Objective The epidemiology of in-hospital death after pediatric sepsis has not been well characterized. We investigated the timing, cause, mode, and attribution of death in children with severe sepsis, hypothesizing that refractory shock leading to early death is rare in the current era. Design Retrospective observational study. Setting Emergency departments and intensive care units at two academic children’s hospitals. Patients Seventy-nine patients <18 years-old treated for severe sepsis/septic shock in 2012–2013 who died prior to hospital discharge. Measurements and Main Results Time to death from sepsis recognition, cause and mode of death, and attribution of death to sepsis were determined from medical records. Organ dysfunction was assessed via daily PELOD-2 scores for seven days preceding death with an increase ≥5 defined as worsening organ dysfunction. The median time to death was 8 (IQR 1–12) days with 25%, 35%, and 49% of cumulative deaths within 1, 3, and 7 days of sepsis recognition, respectively. The most common cause of death was refractory shock (34%), then MODS after shock recovery (27%), neurologic injury (19%), single-organ respiratory failure (9%), and non-septic comorbidity (6%). Early deaths (≤3 days) were mostly due to refractory shock in young, previously healthy patients while MODS predominated after three days. Mode of death was withdrawal in 72%, unsuccessful CPR in 22%, and irreversible loss of neurologic function in 6%. Ninety percent of deaths were attributable to acute or chronic manifestations of sepsis. Only 23% had a rise in PELOD-2 that indicated worsening organ dysfunction. Conclusions Refractory shock remains a common cause of death in pediatric sepsis, especially for early deaths. Later deaths were mostly attributable to MODS, neurologic, and respiratory failure after life-sustaining therapies were limited. A pattern of persistent, rather than worsening, organ dysfunction preceded most deaths.

Critically ill children with severe sepsis or septic shock demonstrate early innate and adaptive immune suppression. Early innate and adaptive immune suppression are associated with longer durations of organ dysfunction and may be useful markers to help guide future investigations of immunomodulatory therapies in children with sepsis.

Critical injury induced immune suppression has been associated with adverse outcomes. This acquired form of immunosuppression is poorly understood in pediatric burn patients, who have infectious complication rates as high as 71%. Our primary objectives were to determine if thermal injury results in early innate immune dysfunction and is associated with increased risk for nosocomial infections (NI). We performed a prospective, longitudinal immune function observational study at a single pediatric burn center. Whole blood samples from burn patients within the first week of injury were used to assess innate immune function. Nosocomial infections were defined using CDC criteria. Immune parameters were compared between patients who went on to develop NI and those that did not. We enrolled a total of 34 patients with 12 developing a NI. Within the first three days of injury, children whom developed NI had significantly lower whole blood ex vivo LPS-induced TNFα production capacity (434 pg/mL vs. 960 pg/mL, p =0.0015), CD14 + monocyte counts (273 cells/µL vs. 508 cells/µL, p =0.01), and % HLA-DR expression on CD14 + monocytes (54% vs. 92%, p =0.02) compared to those that did not develop infection. Plasma cytokine levels did not have a significant difference between the NI and no NI groups. Early innate immune suppression can occur following pediatric thermal injury and appears to be a risk factor for the development of nosocomial infections. Plasma cytokines alone may not be a reliable predictor of the development of NI.

Thermal injury induces concurrent inflammatory and immune dysfunction, which is associated with adverse clinical outcomes. However, these effects in the pediatric population are less studied and there is no standard method to identify those at risk for developing infections. Our goal was to better understand immune dysfunction and identify soluble protein markers following pediatric thermal injury. Further we wanted to determine which early inflammatory, soluble, or immune function markers are most predictive of the development of nosocomial infections (NI) after burn injury. We performed a prospective observational study at a single American Burn Association-verified Pediatric Burn Center. A total of 94 pediatric burn subjects were enrolled and twenty-three of those subjects developed a NI with a median time to diagnosis of 8 days. Whole blood samples, collected within the first 72 hours after injury, were used to compare various markers of inflammation, immune function, and soluble proteins between those who recovered without developing an infection and those who developed a NI after burn injury. Within the first three days of burn injury, innate and adaptive immune function markers (ex vivo lipopolysaccharide-induced tumor necrosis factor alpha production capacity, and ex vivo phytohemagglutinin-induced interleukin-10 production capacity, respectively) were decreased for those subjects who developed a subsequent NI. Further analysis of soluble protein targets associated with these pathways displayed significant increases in soluble CD27, BTLA, and TIM-3 for those who developed a NI. Our findings indicate that suppression of both the innate and adaptive immune function occurs concurrently within the first 72 hours following pediatric thermal injury. At the same time, subjects who developed NI have increased soluble protein biomarkers. Soluble CD27, BTLA, and TIM-3 were highly predictive of the development of subsequent infectious complications. This study identifies early soluble protein makers that are predictive of infection in pediatric burn subjects. These findings should inform future immunomodulatory therapeutic studies.

IMPORTANCE Families and clinicians have limited validated tools available to assist in estimating long-term outcomes early after pediatric cardiac arrest. Blood-based brain-specific biomarkers may be helpful tools to aid in outcome assessment. OBJECTIVETo analyze the association of blood-based brain injury biomarker concentrations with outcomes 1 year after pediatric cardiac arrest. DESIGN, SETTING, AND PARTICIPANTSThe Personalizing Outcomes After Child Cardiac Arrest multicenter prospective cohort study was conducted in pediatric intensive care units at 14 academic referral centers in the US between May 16, 2017, and August 19, 2020, with the primary investigators blinded to 1-year outcomes. The study included 120 children aged 48 hours to 17 years who were resuscitated after cardiac arrest, had pre-cardiac arrest Pediatric Cerebral Performance Category scores of 1 to 3 points, and were admitted to an intensive care unit after cardiac arrest. EXPOSURE Cardiac arrest. MAIN OUTCOMES AND MEASURESThe primary outcome was an unfavorable outcome (death or survival with a Vineland Adaptive Behavior Scales, third edition, score of <70 points) at 1 year after cardiac arrest. Glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal esterase L1 (UCH-L1), neurofilament light (NfL), and tau concentrations were measured in blood samples from days 1 to 3 after cardiac arrest. Multivariate logistic regression and area under the receiver operating characteristic curve (AUROC) analyses were performed to examine the association of each biomarker with outcomes on days 1 to 3. RESULTS Among 120 children with primary outcome data available, the median (IQR) age was 1.0 (0-8.5) year; 71 children (59.2%) were male. A total of 5 children (4.2%) were Asian, 19 (15.8%) were Black, 81 (67.5%) were White, and 15 (12.5%) were of unknown race; among 110 children with data on ethnicity, 11 (10.0%) were Hispanic, and 99 (90.0%) were non-Hispanic. Overall, 70 children (58.3%) had a favorable outcome, and 50 children (41.7%) had an unfavorable outcome, including 43 deaths. On days 1 to 3 after cardiac arrest, concentrations of all 4 measured biomarkers were higher in children with an unfavorable vs a favorable outcome at 1 year. After covariate adjustment, NfL