Background: Hyperlactatemia upon admission is a documented risk factor for mortality in critically ill adult patients. However, the predictive significance of a single lactate measurement at admission for mortality in the general population of critically ill children remains uncertain. This study evaluated the predictive value of blood lactate levels at admission and determined the cut-off values for predicting in-hospital mortality in the critically ill pediatric population. Methods: We enrolled 1109 critically ill children who were admitted to a pediatric intensive care unit between July 2008 and December 2010. Arterial blood samples were collected in the first 2 hours after admission, and the lactate levels were determined. The Pediatric Risk of Mortality III (PRISM III) scores were calculated during the first 24 hours after admission. Results: Of the 1109 children admitted, 115 (10.4%) died in the hospital. The median (interquartile range) blood lactate level in critically ill children was 3.2 mmol/l (2.2-4.8). Among the children, 859 (77.5%) had a lactate concentration >2.0 mmol/l. The blood lactate level upon admission was significantly associated with mortality (odds ratio [OR] = 1.38; 95% confidence interval [CI], 1.30-1.46; p <0.001), even after adjustment for age, gender, and illness severity assessed by PRISM III (OR = 1.27; p <0.001). Multivariate regression analysis showed that a high blood lactate level (OR = 1.17; 95% CI, 1.07-1.29; p = 0.001), a high PRISM III score (OR = 1.15; 95% CI, 1.11-1.20; p <0.001), and a low serum albumin (OR =0.92; 95% CI, 0.88-0.96; p <0.001) were independent risk factors for mortality in critically ill children. Blood lactate achieved an area under-the-receiver-operating-characteristic curve (AUC) of 0.79 (p <0.001) for predicting mortality that was similar to that of PRISM III (AUC = 0.82; p <0.001). The p-value for a comparison of both AUCs was 0.318. Blood lactate displayed a sensitivity of 61% and a specificity of 86% in predicting mortality at the optimal cut-off value of 5.55 mmol/l, and the positive and negative likelihood ratios were 4.5 and 0.45, respectively. Conclusions: A high blood lactate level at admission is independently associated with and predictive of in-hospital mortality in the general population of critically ill children.

Research on acute kidney injury (AKI) has focused on identifying early biomarkers. However, whether AKI could be diagnosed in the absence of the classic signs of clinical AKI and whether the condition of subclinical AKI, identified by damage or functional biomarkers in the absence of oliguria or increased serum creatinine (sCr) levels, is clinically significant remains to be elucidated in critically ill children. The aims of the study were to investigate the associations between urinary cystatin C (uCysC) levels and AKI and mortality and to determine whether uCysC-positive subclinical AKI is associated with adverse outcomes in critically ill neonates and children. In this prospective cohort study, uCysC levels were serially measured during the first week after intensive care unit (ICU) admission in a heterogeneous group of patients (n = 510) presenting to a tertiary neonatal and pediatric ICU. The diagnosis of neonatal AKI that developed during the first week after admission was based on neonatal KDIGO criteria or sCr >1.5 mg/dL, and pediatric AKI was based on Kidney Disease: Improving Global Outcomes (KDIGO) criteria. The term “uCysC(−)” or “uCysC(+)”, indicating the absence or presence of tubular injury, was defined by the optimal peak uCysC cutoff value for predicting ICU mortality. The initial and peak uCysC levels were significantly associated with AKI and mortality, and had an area under the receiver operating characteristic curve of 0.76 and 0.81, respectively, for predicting mortality. At the optimal cutoff value of 1260 ng/mg uCr, the peak uCysC displayed sensitivity of 79.2% and specificity of 72.3% for predicting mortality. Among all patients, 130 (25.5%) developed uCysC(+)/AKI(−) status during the first week after admission. The adjusted odds ratio for patients with uCysC(+)/AKI(−) status in association with an increased risk of mortality compared with that for patients with uCysC(−)/AKI(−) was 9.34 (P < 0.001). Patients with uCysC(+)/AKI(−) spent 2.8 times as long in the ICU as those with uCysC(−)/AKI(−) (P < 0.001). Both initial and peak uCysC levels are associated with AKI and mortality and are independently predictive of mortality in critically ill neonates and children. Subclinical AKI may occur without detectable loss of kidney function, and uCysC-positive subclinical AKI is associated with worse clinical outcomes in this population.

Sepsis represents a complex disease with the dysregulated inflammatory response and high mortality rate. The goal of this study was to identify potential transcriptomic markers in developing pediatric sepsis by a co-expression module analysis of the transcriptomic dataset. Using the R software and Bioconductor packages, we performed a weighted gene co-expression network analysis to identify co-expression modules significantly associated with pediatric sepsis. Functional interpretation (gene ontology and pathway analysis) and enrichment analysis with known transcription factors and microRNAs of the identified candidate modules were then performed. In modules significantly associated with sepsis, the intramodular analysis was further performed and “hub genes” were identified and validated by quantitative real-time PCR (qPCR) in this study. 15 co-expression modules in total were detected, and four modules (“midnight blue”, “cyan”, “brown”, and “tan”) were most significantly associated with pediatric sepsis and suggested as potential sepsis-associated modules. Gene ontology analysis and pathway analysis revealed that these four modules strongly associated with immune response. Three of the four sepsis-associated modules were also enriched with known transcription factors (false discovery rate-adjusted P < 0.05). Hub genes were identified in each of the four modules. Four of the identified hub genes (MYB proto-oncogene like 1, killer cell lectin like receptor G1, stomatin, and membrane spanning 4-domains A4A) were further validated to be differentially expressed between septic children and controls by qPCR. Four pediatric sepsis-associated co-expression modules were identified in this study. qPCR results suggest that hub genes in these modules are potential transcriptomic markers for pediatric sepsis diagnosis. These results provide novel insights into the pathogenesis of pediatric sepsis and promote the generation of diagnostic gene sets.

The aims of this study are to evaluate the relationship between early blood glucose concentrations and mortality and to define a ‘safe range’ of blood glucose concentrations during the first 24 h after pediatric intensive care unit (PICU) admission with the lowest risk of mortality. We further determine whether associations exist between PICU mortality and early hyperglycemia and hypoglycemia occurring within 24 h of PICU admission, even after adjusting for illness severity assessed by the pediatric risk of mortality III (PRISM III) score. This retrospective cohort study included patients admitted to PICU between July 2008 and June 2011 in a tertiary teaching hospital. Both the initial admission glucose values and the mean glucose values over the first 24 h after PICU admission were analyzed. Of the 1349 children with at least one blood glucose value taken during the first 24 h after admission, 129 died during PICU stay. When analyzing both the initial admission and mean glucose values during the first 24 h after admission, the mortality rate was compared among children with glucose concentrations ≤65, 65-90, 90–110, 110–140, 140–200, and >200 mg/dL (≤3.6, 3.6–5.0, 5.0–6.1, 6.1–7.8, 7.8–11.1, and >11.1 mmol/L). Children with glucose concentrations ≤65 mg/dL (3.6 mmol/L) and >200 mg/dL (11.1 mmol/L) had significantly higher mortality rates, indicating a U-shaped relationship between glucose concentrations and mortality. Blood glucose concentrations of 110–140 mg/dL (6.1–7.8 mmol/L), followed by 90–110 mg/dL (5.0–6.1 mmol/L), were associated with the lowest risk of mortality, suggesting that a ‘safe range’ for blood glucose concentrations during the first 24 h after admission in critically ill children exists between 90 and 140 mg/dL (5.0 and 7.8 mmol/L). The odds ratios of early hyperglycemia (>140 mg/dL [7.8 mmol/L]) and hypoglycemia (≤65 mg/dL [3.6 mmol/L]) being associated with increased risk of mortality were 4.13 and 15.13, respectively, compared to those with mean glucose concentrations of 110–140 mg/dL (6.1–7.8 mmol/L) (p <0.001). The association remained significant after adjusting for PRISM III scores (p <0.001). There was a U-shaped relationship between early blood glucose concentrations and PICU mortality in critically ill children. Both early hyperglycemia and hypoglycemia were associated with mortality, even after adjusting for illness severity.

Fibroblast growth factor 23 (FGF23) and insulin-like growth factor binding protein 7 (IGFBP-7) are suggested to be biomarkers for predicting acute kidney injury (AKI). We compared them with proposed AKI biomarker of cystatin C (CysC), and aimed (1) to examine whether concentrations of these biomarkers vary with age, body weight, illness severity assessed by pediatric risk of mortality III score, and kidney function assessed by estimated glomerular filtration rate (eGFR), (2) to determine the association between these biomarkers and AKI, and (3) to evaluate whether these biomarkers could serve as early independent predictors of AKI in critically ill children. This prospective single center study included 144 critically ill patients admitted to the pediatric intensive care unit (PICU) regardless of diagnosis. Serum and spot urine samples were collected during the first 24 h after PICU admission. AKI was diagnosed based on the AKI network (AKIN) criteria. Twenty-one patients developed AKI within 120 h of sample collection, including 11 with severe AKI defined as AKIN stages 2 and 3. Serum FGF23 levels were independently associated with eGFR after adjustment in a multivariate linear analysis (P < 0.001). Urinary IGFBP-7 (Adjusted OR = 2.94 per 1000 ng/mg increase, P = 0.035), serum CysC (Adjusted OR = 5.28, P = 0.005), and urinary CysC (Adjusted OR = 1.13 per 1000 ng/mg increase, P = 0.022) remained significantly associated with severe AKI after adjustment for body weight and illness severity, respectively. Urinary IGFBP-7 level was predictive of severe AKI and achieved the AUC of 0.79 (P = 0.001), but was not better than serum (AUC = 0.89, P < 0.001) and urinary (AUC = 0.88, P < 0.001) CysC in predicting severe AKI. Serum FGF23 levels were inversely related to measures of eGFR. In contrast to serum and urinary FGF23 which are not associated with AKI in a general and heterogeneous PICU population, an increased urinary IGFBP-7 level was independently associated with the increased risk of severe AKI diagnosed within the next 5 days after sampling, but not superior to serum or urinary CysC in predicting severe AKI in critically ill children.