International validation of a urinary biomarker panel for identification of active lupus nephritis in children.

BACKGROUND: Conventional markers of juvenile-onset systemic lupus erythematosus (JSLE) disease activity fail to adequately identify lupus nephritis (LN). While individual novel urine biomarkers are good at detecting LN flares, biomarker panels may improve diagnostic accuracy. The aim of this study was to assess the performance of a biomarker panel to identify active LN in two international JSLE cohorts. METHODS: Novel urinary biomarkers, namely vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein 1 (MCP-1), lipocalin-like prostaglandin D synthase (LPGDS), transferrin (TF), ceruloplasmin, alpha-1-acid glycoprotein (AGP) and neutrophil gelatinase-associated lipocalin (NGAL), were quantified in a cross-sectional study that included participants of the UK JSLE Cohort Study (Cohort 1) and validated within the Einstein Lupus Cohort (Cohort 2). Binary logistic regression modelling and receiver operating characteristic curve analysis [area under the curve (AUC)] were used to identify and assess combinations of biomarkers for diagnostic accuracy. RESULTS: A total of 91 JSLE patients were recruited across both cohorts, of whom 31 (34 %) had active LN and 60 (66 %) had no LN. Urinary AGP, ceruloplasmin, VCAM-1, MCP-1 and LPGDS levels were significantly higher in those patients with active LN than in non-LN patients [all corrected p values (p c) < 0.05] across both cohorts. Urinary TF also differed between patient groups in Cohort 2 (p c = 0.001). Within Cohort 1, the optimal biomarker panel included AGP, ceruloplasmin, LPGDS and TF (AUC 0.920 for active LN identification). These results were validated in Cohort 2, with the same markers resulting in the optimal urine biomarker panel (AUC 0.991). CONCLUSION: In two international JSLE cohorts, urinary AGP, ceruloplasmin, LPGDS and TF demonstrate an 'excellent' ability for accurately identifying active LN in children.

Adrenal responses to a low-dose short synacthen test in children with asthma.

OBJECTIVES: Corticosteroids are known to cause adrenal suppression. The aim of this study was to assess clinical factors affecting responses to a low dose short synacthen test (LDSST) in asthmatic children using corticosteroids. DESIGN: Patients were recruited from secondary care paediatric asthma populations within the UK. PATIENTS: Asthmatic children (5-18 years), receiving corticosteroids, underwent a LDSST (n = 525). MEASUREMENTS: Demographics and corticosteroid doses were tested for association with baseline and peak (stimulated) cortisol concentrations. RESULTS: Baseline cortisol was significantly associated with age (log baseline increased 0·04 nm per year of age, P < 0·0001), but not with gender or corticosteroid dose. Peak cortisol was significantly associated with total corticosteroid cumulative dose (decreased 0·73 nm per 200 mcg/day, P < 0·001) but not with age, gender inhaled/intranasal corticosteroid cumulative dose or number of courses of rescue corticosteroids. Biochemically impaired response (peak cortisol ≤500 nm) occurred in 37·0% (161/435) overall, including children using GINA low (200-500 mcg/day beclomethasone-CFC equivalent 32%, n = 60), medium (501-1000 mcg/day (33%, n = 57) and high (>1000 mcg/day 40%, n = 13) doses of inhaled corticosteroid (ICS) similarly, and 36·6% of those using fluticasone ICS ≥500 mcg/day (71/194). Impaired response was more frequent in patients on regular oral corticosteroids (66%, n = 27, P < 0·001). CONCLUSION: Children with asthma can develop biochemical adrenal suppression at similar frequencies for all ICS preparations and doses. The clinical consequence of biochemical suppression needs further study.

Urine biomarkers for monitoring juvenile lupus nephritis: a prospective longitudinal study.

BACKGROUND: In juvenile-onset systemic lupus erythematosus (JSLE), renal involvement (lupus nephritis) is frequently seen and can result in long-term morbidity. This prospective longitudinal study aimed to identify the utility of standard and/or novel biomarkers for monitoring and predicting lupus nephritis in a real world setting. METHODS: Using an unselected JSLE cohort, urine samples were collected during routine clinical review. Protein concentrations of urinary monocyte chemo-attractant protein 1 (uMCP1) and neutrophil gelatinase-associated lipocalin (uNGAL) were analysed along with standard disease activity markers, and were compared with current and subsequent disease activity. RESULTS: JSLE patients (n = 64; median age 14.1 years) were seen at 3 (interquartile range: 2-5) clinical reviews over 364 (182-532) days. Multivariate analysis demonstrated uMCP1 and serum C3 as independent variables (p < 0.001) for active renal disease at the time of the current review. uMCP1 was an excellent predictor of improved renal disease over time (AUC: 0.81; p = 0.013). uNGAL was a good predictor of worsened renal disease activity (AUC 0.76; p = 0.04) over time. CONCLUSION: Biomarkers (uMCP1, serum C3) can indicate current renal involvement in JSLE, whilst uMCP1 and uNGAL are able to predict subsequent renal disease activity changes. Moving towards biomarker-led monitoring may improve the renal outcome for our patients.

A novel method of collection of saliva for estimation of steroid levels in extremely premature infants.

AIM: The major advantage of salivary cortisol sampling is that it is considerably less invasive than taking a blood sample. However, previous methods of obtaining saliva in premature infants have been poorly tolerated and inaccurate. We describe a simple, non-distressing technique for obtaining saliva samples to assess extremely premature infants' salivary cortisol status. METHODS: We prospectively obtained early morning saliva samples from extremely premature infants. Their gestational age ranged between 23 and 27 weeks. Saliva was obtained using four standard universal swabs by placing one swab at a time in the infant's mouth for 1-2 min. No salivary stimulants were used. RESULTS: There were 65 infants (36 males). Mean gestation was 25.3 ± 1.3 weeks. This technique had a success rate of 85% in obtaining a mean of 150 µL of saliva (range 50-350 µL) by trained staff. No adverse events were recorded. CONCLUSION: We describe a novel, safe, non-distressing and effective method of saliva collection for salivary cortisol measurement in extremely premature infants.

Diagnostic efficacy of activated partial thromboplastin time waveform and procalcitonin analysis in pediatric meningococcal sepsis.

OBJECTIVE: A biphasic activated partial thromboplastin time waveform predicts sepsis and disseminated intravascular coagulation in adults. This has not been previously investigated in children. Our aim is to ascertain whether there are changes in the activated partial thromboplastin time waveform in children with meningococcal disease and to compare its diagnostic use with procalcitonin. SETTING: Alder Hey Children's National Health Service Foundation Trust, Liverpool, UK. PATIENTS: Thirty-six children admitted to the hospital for the treatment of suspected meningococcal disease had activated partial thromboplastin time waveform and procalcitonin analysis performed at admission. The light transmittance level at 18 secs was used to quantitate the waveform. Severity of disease was assessed using the Glasgow Meningococcal Septicaemia Prognostic Score, Pediatric Risk of Mortality III score, and the Pediatric Logistic Organ Dysfunction score. MEASUREMENTS AND MAIN RESULTS: Twenty-four children had proven meningococcal disease, 12 had a presumed viral illness, and 20 control subjects were recruited. Transmittance level at 18 secs was lower in children with meningococcal disease and those with a viral illness (p < .0001) and control subjects (p < .0005). Sensitivity and specificity was 0.91 and 0.96 for transmittance level at 18 secs and 0.92 and 1 for procalcitonin in identifying meningococcal disease. There was a significant difference in procalcitonin between children with meningococcal disease and those with a viral illness and control subjects (p < .0005). A negative correlation was found between transmittance level at 18 secs and length of hospital stay (p < .0001), C-reactive protein (p < .0001), procalcitonin (p < .0001), Glasgow Meningococcal Septicaemia Prognostic Score (p < .01), Pediatric Risk of Mortality III score (p < .0001), and Pediatric Logistic Organ Dysfunction score score (p < .0001). CONCLUSION: The activated partial thromboplastin time waveform is abnormal in children with meningococcal disease and may be a useful adjunct in the diagnosis and management of sepsis in children.

SCAMP: standardised, concentrated, additional macronutrients, parenteral nutrition in very preterm infants: a phase IV randomised, controlled exploratory study of macronutrient intake, growth and other aspects of neonatal care.

BACKGROUND: Infants born <29 weeks gestation are at high risk of neurocognitive disability. Early postnatal growth failure, particularly head growth, is an important and potentially reversible risk factor for impaired neurodevelopmental outcome. Inadequate nutrition is a major factor in this postnatal growth failure, optimal protein and calorie (macronutrient) intakes are rarely achieved, especially in the first week. Infants <29 weeks are dependent on parenteral nutrition for the bulk of their nutrient needs for the first 2-3 weeks of life to allow gut adaptation to milk digestion. The prescription, formulation and administration of neonatal parenteral nutrition is critical to achieving optimal protein and calorie intake but has received little scientific evaluation. Current neonatal parenteral nutrition regimens often rely on individualised prescription to manage the labile, unpredictable biochemical and metabolic control characteristic of the early neonatal period. Individualised prescription frequently fails to translate into optimal macronutrient delivery. We have previously shown that a standardised, concentrated neonatal parenteral nutrition regimen can optimise macronutrient intake. METHODS: We propose a single centre, randomised controlled exploratory trial of two standardised, concentrated neonatal parenteral nutrition regimens comparing a standard macronutrient content (maximum protein 2.8 g/kg/day; lipid 2.8 g/kg/day, dextrose 10%) with a higher macronutrient content (maximum protein 3.8 g/kg/day; lipid 3.8 g/kg/day, dextrose 12%) over the first 28 days of life. 150 infants 24-28 completed weeks gestation and birthweight <1200 g will be recruited. The primary outcome will be head growth velocity in the first 28 days of life. Secondary outcomes will include a) auxological data between birth and 36 weeks corrected gestational age b) actual macronutrient intake in first 28 days c) biomarkers of biochemical and metabolic tolerance d) infection biomarkers and other intravascular line complications e) incidence of major complications of prematurity including mortality f) neurodevelopmental outcome at 2 years corrected gestational age. TRIAL REGISTRATION: Current controlled trials: ISRCTN76597892; EudraCT Number: 2008-008899-14.

Multivariate analyses of factors that affect neonatal screening thyroid stimulating hormone.

AIMS: All screening programmes in the UK use a primary thyroid stimulating hormone (TSH) screen for congenital hypothyroidism. Recent attention has been paid to aspects of screening, such as the relation between blood spot TSH levels and birth weight or gestational age. The aim of our study was to determine the factors affecting screening neonatal TSH levels. METHODS: We conducted a retrospective analysis of blood spot screening TSH levels of all infants screened at a single regional screening laboratory. RESULTS: There were 6498 infants screened during a 12-week period. Screening TSH level showed negative correlation with gestational age and birth weight. Multiple linear regression analysis revealed low birth weight as the only independent factor affecting screening TSH level. CONCLUSIONS: Low birth weight infants appear to be at risk of thyroidal dysfunction. Our study showed that there were clinically significant but weak correlation between higher screening TSH levels and low birth weight. The clinical importance of these findings requires larger prospective studies to further elucidate the relevance of these factors affecting TSH screening levels.

Procalcitonin, C-reactive protein, neutrophil gelatinase-associated lipocalin, resistin and the APTT waveform for the early diagnosis of serious bacterial infection and prediction of outcome in critically ill children.

OBJECTIVE: Bacterial Infections remains a leading cause of death in the Paediatric Intensive Care Unit (PICU). In this era of rising antimicrobial resistance, new tools are needed to guide antimicrobial use. The aim of this study was to investigate the accuracy of procalcitonin (PCT), neutrophil gelatinase-associated lipocalin (NGAL), resistin, activated partial thromboplastin time (aPTT) waveform and C-reactive protein (CRP) for the diagnosis of serious bacterial infection (SBI) in children on admission to PICU and their use as prognostic indicators. SETTING: A regional PICU in the United Kingdom. PATIENTS: Consecutive PICU admissions between October 2010 and June 2012. MEASUREMENTS: Blood samples were collected daily for biomarker measurement. The primary outcome measure was performance of study biomarkers for diagnosis of SBI on admission to PICU based on clinical, radiological and microbiological criteria. Secondary outcomes included durations of PICU stay and invasive ventilation and 28-day mortality. Patients were followed up to day 28 post-admission. MAIN RESULTS: A total of 657 patients were included in the study. 92 patients (14%) fulfilled criteria for SBI. 28-day mortality was 2.6% (17/657), but 8.7% (8/92) for patients with SBI. The combination of PCT, resistin, plasma NGAL and CRP resulted in the greatest net reclassification improvement compared to CRP alone (0.69, p<0.005) with 10.5% reduction in correct classification of patients with SBI (p 0.52) but a 78% improvement in correct classification of patients without events (p <0.005). A statistical model of prolonged duration of PICU stay found log-transformed maximum values of biomarkers performed better than first recorded biomarkers. The final model included maximum values of CRP, plasma NGAL, lymphocyte and platelet count (AUC 79%, 95% CI 73.7% to 84.2%). Longitudinal profiles of biomarkers showed PCT levels to decrease most rapidly following admission SBI. CONCLUSION: Combinations of biomarkers, including PCT, may improve accurate and timely identification of SBI on admission to PICU.

Guardianship in hospitals: a collaborative pilot project.

Objectives This paper describes the development, implementation and preliminary results of a collaborative pilot project aimed at reducing the time hospital-based patients with cognitive impairments spend waiting for the allocation of legally appointed Advocate Guardian decision makers from the Office of the Public Advocate (OPA). The aim of the study was to investigate the effect of increased availability of public advocate guardians on guardian allocation waits, patient discharge outcomes and healthcare system demand. Methods A multi-institutional pilot program created a dedicated hospital guardian team within OPA, funded by the health networks, to reduce the time to guardian allocation for patients within each network. A multisite, quasi-experimental historical control group design was used, with initial data collection over 12 months, followed by study of 12-month post-implementation cohorts. Results Under the pilot program, the time from guardianship order lodgement to guardian allocation decreased significantly from 46.5 to 22.9 days, halving the average time hospital-based patients spend waiting for a guardian (difference -23.55 days, two-sample t(154) = -6.575, P < 0.0001, 95% confidence interval [-30.65, -16.48].). Mean total length of stay decreased from 163.2 to 148.5 days. The estimated value of the reduction in allocation wait time was A$15473 per patient, or A$5 of resources released per A$1 spent on increased staffing. Conclusions Direction of a small amount of resources from health services to staff within OPA appears to have created much greater savings for the health services involved. The pilot program has reduced the period of time vulnerable patients spend waiting in hospital for a guardian. What is known about the topic? Guardianship resources are under increasing stress, with demand outstripping funding and hospital-based applicants deprioritised due to assumptions of lower risk, leading to extensive wait times for guardian allocation. What does this paper add? The paper quantifies the impact of greater guardianship resourcing on access to both guardianship and healthcare resources, highlighting benefits for vulnerable patient groups, healthcare system sustainability and access to both guardianship and healthcare resources for the broader community. What are the implications for clinicians? Improving patient flow through healthcare systems may involve allocating resources to services that are managed outside the healthcare system where 'bottlenecks', such as wait times for guardian allocation, have been identified.

Identifying critically ill children at high risk of acute kidney injury and renal replacement therapy.

Acute kidney injury (AKI), a common complication in paediatric intensive care units (PICU), is associated with increased morbidity and mortality. In this single centre, prospective, observational cohort study, neutrophil gelatinase-associated lipocalin in urine (uNGAL) and plasma (pNGAL) and renal angina index (RAI), and combinations of these markers, were assessed for their ability to predict severe (stage 2 or 3) AKI in children and young people admitted to PICU. In PICU children and young people had initial and serial uNGAL and pNGAL measurements, RAI calculation on day 1, and collection of clinical data, including serum creatinine measurements. Primary outcomes were severe AKI and renal replacement therapy (RRT). Secondary outcomes were length of stay, hospital acquired infection and mortality. The area under the Receiver Operating Characteristic (ROC) curves and Youden index was used to determine biomarker performance and identify optimum cut-off values. Of 657 children recruited, 104 met criteria for severe AKI (15∙8%) and 47 (7∙2%) required RRT. Severe AKI was associated with increased length of stay, hospital acquired infection, and mortality. The area under the curve (AUC) for severe AKI prediction for Day 1 uNGAL, Day 1 pNGAL and RAI were 0.75 (95% Confidence Interval [CI] 0∙69, 0∙81), 0∙64 (95% CI 0∙56, 0∙72), and 0.73 (95% CI 0∙65, 0∙80) respectively. The optimal combination of measures was RAI and day 1 uNGAL, giving an AUC of 0∙80 for severe AKI prediction (95% CI 0∙71, 0∙88). In this heterogenous PICU cohort, urine or plasma NGAL in isolation had poorer prediction accuracy for severe AKI than in previously reported homogeneous populations. However, when combined together with RAI, they produced good prediction for severe AKI.

A reference interval for sweat chloride in infants aged between five and six weeks of age.

BACKGROUND: This study was designed to establish a reference interval for sweat chloride for infants without evidence of cystic fibrosis (CF), aged between 5 wk and 6 wk, a time when sweat testing is an integral part of newborn screening for CF. In addition, we compared the gold standard method of sweat testing (quantitative pilocarpine iontophoresis [QPIT, coulometry]) with an emerging methodology (Macroduct [ISE]). METHODS: This was a prospective study on healthy infants at 5-6 wk of age. Sweat collection was undertaken at home on both outer thigh areas using two methods (QPIT and Macroduct ). The order of testing was randomly assigned. Filter paper samples (QPIT) were analysed using flame photometry and coulometry. Macroduct samples were analysed using ion-selective electrodes (ISE, Abbott Architect c8000, UK). RESULTS: Insufficient sweat was collected on 28 occasions with the QPIT (coulometry) method and on 31 with the Macroduct (ISE) capillary system. We achieved a 92% success rate in undertaking two sweat collections consecutively (n = 177). Sweat chloride concentrations were normally distributed with excellent limits of agreement between the two methods of sweat collection and analysis (n = 150). Median (IQR) sweat chloride was 11.2 mmol/L (8-13) with QPIT (coulometry) method with a 99.5th centile (n = 165) of 24 mmol/L. CONCLUSION: The Macroduct (ISE) capillary sweat collection system is valid in this age group. Sweat chloride concentrations above 30 mmol/L should prompt assessment in a specialist CF centre.

The Challenges of Cortisol Replacement Therapy in Childhood: Observations from a Case Series of Children Treated with Modified-Release Hydrocortisone.

BACKGROUND: Hydrocortisone is the preferred treatment for adrenal insufficiency in childhood. A small minority of children experience low cortisol concentrations and symptoms of cortisol insufficiency, poorly responsive to modifications in dosing. We speculated that treatment with modified-release hydrocortisone Plenadren® may be beneficial in these selected patients. OBJECTIVE: The aim of this article was to report cortisol profiles during treatment with standard formulation hydrocortisone and Plenadren, and growth and weight gain during treatment with Plenadren in selected children with adrenal insufficiency. PATIENTS AND METHODS: Data are reported as median (range). Eight patients (5 male) age 11.0 years (8.8-13.3), with adrenal insufficiency for 4.3 years (2.2-10.0) were treated with Plenadren in doses derived from cortisol concentrations measured during treatment with standard formulation hydrocortisone. RESULTS: Plasma cortisol was 262 nmol/L (114-654) 2 h after the morning dose (hydrocortisone dose 6.1 mg/m2 [4.3-7.1]) of standard formulation hydrocortisone. After 4 h, cortisol concentration was 81 nmol/L (56-104) and was < 100 nmol/L in six patients. Two hours after Plenadren administration (hydrocortisone dose 12.1 mg/m2 [8.3-17.6]), plasma cortisol concentration was 349 nmol/L (150-466), and after 4 h it was 239 nmol/L (99-375) and < 100 nmol/L in one patient. Six hours after the Plenadren dose, cortisol concentration was < 100 nmol/L in four patients and after 8 h cortisol concentration was < 100 nmol/L in seven patients (sample not obtained in one patient). Six patients elected to continue treatment with Plenadren. After 4.2 years (2.7-6.0), change in height standard deviation score (SDS) was 0.1 SD (- 0.2 to 0.2) and body mass index SDS was 0.3 SD (0-1.1). CONCLUSION: Smoother cortisol profiles and more sustained cortisol exposure were achieved during treatment with Plenadren, which was the preferred treatment in most patients. Robust clinical trials are required to determine the place of this medication in paediatric practice.

Growth hormone prescribing and initial BMI SDS: Increased biochemical adverse effects and costs in obese children without additional gain in height.

BACKGROUND: Recombinant human growth hormone (rhGH) treatment in children is usually prescribed using actual body weight. This may result in inappropriately high doses in obese children. METHODS: Retrospective audit of all paediatric patients treated with rhGH 2010-14 at a tertiary paediatric hospital in the UK. Change in height SDS and IGF-I SDS during the first year of treatment was stratified by initial BMI SDS in a mixed cohort, and a subgroup of GH deficient (GHD) patients. Alternative doses for those BMI SDS ≥2.0 (Obese) were calculated using BSA, IBW and LBW. RESULTS: 354 patients (133 female) received rhGH, including 213 (60.2%) with GHD. Obesity was present in 40 patients (11.3%) of the unselected cohort, and 32 (15.0%) of the GHD cohort. For GHD patients, gain in height SDS was directly related to BMI SDS, except in obese patients (p<0.05). For both the entire cohort, and GHD patients only, IGF-1 SDS was significantly higher in obese patients (p<0.0001 for both groups). Cross sectional data identified 265 children receiving rhGH, 81 (30.5%) with a BMI-SDS ≥1.75. Alternate prescribing strategies for rhGH prescribing in obese patients suggest a saving of 27% - 38% annually. CONCLUSIONS: Gain in IGF-I SDS is greater in obese children, and is likely to be related to relatively higher doses of rhGH. Additional gain in height was not achieved at the higher doses administered to obese children. Alternative dosing strategies in the obese patient population should be examined in rigorous clinical trials.

Predicting Risk of Serious Bacterial Infections in Febrile Children in the Emergency Department.

BACKGROUND: Improving the diagnosis of serious bacterial infections (SBIs) in the children's emergency department is a clinical priority. Early recognition reduces morbidity and mortality, and supporting clinicians in ruling out SBIs may limit unnecessary admissions and antibiotic use. METHODS: A prospective, diagnostic accuracy study of clinical and biomarker variables in the diagnosis of SBIs (pneumonia or other SBI) in febrile children <16 years old. A diagnostic model was derived by using multinomial logistic regression and internally validated. External validation of a published model was undertaken, followed by model updating and extension by the inclusion of procalcitonin and resistin. RESULTS: There were 1101 children studied, of whom 264 had an SBI. A diagnostic model discriminated well between pneumonia and no SBI (concordance statistic 0.84, 95% confidence interval 0.78-0.90) and between other SBIs and no SBI (0.77, 95% confidence interval 0.71-0.83) on internal validation. A published model discriminated well on external validation. Model updating yielded good calibration with good performance at both high-risk (positive likelihood ratios: 6.46 and 5.13 for pneumonia and other SBI, respectively) and low-risk (negative likelihood ratios: 0.16 and 0.13, respectively) thresholds. Extending the model with procalcitonin and resistin yielded improvements in discrimination. CONCLUSIONS: Diagnostic models discriminated well between pneumonia, other SBIs, and no SBI in febrile children in the emergency department. Improvements in the classification of nonevents have the potential to reduce unnecessary hospital admissions and improve antibiotic prescribing. The benefits of this improved risk prediction should be further evaluated in robust impact studies.

Myocardial injury in infants ventilated on the paediatric intensive care unit: a case control study.

INTRODUCTION: Cardiac troponin T (cTnT) has been used to assess prevalence of myocardial injury in critically ill children. The majority of studies investigated patients undergoing cardiac surgery. Myocardial injury has been associated with increased mortality. Our objectives were to investigate whether cTnT levels are elevated in infants without congenital heart disease admitted to the paediatric intensive care unit (PICU) and whether levels are associated with increased disease severity. METHODS: We measured cTnT in consecutive infants (<12 months old) without congenital heart disease admitted to the PICU and healthy infants. The Paediatric Index of Mortality (PIM) score was determined in patients on the PICU. RESULTS: We recruited 107 infants: 47 infants admitted to the PICU and 60 healthy controls. Controls were, with a median (interquartile range (IQR)) age of 20 (12 to 34) weeks, significantly older than cases, with a median age of 6.5 (0.3 to 20.6) weeks. CTnT levels were, with a median (IQR) of 18 (10 to 60) pg/ml, significantly higher in admissions to the PICU than in controls, with a median level of 10 (10 to 10) pg/ml (95th centile of 20 pg/ml) (p < 0.001). There was a significant positive correlation (r = 0.41, p = 0.004) between PIM score and cTnT levels. Admissions under one month old had higher cTnT levels than older patients (p = 0.013) but the PIM score was not significantly different between them. When corrected for age and weight the correlation of PIM and cTnT was no longer significant. CONCLUSION: Infants on the PICU in the neonatal period have higher cTnT levels compared to older infants despite not having more severe disease.

Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport.

OBJECTIVES: To test the hypothesis that meningococcal septicemia-related pulmonary edema is associated with a systemic abnormality of epithelial sodium and chloride transport and to investigate an association with hormones regulating Na transport. DESIGN: Prospective observational study. SETTING: The 24-bed pediatric intensive care unit and pediatric wards of Royal Liverpool Children's Hospital. PATIENTS: Consecutive children admitted to the pediatric intensive care unit and pediatric wards with a diagnosis of meningococcal septicemia and children (controls) with noninfectious critical illness receiving ventilatory support in the pediatric intensive care unit. MEASUREMENTS AND MAIN RESULTS: We measured sweat and saliva electrolytes, renal electrolyte excretion, nasal potential difference, and aldosterone, thyroxine, and cortisol levels. Pulmonary edema was diagnosed by chest radiography and its severity quantified by calculation of ventilation index at admission and duration of mechanical ventilation. We recruited 17 patients with severe meningococcal septicemia (nine patients with pulmonary edema), 14 patients with mild meningococcal septicemia, and 20 controls. Sweat and saliva Na and Cl concentrations and renal Na excretion were significantly (p < .05) higher in patients with pulmonary edema compared with controls. Nasal potential difference and amiloride response in patients with pulmonary edema were not significantly different to controls, but response to a low Cl solution was reduced in the nasal airway of patients with pulmonary edema (p < .05). Sweat and saliva chloride concentrations correlated significantly and better with ventilation index and duration of ventilation than sodium concentrations. Aldosterone, thyroxine, and cortisol levels were not significantly different between groups. CONCLUSIONS: We have confirmed that meningococcal septicemia-related pulmonary edema is associated with reduced systemic sodium and chloride transport. Features of reduced Cl transport were most closely associated with markers of respiratory compromise, and this was supported by the reduced chloride channel function detected on nasal potential difference measurement.

How stressful is the Newborn Life Support airway test? An observational study.

Objectives: To determine whether there is a significant stress response to the Newborn Life Support airway test (NLSAT) among healthcare professionals in the UK. Design: Quantitative study measuring both stress and anxiety of candidates on Newborn Life Support (NLS) courses measuring salivary cortisol levels along with validated anxiety questionnaires (State Trait Anxiety Inventory). Setting: UK NLS course centres. Participants: 80 healthcare professionals (nurses, doctors and midwives) on NLS courses. Interventions: Stress levels measured (cortisol swabs and State-Trait Anxiety Inventory (STAI)) at baseline, immediately before and 20 min after starting the NLSAT. Results: Cortisol measurements failed to detect any significant rise in stress levels as a result of the NLSAT. Significant anxiety was induced by the NLSAT based on STAI scores. STAI scores rose significantly in all professionals from baseline to post-NLSAT, with the greatest change detected for midwives (+11.82 (SD 7.64, p<0.001)) compared with nurses (+8.86 (SD 12.1, p<0.001)) and doctors (+7.96 (SD 2.9.69, p<0.001)). Experience had no impact on stress levels. Conclusions: Anxiety levels induced by the NLSAT are significant and should be considered when instructing and developing the NLS course.

Measurement of HbA1c in multicentre diabetes trials - should blood samples be tested locally or sent to a central laboratory: an agreement analysis.

BACKGROUND: Glycated haemoglobin (HbA1c) is an important outcome measure in diabetes clinical trials. For multicentre designs, HbA1c can be measured locally at participating centres or by sending blood samples to a central laboratory. This study analyses the agreement between local and central measurements, using 1-year follow-up data collected in a multicentre randomised controlled trial (RCT) of newly diagnosed children with type I diabetes. METHODS: HbA1c measurements were routinely analysed both locally and centrally at baseline and then at 3, 6, 9 and 12 months and the data reported in mmol/mol. Agreement was assessed by calculating the bias and 95 % limits of agreement, using the Bland-Altman analysis method. A predetermined benchmark for clinically acceptable margin of error between measurements was subjectively set as ±10 % for HbA1c. The percentage of pairs of measurements that were classified as clinically acceptable was calculated. Descriptive statistics were used to examine the agreement within centres. Treatment group was not considered. RESULTS: Five hundred and ninety pairs of measurement, representing 255 children and 15 trial centres across four follow-up time points, were compared. There was no significant bias: local measurements were an average of 0.16 mmol/mol (SD = 4.5, 95 % CI -0.2 to 0.5) higher than central. The 95 % limits of agreement were -8.6 to 9.0 mmol/mol (local minus central). Eighty percent of local measurements were within ±10 % of corresponding central measurements. Some trial centres were more varied in the differences observed between local and central measurements: IQRs ranging from 3 to 9 mmol/mol; none indicated systematic bias. CONCLUSIONS: Variation in agreement between HbA1c measurements was greater than had been expected although no overall bias was detected and standard deviations were similar. Discrepancies were present across all participating centres. These findings have implications for the comparison of standards of clinical care between centres, the design of future multicentre RCTs and existing quality assurance processes for HbA1c measurements. We recommend that centralised HbA1c measurement is preferable in the multicentre clinical trial setting. TRIAL REGISTRATION: Eudract No. 2010-023792-25 , registered on 4 November 2010.

Interleukin 9 production in the lungs of infants with severe respiratory syncytial virus bronchiolitis.

BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis is the most prevalent acute wheezing disorder in infants and is associated with recurrent wheeze and asthma in childhood. Interleukin 9, a type 2 cytokine has been proposed as a key cytokine in susceptibility to asthma. We aimed to investigate whether interleukin 9 was produced in the lungs of infants with severe RSV disease and if found, from which cells it originated. METHODS: We did 150 non-bronchoscopic bronchoalveolar lavages during the course of ventilation in 24 term infants and 21 preterm infants ventilated for RSV bronchiolitis. We also did 10 bronchoalveolar lavages on the day of intubation in 10 control infants ventilated for non-respiratory causes. We measured pulmonary interleukin 9 mRNA and protein in samples from all groups. We used immunostaining to identify the cells that produce interleukin 9. FINDINGS: Interleukin 9 mRNA expression, which persisted over the course of ventilation, was noted in all infants with bronchiolitis. Three of the control group also showed interleukin 9 mRNA expression. Median interleukin 9 protein concentration on day 1 (1.9 microg/L [range 0.1-36.2]) was significantly greater in term infants with bronchiolitis than either preterm infants (0.4 microg/L [0.1-2.9]; p<0.05) or the control group (0.7 microg/L [0.4-2.5]; p<0.05). There was a trend for interleukin 9 protein concentrations in term, but not preterm infants to decrease over time. Immunostained cell smears showed that most interleukin 9 expression in bronchoalveolar lavage was by neutrophils. INTERPRETATION: In term infants with RSV bronchiolitis, we noted large amounts of interleukin 9 mRNA and interleukin 9 protein. Neutrophils seem to be the main source of this type 2 cytokine. Interleukin 9 production by neutrophils may contribute to the pathogenesis of RSV disease. These findings may be relevant to other disease processes in the lung where neutrophils are the predominant inflammatory cell type.