Early, Persistent Lymphopenia Is Associated With Prolonged Multiple Organ Failure and Mortality in Septic Children.

OBJECTIVES: Sepsis-associated immune suppression correlates with poor outcomes. Adult trials are evaluating immune support therapies. Limited data exist to support consideration of immunomodulation in pediatric sepsis. We tested the hypothesis that early, persistent lymphopenia predicts worse outcomes in pediatric severe sepsis. DESIGN: Observational cohort comparing children with severe sepsis and early, persistent lymphopenia (absolute lymphocyte count < 1,000 cells/µL on 2 d between study days 0-5) to children without. The composite outcome was prolonged multiple organ dysfunction syndrome (MODS, organ dysfunction beyond day 7) or PICU mortality. SETTING: Nine PICUs in the National Institutes of Health Collaborative Pediatric Critical Care Research Network between 2015 and 2017. PATIENTS: Children with severe sepsis and indwelling arterial and/or central venous catheters. INTERVENTIONS: Blood sampling and clinical data analysis. MEASUREMENTS AND MAIN RESULTS: Among 401 pediatric patients with severe sepsis, 152 (38%) had persistent lymphopenia. These patients were older, had higher illness severity, and were more likely to have underlying comorbidities including solid organ transplant or malignancy. Persistent lymphopenia was associated with the composite outcome prolonged MODS or PICU mortality (66/152, 43% vs 45/249, 18%; p < 0.01) and its components prolonged MODS (59/152 [39%] vs 43/249 [17%]), and PICU mortality (32/152, 21% vs 12/249, 5%; p < 0.01) versus children without. After adjusting for baseline factors at enrollment, the presence of persistent lymphopenia was associated with an odds ratio of 2.98 (95% CI [1.85-4.02]; p < 0.01) for the composite outcome. Lymphocyte count trajectories showed that patients with persistent lymphopenia generally did not recover lymphocyte counts during the study, had lower nadir whole blood tumor necrosis factor-α response to lipopolysaccharide stimulation, and higher maximal inflammatory markers (C-reactive protein and ferritin) during days 0-3 ( p < 0.01). CONCLUSIONS: Children with severe sepsis and persistent lymphopenia are at risk of prolonged MODS or PICU mortality. This evidence supports testing therapies for pediatric severe sepsis patients risk-stratified by early, persistent lymphopenia.

Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: a causal inference analysis.

BACKGROUND: One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (> 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network's objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. METHODS: We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level > 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. RESULTS: Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value < 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1ß, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1ß, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value < 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. CONCLUSIONS: These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis.

Acute Disorders of Consciousness in Pediatric Severe Sepsis and Organ Failure: Secondary Analysis of the Multicenter Phenotyping Sepsis-Induced Multiple Organ Failure Study.

OBJECTIVES: Acute disorders of consciousness (DoC) in pediatric severe sepsis are associated with increased risk of morbidity and mortality. We sought to examine the frequency of and factors associated with DoC in children with sepsis-induced organ failure. DESIGN: Secondary analysis of the multicenter Phenotyping Sepsis-Induced Multiple Organ Failure Study (PHENOMS). SETTING: Nine tertiary care PICUs in the United States. PATIENTS: Children less than 18 years old admitted to a PICU with severe sepsis and at least one organ failure during a PICU stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was frequency of DoC, defined as Glasgow Coma Scale (GCS) less than 12 in the absence of sedatives during an ICU stay, among children with severe sepsis and the following: single organ failure, nonphenotypeable multiple organ failure (MOF), MOF with one of the PHENOMS phenotypes (immunoparalysis-associated MOF [IPMOF], sequential liver failure-associated MOF, thrombocytopenia-associated MOF), or MOF with multiple phenotypes. A multivariable logistic regression analysis was performed to evaluate the association between clinical variables and organ failure groups with DoC. Of 401 children studied, 71 (18%) presented with DoC. Children presenting with DoC were older (median 8 vs 5 yr; p = 0.023), had increased hospital mortality (21% vs 10%; p = 0.011), and more frequently presented with both any MOF (93% vs 71%; p < 0.001) and macrophage activation syndrome (14% vs 4%; p = 0.004). Among children with any MOF, those presenting with DoC most frequently had nonphenotypeable MOF and IPMOF (52% and 34%, respectively). In the multivariable analysis, older age (odds ratio, 1.07; 95% CI, 1.01-1.12) and any MOF (3.22 [1.19-8.70]) were associated with DoC. CONCLUSIONS: One of every five children with severe sepsis and organ failure experienced acute DoC during their PICU stay. Preliminary findings suggest the need for prospective evaluation of DoC in children with sepsis and MOF.

Anticoagulation practices associated with bleeding and thrombosis in pediatric extracorporeal membrane oxygenation; a multi-center secondary analysis.

To determine associations between anticoagulation practices and bleeding and thrombosis during pediatric extracorporeal membrane oxygenation (ECMO), we performed a secondary analysis of prospectively collected data which included 481 children (<19 years), between January 2012 and September 2014. The primary outcome was bleeding or thrombotic events. Bleeding events included a blood product transfusion >80 ml/kg on any day, pulmonary hemorrhage, or intracranial bleeding, Thrombotic events included pulmonary emboli, intracranial clot, limb ischemia, cardiac clot, and arterial cannula or entire circuit change. Bleeding occurred in 42% of patients. Five percent of subjects thrombosed, of which 89% also bled. Daily bleeding odds were independently associated with day prior activated clotting time (ACT) (OR 1.03, 95% CI= 1.00, 1.05, p=0.047) and fibrinogen levels (OR 0.90, 95% CI 0.84, 0.96, p <0.001). Thrombosis odds decreased with increased day prior heparin dose (OR 0.88, 95% CI 0.81, 0.97, p=0.006). Lower ACT values and increased fibrinogen levels may be considered to decrease the odds of bleeding. Use of this single measure, however, may not be sufficient alone to guide optimal anticoagulation practice during ECMO.

Prevalence of Pathogenic and Potentially Pathogenic Inborn Error of Immunity Associated Variants in Children with Severe Sepsis.

PURPOSE: Our understanding of inborn errors of immunity is increasing; however, their contribution to pediatric sepsis is unknown. METHODS: We used whole-exome sequencing (WES) to characterize variants in genes related to monogenic immunologic disorders in 330 children admitted to intensive care for severe sepsis. We defined candidate variants as rare variants classified as pathogenic or potentially pathogenic in QIAGEN's Human Gene Mutation Database or novel null variants in a disease-consistent inheritance pattern. We investigated variant correlation with infection and inflammatory phenotype. RESULTS: More than one in two children overall and three of four African American children had immunodeficiency-associated variants. Children with variants had increased odds of isolating a blood or urinary pathogen (blood: OR 2.82, 95% CI: 1.12-7.10, p = 0.023, urine: OR: 8.23, 95% CI: 1.06-64.11, p = 0.016) and demonstrating increased inflammation with hyperferritinemia (ferritin [Formula: see text] ng/mL, OR: 2.16, 95% CI: 1.28-3.66, p = 0.004), lymphopenia (lymphocyte count < 1000/µL, OR: 1.66, 95% CI: 1.06 - 2.60, p = 0.027), thrombocytopenia (platelet count < 150,000/µL, OR: 1.76, 95% CI: 1.12-2.76, p = 0.013), and CRP greater than 10 mg/dl (OR: 1.71, 95% CI: 1.10-2.68, p = 0.017). They also had increased odds of requiring extracorporeal membrane oxygenation (ECMO, OR: 4.19, 95% CI: 1.21-14.5, p = 0.019). CONCLUSION: Herein, we describe the genetic findings in this severe pediatric sepsis cohort and their microbiologic and immunologic significance, providing evidence for the phenotypic effect of these variants and rationale for screening children with life-threatening infections for potential inborn errors of immunity.

Machine learning derivation of four computable 24-h pediatric sepsis phenotypes to facilitate enrollment in early personalized anti-inflammatory clinical trials.

BACKGROUND: Thrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions. METHODS: We applied consensus, k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin. RESULTS: Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p < 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p < 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p < 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p < 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI [18.83-136.83], p < 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI [13.26-137.75], p < 0.0001). CONCLUSIONS: Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership ( www.pedsepsis.pitt.edu ) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies.

Mortality Risk in Pediatric Sepsis Based on C-reactive Protein and Ferritin Levels.

OBJECTIVES: Interest in using bedside C-reactive protein (CRP) and ferritin levels to identify patients with hyperinflammatory sepsis who might benefit from anti-inflammatory therapies has piqued with the COVID-19 pandemic experience. Our first objective was to identify patterns in CRP and ferritin trajectory among critically ill pediatric sepsis patients. We then examined the association between these different groups of patients in their inflammatory cytokine responses, systemic inflammation, and mortality risks. DATA SOURCES: A prospective, observational cohort study. STUDY SELECTION: Children with sepsis and organ failure in nine pediatric intensive care units in the United States. DATA EXTRACTION: Two hundred and fifty-five children were enrolled. Five distinct clinical multi-trajectory groups were identified. Plasma CRP (mg/dL), ferritin (ng/mL), and 31 cytokine levels were measured at two timepoints during sepsis (median Day 2 and Day 5). Group-based multi-trajectory models (GBMTM) identified groups of children with distinct patterns of CRP and ferritin. DATA SYNTHESIS: Group 1 had normal CRP and ferritin levels ( n = 8; 0% mortality); Group 2 had high CRP levels that became normal, with normal ferritin levels throughout ( n = 80; 5% mortality); Group 3 had high ferritin levels alone ( n = 16; 6% mortality); Group 4 had very high CRP levels, and high ferritin levels ( n = 121; 11% mortality); and Group 5 had very high CRP and very high ferritin levels ( n = 30; 40% mortality). Cytokine responses differed across the five groups, with ferritin levels correlated with macrophage inflammatory protein 1α levels and CRP levels reflective of many cytokines. CONCLUSIONS: Bedside CRP and ferritin levels can be used together to distinguish groups of children with sepsis who have different systemic inflammation cytokine responses and mortality risks. These data suggest future potential value in personalized clinical trials with specific targets for anti-inflammatory therapies.

Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children.

BACKGROUND: Targeted temperature management is recommended for comatose adults and children after out-of-hospital cardiac arrest; however, data on temperature management after in-hospital cardiac arrest are limited. METHODS: In a trial conducted at 37 children's hospitals, we compared two temperature interventions in children who had had in-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS-II score of at least 70 before the cardiac arrest. RESULTS: The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS-II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P=0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS-II score from baseline to 12 months did not differ significantly between the groups (P=0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did not differ significantly between the hypothermia group and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P=0.56). The incidences of blood-product use, infection, and serious adverse events, as well as 28-day mortality, did not differ significantly between groups. CONCLUSIONS: Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087 .).

Survival and Hemodynamics During Pediatric Cardiopulmonary Resuscitation for Bradycardia and Poor Perfusion Versus Pulseless Cardiac Arrest.

OBJECTIVES: The objective of this study was to compare survival outcomes and intra-arrest arterial blood pressures between children receiving cardiopulmonary resuscitation for bradycardia and poor perfusion and those with pulseless cardiac arrests. DESIGN: Prospective, multicenter observational study. SETTING: PICUs and cardiac ICUs of the Collaborative Pediatric Critical Care Research Network. PATIENTS: Children (< 19 yr old) who received greater than or equal to 1 minute of cardiopulmonary resuscitation with invasive arterial blood pressure monitoring in place. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 164 patients, 96 (59%) had bradycardia and poor perfusion as the initial cardiopulmonary resuscitation rhythm. Compared to those with initial pulseless rhythms, these children were younger (0.4 vs 1.4 yr; p = 0.005) and more likely to have a respiratory etiology of arrest (p < 0.001). Children with bradycardia and poor perfusion were more likely to survive to hospital discharge (adjusted odds ratio, 2.31; 95% CI, 1.10-4.83; p = 0.025) and survive with favorable neurologic outcome (adjusted odds ratio, 2.21; 95% CI, 1.04-4.67; p = 0.036). There were no differences in diastolic or systolic blood pressures or event survival (return of spontaneous circulation or return of circulation via extracorporeal cardiopulmonary resuscitation). Among patients with bradycardia and poor perfusion, 49 of 96 (51%) had subsequent pulselessness during the cardiopulmonary resuscitation event. During cardiopulmonary resuscitation, these patients had lower diastolic blood pressure (point estimate, -6.68 mm Hg [-10.92 to -2.44 mm Hg]; p = 0.003) and systolic blood pressure (point estimate, -12.36 mm Hg [-23.52 to -1.21 mm Hg]; p = 0.032) and lower rates of return of spontaneous circulation (26/49 vs 42/47; p < 0.001) than those who were never pulseless. CONCLUSIONS: Most children receiving cardiopulmonary resuscitation in ICUs had an initial rhythm of bradycardia and poor perfusion. They were more likely to survive to hospital discharge and survive with favorable neurologic outcomes than patients with pulseless arrests, although there were no differences in immediate event outcomes or intra-arrest hemodynamics. Patients who progressed to pulselessness after cardiopulmonary resuscitation initiation had lower intra-arrest hemodynamics and worse event outcomes than those who were never pulseless.

Platelet Transfusion Practice and Related Outcomes in Pediatric Extracorporeal Membrane Oxygenation.

OBJECTIVE: To describe factors associated with platelet transfusion during pediatric extracorporeal membrane oxygenation and the relationships among platelet transfusion, complications, and mortality. DESIGN: Secondary analysis of data collected prospectively by the Collaborative Pediatric Critical Care Research Network between December 2012 and September 2014. SETTING: Eight Collaborative Pediatric Critical Care Research Network-affiliated hospitals. PATIENTS: Age less than 19 years old and treated with extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 511 children, 496 (97.1%) received at least one platelet transfusion during extracorporeal membrane oxygenation. Neonatal age, venoarterial extracorporeal membrane oxygenation, and various acute and chronic diagnoses were associated with increased average daily platelet transfusion volume (milliliters per kilogram body weight). On multivariable analysis, average daily platelet transfusion volume was independently associated with mortality (per 1 mL/kg; odds ratio, 1.05; CI, 1.03-1.08; p < 0.001), whereas average daily platelet count was not (per 1 × 10/L up to 115 × 10/L; odds ratio, 1.00; CI, 0.98-1.01; p = 0.49). Variables independently associated with increased daily bleeding risk included increased platelet transfusion volume on the previous extracorporeal membrane oxygenation day, a primary cardiac indication for extracorporeal membrane oxygenation, adolescent age, and an acute diagnosis of congenital cardiovascular disease. Variables independently associated with increased daily thrombotic risk included increased platelet transfusion volume on the previous extracorporeal membrane oxygenation day and venoarterial extracorporeal membrane oxygenation. Variables independently associated with decreased daily thrombotic risk included full-term neonatal age and an acute diagnosis of airway abnormality. CONCLUSIONS: Platelet transfusion was common in this multisite pediatric extracorporeal membrane oxygenation cohort. Platelet transfusion volume was associated with increased risk of mortality, bleeding, and thrombosis.

Association Between Diastolic Blood Pressure During Pediatric In-Hospital Cardiopulmonary Resuscitation and Survival.

BACKGROUND: On the basis of laboratory cardiopulmonary resuscitation (CPR) investigations and limited adult data demonstrating that survival depends on attaining adequate arterial diastolic blood pressure (DBP) during CPR, the American Heart Association recommends using blood pressure to guide pediatric CPR. However, evidence-based blood pressure targets during pediatric CPR remain an important knowledge gap for CPR guidelines. METHODS: All children ≥37 weeks' gestation and <19 years old in Collaborative Pediatric Critical Care Research Network intensive care units with chest compressions for ≥1 minute and invasive arterial blood pressure monitoring before and during CPR between July 1, 2013, and June 31, 2016, were included. Mean DBP during CPR and Utstein-style standardized cardiac arrest data were collected. The hypothesis was that DBP ≥25 mm Hg during CPR in infants and ≥30 mm Hg in children ≥1 year old would be associated with survival. Primary outcome was survival to hospital discharge. Secondary outcome was survival to hospital discharge with favorable neurological outcome, defined as Pediatric Cerebral Performance Categories 1 to 3 or no worse than prearrest baseline. Multivariable Poisson regression models with robust error estimates were used to estimate the relative risk of outcomes. RESULTS: Blinded investigators analyzed blood pressure waveforms during CPR from 164 children, including 60% <1 year old, 60% with congenital heart disease, and 54% after cardiac surgery. The immediate cause of arrest was hypotension in 67%, respiratory decompensation in 44%, and arrhythmia in 19%. Median duration of CPR was 8 minutes (quartiles, 3 and 27 minutes). Ninety percent survived the event, 68% with return of spontaneous circulation and 22% by extracorporeal life support. Forty-seven percent survived to hospital discharge, and 43% survived to discharge with favorable neurological outcome. Maintaining mean DBP ≥25 mm Hg in infants and ≥30 mm Hg in children ≥1 year old occurred in 101 of 164 children (62%) and was associated with survival (adjusted relative risk, 1.7; 95% confidence interval, 1.2-2.6; P=0.007) and survival with favorable neurological outcome (adjusted relative risk, 1.6; 95% confidence interval, 1.1-2.5; P=0.02). CONCLUSIONS: These data demonstrate that mean DBP ≥25 mm Hg during CPR in infants and ≥30 mm Hg in children ≥1 year old was associated with greater likelihood of survival to hospital discharge and survival with favorable neurological outcome.

Ventilation Rates and Pediatric In-Hospital Cardiac Arrest Survival Outcomes.

OBJECTIVES: The objective of this study was to associate ventilation rates during in-hospital cardiopulmonary resuscitation with 1) arterial blood pressure during cardiopulmonary resuscitation and 2) survival outcomes. DESIGN: Prospective, multicenter observational study. SETTING: Pediatric and pediatric cardiac ICUs of the Collaborative Pediatric Critical Care Research Network. PATIENTS: Intubated children (≥ 37 wk gestation and < 19 yr old) who received at least 1 minute of cardiopulmonary resuscitation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Arterial blood pressure and ventilation rate (breaths/min) were manually extracted from arterial line and capnogram waveforms. Guideline rate was defined as 10 ± 2 breaths/min; high ventilation rate as greater than or equal to 30 breaths/min in children less than 1 year old, and greater than or equal to 25 breaths/min in older children. The primary outcome was survival to hospital discharge. Regression models using Firth penalized likelihood assessed the association between ventilation rates and outcomes. Ventilation rates were available for 52 events (47 patients). More than half of patients (30/47; 64%) were less than 1 year old. Eighteen patients (38%) survived to discharge. Median event-level average ventilation rate was 29.8 breaths/min (interquartile range, 23.8-35.7). No event-level average ventilation rate was within guidelines; 30 events (58%) had high ventilation rates. The only significant association between ventilation rate and arterial blood pressure occurred in children 1 year old or older and was present for systolic blood pressure only (-17.8 mm Hg/10 breaths/min; 95% CI, -27.6 to -8.1; p < 0.01). High ventilation rates were associated with a higher odds of survival to discharge (odds ratio, 4.73; p = 0.029). This association was stable after individually controlling for location (adjusted odds ratio, 5.97; p = 0.022), initial rhythm (adjusted odds ratio, 3.87; p = 0.066), and time of day (adjusted odds ratio, 4.12; p = 0.049). CONCLUSIONS: In this multicenter cohort, ventilation rates exceeding guidelines were common. Among the range of rates delivered, higher rates were associated with improved survival to hospital discharge.

A Multicenter Network Assessment of Three Inflammation Phenotypes in Pediatric Sepsis-Induced Multiple Organ Failure.

OBJECTIVES: Ongoing adult sepsis clinical trials are assessing therapies that target three inflammation phenotypes including 1) immunoparalysis associated, 2) thrombotic microangiopathy driven thrombocytopenia associated, and 3) sequential liver failure associated multiple organ failure. These three phenotypes have not been assessed in the pediatric multicenter setting. We tested the hypothesis that these phenotypes are associated with increased macrophage activation syndrome and mortality in pediatric sepsis. DESIGN: Prospective severe sepsis cohort study comparing children with multiple organ failure and any of these phenotypes to children with multiple organ failure without these phenotypes and children with single organ failure. SETTING: Nine PICUs in the Eunice Kennedy Shriver National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. PATIENTS: Children with severe sepsis and indwelling arterial or central venous catheters. INTERVENTIONS: Clinical data collection and twice weekly blood sampling until PICU day 28 or discharge. MEASUREMENTS AND MAIN RESULTS: Of 401 severe sepsis cases enrolled, 112 (28%) developed single organ failure (0% macrophage activation syndrome 0/112; < 1% mortality 1/112), whereas 289 (72%) developed multiple organ failure (9% macrophage activation syndrome 24/289; 15% mortality 43/289). Overall mortality was higher in children with multiple organ and the phenotypes (24/101 vs 20/300; relative risk, 3.56; 95% CI, 2.06-6.17). Compared to the 188 multiple organ failure patients without these inflammation phenotypes, the 101 multiple organ failure patients with these phenotypes had both increased macrophage activation syndrome (19% vs 3%; relative risk, 7.07; 95% CI, 2.72-18.38) and mortality (24% vs 10%; relative risk, 2.35; 95% CI, 1.35-4.08). CONCLUSIONS: These three inflammation phenotypes were associated with increased macrophage activation syndrome and mortality in pediatric sepsis-induced multiple organ failure. This study provides an impetus and essential baseline data for planning multicenter clinical trials targeting these inflammation phenotypes in children.

Survival and Cardiopulmonary Resuscitation Hemodynamics Following Cardiac Arrest in Children With Surgical Compared to Medical Heart Disease.

OBJECTIVES: To assess the association of diastolic blood pressure cutoffs (≥ 25 mm Hg in infants and ≥ 30 mm Hg in children) during cardiopulmonary resuscitation with return of spontaneous circulation and survival in surgical cardiac versus medical cardiac patients. Secondarily, we assessed whether these diastolic blood pressure targets were feasible to achieve and associated with outcome in physiology unique to congenital heart disease (single ventricle infants, open chest), and influenced outcomes when extracorporeal cardiopulmonary resuscitation was deployed. DESIGN: Multicenter, prospective, observational cohort analysis. SETTING: Tertiary PICU and cardiac ICUs within the Collaborative Pediatric Critical Care Research Network. PATIENTS: Patients with invasive arterial catheters during cardiopulmonary resuscitation and surgical cardiac or medical cardiac illness category. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hemodynamic waveforms during cardiopulmonary resuscitation were analyzed on 113 patients, 88 surgical cardiac and 25 medical cardiac. A similar percent of surgical cardiac (51/88; 58%) and medical cardiac (17/25; 68%) patients reached the diastolic blood pressure targets (p = 0.488). Achievement of diastolic blood pressure target was associated with improved survival to hospital discharge in surgical cardiac patients (p = 0.018), but not medical cardiac patients (p = 0.359). Fifty-three percent (16/30) of patients with single ventricles attained the target diastolic blood pressure. In patients with an open chest at the start of chest compressions, 11 of 20 (55%) attained the target diastolic blood pressure. In the 33 extracorporeal cardiopulmonary resuscitation patients, 16 patients (48%) met the diastolic blood pressure target with no difference between survivors and nonsurvivors (p = 0.296). CONCLUSIONS: During resuscitation in an ICU, with invasive monitoring in place, diastolic blood pressure targets of greater than or equal to 25 mm Hg in infants and greater than or equal to 30 mm Hg in children can be achieved in patients with both surgical and medical heart disease. Achievement of diastolic blood pressure target was associated with improved survival to hospital discharge in surgical cardiac patients, but not medical cardiac patients. Diastolic blood pressure targets were feasible to achieve in 1) single ventricle patients, 2) open chest physiology, and 3) extracorporeal cardiopulmonary resuscitation patients.

Development of the Pediatric Extracorporeal Membrane Oxygenation Prediction Model for Risk-Adjusting Mortality.

OBJECTIVES: To develop a prognostic model for predicting mortality at time of extracorporeal membrane oxygenation initiation for children which is important for determining center-specific risk-adjusted outcomes. DESIGN: Multivariable logistic regression using a large national cohort of pediatric extracorporeal membrane oxygenation patients. SETTING: The ICUs of the eight tertiary care children's hospitals of the Collaborative Pediatric Critical Care Research Network. PATIENTS: Five-hundred fourteen children (< 19 yr old), enrolled with an initial extracorporeal membrane oxygenation run for any indication between January 2012 and September 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 514 first extracorporeal membrane oxygenation runs were analyzed with an overall mortality of 45% (n = 232). Weighted logistic regression was used for model selection and internal validation was performed using cross validation. The variables included in the Pediatric Extracorporeal Membrane Oxygenation Prediction model were age (pre-term neonate, full-term neonate, infant, child, and adolescent), indication for extracorporeal membrane oxygenation (extracorporeal cardiopulmonary resuscitation, cardiac, or respiratory), meconium aspiration, congenital diaphragmatic hernia, documented blood stream infection, arterial blood pH, partial thromboplastin time, and international normalized ratio. The highest risk of mortality was associated with the presence of a documented blood stream infection (odds ratio, 5.26; CI, 1.90-14.57) followed by extracorporeal cardiopulmonary resuscitation (odds ratio, 4.36; CI, 2.23-8.51). The C-statistic was 0.75 (95% CI, 0.70-0.80). CONCLUSIONS: The Pediatric Extracorporeal Membrane Oxygenation Prediction model represents a model for predicting in-hospital mortality among children receiving extracorporeal membrane oxygenation support for any indication. Consequently, it holds promise as the first comprehensive pediatric extracorporeal membrane oxygenation risk stratification model which is important for benchmarking extracorporeal membrane oxygenation outcomes across many centers.

Therapeutic hypothermia after out-of-hospital cardiac arrest in children.

BACKGROUND: Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. METHODS: We conducted this trial of two targeted temperature interventions at 38 children's hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. RESULTS: A total of 295 patients underwent randomization. Among the 260 patients with data that could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. CONCLUSIONS: In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH ClinicalTrials.gov number, NCT00878644.).

RBC Transfusion Practice in Pediatric Extracorporeal Membrane Oxygenation Support.

OBJECTIVES: To determine RBC transfusion practice and relationships between RBC transfusion volume and mortality in infants and children treated with extracorporeal membrane oxygenation. DESIGN: Secondary analysis of a multicenter prospective observational study. SETTING: Eight pediatric institutions within the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Collaborative Pediatric Critical Care Research Network. PATIENTS: Patients age less than 19 years old treated with extracorporeal membrane oxygenation at a participating center. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical data and target hemoglobin or hematocrit values (if set) were recorded daily by trained bedside extracorporeal membrane oxygenation specialists and research coordinators. Laboratory values, including hemoglobin and hematocrit, were recorded daily using the value obtained closest to 8:00 AM. RBC transfusion was recorded as total daily volume in mL/kg. Multivariable logistic regression was used to determine the relationship between RBC transfusion volume and hospital mortality, accounting for potential confounders. Average goal hematocrits varied across the cohort with a range of 27.5-41.3%. Overall, actual average daily hematocrit was 36.8%, and average RBC transfusion volume was 29.4 mL/kg/d (17.4-49.7 mL/kg/d) on extracorporeal membrane oxygenation. On multivariable analysis, each additional 10 mL/kg/d of RBC transfusion volume was independently associated with a 9% increase in odds of hospital mortality (adjusted odds ratio, 1.09 [1.02-1.16]; p = 0.009). CONCLUSIONS: In this multicenter cohort of pediatric extracorporeal membrane oxygenation patients, daily hematocrit levels were maintained at normal or near-normal values and RBC transfusion burden was high. RBC transfusion volume was independently associated with odds of mortality. Future clinical studies to identify optimum RBC transfusion thresholds for pediatric extracorporeal membrane oxygenation are urgently needed.

PICU Autopsies: Rates, Patient Characteristics, and the Role of the Medical Examiner.

OBJECTIVES: Autopsy rates in North American Children's hospitals have not been recently evaluated. Our objectives were 1) to determine the autopsy rates from patients cared for in PICUs during a portion of their hospital stay, 2) to identify patient characteristics associated with autopsies, and 3) to understand the relative role of medical examiner cases. DESIGN: Secondary analysis of data prospectively collected from a sample of patients (n = 10,078) admitted to PICUs affiliated with the Collaborative Pediatric Critical Care Research Network between December 2011 and April 2013. SETTING: Eight quaternary care PICUs. PATIENTS: Patients in the primary study were less than 18 years old, admitted to a PICU and not moribund on PICU admission. Patients included in this analysis were those who died during their hospital stay. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sociodemographic, clinical, hospital, and PICU data were compared between patients who had autopsies conducted and those who did not and between medical examiner and nonmedical examiner autopsies. Of 10,078 patients, 275 died of which 36% (n = 100) had an autopsy performed. Patients with cancer who died were less likely to receive autopsies (p = 0.005), whereas those who died after trauma or cardiac arrest had autopsies performed more often (p < 0.01). Autopsies were more common in patients with greater physiologic instability at admission (p < 0.001), and those who received more aggressive PICU care. Medical examiner cases comprised nearly half of all autopsies (n = 47; 47%) were conducted in patients presenting with greater physiologic instability (p < 0.001) and more commonly after catastrophic events such as cardiac arrest or trauma (p < 0.001). CONCLUSIONS: In this first multicenter analysis of autopsy rates in children, 36% of deaths had autopsies conducted, of which nearly half were conducted by the medical examiner. Deaths with autopsy are more likely to be previously healthy children that had catastrophic events prior to admission.

Hemolysis During Pediatric Extracorporeal Membrane Oxygenation: Associations With Circuitry, Complications, and Mortality.

OBJECTIVES: To describe factors associated with hemolysis during pediatric extracorporeal membrane oxygenation and the relationships between hemolysis, complications, and mortality. DESIGN: Secondary analysis of data collected prospectively by the Collaborative Pediatric Critical Care Research Network between December 2012 and September 2014. SETTING: Three Collaborative Pediatric Critical Care Research Network-affiliated hospitals. PATIENTS: Age less than 19 years and treated with extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hemolysis was defined based on peak plasma free hemoglobin levels during extracorporeal membrane oxygenation and categorized as none (< 0.001 g/L), mild (0.001 to < 0.5 g/L), moderate (0.5 to < 1.0 g/L), or severe (≥ 1.0 g/L). Of 216 patients, four (1.9%) had no hemolysis, 67 (31.0%) had mild, 51 (23.6%) had moderate, and 94 (43.5%) had severe. On multivariable analysis, variables independently associated with higher daily plasma free hemoglobin concentration included the use of in-line hemofiltration or other continuous renal replacement therapy, higher hemoglobin concentration, higher total bilirubin concentration, lower mean heparin infusion dose, lower body weight, and lower platelet count. Using multivariable Cox modeling, daily plasma free hemoglobin was independently associated with development of renal failure during extracorporeal membrane oxygenation (defined as creatinine > 2 mg/dL [> 176.8 µmol/L] or use of in-line hemofiltration or continuous renal replacement therapy) (hazard ratio, 1.04; 95% CI, 1.02-1.06; p < 0.001), but not mortality (hazard ratio, 1.01; 95% CI, 0.99-1.04; p = 0.389). CONCLUSIONS: Hemolysis is common during pediatric extracorporeal membrane oxygenation. Hemolysis may contribute to the development of renal failure, and therapies used to manage renal failure such as in-line hemofiltration and other forms of continuous renal replacement therapy may contribute to hemolysis. Hemolysis was not associated with mortality after controlling for other factors. Monitoring for hemolysis should be a routine part of extracorporeal membrane oxygenation practice, and efforts to reduce hemolysis may improve patient care.

Hyperoxia and Hypocapnia During Pediatric Extracorporeal Membrane Oxygenation: Associations With Complications, Mortality, and Functional Status Among Survivors.

OBJECTIVES: To determine the frequency of hyperoxia and hypocapnia during pediatric extracorporeal membrane oxygenation and their relationships to complications, mortality, and functional status among survivors. DESIGN: Secondary analysis of data collected prospectively by the Collaborative Pediatric Critical Care Research Network. SETTING: Eight Collaborative Pediatric Critical Care Research Network-affiliated hospitals. PATIENTS: Age less than 19 years and treated with extracorporeal membrane oxygenation. INTERVENTIONS: Hyperoxia was defined as highest PaO2 greater than 200 Torr (27 kPa) and hypocapnia as lowest PaCO2 less than 30 Torr (3.9 kPa) during the first 48 hours of extracorporeal membrane oxygenation. Functional status at hospital discharge was evaluated among survivors using the Functional Status Scale. MEASUREMENTS AND MAIN RESULTS: Of 484 patients, 420 (86.7%) had venoarterial extracorporeal membrane oxygenation and 64 (13.2%) venovenous; 69 (14.2%) had extracorporeal membrane oxygenation initiated during cardiopulmonary resuscitation. Hyperoxia occurred in 331 (68.4%) and hypocapnia in 98 (20.2%). Hyperoxic patients had higher mortality than patients without hyperoxia (167 [50.5%] vs 48 [31.4%]; p < 0.001), but no difference in functional status among survivors. Hypocapnic patients were more likely to have a neurologic event (49 [50.0%] vs 143 (37.0%]; p = 0.021) or hepatic dysfunction (49 [50.0%] vs 121 [31.3%]; p < 0.001) than patients without hypocapnia, but no difference in mortality or functional status among survivors. On multivariable analysis, factors independently associated with increased mortality included highest PaO2 and highest blood lactate concentration in the first 48 hours of extracorporeal membrane oxygenation, congenital diaphragmatic hernia, and being a preterm neonate. Factors independently associated with lower mortality included meconium aspiration syndrome. CONCLUSIONS: Hyperoxia is common during pediatric extracorporeal membrane oxygenation and associated with mortality. Hypocapnia appears to occur less often and although associated with complications, an association with mortality was not observed.