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.

Higher Survival With the Use of Extracorporeal Cardiopulmonary Resuscitation Compared With Conventional Cardiopulmonary Resuscitation in Children Following Cardiac Surgery: Results of an Analysis of the Get With The Guidelines-Resuscitation Registry.

OBJECTIVES: Extracorporeal membrane oxygenation to support cardiopulmonary resuscitation (CPR) is increasingly used in children suffering cardiac arrest after cardiac surgery. However, its efficacy in promoting survival has not been evaluated. We compared survival of pediatric cardiac surgery patients suffering in-hospital cardiac arrest who were resuscitated with extracorporeal CPR (E-CPR) to those resuscitated with conventional CPR (C-CPR) using propensity matching. DESIGN: Retrospective study using multicenter data from the American Heart Association Get With The Guidelines-Resuscitation registry (2008-2020). SETTING: Multicenter cardiac arrest database containing cardiac arrest and CPR data from U.S. hospitals. PATIENTS: Cardiac surgical patients younger than 18 years old who suffered in-hospital cardiac arrest and received greater than or equal to 10 minutes of CPR. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 1223 patients, 741 (60.6%) received C-CPR and 482 (39.4%) received E-CPR. E-CPR utilization increased over the study period ( p < 0.001). Duration of CPR was longer in E-CPR compared with C-CPR recipients (42 vs. 26 min; p < 0.001). In a propensity score matched cohort (382 E-CPR recipients, 382 C-CPR recipients), E-CPR recipients had survival to discharge (odds ratio [OR], 2.22; 95% CI, 1.7-2.9; p < 0.001). E-CPR survival was only higher when CPR duration was greater than 18 minutes. Propensity matched analysis using patients from institutions contributing at least one E-CPR case ( n = 35 centers; 353 E-CPR recipients, 353 C-CPR recipients) similarly demonstrated improved survival in E-CPR recipients compared with those who received C-CPR alone (OR, 2.08; 95% CI, 1.6-2.8; p < 0.001). CONCLUSIONS: E-CPR compared with C-CPR improved survival in children suffering cardiac arrest after cardiac surgery requiring CPR greater than or equal to 10 minutes.

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.

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.

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.

International Consensus Criteria for Pediatric Sepsis and Septic Shock.

Importance: Sepsis is a leading cause of death among children worldwide. Current pediatric-specific criteria for sepsis were published in 2005 based on expert opinion. In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection, but it excluded children. Objective: To update and evaluate criteria for sepsis and septic shock in children. Evidence Review: The Society of Critical Care Medicine (SCCM) convened a task force of 35 pediatric experts in critical care, emergency medicine, infectious diseases, general pediatrics, nursing, public health, and neonatology from 6 continents. Using evidence from an international survey, systematic review and meta-analysis, and a new organ dysfunction score developed based on more than 3 million electronic health record encounters from 10 sites on 4 continents, a modified Delphi consensus process was employed to develop criteria. Findings: Based on survey data, most pediatric clinicians used sepsis to refer to infection with life-threatening organ dysfunction, which differed from prior pediatric sepsis criteria that used systemic inflammatory response syndrome (SIRS) criteria, which have poor predictive properties, and included the redundant term, severe sepsis. The SCCM task force recommends that sepsis in children be identified by a Phoenix Sepsis Score of at least 2 points in children with suspected infection, which indicates potentially life-threatening dysfunction of the respiratory, cardiovascular, coagulation, and/or neurological systems. Children with a Phoenix Sepsis Score of at least 2 points had in-hospital mortality of 7.1% in higher-resource settings and 28.5% in lower-resource settings, more than 8 times that of children with suspected infection not meeting these criteria. Mortality was higher in children who had organ dysfunction in at least 1 of 4-respiratory, cardiovascular, coagulation, and/or neurological-organ systems that was not the primary site of infection. Septic shock was defined as children with sepsis who had cardiovascular dysfunction, indicated by at least 1 cardiovascular point in the Phoenix Sepsis Score, which included severe hypotension for age, blood lactate exceeding 5 mmol/L, or need for vasoactive medication. Children with septic shock had an in-hospital mortality rate of 10.8% and 33.5% in higher- and lower-resource settings, respectively. Conclusions and Relevance: The Phoenix sepsis criteria for sepsis and septic shock in children were derived and validated by the international SCCM Pediatric Sepsis Definition Task Force using a large international database and survey, systematic review and meta-analysis, and modified Delphi consensus approach. A Phoenix Sepsis Score of at least 2 identified potentially life-threatening organ dysfunction in children younger than 18 years with infection, and its use has the potential to improve clinical care, epidemiological assessment, and research in pediatric sepsis and septic shock around the world.

Development and Validation of the Phoenix Criteria for Pediatric Sepsis and Septic Shock.

Importance: The Society of Critical Care Medicine Pediatric Sepsis Definition Task Force sought to develop and validate new clinical criteria for pediatric sepsis and septic shock using measures of organ dysfunction through a data-driven approach. Objective: To derive and validate novel criteria for pediatric sepsis and septic shock across differently resourced settings. Design, Setting, and Participants: Multicenter, international, retrospective cohort study in 10 health systems in the US, Colombia, Bangladesh, China, and Kenya, 3 of which were used as external validation sites. Data were collected from emergency and inpatient encounters for children (aged <18 years) from 2010 to 2019: 3 049 699 in the development (including derivation and internal validation) set and 581 317 in the external validation set. Exposure: Stacked regression models to predict mortality in children with suspected infection were derived and validated using the best-performing organ dysfunction subscores from 8 existing scores. The final model was then translated into an integer-based score used to establish binary criteria for sepsis and septic shock. Main Outcomes and Measures: The primary outcome for all analyses was in-hospital mortality. Model- and integer-based score performance measures included the area under the precision recall curve (AUPRC; primary) and area under the receiver operating characteristic curve (AUROC; secondary). For binary criteria, primary performance measures were positive predictive value and sensitivity. Results: Among the 172 984 children with suspected infection in the first 24 hours (development set; 1.2% mortality), a 4-organ-system model performed best. The integer version of that model, the Phoenix Sepsis Score, had AUPRCs of 0.23 to 0.38 (95% CI range, 0.20-0.39) and AUROCs of 0.71 to 0.92 (95% CI range, 0.70-0.92) to predict mortality in the validation sets. Using a Phoenix Sepsis Score of 2 points or higher in children with suspected infection as criteria for sepsis and sepsis plus 1 or more cardiovascular point as criteria for septic shock resulted in a higher positive predictive value and higher or similar sensitivity compared with the 2005 International Pediatric Sepsis Consensus Conference (IPSCC) criteria across differently resourced settings. Conclusions and Relevance: The novel Phoenix sepsis criteria, which were derived and validated using data from higher- and lower-resource settings, had improved performance for the diagnosis of pediatric sepsis and septic shock compared with the existing IPSCC criteria.

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.

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.

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.

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.

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.

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.

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.

DDX58 Is Associated With Susceptibility to Severe Influenza Virus Infection in Children and Adolescents.

BACKGROUND: Seasonal influenza virus infection causes a range of disease severity, including lower respiratory tract infection with respiratory failure. We evaluated the association of common variants in interferon (IFN) regulatory genes with susceptibility to critical influenza infection in children. METHODS: We performed targeted sequencing of 69 influenza-associated candidate genes in 348 children from 24 US centers admitted to the intensive care unit with influenza infection and lacking risk factors for severe influenza infection (PICFlu cohort, 59.4% male). As controls, whole genome sequencing from 675 children with asthma (CAMP cohort, 62.5% male) was compared. We assessed functional relevance using PICFlu whole blood gene expression levels for the gene and calculated IFN gene signature score. RESULTS: Common variants in DDX58, encoding the retinoic acid-inducible gene I (RIG-I) receptor, demonstrated association above or around the Bonferroni-corrected threshold (synonymous variant rs3205166; intronic variant rs4487862). The intronic single-nucleotide polymorphism rs4487862 minor allele was associated with decreased DDX58 expression and IFN signature (P < .05 and P = .0009, respectively) which provided evidence supporting the genetic variants' impact on RIG-I and IFN immunity. CONCLUSIONS: We provide evidence associating common gene variants in DDX58 with susceptibility to severe influenza infection in children. RIG-I may be essential for preventing life-threatening influenza-associated disease.

Pediatric ECMO: unfavorable outcomes are associated with inflammation and endothelial activation.

BACKGROUND: Inflammatory and endothelial activation responses during extracorporeal membrane oxygenation (ECMO) support in children are poorly understood. In this study, we aimed to determine if circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and with neurologic outcomes in children on ECMO. METHODS: We conducted a secondary analysis of a two-center prospective observational study of 99 neonatal and pediatric ECMO patients. Inflammatory (interferon gamma [IFNγ], interleukin-6 [IL-6], IL-1ß, tumor necrosis factor alpha [TNFα]), endothelial activation (E-selectin, P-selectin, intercellular adhesion molecule-3 [ICAM-3], thrombomodulin [TM]), and fibrinolytic markers (tissue plasminogen activator [tPA], plasminogen activator inhibitor-1 [PAI-1]) were measured in plasma on days 1, 2, 3, 5, 7, and every third day thereafter during the ECMO course. RESULTS: All ECMO day 1 inflammatory biomarkers were significantly elevated in children with abnormal vs. normal neuroimaging. ECMO day 1 and peak levels of IL-6 and PAI-1 were significantly elevated in children who died compared to those who survived to hospital discharge. Tested biomarkers showed no significant association with long-term neurobehavioral outcomes measured using the Vineland Adaptive Behavioral Scales, Second Edition. CONCLUSIONS: High levels of circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and abnormal neuroimaging in children on ECMO. IMPACT: The inflammatory, endothelial activation, and fibrinolytic profile of children on ECMO differs by primary indication for extracorporeal support. Proinflammatory biomarkers on ECMO day 1 are associated with abnormal neurologic imaging in children on ECMO in univariable but not multivariable models. In multivariable models, a pronounced proinflammatory and prothrombotic biomarker profile on ECMO day 1 and longitudinally was significantly associated with mortality. Further studies are needed to identify inflammatory, endothelial, and fibrinolytic profiles associated with increased risk for neurologic injury and mortality through potential mediation of bleeding and thrombosis.

Extracorporeal Membrane Oxygenation Outcomes in Children With Preexisting Neurologic Disorders or Neurofunctional Disability.

OBJECTIVE: Patient selection for pediatric extracorporeal membrane oxygenation (ECMO) support has broadened over the years to include children with pre-existing neurologic morbidities. We aimed to determine the prevalence and nature of pre-ECMO neurologic disorders or disability and investigate the association between pre-ECMO neurologic disorders or disability and mortality and unfavorable neurologic outcome. DESIGN: Multicenter retrospective observational cohort study. SETTING: Eight hospitals reporting to the Pediatric ECMO Outcomes Registry between October 2011 and June 2019. PATIENTS: Children younger than 18 years supported with venoarterial or venovenous ECMO. INTERVENTIONS: The primary exposure was presence of pre-ECMO neurologic disorders or moderate-to-severe disability, defined as Pediatric Cerebral Performance Category (PCPC) or Pediatric Overall Performance Category (POPC) 3-5. The primary outcome was unfavorable outcome at hospital discharge, defined as in-hospital mortality or survival with moderate-to-severe disability (discharge PCPC 3-5 with deterioration from baseline). MEASUREMENTS AND MAIN RESULTS: Of 598 children included in the final cohort, 68 of 598 (11%) had a pre-ECMO neurologic disorder, 70 of 595 (12%) had a baseline PCPC 3-5, and 189 of 592 (32%) had a baseline POPC 3-5. The primary outcome of in-hospital mortality ( n = 267) or survival with PCPC 3-5 with deterioration from baseline ( n = 39) was observed in 306 of 598 (51%). Overall, one or more pre-ECMO neurologic disorders or disability were present in 226 of 598 children (38%) but, after adjustment for age, sex, diagnostic category, pre-ECMO cardiac arrest, and ECMO mode, were not independently associated with increased odds of unfavorable outcome (unadjusted odds ratio [OR], 1.34; 95% CI, 1.07-1.69; multivariable adjusted OR, 1.30; 95% CI, 0.92-1.82). CONCLUSIONS: In this exploratory study using a multicenter pediatric ECMO registry, more than one third of children requiring ECMO support had pre-ECMO neurologic disorders or disability. However, pre-existing morbidities were not independently associated with mortality or unfavorable neurologic outcomes at hospital discharge after adjustment for diagnostic category and other covariates.

Plasma and Platelet Transfusions Strategies in Neonates and Children Undergoing Cardiac Surgery With Cardiopulmonary Bypass or Neonates and Children Supported by Extracorporeal Membrane Oxygenation: From the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding.

OBJECTIVES: To present the recommendations and consensus statements with supporting literature for plasma and platelet transfusions in critically ill neonates and children undergoing cardiac surgery with cardiopulmonary bypass or supported by extracorporeal membrane oxygenation from the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding. DESIGN: Systematic review and consensus conference of international, multidisciplinary experts in platelet and plasma transfusion management of critically ill children. SETTING: Not applicable. PATIENTS: Critically ill neonates and children following cardiopulmonary bypass or supported by extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A panel of nine experts developed evidence-based and, when evidence was insufficient, expert-based statements for plasma and platelet transfusions in critically ill neonates and children following cardiopulmonary bypass or supported by extracorporeal membrane oxygenation. These statements were reviewed and ratified by the 29 Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding experts. A systematic review was conducted using MEDLINE, EMBASE, and Cochrane Library databases, from inception to December 2020. Consensus was obtained using the Research and Development/University of California, Los Angeles Appropriateness Method. Results were summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. We developed one good practice statement, two recommendations, and three expert consensus statements. CONCLUSIONS: Whereas viscoelastic testing and transfusion algorithms may be considered, in general, evidence informing indications for plasma and platelet transfusions in neonatal and pediatric patients undergoing cardiac surgery with cardiopulmonary bypass or those requiring extracorporeal membrane oxygenation support is lacking.

Research Priorities for Plasma and Platelet Transfusion Strategies in Critically Ill Children: From the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding.

OBJECTIVES: To present a list of high-priority research initiatives for the study of plasma and platelet transfusions in critically ill children from the Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding. DESIGN: Systematic review and consensus conference of international, multidisciplinary experts in platelet and plasma transfusion management of critically ill children. SETTING: Not applicable. PATIENTS: Critically ill pediatric patients at risk of bleeding and receiving plasma and/or platelet transfusions. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A panel of 13 experts developed research priorities for the study of plasma and platelet transfusions in critically ill children which were reviewed and ratified by the 29 Transfusion and Anemia EXpertise Initiative-Control/Avoidance of Bleeding experts. The specific priorities focused on the following subpopulations: severe trauma, traumatic brain injury, intracranial hemorrhage, cardiopulmonary bypass surgery, extracorporeal membrane oxygenation, oncologic diagnosis or stem cell transplantation, acute liver failure and/or liver transplantation, noncardiac surgery, invasive procedures outside of the operating room, and sepsis and/or disseminated intravascular coagulation. In addition, tests to guide plasma and platelet transfusion, as well as component selection and processing, were addressed. We developed four general overarching themes and 14 specific research priorities using modified Research and Development/University of California, Los Angeles methodology. CONCLUSIONS: Studies are needed to focus on the efficacy/harm, dosing, timing, and outcomes of critically ill children who receive plasma and/or platelet transfusions. The completion of these studies will facilitate the development of evidence-based recommendations.