Rationale: Limited data exist about the international burden of severe sepsis in critically ill children.Objectives: To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials.Methods: A point prevalence study was conducted on 5 days throughout 2013-2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator-and vasoactive-free days at Day 28, functional status, and mortality.Measurements and Main Results: Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6-8.9%). The patients' median age was 3.0 (interquartile range [IQR], 0.7-11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resourcelimited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5-10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,437 patients per group.Conclusions: Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted.

In children who suffer out of hospital cardiac arrest, targeted hypothermia at 33.0 C confers no benefit when compared to targeted normothermia at 36.8 C. Level of evidence: 2B (RCT with wide CIs)Appraised by: Andrew Claxton Citation: Moler FW, Silverstein FS, Holubkov R and the THAPCA Trial Investigators. Therapeutic hypothermia after out-of-hospital cardiac arrest in children. N Eng

A reliable system to identify, mitigate, and escalate risk was associated with a near 50% reduction in UNSAFE transfers and SSEs.

Objective-To validate serum neutrophil gelatinase-associated lipocalin (NGAL) as an early biomarker for acute kidney injury (AKI) in critically ill children with septic shock.Design-Observational cohort study. Setting-15 North American pediatric intensive care units (PICU).Patients-A total of 143 critically ill children with SIRS or septic shock and 25 healthy controls. Interventions-None.Measurements and Main Results-Serum NGAL was measured during the first 24 hours of admission to the PICU. AKI was defined as a blood urea nitrogen (BUN) concentration > 100 mg/ dL, serum creatinine > 2 mg/dL in the absence of pre-existing renal disease, or the need for dialysis. There was a significant difference in serum NGAL between healthy children (median 80 ng/mL, IQR 55.5-85.5 ng/mL), critically ill children with SIRS (median 107.5 ng/mL, IQR 89-178.5 ng/mL), and critically ill children with septic shock (median 302 ng/mL, IQR 151-570 ng/mL; p<0.001). AKI developed in 22 out of 143 (15.4%) critically ill children. Serum NGAL was significantly increased in critically ill children with AKI (median 355 ng/mL, IQR 166-1322 ng/mL) compared to those without AKI (median 186 ng/mL, IQR 98-365 ng/mL; p=0.009).Conclusions-Serum NGAL is a highly sensitive, but nonspecific predictor of AKI in critically ill children with septic shock. Further validation of serum NGAL as a biomarker of AKI in this population is warranted.

Reliable prediction of severe acute kidney injury (AKI) has the potential to optimize treatment. Here we operationalized the empiric concept of renal angina with a renal angina index (RAI) and determined the predictive performance of RAI. This was assessed on admission to the pediatric intensive care unit, for subsequent severe AKI (over 200% rise in serum creatinine) 72 h later (Day-3 AKI). In a multicenter four cohort appraisal (one derivation and three validation), incidence rates for a Day 0 RAI of 8 or more were 15–68% and Day-3 AKI was 13–21%. In all cohorts, Day-3 AKI rates were higher in patients with an RAI of 8 or more with the area under the curve of RAI for predicting Day-3 AKI of 0.74–0.81. An RAI under 8 had high negative predictive values (92–99%) for Day-3 AKI. RAI outperformed traditional markers of pediatric severity of illness (Pediatric Risk of Mortality-II) and AKI risk factors alone for prediction of Day-3 AKI. Additionally, the RAI outperformed all KDIGO stages for prediction of Day-3 AKI. Thus, we operationalized the renal angina concept by deriving and validating the RAI for prediction of subsequent severe AKI. The RAI provides a clinically feasible and applicable methodology to identify critically ill children at risk of severe AKI lasting beyond functional injury. The RAI may potentially reduce capricious AKI biomarker use by identifying patients in whom further testing would be most beneficial.

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 ...

Background and objectives Novel AKI biomarkers carry variable performance for prediction of AKI in patients with heterogeneous illness. Until utility is demonstrated in critically ill patients outside of the cardiopulmonary bypass population, AKI biomarkers are unlikely to gain widespread implementation. Operationalization of an AKI risk stratification methodology, termed renal angina, was recently reported to enhance prediction at the time of intensive care unit admission for persistent severe AKI. The renal angina index (RAI) was developed to provide the clinical context to direct AKI biomarker testing. This study tested the hypothesis that incorporation of AKI biomarkers in patients fulfilling renal angina improves the prediction of persistent severe AKI.Design, setting, participants, & measurements In a multicenter study of 214 patients admitted to the pediatric intensive care unit with sepsis, the discrimination of plasma neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-8 (MMP-8), and neutrophil elastase-2 (Ela-2) were determined individually and in combination with the RAI for severe AKI. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated. Conclusions This study shows that incorporation of AKI biomarkers into the RAI improves discrimination for severe AKI. The RAI optimizes the utility of AKI biomarkers in a heterogeneous, critically ill patient population.

Objective Septic shock heterogeneity has important implications for clinical trial implementation and patient management. We previously addressed this heterogeneity by identifying 3 putative subclasses of children with septic shock based exclusively on a 100-gene expression signature. Here we attempted to prospectively validate the existence of these gene expression-based subclasses in a validation cohort. Design Prospective observational study involving microarray-based bioinformatics. Setting Multiple pediatric intensive care units in the United States. Patients Separate derivation (n=98) and validation (n=82) cohorts of children with septic shock. Interventions None other than standard care. Measurements and Main Results Gene expression mosaics of the 100 class-defining genes were generated for 82 individual patients in the validation cohort. Using computer-based image analysis, patients were classified into 1 of 3 subclasses (“A”, “B”, or “C”) based on color and pattern similarity relative to reference mosaics generated from the original derivation cohort. After subclassification, the clinical database was mined for phenotyping. Subclass A patients had higher illness severity relative to subclasses B and C, as measured by maximal organ failure, fewer ICU-free days, and a higher PRISM score. Patients in subclass A were characterized by repression of genes corresponding to adaptive immunity and glucocorticoid receptor signaling. Separate subclass assignments were conducted by 21 individual clinicians, using visual inspection. The consensus classification of the clinicians had modest agreement with the computer algorithm. Conclusions We have validated the existence of subclasses of children with septic shock based on a biologically relevant, 100-gene expression signature. The subclasses have relevant clinical differences.