Threshold for toxicity from hyperammonemia in critically ill children.

BACKGROUND & AIMS: Hyperammonemia results from reduction of hepatocyte function or enzyme of urea cycle deficiency. Hyperammonemia contributes to cerebral edema that may lead to cerebral herniation. The threshold of toxicity of ammonemia is unknown. METHODS: We conducted a retrospective observational study in our pediatric intensive care unit. All children who developed hyperammonemia from January 2000 to April 2009 were included. Clinical and laboratory data at admission, specific treatments implemented, and ammonemias the first 7 days after inclusion were collected. The outcome assessed was 28 day mortality. Risk of mortality was estimated by a logistic regression model. RESULTS: Ninety patients with liver failure (63.3%) and primary or secondary urea cycle defect (23.3%) were included. Patients with urea cycle defects were more likely to receive ammonia scavengers than patients with liver failure (47.6% versus 3.5%). The 28 day mortality rate was 31.1%. Risk of mortality increased according to the ammonemia within 48 h: odds ratio 1.5, 1.9, 3.3, 2.4 for ammonemia above 100, 150, 200, and 300 µmol/L, respectively. Peak ammonemia ≥200 µmol/L within the first 48 h was an independent risk factor for mortality, with greater risk found in liver failure than in urea cycle defect. CONCLUSIONS: Our study identifies a threshold of exposure to ammonia (≥200 µmol/L) above which mortality increases significantly, especially in liver failure. Specific treatments of hyperammonemia are rarely used in liver failure when compared with urea cycle defect even though use of ammonia scavengers may help to decrease ammonemia.

Value of amino-terminal pro B-natriuretic peptide in diagnosing Kawasaki disease.

BACKGROUND: The aim of the present study was to investigate the diagnostic value of the N-terminal B-type natriuretic peptide (NT-proBNP) in acute Kawasaki disease (KD) given that the clinical criteria and the current basic laboratory tests lack the necessary specificity for accurate diagnosis. METHODS: Basic biological tests and serum NT-proBNP levels obtained from acute KD patients were compared to that of febrile controls. NT-proBNP was considered abnormal based on the following definitions: above a cut-off determined on receiver operator characteristic (ROC) analysis, above the upper limit for age, or above 2 SD calculated from healthy children. Analyses were also performed for KD cases with complete or incomplete criteria combined and separately. RESULTS: There were 81 patients and 49 controls aged 3.60 ± 2.77 versus 4.25 ± 3.88 years (P= 0.69). ROC analysis yielded significant area under the curve for NT-proBNP. The sensitivity, specificity, positive and negative predictive values were 70.4-88.9%, 69.4-91.8%, 82.8-93.4%, and 65.2-79.1%. The odds ratios based on NT-proBNP definitions varied between 18.13 (95% confidence interval [CI]: 7.21-45.57), 20.82 (95%CI: 8.18-53.0), and 26.71 (95%CI: 8.64-82.57; P < 0.001). Results were reproducible for cases with complete or incomplete criteria separately. CONCLUSION: NT-proBNP is a reliable marker for the diagnosis of KD. Prospective clinical studies with emphasis on NT-proBNP in a diagnostic algorithm are needed.

Impact of procalcitonin on the management of children aged 1 to 36 months presenting with fever without source: a randomized controlled trial.

OBJECTIVE: The aim of the study was to evaluate the impact of procalcitonin (PCT) measurement on antibiotic use in children with fever without source. METHOD: Children aged 1 to 36 months presenting to a pediatric emergency department (ED) with fever and no identified source of infection were eligible to be included in a randomized controlled trial. Patients were randomly assigned to 1 of 2 groups as follows: PCT+ (result revealed to the attending physician) and PCT- (result not revealed). Patients from both groups also had complete blood count, blood culture, urine analysis, and culture performed. Chest radiography or lumbar puncture could be performed if required. RESULTS: Of the 384 children enrolled and equally randomized into the PCT+ and PCT- groups, 62 (16%) were diagnosed with a serious bacterial infection (urinary tract infection, pneumonia, occult bacteremia, or bacterial meningitis) by primary ED investigation. Ten were also found to be neutropenic (<500 x 10(6)/L). Of the remaining undiagnosed patients, 14 (9%) of 158 received antibiotics in the PCT+ group vs 16 (10%) of 154 in the PCT- group (Delta -2%; 95% confidence interval [CI], -8 to 5). A strategy to treat all patients with PCT of 0.5 ng/mL or greater with prophylactic antibiotic in this group of patients would have resulted in an increase in antibiotic use by 24% (95% CI, 15-33). CONCLUSION: Semiquantitative PCT measurement had no impact on antibiotic use in children aged 1 to 36 months who presented with fever without source. However, a strategy to use prophylactic antibiotics in all patients with abnormal PCT results would have resulted in an increase use of antibiotics.

Length of storage and in vitro immunomodulation induced by prestorage leukoreduced red blood cells.

BACKGROUND: The relationship between length of storage of red blood cell (RBC) units and biochemical changes has been well studied, but little is known about the progression of cellular immunomodulative properties in blood recipients. This study aims to quantify in vitro T-cell activation and cytokine release by white blood cells, after incubation with supernatants from leukoreduced RBCs. STUDY DESIGN AND METHODS: Whole blood cultures were incubated with supernatant from five leukoreduced RBC units stored for 1, 6, 10, 15, 24, and 42 days. Supernatant-induced T-cell activation was evaluated by quantifying CD25 expression. Supernatant-induced cytokine production was determined by measuring interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha levels. RESULTS: No cytokines were detected in RBC supernatants even after 42 days of storage. However, IL-6 levels in whole blood culture increased significantly when incubated with supernatant from RBC units stored for 1, 6, and 15 days, by factors of 1.7 +/- 0.3, 1.7 +/- 0.3, and 1.4 +/- 0.3, respectively. TNF-alpha levels were significantly decreased on Days 24 and 42 of storage by factors of 0.50 +/- 0.42 and 0.33 +/- 0.21, respectively. IL-10 levels were significantly increased on Days 1 and 42 of storage by factors of 2.3 +/- 1.3 and 3.2 +/- 2.8, respectively. After an initial increase in IL-6 and TNF-alpha production, there was a significant linear decrease in their levels measured from units stored for longer times. No significant changes in CD25 expression were observed over time. CONCLUSION: Although no cytokines were measured in the supernatants from leukoreduced RBCs, these supernatants exhibited variable immunomodulatory effects related to their length of storage.

Natriuretic peptide as an adjunctive diagnostic test in the acute phase of Kawasaki disease.

Coronary arteritis rather than myocardial involvement is typically emphasized in Kawasaki disease (KD). Moreover, the criteria and the usual biological markers oversee the importance of cardiac-specific markers in diagnosing this disease. We sought to study the clinical usefulness of measuring B-type natriuretic peptide (BNP) and its N-terminal moiety (NT-proBNP) at the onset of KD. Our objective was to evaluate blood concentrations of BNP and NT-proBNP during the acute and subacute phases of KD. We conducted a prospective study comparing newly diagnosed KD patients to non-KD febrile controls. Blood specimens were collected at presentation, 6-12 h after intravenous immunoglobulin (IVIG) therapy, 1-2 weeks later, and 2-3 months later, or only upon reenrollment for controls. Forty-there KD and 19 control patients were enrolled consecutively. The mean age was 47.1 +/- 34.3 and 62.2 +/- 44.9 months, respectively (p = NS). Pre-IVIG NT-proBNP levels were significantly higher in KD patients than in controls (923.6 +/- 1361.7 vs. 186.2 +/- 198.0 ng/L; p < 0.001), with no statistical difference for BNP (141.9 +/- 227.5 vs. 59.9 +/- 72.4 ng/L; p = 0.112). In conclusion, our data indicate that NT-proBNP is a better marker of myocardial involvement in acute KD than BNP, particularly in cases with incomplete diagnostic criteria, and suggest that it may be a valid adjunctive diagnostic method to support the diagnosis of KD.

False positives in plasma ammonia measurement and their clinical impact in a pediatric population.

OBJECTIVE: Plasma ammonia measurement is greatly influenced by pre-analytical conditions, which may lead to false positives. We wanted to evaluate the prevalence and clinical impact of plasma ammonia false positives in a pediatric population. DESIGN AND METHODS: Over a 28-month period, charts of patients with elevated ammonemia were retrospectively reviewed to identify false positives defined as elevated concentrations that subsequently normalized without plausible explanation for the elevations. RESULTS: 1880 Ammonia measurements were available in 479 patients. Elevated results that subsequently normalized were found in 86 patients. Forty-one (48%) of these patients had most likely falsely elevated ammonemia. Additional blood sampling and laboratory testing were the most frequent consequences of false positives. CONCLUSION: There is a high proportion of false positives among elevated plasma ammonia measurements. Capillary samples and delay between sampling and centrifugation are possible contributing factors. Clinical consequences of false positives were most often limited.

Neonate capillary blood gas reference values.

OBJECTIVES: Because biological data are instrument-dependent and because technology has evolved over the last two decades, the published capillary blood reference values for blood gases, lactate, ionized calcium (iCa) and glucose may not reflect the present day situation. Hence, we report such values for healthy term neonates at 48 +/- 12 h of life. DESIGN AND METHODS: The Institution Ethics Review Board for Research on Human Subjects has accepted the protocol. Extra blood sample was obtained at the time heel-pricks were performed in the frame of the Quebec genetic screening program. One hundred twenty-six term neonates (39.6 +/- 1.2 weeks of gestation) were included in the study. pH, pO2, pCO2, lactate, ionized calcium and glucose were simultaneously measured with selective electrodes on the ABL 735 blood gas analyzer (Radiometer). RESULTS: All variables exhibited a Gaussian distribution. Since there was no gender effect, all data were pooled.

CLSI-based transference of the CALIPER database of pediatric reference intervals from Abbott to Beckman, Ortho, Roche and Siemens Clinical Chemistry Assays: direct validation using reference samples from the CALIPER cohort.

OBJECTIVES: The CALIPER program recently established a comprehensive database of age- and sex-stratified pediatric reference intervals for 40 biochemical markers. However, this database was only directly applicable for Abbott ARCHITECT assays. We therefore sought to expand the scope of this database to biochemical assays from other major manufacturers, allowing for a much wider application of the CALIPER database. DESIGN AND METHODS: Based on CLSI C28-A3 and EP9-A2 guidelines, CALIPER reference intervals were transferred (using specific statistical criteria) to assays performed on four other commonly used clinical chemistry platforms including Beckman Coulter DxC800, Ortho Vitros 5600, Roche Cobas 6000, and Siemens Vista 1500. The resulting reference intervals were subjected to a thorough validation using 100 reference specimens (healthy community children and adolescents) from the CALIPER bio-bank, and all testing centers participated in an external quality assessment (EQA) evaluation. RESULTS: In general, the transferred pediatric reference intervals were similar to those established in our previous study. However, assay-specific differences in reference limits were observed for many analytes, and in some instances were considerable. The results of the EQA evaluation generally mimicked the similarities and differences in reference limits among the five manufacturers' assays. In addition, the majority of transferred reference intervals were validated through the analysis of CALIPER reference samples. CONCLUSIONS: This study greatly extends the utility of the CALIPER reference interval database which is now directly applicable for assays performed on five major analytical platforms in clinical use, and should permit the worldwide application of CALIPER pediatric reference intervals.

Pregnancy outcomes in women with and without gestational diabetes mellitus according to the International Association of the Diabetes and Pregnancy Study Groups criteria.

OBJECTIVE: To estimate the incidence of gestational diabetes mellitus (GDM) according to The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria and the pregnancy complications in women fulfilling these criteria but who are not considered diabetic according to the Canadian Diabetes Association criteria. METHODS: We estimated the rate of GDM according to the IADPSG criteria from November 2008 to October 2010. Then, we conducted a chart review to compare maternal and neonatal outcomes between women classified as GDM according to the IADPSG criteria but not by the Canadian Diabetes Association criteria (group 1; n=186) and nondiabetic women according to both criteria (group 2; n=372). Results were expressed as crude (odds ratio [OR]) or adjusted OR and 95% confidence interval (CI). The study has a statistical power of 80% to detect a difference between 16% and 8% in large for gestational age newborns (α level of 0.05; two-tailed). RESULTS: The rate of GDM using the IADPSG criteria was 27.51% (95% CI 25.92-29.11). Group 1 presented similar rates of large-for-gestational-age newborns (9.1% compared with 5.9%, adjusted OR 1.58, 95% CI 0.79-3.13; P=.19), delivery complications (37.1% compared with 30.1%, OR 1.37, 95% CI 0.95-1.98; P=.10), preeclampsia (6.5% compared with 2.7%, adjusted OR 2.40, 95% CI 0.92-6.27; P=.07), prematurity (6.5% compared with 2.7%, OR 1.10, 95% CI 0.53-2.27; P=.85), neonatal complications at delivery (13.4% compared with 9.7%, OR 1.45, 95% CI 0.84-2.49; P=.20), and metabolic complications (10.8% compared with 14.2%, OR 0.73, 95% CI 0.42-1.26; P=.29) compared with group 2. CONCLUSION: Women classified as nondiabetic by the Canadian Diabetes Association Criteria but considered GDM according to the IADPSG criteria have similar pregnancy outcomes as women without GDM. More randomized studies with cost-effectiveness analyses are needed before implementation of these criteria. LEVEL OF EVIDENCE: II.

Maternal and fetal IGF-I and IGF-II levels, fetal growth, and gestational diabetes.

CONTEXT: It remains uncertain whether maternal IGF-I is associated with fetal growth. Little is known about the role of maternal IGF-II in fetal growth and whether IGF-I or IGF-II is implicated in fetal hypertrophy in gestational diabetes. OBJECTIVE: The objective of the study was to assess maternal and fetal IGF-I and IGF-II levels in association with fetal growth and gestational diabetes. STUDY DESIGN, POPULATION, AND OUTCOMES: A singleton pregnancy cohort study (n = 307). The primary outcome was birth weight. RESULTS: Maternal plasma concentrations increased by an average of 55.4% for IGF-I and 11.8% for IGF-II between 24-28 and 32-35 weeks of gestation. The maternal IGF-I but not IGF-II level was correlated with birth weight and placental weight. Adjusting for maternal and infant characteristics, each SD increase in maternal IGF-I level at 24-28 weeks was associated with a 75-g (95% confidence intervals 29-120) increase in birth weight, a 20-g (7-33) increase in placental weight, and a 1.91-fold (1.28-2.86) higher odds of macrosomia (birth weight > 90th percentile). Similar associations were observed for the maternal IGF-I level at 32-35 weeks. Maternal and fetal IGF-I (but not IGF-II) levels were significantly higher in gestational diabetic than in nondiabetic pregnancies. The significantly higher birth weight z scores in diabetic pregnancies disappeared after adjusting for maternal and fetal IGF-I levels alone. CONCLUSIONS: Higher maternal IGF-I (but not IGF-II) levels at mid- and late gestation may indicate greater placental and fetal growth. IGF-I (but not IGF-II) may be implicated in fetal hypertrophy in gestational diabetes.

Markers for bacterial infection in children with fever without source.

OBJECTIVES: To compare the diagnostic properties of procalcitonin (PCT), C reactive protein (CRP), total white blood cells count (WBC), absolute neutrophil count (ANC) and clinical evaluation to detect serious bacterial infection (SBI) in children with fever without source. DESIGN: Prospective cohort study. SETTING: Paediatric emergency department of a tertiary care hospital. PARTICIPANTS: Children aged 1-36 months with fever and no identified source of infection. INTERVENTION: Complete blood count, blood culture, urine analysis and culture. PCT and CRP were also measured and SBI probability evaluated clinically with a visual analogue scale before disclosing tests results. Outcome measure Area under the curves (AUC) of the receiver operating characteristic curves. RESULTS: Among the 328 children included in the study, 54 (16%) were diagnosed with an SBI: 48 urinary tract infections, 4 pneumonias, 1 meningitis and 1 bacteraemia. The AUC were similar for PCT (0.82; 95% CI 0.77 to 0.86), CRP (0.88; 95% CI 0.84 to 0.91), WBC (0.81; 95% CI 0.76 to 0.85) and ANC (0.80; 95% CI 0.75 to 0.84). The only statistically significant difference was between CRP and ANC (Δ AUC 0.08; 95% CI 0.01 to 0.16). It is important to note that all the surrogate markers were statistically superior to the clinical evaluation that had an AUC of only 0.59 (95% CI 0.54 to 0.65). CONCLUSION: The study data demonstrate that CRP, PCT, WBC and ANC had almost similar diagnostic properties and were superior to clinical evaluation in predicting SBI in children aged 1 month to 3 years.

Biological variation of glycated haemoglobin in a paediatric population and its application to calculation of significant change between results.

BACKGROUND: To determine precisely the probability that a change between two glycated haemoglobin A1c (HbA1c) results is significant and that clinical actions may be required, the biological variation of HbA1c must be known. However, it has not been evaluated in a paediatric population. We therefore determined the long-term biological variation of HbA1c in a paediatric population and used it to generate a probability curve for significant changes between two consecutive HbA1c measurements. METHODS: A group of 24 boys and 14 girls with cystic fibrosis (CF) but without diabetes or impaired glucose tolerance has been selected. HbA1c has been measured at least five times over five consecutive years for all subjects. We have used the Fraser and Harris method to calculate within-subject biological variation (CV(I)), which allowed the determination of the probability that a change is significant between results. RESULTS: As within-subject variances are equivalent for girls and boys (P > 0.1), both genders were merged for biological variation analysis. The CV(I) calculated for HbA1c was 4.8% and the between-subject variation (CV(G)) was 12.8%. Then, a probability curve based on the CV(I) found was generated and showed that a change of 14% between two consecutive HbA1c results corresponding to a probability of 95% was significant. CONCLUSIONS: We determined for the first time the biological variation of HbA1c in a paediatric population, which is higher than the ones found for adult populations. The probability curves generated from these data could be invaluable tools for clinicians to balance HbA1c results with other clinical parameters.

Comparison of procalcitonin measurement by a semi-quantitative method and an ultra-sensitive quantitative method in a pediatric emergency department.

OBJECTIVE: To compare procalcitonin measurements between semi-quantitative and quantitative assays. METHOD: Procalcitonin was measured with the PCT-Q and the Kryptor assays in a pediatric emergency department. RESULTS: Among the 359 pairs of results, 103 had discordant results. The linear weighted kappa was 0.44 (95% CI 0.36, 0.51). The concordant/discordant results distribution varied depending on the laboratory technician (p=0.018). CONCLUSION: Agreement between procalcitonin measured semi-quantitatively and quantitatively was moderate. This is probably due to a subjective interpretation of the assay result.