IntroductionThe intrinsic heterogeneity of clinical septic shock is a major challenge. For clinical trials, individual patient management, and quality improvement efforts, it is unclear which patients are least likely to survive and thus benefit from alternative treatment approaches. A robust risk stratification tool would greatly aid decision-making. The objective of our study was to derive and test a multi-biomarker-based risk model to predict outcome in pediatric septic shock.MethodsTwelve candidate serum protein stratification biomarkers were identified from previous genome-wide expression profiling. To derive the risk stratification tool, biomarkers were measured in serum samples from 220 unselected children with septic shock, obtained during the first 24 hours of admission to the intensive care unit. Classification and Regression Tree (CART) analysis was used to generate a decision tree to predict 28-day all-cause mortality based on both biomarkers and clinical variables. The derived tree was subsequently tested in an independent cohort of 135 children with septic shock.ResultsThe derived decision tree included five biomarkers. In the derivation cohort, sensitivity for mortality was 91% (95% CI 70 - 98), specificity was 86% (80 - 90), positive predictive value was 43% (29 - 58), and negative predictive value was 99% (95 - 100). When applied to the test cohort, sensitivity was 89% (64 - 98) and specificity was 64% (55 - 73). In an updated model including all 355 subjects in the combined derivation and test cohorts, sensitivity for mortality was 93% (79 - 98), specificity was 74% (69 - 79), positive predictive value was 32% (24 - 41), and negative predictive value was 99% (96 - 100). False positive subjects in the updated model had greater illness severity compared to the true negative subjects, as measured by persistence of organ failure, length of stay, and intensive care unit free days.ConclusionsThe pediatric sepsis biomarker risk model (PERSEVERE; PEdiatRic SEpsis biomarkEr Risk modEl) reliably identifies children at risk of death and greater illness severity from pediatric septic shock. PERSEVERE has the potential to substantially enhance clinical decision making, to adjust for risk in clinical trials, and to serve as a septic shock-specific quality metric.

IntroductionDifferentiating between sterile inflammation and bacterial infection in critically ill patients with fever and other signs of the systemic inflammatory response syndrome (SIRS) remains a clinical challenge. The objective of our study was to mine an existing genome-wide expression database for the discovery of candidate diagnostic biomarkers to predict the presence of bacterial infection in critically ill children.MethodsGenome-wide expression data were compared between patients with SIRS having negative bacterial cultures (n = 21) and patients with sepsis having positive bacterial cultures (n = 60). Differentially expressed genes were subjected to a leave-one-out cross-validation (LOOCV) procedure to predict SIRS or sepsis classes. Serum concentrations of interleukin-27 (IL-27) and procalcitonin (PCT) were compared between 101 patients with SIRS and 130 patients with sepsis. All data represent the first 24 hours of meeting criteria for either SIRS or sepsis.ResultsTwo hundred twenty one gene probes were differentially regulated between patients with SIRS and patients with sepsis. The LOOCV procedure correctly predicted 86% of the SIRS and sepsis classes, and Epstein-Barr virus-induced gene 3 (EBI3) had the highest predictive strength. Computer-assisted image analyses of gene-expression mosaics were able to predict infection with a specificity of 90% and a positive predictive value of 94%. Because EBI3 is a subunit of the heterodimeric cytokine, IL-27, we tested the ability of serum IL-27 protein concentrations to predict infection. At a cut-point value of ≥5 ng/ml, serum IL-27 protein concentrations predicted infection with a specificity and a positive predictive value of >90%, and the overall performance of IL-27 was generally better than that of PCT. A decision tree combining IL-27 and PCT improved overall predictive capacity compared with that of either biomarker alone.ConclusionsGenome-wide expression analysis has provided the foundation for the identification of IL-27 as a novel candidate diagnostic biomarker for predicting bacterial infection in critically ill children. Additional studies will be required to test further the diagnostic performance of IL-27.The microarray data reported in this article have been deposited in the Gene Expression Omnibus under accession number GSE4607.

Background: Multi-institutional, international practice variation of pediatric anaphylaxis management by healthcare providers has not been reported.Objective: Characterize variability in epinephrine administration for pediatric anaphylaxis across institutions, including frequency and types of medication errors. Methods:A prospective, observational, study using a standardized in situ simulated anaphylaxis scenario was performed across 28 healthcare institutions in six countries. The on-duty healthcare team was called for a child (patient simulator) in anaphylaxis. Real medications and supplies were obtained from their actual locations. Demographic data about team members, institutional protocols for anaphylaxis, timing of epinephrine delivery, medication errors, and systems safety issues discovered during the simulation were collected.Results: Thirty-seven in situ simulations were performed. Anaphylaxis guidelines existed in 41% (15/37) of institutions. Teams used a cognitive aid for medication dosing 41% (15/37) of the time and 32% (12/37) for preparation. Epinephrine auto injectors (EAIs) were not available in 54% (20/37) of institutions and were used in only 14% (5/37) simulations. Median time to epinephrine administration was 95 seconds (IQR 77, 252) for EAI and 263 seconds (IQR 146, 407.5) for manually prepared epinephrine (p=.12). At least one medication error occurred in 68% (25/37) of simulations. Prior nursing experience with epinephrine administration for anaphylaxis was associated with fewer preparation (p=.04) and administration (p=.01) errors.Latent safety threats (LSTs) were reported by 30% (11/37) of institutions, more than half of these (6/11) involved a cognitive aid. Conclusion and Relevance:A multicenter, international study of simulated pediatric anaphylaxis reveals: 1) variation in management between institutions in usage of protocols,

Severe psychological distress as categorized by simulation personnel using the Simulation Participant Psychological Safety Algorithm is rare, with mild and moderate events being more common. The algorithm was used to teach simulation educators how to assist a participant who may be psychologically distressed and document perceived event severity.

Tonometry is a useful screening surrogate measure of intracranial pressure in children with traumatic brain injuries, but seems to lack the accuracy necessary for close management of intracranial pressure in the acute posttraumatic period.