The major new recommendation in the 2014 update is consideration of institution-specific use of 1) a "recognition bundle" containing a trigger tool for rapid identification of patients with septic shock, 2) a "resuscitation and stabilization bundle" to help adherence to best practice principles, and 3) a "performance bundle" to identify and overcome perceived barriers to the pursuit of best practice principles.

Background: The American College of Critical Care Medicine (ACCM) provided 2002 and 2007 guidelines for hemodynamic support of newborn and pediatric septic shock.

Precise monitoring of the rapidly changing immune status during the course of a disease requires multiplex analysis of cytokines from frequently sampled human blood. However, the current lack of rapid, multiplex, and low volume assays makes immune monitoring for clinical decision-making (e.g., critically ill patients) impractical. Without such assays, immune monitoring is even virtually impossible for infants and neonates with infectious diseases and/or immune mediated disorders as access to their blood in large quantities is prohibited. Localized surface plasmon resonance (LSPR)-based microfluidic optical biosensing is a promising approach to fill this technical gap as it could potentially permit real-time refractometric detection of biomolecular binding on a metallic nanoparticle surface and sensor miniaturization, both leading to rapid and sample-sparing analyte analysis. Despite this promise, practical implementation of such a microfluidic assay for cytokine biomarker detection in serum samples has not been established primarily due to the limited sensitivity of LSPR biosensing. Here, we developed a high-throughput, label-free, multiarrayed LSPR optical biosensor device with 480 nanoplasmonic sensing spots in microfluidic channel arrays and demonstrated parallel multiplex immunoassays of six cytokines in a complex serum matrix on a single device chip while overcoming technical limitations. The device was fabricated using easy-to-implement, one-step microfluidic patterning and antibody conjugation of gold nanorods (AuNRs). When scanning the scattering light intensity across the microarrays of AuNR ensembles with dark-field imaging optics, our LSPR biosensing technique allowed for high-sensitivity quantitative cytokine measurements at concentrations down to 5–20 pg/mL from a 1 µL serum sample. Using the nanoplasmonic biosensor microarray device, we demonstrated the ability to monitor the inflammatory responses of infants following cardiopulmonary bypass (CPB) surgery through tracking the time-course variations of their serum cytokines. The whole parallel on-chip assays, which involved the loading, incubation, and washing of samples and reagents, and 10-fold replicated multianalyte detection for each sample using the entire biosensor arrays, were completed within 40 min.

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.

Purpose In pediatric intensive care unit (PICU) patients, fluid overload (FO) at initiation of continuous renal replacement therapy (CRRT) has been reported to be an independent risk factor for mortality. Previous studies have calculated FO based on daily fluid balance during ICU admission, which is labor intensive and error prone. We hypothesized that a weight-based definition of FO at CRRT initiation would correlate with the fluid balance method and prove predictive of outcome. Methods This is a retrospective single-center review of PICU patients requiring CRRT from July 2006 through February 2010 (n = 113). We compared the degree of FO at CRRT initiation using the standard fluid balance method versus methods based on patient weight changes assessed by both univariate and multivariate analyses. Results The degree of fluid overload at CRRT initiation was significantly greater in nonsurvivors, irrespective of which method was used. The univariate odds ratio for PICU mortality per 1% increase in FO was 1.056 [95% confidence interval (CI) 1.025, 1.087] by the fluid balance method, 1.044 (95% CI 1.019, 1.069) by the weight-based method using PICU admission weight, and 1.045 (95% CI 1.022, 1.07) by the weight-based method using hospital admission weight. On multivariate analyses, all three methods approached significance in predicting PICU survival. Conclusions Our findings suggest that weight-based definitions of FO are useful in defining FO at CRRT initiation and are associated with increased mortality in a broad PICU patient population. This study provides evidence for a more practical weight-based definition of FO that can be used at the bedside.

Invasion of the human by a pathogen necessitates an immune response to control and eradicate it. When this response is inadequately regulated, systemic manifestations can result commonly manifested in physiologic changes described as "sepsis". Recognition, diagnosis, and management of sepsis remain among the greatest challenges shared by the fields of neonatology and pediatric critical care medicine. Sepsis remains among the leading causes of death in both developed and under-developed countries with an incidence that is predicted to increase each year. Despite these sobering statistics, promising therapies derived from pre-clinical models have universally failed to obviate the substantial mortality and morbidity associated with sepsis. Thus, there remains a need for well-designed epidemiologic and mechanistic studies of neonatal and pediatric sepsis to improve our understanding of the causes-both early and late-of deaths attributed to the syndrome. In reviewing the definitions and epidemiology, developmental influences and regulation of the host response to sepsis, it is anticipated that an improved understanding of this host response will assist clinician-investigators in identifying improved therapeutic strategies. Keywords sepsis; septic shock; developmental influence; hemodynamics; coagulation cascade; immune function Definitions characterizing the host responses in sepsis"Sepsis" referring to the "decomposition of animal or vegetable organic matter in the presence of bacteria" 1 first appeared over 2700 years ago in the poems of Homer. Hippocrates also used the term "sepsis" and believed the decomposition could release "dangerous principles" that could cause "auto-intoxication" 2 . Lewis Thomas furthered this concept when he proposed that the clinical responses seen in sepsis were the result of the host's response to the infectious agent 3 . In 1991, an American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was convened to create a framework in which to define the systemic response to sepsis which resulted in defining criteria for the systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis and septic shock 4, 5 . These criteria were refined a decade later (2001) Through clinical observations, pediatricians and neonatologists had recognized that the systemic inflammatory response of tachycardia, tachypnea, hyperthermia and leukocytosis (Table 1) most commonly triggered by infection, could also be present following trauma, burn injury, pancreatitis and various other insults. As a result, this physiologic response was defined as the systemic inflammatory response syndrome (SIRS) with no reference to the presence of infection. Sepsis was defined as a SIRS response associated with infection based on either microbiologic cultures or strong clinical evidence of the presence of an infection. Severe sepsis was defined as sepsis plus evidence of organ dysfunction define around pediatric parameters (Table 2) while septic shock was defined as sepsis criteria ...

Objective In pediatric patients fluid overload (FO) at continuous renal replacement (CRRT) initiation is associated with increased mortality. The aim of this study was to characterize the association between fluid overload at CRRT initiation, fluid removal during CRRT, the kinetics of fluid removal and mortality in a large pediatric population receiving CRRT while on extracorporeal membrane oxygenation (ECMO). Design Retrospective chart review. Setting Tertiary children’s hospital Patients ECMO patients requiring CRRT from July 2006 to September 2010 Interventions None Measurements and Main Results Overall ICU survival was 34% for 53 patients that were initiated on CRRT while on ECMO during the study period. Median FO at CRRT initiation was significantly lower in survivors compared to non-survivors (24.5 vs. 38%, p=0.006). Median FO at CRRT discontinuation was significantly lower in survivors compared to non-survivors (7.1 vs. 17.5%, p=0.035). After adjusting for percent FO at CRRT initiation, age and severity of illness, the change in FO at CRRT discontinuation was not significantly associated with mortality (p=0.212). Models investigating the rates of fluid removal in different periods, age, severity of illness and fluid overload at CRRT initiation found that fluid overload at CRRT initiation was the most consistent predictor of survival. Conclusions Our data demonstrates an association between FO at CRRT initiation and mortality in pediatric patients receiving ECMO. The degree of FO at CRRT discontinuation is also associated with mortality, but appears to reflect the effect of FO at initiation. Furthermore, correction of FO to ≤ 10% was not associated with improved survival. These results suggest that intervening prior to the development of significant FO may be more clinically effective than attempting fluid removal after significant fluid overload has developed. Our findings suggest a role for earlier initiation of CRRT in this population, and warrant further clinical studies.

Using the KDIGO criteria to define AKI, we observed a high prevalence of AKI among critically ill children. Worsening stages of AKI were associated with increased ICU LOS, and AKI was independently associated with prolonged mechanical ventilation and increased mortality. The KDIGO criteria describe clinically relevant AKI in a broad pediatric critical care population.