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The Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network originated over 20 years ago to foster research to optimize the care of critically ill infants and children. Over this period, PALISI has seen two major evolutions: formalization of our network infrastructure and a broadening of our clinical research focus. First, the network is unique in that its activities and meetings are funded by subscriptions from members who now comprise a multidisciplinary group of investigators from over 90 PICUs all over the United States (US) and Canada, with collaborations across the globe. In 2020, the network converted into a standalone, nonprofit organizational structure (501c3), making the PALISI Network formally independent of academic and clinical institutions or professional societies. Such an approach allows us to invest in infrastructure and future initiatives with broader opportunities for fund raising. Second, our research investigations have expanded beyond the original focus on sepsis and acute lung injury, to incorporate the whole field of pediatric critical care, for example, efficient liberation from mechanical ventilator support, prudent use of blood products, improved safety of intubation practices, optimal sedation practices and glucose control, and pandemic research on influenza and COVID-19. Our network approach in each field follows, where necessary, the full spectrum of clinical and translational research, including: immunobiology studies for understanding basic pathologic mechanisms; surveys to explore contemporary clinical practice; consensus conferences to establish agreement about literature evidence; observational prevalence and incidence studies to measure scale of a clinical issue or question; case control studies as preliminary best evidence for design of definitive prospective studies; and, randomized controlled trials for informing clinical care. As a research network, PALISI and its related subgroups have published over 350 peer-reviewed publications from 2002 through September 2022.

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 to18 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 versus 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 (p0.0001 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.

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.Multicenter retrospective observational cohort study.Eight hospitals reporting to the Pediatric ECMO Outcomes Registry between October 2011 and June 2019.Children younger than 18 years supported with venoarterial or venovenous ECMO.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).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).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.

Hemorrhagic shock in pediatric trauma patients remains a challenging yet preventable cause of death. There is little high-quality evidence available to guide specific aspects of hemorrhage control and specific resuscitation practices in this population. We sought to generate clinical recommendations, expert consensus, and good practice statements to aid providers in care for these difficult patients.The Pediatric Traumatic Hemorrhagic Shock Consensus Conference process included systematic reviews related to six subtopics and one consensus meeting. A panel of 16 consensus multidisciplinary committee members evaluated the literature related to 6 specific topics: (1) blood products and fluid resuscitation for hemostatic resuscitation, (2) utilization of prehospital blood products, (3) use of hemostatic adjuncts, (4) tourniquet use, (5) prehospital airway and blood pressure management, and (6) conventional coagulation tests or thromboelastography-guided resuscitation. A total of 21 recommendations are detailed in this article: 2 clinical recommendations, 14 expert consensus statements, and 5 good practice statements. The statement, the panel's voting outcome, and the rationale for each statement intend to give pediatric trauma providers the latest evidence and guidance to care for pediatric trauma patients experiencing hemorrhagic shock. With a broad multidisciplinary representation, the Pediatric Traumatic Hemorrhagic Shock Consensus Conference systematically evaluated the literature and developed clinical recommendations, expert consensus, and good practice statements concerning topics in traumatically injured pediatric patients with hemorrhagic shock.

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 patients with ARDS will on occasion need venovenous extracorporeal membrane oxygenation (VV-ECMO) for organ support. As these patients recover, they may benefit from lung recruitment maneuvers including flexible bronchoscopy (FB). The objective of this study was to assess the clinical course of patients who underwent FB while on VV-ECMO for ARDS.This was a secondary analysis of a retrospective multi-center cohort at 10 United States pediatric academic quaternary care centers. Data were collected on 204 subjects age 14 d-18 y on VV-ECMO.271 FBs were performed on 129 (63%) subjects. Pre-FB tidal volume was 1.8 mL/kg compared to 2.22 mL/kg following FB (FB can be performed on patients while anticoagulated on VV-ECMO with a low incidence of complications. FB may be beneficial especially when performed early in the course of VV-ECMO.

Research evaluating hemostatic agents for the treatment of clinically significant bleeding has been hampered by inconsistency and lack of standardized primary clinical trial outcomes. Clinical trials of hemostatic agents in both cardiac surgery and mechanical circulatory support, such as extracorporeal membrane oxygenation and ventricular assist devices, are examples of studies that lack implementation of universally accepted outcomes.A subgroup of experts convened by the National Heart, Lung, and Blood Institute and the US Department of Defense developed consensus recommendations for primary outcomes in cardiac surgery and mechanical circulatory support.For cardiac surgery the primary efficacy endpoint of total allogeneic blood products (units vs mL/kg for pediatric patients) administered intraoperatively and postoperatively through day 5 or hospital discharge is recommended. For mechanical circulatory support outside the perioperative period the recommended primary outcome for extracorporeal membrane oxygenation is a 5-point ordinal score of thrombosis and bleeding severity adapted from the Common Terminology Criteria for Adverse Events version 5.0. The recommended primary endpoint for ventricular assist device is freedom from disabling stroke (Common Terminology Criteria for Adverse Events AE ≥ grade 3) through day 180.The proposed composite risk scores could impact the design of upcoming clinical trials and enable comparability of future investigations. Harmonizing and disseminating global consensus definitions and management guidelines can also reduce patient heterogeneity that would confound standardized primary outcomes in future research.

Prior criteria for organ dysfunction in critically ill children were based mainly on expert opinion. We convened the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) expert panel to summarize data characterizing single and multiple organ dysfunction and to derive contemporary criteria for pediatric organ dysfunction. The panel was composed of 88 members representing 47 institutions and 7 countries. We conducted systematic reviews of the literature to derive evidence-based criteria for single organ dysfunction for neurologic, cardiovascular, respiratory, gastrointestinal, acute liver, renal, hematologic, coagulation, endocrine, endothelial, and immune system dysfunction. We searched PubMed and Embase from January 1992 to January 2020. Study identification was accomplished using a combination of medical subject headings terms and keywords related to concepts of pediatric organ dysfunction. Electronic searches were performed by medical librarians. Studies were eligible for inclusion if the authors reported original data collected in critically ill children; evaluated performance characteristics of scoring tools or clinical assessments for organ dysfunction; and assessed a patient-centered, clinically meaningful outcome. Data were abstracted from each included study into an electronic data extraction form. Risk of bias was assessed using the Quality in Prognosis Studies tool. Consensus was achieved for a final set of 43 criteria for pediatric organ dysfunction through iterative voting and discussion. Although the PODIUM criteria for organ dysfunction were limited by available evidence and will require validation, they provide a contemporary foundation for researchers to identify and study single and multiple organ dysfunction in critically ill children.

OBJECTIVES The goal of this study was to determine the incidence, prognostic performance, and generalizability of the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) organ dysfunction criteria using electronic health record (EHR) data. Additionally, we sought to compare the performance of the PODIUM criteria with the organ dysfunction criteria proposed by the 2005 International Pediatric Sepsis Consensus Conference (IPSCC). METHODS Retrospective observational cohort study of critically ill children at 2 medical centers in the United States between 2010 and 2018. We assessed prevalence of organ dysfunction based on the PODIUM and IPSCC criteria for each 24-hour period from admission to 28 days. We studied the prognostic performance of the criteria to discriminate in-hospital mortality. RESULTS Overall, 22 427 PICU admissions met inclusion criteria, and in-hospital mortality was 2.3%. The cumulative incidence of each PODIUM organ dysfunction ranged from 15% to 30%, with an in-hospital mortality of 6% to 10% for most organ systems. The number of concurrent PODIUM organ dysfunctions demonstrated good-to-excellent discrimination for in-hospital mortality (area under the curve 0.87–0.93 for day 1 through 28) and compared favorably to the IPSCC criteria (area under the curve 0.84–0.92, P < .001 to P = .06). CONCLUSIONS We present the first evaluation of the PODIUM organ dysfunction criteria in 2 EHR databases. The use of the PODIUM organ dysfunction criteria appears promising for epidemiologic and clinical research studies using EHR data. More studies are needed to evaluate the PODIUM criteria that are not routinely collected in structured format in EHR databases.

Previous studies of severe acute respiratory syndrome coronavirus 2 infection in infants have incompletely characterized factors associated with severe illness or focused on infants born to mothers with coronavirus disease 2019 (COVID-19). Here we highlight demographics, clinical characteristics and laboratory values that differ between infants with and without severe acute COVID-19.Active surveillance was performed by the Overcoming COVID-19 network to identify children and adolescents with severe acute respiratory syndrome coronavirus 2-related illness hospitalized at 62 sites in 31 states from March 15 to December 27, 2020. We analyzed patients7 days to1 year old hospitalized with symptomatic acute COVID-19.We report 232 infants7 days to1 year of age hospitalized with acute symptomatic COVID-19 from 37 US hospitals in our cohort from March 15 to December 27, 2020. Among 630 cases of severe COVID-19 in patients7 days to18 years old, 128 (20.3%) were infants. In infants with severe illness from the entire study period, the median age was 2 months, 66% were from racial and ethnic minority groups, 66% were previously healthy, 73% had respiratory complications, 13% received mechanical ventilation and1% died.Infants accounted for over a fifth of children18 years of age hospitalized for severe acute COVID-19, commonly manifesting with respiratory symptoms and complications. Although most infants hospitalized with COVID-19 did not suffer significant complications, longer term outcomes remain unclear. Notably, 75% of infants with severe disease were6 months of age in this cohort study period, which predated maternal COVID-19 vaccination, underscoring the importance of maternal vaccination for COVID-19 in protecting the mother and infant.

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-1β, 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.

No studies exist comparing various femoral artery cannula sizes in children on ECMO. We hypothesize that smaller arterial cannulas provide adequate flow in children while decreasing vascular complications.We performed a retrospective review of the ELSO database from 2012-2017. We included children undergoing femoral venoarterial ECMO between ages 12 and 18 years and weighing more than 30 kg. Arterial cannula sizes were grouped as: 15-16Fr, 17-18Fr, 19-20Fr and ≥21Fr. Arterial pump flow, bleeding complications, limb ischemia, and mechanical complications were compared by cannula size. Distal perfusion catheter and percutaneous placement were also compared for complications.A total of 429 patients were included with 28.2% 15-16Fr, 32.2% 17-18Fr, 22.8% 19-20Fr, and 16.8% ≥ 21Fr arterial femoral cannulas. Median age was lower in the 15-16Fr group compared to the largest cannula group (14.7 years vs 15.5 years, p 0.01). The overall mean arterial flow was 57.4 +/- 17.0 mL/kg/min with no difference in mean arterial flow rates among the cannula size groups (p = 0.85). There were no significant differences in all complications, bleeding or mechanical complications by arterial cannula size group. However, there was an increased risk of limb ischemia in the ≥21Fr group compared to the 15-16Fr group (OR 4.38, 95% CI 1.24-15.43; p = 0.02). Distal perfusion catheter was shown to increase the risk of mechanical complications (OR 1.78; 95% CI 1.03-3.07; p = 0.04) but did not make a statistically significant difference in limb ischemia (OR 0.37; 95% CI 0.12-1.11; p = 0.07).Review of the ELSO database demonstrates that the use of larger arterial cannulas compared to 15-16Fr cannulas are not needed to achieve similar pump flows for hemodynamic support but the largest cannula sizes may increase the risk of ischemic complications.

In 2020 during the COVID-19 pandemic, neurologic involvement was common in children and adolescents hospitalized in the United States for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related complications.To provide an update on the spectrum of SARS-CoV-2-related neurologic involvement among children and adolescents in 2021.Case series investigation of patients reported to public health surveillance hospitalized with SARS-CoV-2-related illness between December 15, 2020, and December 31, 2021, in 55 US hospitals in 31 states with follow-up at hospital discharge. A total of 2253 patients were enrolled during the investigation period. Patients suspected of having multisystem inflammatory syndrome in children (MIS-C) who did not meet criteria (n = 85) were excluded. Patients (21 years) with positive SARS-CoV-2 test results (reverse transcriptase-polymerase chain reaction and/or antibody) meeting criteria for MIS-C or acute COVID-19 were included in the analysis.SARS-CoV-2 infection.Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening neurologic involvement was adjudicated by experts based on clinical and/or neuroradiological features. Type and severity of neurologic involvement, laboratory and imaging data, vaccination status, and hospital discharge outcomes (death or survival with new neurologic deficits).Of 2168 patients included (58% male; median age, 10.3 years), 1435 (66%) met criteria for MIS-C, and 476 (22%) had documented neurologic involvement. Patients with neurologic involvement vs without were older (median age, 12 vs 10 years) and more frequently had underlying neurologic disorders (107 of 476 [22%] vs 240 of 1692 [14%]). Among those with neurologic involvement, 42 (9%) developed acute SARS-CoV-2-related life-threatening conditions, including central nervous system infection/demyelination (n = 23; 15 with possible/confirmed encephalitis, 6 meningitis, 1 transverse myelitis, 1 nonhemorrhagic leukoencephalopathy), stroke (n = 11), severe encephalopathy (n = 5), acute fulminant cerebral edema (n = 2), and Guillain-Barré syndrome (n = 1). Ten of 42 (24%) survived with new neurologic deficits at discharge and 8 (19%) died. Among patients with life-threatening neurologic conditions, 15 of 16 vaccine-eligible patients (94%) were unvaccinated.SARS-CoV-2-related neurologic involvement persisted in US children and adolescents hospitalized for COVID-19 or MIS-C in 2021 and was again mostly transient. Central nervous system infection/demyelination accounted for a higher proportion of life-threatening conditions, and most vaccine-eligible patients were unvaccinated. COVID-19 vaccination may prevent some SARS-CoV-2-related neurologic complications and merits further study.

OBJECTIVE Our objective is to characterize the incidence of tracheostomy placement and of new requirement for long-term mechanical ventilation after extracorporeal membrane oxygenation (ECMO) among children with acute respiratory failure. We examine whether an association exists between demographics, pre-ECMO and ECMO clinical factors, and the placement of a tracheostomy or need for long-term mechanical ventilation. METHODS A retrospective multicenter cohort study was conducted at 10 quaternary care pediatric academic centers, including children supported with veno-venous (V-V) ECMO from 2011 to 2016. RESULTS Among 202 patients, 136 (67%) survived to ICU discharge. All tracheostomies were placed after ECMO decannulation, in 22 patients, with 19 of those surviving to ICU discharge (14% of survivors). Twelve patients (9% of survivors) were discharged on long-term mechanical ventilation. Tracheostomy placement and discharge on home ventilation were not associated with pre-ECMO severity of illness or pre-existing chronic illness. Patients who received a tracheostomy were older and weighed more than patients who did not receive a tracheostomy, although this association did not exist among patients discharged on home ventilation. ECMO duration was longer in those who received a tracheostomy compared with those who did not, as well as for those discharged on home ventilation, compared to those who were not. CONCLUSION The 14% rate for tracheostomy placement and 9% rate for discharge on long-term mechanical ventilation after V-V ECMO are important patient-centered findings. This study informs anticipatory guidance provided to families of patients requiring prolonged respiratory ECMO support, and lays the foundation for future research.

Although extracorporeal cardiopulmonary resuscitation (ECPR) is increasingly utilized in the pediatric critical care environment, our understanding regarding pediatric candidacy for ECPR remains unknown. Our objective is to explore current practice and indications for pediatric ECPR. Scenario-based, self-administered, online survey, evaluating clinical determinants that may impact pediatric ECPR initiation with respect to four scenarios: postoperative cardiac surgery, cardiac failure secondary to myocarditis, septic shock, and chronic respiratory failure in a former preterm child. Responders are pediatric critical care physicians from four societies. 249 physicians, mostly from North America, answered the survey. In cardiac scenarios, 40% of the responders would initiate ECPR, irrespective of CPR duration, compared with less than 20% in noncardiac scenarios. Nearly 33% of responders would consider ECPR if CPR duration was less than 60 minutes in noncardiac scenarios. Factors strongly decreasing the likelihood to initiate ECPR were out-of-hospital unwitnessed cardiac arrest and blood pH6.60. Additional factors reducing this likelihood were multiple organ failure, pre-existing neurologic delay,10 doses of adrenaline, poor CPR quality, and lactate18 mmol/l. Pediatric intensive care unit location for cardiac arrest, good CPR quality, 24/7 in-house extracorporeal membrane oxygenation (ECMO) team moderately increase the likelihood of initiating ECPR. This international survey of pediatric ECPR initiation practices reveals significant differences regarding ECPR candidacy based on patient category, location of arrest, duration of CPR, witness status, and last blood pH. Further research identifying prognostic factors measurable before ECMO initiation should help define the optimal ECPR initiation strategy.

Objectives To compare current practices within the United States of anticoagulation management and blood transfusion in neonatal and pediatric extracorporeal membrane oxygenation patients with a 2013 international report. Design Cross-sectional survey distributed between August and December 2019. Setting Extracorporeal Life Support Organization-registered neonatal and pediatric extracorporeal membrane oxygenation centers in the United States. Participants Extracorporeal membrane oxygenation medical directors. Interventions None. Measurements and main results Eighty-three medical directors at 108 centers responded. After removing four duplicate responses, 79 surveys were analyzed. Seventy-nine percent (n = 62) report a written extracorporeal membrane oxygenation protocol for both anticoagulation and blood product management. Ninety-four percent (n = 74) report unfractionated heparin as their primary anticoagulant; the remaining use the direct thrombin inhibitor, bivalirudin. Ninety percent (n = 71) report measuring antifactor Xa levels. Most centers report using a combination of assays to monitor heparin therapy, either antifactor Xa and activated partial thromboplastin time (54%) or more commonly antifactor Xa and activated clotting time (68%). Forty-one percent use viscoelastic tests to aid management. Goal monitoring levels and interventions generated by out of range values are variable. Fifty-one percent will replace antithrombin. Platelet transfusion thresholds vary by age and center with ranges from 50,000 to 100,000 cells/µL. Eighty-two percent of respondents are willing to participate in a randomized controlled trial comparing anticoagulation strategies for patients receiving extracorporeal membrane oxygenation. Conclusions Compared with the 2013 pediatric population, extracorporeal membrane oxygenation center anticoagulation and blood transfusion approaches continue to vary widely. Most report continued use of heparin as their primary anticoagulant and follow a combination of monitoring assays with the majority using the antifactor Xa assay in their practices, a significant shift from prior results. Antithrombin activity levels and viscoelastic tests are followed by a growing number of centers. Platelet transfusion thresholds continue to vary widely. Future research is needed to establish optimal anticoagulation and blood transfusion management.

Background Cardiopulmonary resuscitation (CPR) in the delivery room (DR) after birth is rare. We hypothesized that factors related to maternal, delivery, infant and resuscitation event characteristics associated with outcomes could be identified. We also hypothesized there would be substantial variation from the Neonatal Resuscitation Program (NRP) algorithm. Methods Retrospective review of all neonates receiving chest compressions in the DR from the AHA Get With The Guidelines—Resuscitation registry from 2001 to 2014. The primary outcome was return of spontaneous circulation (ROSC) in the DR. Secondary outcome was survival to hospital discharge. Descriptive statistics were used to characterize data. Odds ratios with confidence intervals were calculated as appropriate to compare survivors and non-survivors. Results There were 1153 neonates who received chest compressions in the DR. ROSC was achieved in 968 (84%) newborns and 761 (66%) survived to hospital discharge. Fifty-one percent of the cohort received chest compressions without medications. Cardiac compressions were initiated within the first minute of life in 76% of the events, and prior to endotracheal intubation in 79% of the events. In univariate analysis, factors such as prematurity, number of endotracheal intubation attempts, increased time to first adrenaline dose, and CPR duration were associated with decreased odds of ROSC in the DR. Longer CPR duration was associated with decreased odds of ROSC in multivariate analysis. Conclusion In this cohort of infants receiving chest compressions following delivery, recognizable pre-birth risk factors as well as resuscitation interventions associated with increased and decreased odds of achieving ROSC were identified. Chest compressions were frequently initiated in the first minute of the event and often prior to endotracheal intubation. Further investigations should focus on methods to decrease time to critical resuscitation interventions, such as successful endotracheal intubation and administration of the first dose of adrenaline, in order to improve DR-CPR outcomes.

Extracorporeal membrane oxygenation is extracorporeal life support for life-threatening cardiopulmonary failure. Since its introduction, the use of extracorporeal membrane oxygenation has expanded to patients with more complex comorbidities without change in patient mortality rates. Although many patients survive, significant neurological complications like seizures, ischemic strokes, and intracranial hemorrhage can occur during extracorporeal membrane oxygenation care. The risks of these complications often add to the complexity of decision-making surrounding extracorporeal membrane oxygenation support. In this review, we discuss the pathophysiology and incidence of neurological complications in children supported on extracorporeal membrane oxygenation, factors influencing the incidence of these complications, commonly used neurological monitoring modalities, and outcomes for this complex patient population. We discuss the current literature on the use of electroencephalography for both seizure detection and monitoring of background electroencephalographic changes, in addition to the use of less commonly used imaging modalities like transcranial Doppler. We summarize the knowledge gaps and the lack of clinical consensus guidelines for managing these potentially life-changing neurological complications. Finally, we discuss future work to further understand the pathophysiology of extracorporeal membrane oxygenation-related neurological complications.

Clinical differences between critical illness from influenza infection versus coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients.We compared U.S. children (8 months to 17 years) admitted to the intensive care or high acuity unit with influenza (17 hospitals, 12/19/2019-3/9/2020) or COVID-19 (52 hospitals, 3/15/2020-12/31/2020). We compared demographics, underlying conditions, clinical presentation, severity, and outcomes. Using mixed-effects models, we assessed the odds of death or requiring life-support for influenza versus COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity.Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median 5.2 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%). 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% CI: 0.78-2.15; P = 0.32]). Median duration of hospital stay was shorter for influenza than COVID-19 (5 versus 7 days).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.

CONTEXT Cardiovascular dysfunction is associated with poor outcomes in critically ill children. OBJECTIVE We aim to derive an evidence-informed, consensus-based definition of cardiovascular dysfunction in critically ill children. DATA SOURCES Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020 using medical subject heading terms and text words to define concepts of cardiovascular dysfunction, pediatric critical illness, and outcomes of interest. STUDY SELECTION Studies were included if they evaluated critically ill children with cardiovascular dysfunction and assessment and/or scoring tools to screen for cardiovascular dysfunction and assessed mortality, functional status, organ-specific, or other patient-centered outcomes. Studies of adults, premature infants (≤36 weeks gestational age), animals, reviews and/or commentaries, case series (sample size ≤10), and non–English-language studies were excluded. Studies of children with cyanotic congenital heart disease or cardiovascular dysfunction after cardiopulmonary bypass were excluded. DATA EXTRACTION Data were abstracted from each eligible study into a standard data extraction form, along with risk-of-bias assessment by a task force member. RESULTS Cardiovascular dysfunction was defined by 9 elements, including 4 which indicate severe cardiovascular dysfunction. Cardiopulmonary arrest (>5 minutes) or mechanical circulatory support independently define severe cardiovascular dysfunction, whereas tachycardia, hypotension, vasoactive-inotropic score, lactate, troponin I, central venous oxygen saturation, and echocardiographic estimation of left ventricular ejection fraction were included in any combination. There was expert agreement (>80%) on the definition. LIMITATIONS All included studies were observational and many were retrospective. CONCLUSIONS The Pediatric Organ Dysfunction Information Update Mandate panel propose this evidence-informed definition of cardiovascular dysfunction.

CONTEXT Multiple scores exist to characterize organ dysfunction in children. OBJECTIVE To review the literature on multiple organ dysfunction (MOD) scoring systems to estimate severity of illness and to characterize the performance characteristics of currently used scoring tools and clinical assessments for organ dysfunction in critically ill children. DATA SOURCES Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020. STUDY SELECTION Studies were included if they evaluated critically ill children with MOD, evaluated the performance characteristics of scoring tools for MOD, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. DATA EXTRACTION Data were abstracted into a standard data extraction form by a task force member. RESULTS Of 1152 unique abstracts screened, 156 full text studies were assessed including a total of 54 eligible studies. The most commonly reported scores were the Pediatric Logistic Organ Dysfunction Score (PELOD), pediatric Sequential Organ Failure Assessment score (pSOFA), Pediatric Index of Mortality (PIM), PRISM, and counts of organ dysfunction using the International Pediatric Sepsis Definition Consensus Conference. Cut-offs for specific organ dysfunction criteria, diagnostic elements included, and use of counts versus weighting varied substantially. LIMITATIONS While scores demonstrated an increase in mortality associated with the severity and number of organ dysfunctions, the performance ranged widely. CONCLUSIONS The multitude of scores on organ dysfunction to assess severity of illness indicates a need for unified and data-driven organ dysfunction criteria, derived and validated in large, heterogenous international databases of critically ill children.

Though commonly used for adjustment of risk, severity of illness and mortality risk prediction scores, based on the first 24 h of intensive care unit (ICU) admission, have not been validated in the pediatric extracorporeal membrane oxygenation (ECMO) population. We aimed to determine the association of Pediatric Index of Mortality 2 (PIM2), Pediatric Risk of Mortality Score III (PRISM III) and Pediatric Logistic Organ Dysfunction (PELOD) scores with mortality in pediatric patients on ECMO. This was a retrospective cohort study of children ≤18 years of age included in the Pediatric ECMO Outcomes Registry (PEDECOR) from 2014 to 2018. Logistic regression and Receiver Operating Characteristics (ROC) curves were used to calculate the area under the curve (AUC) to evaluate association of mortality with the scores. Of the 655 cases, 289 (44.1%) did not survive until hospital discharge. AUCs for PIM2, PRISM III, and PELOD predicting mortality were 0.52, 0.52, and 0.51 respectively. PIM2, PRISM III, and PELOD scores are not associated with odds of mortality for pediatric patients receiving ECMO. These scores for a general pediatric ICU population should not be used for prognostication or risk stratification of a select population such as ECMO patients.

BACKGROUND: Venovenous extracorporeal membrane oxygenation (VV-ECMO) is used when mechanical ventilation can no longer support oxygenation or ventilation, or if the risk of ventilator-induced lung injury is considered excessive. The optimum mechanical ventilation strategy once on ECMO is unknown. We sought to describe the practice of mechanical ventilation in children on VV-ECMO and to determine whether mechanical ventilation practices are associated with clinical outcomes. METHODS: We conducted a multicenter retrospective cohort study in 10 pediatric academic centers in the United States. Children age 14 d through 18 y on VV-ECMO from 2011 to 2016 were included. Exclusion criteria were preexisting chronic respiratory failure, primary diagnosis of asthma, cyanotic heart disease, or ECMO as a bridge to lung transplant. RESULTS: Conventional mechanical ventilation was used in about 75% of children on VV-ECMO; the remaining subjects were managed with a variety of approaches. With the exception of PEEP, there was large variation in ventilator settings. Ventilator mode and pressure settings were not associated with survival. Mean ventilator FIO2 on days 1–3 was higher in nonsurvivors than in survivors (0.5 vs 0.4, P = .009). In univariate analysis, other risk factors for mortality were female gender, higher Pediatric Risk Estimate Score for Children Using Extracorporeal Respiratory Support (Ped-RESCUERS), diagnosis of cancer or stem cell transplant, and number of days intubated prior to initiation of ECMO (all P 0.5) (46% vs 22%, P = .001). CONCLUSIONS: Ventilator mode and some settings vary in practice. The only ventilator setting associated with mortality was FIO2, even after adjustment for disease severity. Ventilator FIO2 is a modifiable setting that may contribute to mortality in children on VV-ECMO.

Objectives:To make practical and evidence-based recommendations on improving understanding of bleeding and thrombosis with pediatric extracorporeal life support and to make recommendations for research directions.Data Sources:Evaluation of literature and consensus conferences of pediatric critical c

We performed a multicenter retrospective cohort study of children with 14 days to 18 years of age in the United States from 2011 to 2016 with cancer or hematopoietic cell transplant (HCT) who were supported with veno-venous extracorporeal membrane oxygenation (V-V ECMO). We compared the outcomes of children with oncological diagnoses or HCT supported with V-V ECMO to other children who have received V-V ECMO support. In this cohort of 204 patients supported with V-V ECMO, 30 (15%) had a diagnosis of cancer or a history of HCT. There were 21 patients who had oncological diagnoses without HCT and 9 children were post-HCT. The oncology/HCT group had a higher overall ICU mortality (67% vs. 28%, P < 0.001), mortality on ECMO (43% vs. 21%, P < 0.01), and ICU mortality among ECMO survivors (35% vs. 8%, P < 0.01). The oncology/HCT group had a higher rate of conversion to veno-arterial (V-A) ECMO (23% vs. 9%, P = 0.02) (RR, 2.5; 95% CI, 1.1-5.6). Children with cancer or HCT were older (6.6 vs. 2.9 years, P = 0.02) and had higher creatinine levels (0.65 vs. 0.4 mg/dL, P = 0.04) but were similar to the rest of the cohort for other pre-ECMO variables. For post-HCT patients, survival was significantly worse for those whose indication for HCT was cancer or immunodeficiency (0/6) as compared to other nonmalignant indications (3/3) (P = 0.01).

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.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-1β, 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.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.High levels of circulating inflammatory, endothelial activation, and fibrinolytic markers are associated with mortality and abnormal neuroimaging in children on ECMO.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.

Background It is unclear how acute coronavirus disease 2019 (COVID-19)-directed therapies are used in children with life-threatening COVID-19 in US hospitals. We described characteristics of children hospitalized in the intensive care unit or step-down unit (ICU/SDU) who received COVID-19-directed therapies and the specific therapies administered. Methods Between March 15, 2020 and December 27, 2020, children, No therapies for acute coronavirus disease 2019 (COVID-19) have been tested in children to establish effectiveness. Despite this, across 48 hospitals, 235/424 children (55%) admitted to the intensive care or step-down unit with COVID-19 received directed therapies. Systemic steroids and remdesivir were most commonly administered, with use rising from March 2020 to December 2020.

The aim of this study was to determine if plasma cyclohexanone and metabolites are associated with clinical outcomes of children on extracorporeal membrane oxygenation (ECMO) support. We performed a secondary analysis of a prospective observational study of children on ECMO support at two academic centers between July 2010 and June 2015. We measured plasma cyclohexanone and metabolites on the first and last days of ECMO support. Unfavorable outcome was defined as in-hospital death or discharge Pediatric Cerebral Performance Category score > 2 or decline ≥ 1 from baseline. Among 90 children included, 49 (54%) had unfavorable outcome at discharge. Cyclohexanediol, a cyclohexanone metabolite, was detected in all samples and at both time points; concentrations on the first ECMO day were significantly higher in those with unfavorable versus favorable outcome at hospital discharge (median, 5.7 ng/µl; interquartile range [IQR], 3.3-10.6 ng/µl vs. median, 4.2 ng/µl; IQR, 1.7-7.3 ng/µl; p = 0.04). Twofold higher cyclohexanediol concentrations on the first ECMO day were associated with increased risk of unfavorable outcome at hospital discharge (multivariable-adjusted hazard ratio [HR], 1.24 [95% CI, 1.05-1.48]). Higher cyclohexanediol concentrations on the first ECMO day were not significantly associated with new abnormal neuroimaging or 1-year Vineland Adaptive Behavior Scales-II score < 85 or death among survivors.

Patients with respiratory failure requiring inotropes or vasopressors are often placed on venoarterial (VA) extracorporeal membrane oxygenation (ECMO), as venovenous (VV) ECMO does not provide direct circulatory support. This retrospective multicenter study compared outcomes for 103 pediatric patients, with hemodynamic compromise, placed on VV ECMO for respiratory failure to those placed on VA ECMO. The primary outcome was survival to hospital discharge. Fifty-seven (55%) study participants were supported on VV ECMO. The two groups had similar PRISM III scores at pediatric intensive care unit (PICU) admission, and vasoactive-inotropic scores at ECMO cannulation. More VV ECMO patients received inhaled nitric oxide (iNO) (54.4 vs. 34.8%; p = 0.04) and had a higher oxygenation index (median 41.5 vs. 19.5; p = 0.04) pre-ECMO. More VA ECMO patients had cardiac dysfunction and cardiac arrest pre-ECMO (50 vs. 14%; p < 0.0001). In univariable analysis, survival to hospital discharge was higher in the VV vs. VA ECMO group (72 vs. 44%; p = 0.005), however, in multivariable models, cannulation type was confounded by cardiopulmonary resuscitation and was not independently associated with survival. VV survivors had longer ECMO duration compared with VA survivors (median, 7 vs. 4.5 days; p = 0.036) but similar PICU and hospital days. No significant difference was noted in functional outcomes or comorbidities at discharge. Cannulation type is not independently associated with survival to hospital discharge in pediatric patients on vasoactive infusions at the time of ECMO cannulation for respiratory indications.

BACKGROUND Marfan syndrome and Loeys-Dietz syndrome are connective tissue disorders associated with cardiac and vascular disease. Patients often require surgical repair, but limited data exist to describe their perioperative management. AIMS Our goals were to review the perioperative features of patients with Marfan and Loeys-Dietz syndrome that may affect anesthesia care and to describe the differences in preoperative clinical characteristics and intra-operative anesthetic management. METHODS We conducted a retrospective cohort study of patients with Marfan and Loeys-Dietz syndrome who underwent cardiac surgery at a single institution. We collected demographic and perioperative data from the electronic medical record and performed descriptive statistics to characterize the patient populations and describe their anesthetic management. RESULTS In 71 patients (40 Marfan, 31 Loeys-Dietz), we found significant differences between the Marfan and Loeys-Dietz patients in airway difficulty, preoperative weight, blood utilization, valvular disease, and age at first cardiac surgery. Patients with Loeys-Dietz syndrome had higher preoperative rates of severe noncardiac comorbidities, including gastroesophageal reflux and asthma that required chronic medical therapy. CONCLUSIONS Despite undergoing similar surgical procedures, patients with Marfan and Loeys-Dietz syndrome have different intrinsic patient characteristics and comorbidities that may affect their perioperative care. This retrospective cohort study identified some factors, but additional collection and reporting of patient data based on multicenter experience are essential for the ongoing optimization of perioperative care in these patient populations.

Sepsis is a syndrome which afflicts both adults and children, with many disease courses and diverse outcomes. Understanding of sepsis pathophysiology has changed over time; the Sepsis-3 criteria define sepsis in adults as organ dysfunction, quantified by SOFA score, caused by dysregulated immune response to infection. However, pediatric consensus definitions still utilize the SIRS-based Sepsis-2 criteria, though individual groups have attempted to adapt the Sepsis-3 criteria for children. We evaluate age-adjusted Sepsis-3 criteria on 2,384 pediatric patients admitted to the Johns Hopkins PICU, and apply previously-published methods for early prediction of septic shock. We obtain best early prediction performance of 0.96 AUC, 49.9% overall PPV, and a 5.8-hour median EWT using Sepsis-3 labels based on age-adjusted SOFA score. Through analyses of risk score evolution over time, we corroborate our past finding of an abrupt transition preceding onset of septic shock in children, and are able to stratify pediatric sepsis patients using their first post-threshold-crossing risk score.

BackgroundThere is an ongoing critical need to improve therapeutic strategies for COVID-19 pneumonia, particularly in the most severely affected patients. Adult mesenchymal stem cell (MSC) infusions have the potential to benefit critically ill patients with acute respiratory syndrome SARS-COV-2 infection, but clinical data supporting efficacy are lacking.MethodsWe conducted a case-control study of critically ill patients with laboratory-confirmed COVID-19, severe acute respiratory distress syndrome (ARDS). To evaluate clinical responsiveness in the most critically ill patient we examined outcomes in a sub-group of those requiring extracorporeal membrane oxygenation (ECMO) support. Patients (n=9) were administered with up to 3 infusions of intravenous (IV) MSCs and compared to a local ECMO control group (n=31). The primary outcome was safety, and the secondary outcomes were all-cause mortality (or rate of hospital discharge), cytokine levels, and viral clearance.FindingsMSC infusions (12 patients) were well tolerated and no side effects occurred. Of ECMO patients receiving MSC infusions, 2 out of 9 died (22.2%; 95%CI: 2.8%, 60.0%) compared with a mortality of 15 of 31 (48.4%; 95%CI: 30.2%, 66.9%; p = 0.25) in the ECMO control group. Isolated plasma exosomes containing the SARS-COV-2 Spike protein decreased after MSC infusions between day 14 or 21 after administration (p=0.003 and p=0.005, respectively) and was associated with a decrease in COVID-19 IgG Spike protein titer at same time points (p = 0.006 and p=0.007, respectively). Control ECMO patients receiving convalescent plasma did not clear COVID-19 IgG over the same time frame.InterpretationTogether these findings suggest that MSC IV infusion is well tolerated in patients with a broad range of severity including the most severe COVID-19 ARDS requiring ECMO. These data also raise the possibility that MSCs, in addition to exerting an immunomodulatory effect, contribute to viral clearance and strongly support the conduct of randomized placebo-controlled trial.

BACKGROUND Patients requiring extracorporeal membrane oxygenation (ECMO) support are critically ill and have substantial transfusion requirements, which convey both risks and benefits. A retrospective analysis was conducted to assess the association between blood component administration and adverse outcomes in adult, pediatric, and neonatal ECMO patients. METHODS We evaluated 217 ECMO patients at a single center hospitalized between January 2009 and June 2016. Three cohorts (88 adult, 57 pediatric, and 72 neonatal patients) were included for assessment of patient characteristics, blood utilization, and clinical outcomes. Univariable and multivariable analyses were used to assess the association between transfusions and clinical outcomes (primary outcome: mortality and secondary outcomes: morbid events). The analysis included the main exposure of interest (total number of blood component units transfused) and potential confounding variables (age group cohort, case mix index, sex, ECMO mode and duration, and primary ECMO indication). RESULTS After adjustment for confounders, with each additional blood component unit transfused, there was an estimated increase in odds for mortality by 1% (odds ratio [OR] = 1.01; 95% confidence interval [CI], 1.00-1.02; P = .013) and an increase in odds for thrombotic events by 1% (OR = 1.01; 95% CI, 1.00-1.02; P = .007). Mortality was higher in the adult (57 of 88; 64.8%) and pediatric (37 of 57; 64.9%) than in the neonatal cohort (19 of 72; 26.4%) (P < .0001). Median total blood components transfused per day followed a similar pattern for the adult (2.3 units; interquartile range [IQR] = 0.8-7.0), pediatric (2.9 units; IQR = 1.1-10), and neonatal (1.0 units; IQR = 0.7-1.6) cohorts (P < .0001). Over the entire hospitalization, the total median blood components transfused was highest in the neonatal (41 units; IQR = 24-94) and pediatric (41 units; IQR = 17-113) compared to the adult (30 units; IQR = 9-58) cohort (P = .007). There was no significant interaction between total units transfused over the hospital stay and age cohort for mortality (P = .35). CONCLUSIONS Given the association between transfusion and adverse outcomes, effective blood management strategies may be beneficial in ECMO patients.