8-36.0), respectively. In the protocol that restricted AT activity measurements to clinical scenarios concerning for heparin resistance, there was significantly higher dosing in conjunction with significantly fewer overall administrations. Approximately one third of AT activity remained deficient after repletion. There was no difference in mechanical complications, reasons for discontinuation of ECMO support, time on ECMO or survival between protocols. CONCLUSIONS: There was a high prevalence of AT deficiency in paediatric ECMO patients. An AT replacement protocol based on evaluating heparin resistance is associated with fewer AT administrations, with similar circuit and patient outcomes. Further data are needed to identify optimal dosing strategies.

Neuromonitoring During ECMO Support in Children.

Extracorporeal membrane oxygenation is a potentially lifesaving intervention for children with severe cardiac or respiratory failure. It is used with increasing frequency and in increasingly more complex and severe diseases. Neurological injuries are important causes of morbidity and mortality in children treated with extracorporeal membrane oxygenation and include ischemic stroke, intracranial hemorrhage, hypoxic-ischemic injury, and seizures. In this review, we discuss the epidemiology and pathophysiology of neurological injury in patients supported with extracorporeal membrane oxygenation, and we review the current state of knowledge for available modalities of monitoring neurological function in these children. These include structural imaging with computed tomography and ultrasound, cerebral blood flow monitoring with near-infrared spectroscopy and transcranial Doppler ultrasound, and physiological monitoring with electroencephalography and plasma biomarkers. We highlight areas of need and emerging advances that will improve our understanding of neurological injury related to extracorporeal membrane oxygenation and help to reduce the burden of neurological sequelae in these children.

Executive Summary of the Second International Guidelines for the Diagnosis and Management of Pediatric Acute Respiratory Distress Syndrome (PALICC-2).

OBJECTIVES: We sought to update our 2015 work in the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS), considering new evidence and topic areas that were not previously addressed. DESIGN: International consensus conference series involving 52 multidisciplinary international content experts in PARDS and four methodology experts from 15 countries, using consensus conference methodology, and implementation science. SETTING: Not applicable. PATIENTS: Patients with or at risk for PARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eleven subgroups conducted systematic or scoping reviews addressing 11 topic areas: 1) definition, incidence, and epidemiology; 2) pathobiology, severity, and risk stratification; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive respiratory support; 8) extracorporeal support; 9) morbidity and long-term outcomes; 10) clinical informatics and data science; and 11) resource-limited settings. The search included MEDLINE, EMBASE, and CINAHL Complete (EBSCOhost) and was updated in March 2022. Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to summarize evidence and develop the recommendations, which were discussed and voted on by all PALICC-2 experts. There were 146 recommendations and statements, including: 34 recommendations for clinical practice; 112 consensus-based statements with 18 on PARDS definition, 55 on good practice, seven on policy, and 32 on research. All recommendations and statements had agreement greater than 80%. CONCLUSIONS: PALICC-2 recommendations and consensus-based statements should facilitate the implementation and adherence to the best clinical practice in patients with PARDS. These results will also inform the development of future programs of research that are crucially needed to provide stronger evidence to guide the pediatric critical care teams managing these patients.

Methodology of the Second Pediatric Acute Lung Injury Consensus Conference.

OBJECTIVES: This article describes the methodology used for The Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2). The PALLIC-2 sought to develop evidence-based clinical recommendations and when evidence was lacking, expert-based consensus statements and research priorities for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS). DATA SOURCES: Electronic searches were conducted using PubMed, Embase, and Cochrane Library (CENTRAL) databases from 2012 to March 2022. STUDY SELECTION: Content was divided into 11 sections related to PARDS, with abstract and full text screening followed by data extraction for studies which met inclusion with no exclusion criteria. DATA EXTRACTION: We used a standardized data extraction form to construct evidence tables, grade the evidence, and formulate recommendations or statements using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. DATA SYNTHESIS: This consensus conference was comprised of a multidisciplinary group of international experts in pediatric critical care, pulmonology, respiratory care, and implementation science which followed standards set by the Institute of Medicine, using the GRADE system and Research And Development/University of California, Los Angeles appropriateness method, modeled after PALICC 2015. The panel of 52 content and four methodology experts had several web-based meetings over the course of 2 years. We conducted seven systematic reviews and four scoping reviews to cover the 11 topic areas. Dissemination was via primary publication listing all statements and separate supplemental publications for each subtopic that include supporting arguments for each recommendation and statement. CONCLUSIONS: A consensus conference of experts from around the world developed recommendations and consensus statements for the definition and management of PARDS and identified evidence gaps which need further research.

Cardiac Dysfunction Biomarkers Are Associated With Potential for Successful Separation From Extracorporeal Membrane Oxygenation in Children.

Biomarkers of cardiac dysfunction may aid in decision making about organ recovery and optimal timing of separation from extracorporeal membrane oxygenation (ECMO). We conducted a prospective observational study of children from 0 to <18 years who underwent ECMO between 7/2010 and 6/2015 in a single center. In this pilot study, we aimed to determine whether Suppression of tumorigenicity 2 (ST2), N -terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3, and endostatin were associated with ability to separate from ECMO. Fifty neonatal and pediatric participants supported on venoarterial ECMO were included (median age 13 days, 50% male). Twelve (24%) participants were unable to separate from extracorporeal support. Plasma ST2 concentrations at cannulation were higher in children who were ultimately unable to separate versus those who successfully separated from ECMO (median 395.3 ng/mL vs. 207.4 ng/mL, p = 0.012). ST2 and NT-proBNP concentrations decreased significantly from the first to the last ECMO day in patients successfully separated from ECMO ( p < 0.0001 and p = 0.017, respectively). Endostatin concentrations increased significantly from the first to the last ECMO day in both groups. Galectin-3 concentrations were not associated with the ability to separate from ECMO. Cardiac dysfunction biomarkers, particularly ST2, may aid in decannulation decision-making in pediatric ECMO patients. These results should be validated with a larger study.

Life-Threatening Complications of Influenza vs Coronavirus Disease 2019 (COVID-19) in US Children.

BACKGROUND: Clinical differences between critical illness from influenza infection vs coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients. METHODS: We compared demographics, clinical characteristics, and outcomes of US children (aged 8 months to 17 years) admitted to the intensive care or high-acuity unit with influenza or COVID-19. Using mixed-effects models, we assessed the odds of death or requiring life support for influenza vs COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity. RESULTS: Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median, 5.2 years vs 13.8 years), less likely to be non-Hispanic Black (14.5% vs 27.6%) or Hispanic (24.0% vs 36.2%), and less likely to have ≥1 underlying condition (66.4% vs 78.5%) or be obese (21.4% vs 42.2%), and a shorter hospital stay (median, 5 days vs 7 days). They were similarly likely to require invasive mechanical ventilation (both 30.2%), vasopressor support (19.6% and 19.9%), or extracorporeal membrane oxygenation (2.2% and 2.9%). Four children with influenza (2.2%) and 11 children with COVID-19 (2.9%) died. The odds of death or requiring life support in children with influenza vs COVID-19 were similar (adjusted odds ratio, 1.30; 95% confidence interval, .78-2.15; P = .32). CONCLUSIONS: Despite differences in demographics and clinical characteristics of children with influenza or COVID-19, the frequency of life-threatening complications was similar. Our findings highlight the importance of implementing prevention measures to reduce transmission and disease severity of influenza and COVID-19.