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BackgroundAlthough high-flow nasal cannula therapy (HFNC) has become a popular mode of non-invasive respiratory support (NRS) in critically ill children, there are no randomised controlled trials (RCTs) comparing it with continuous positive airway pressure (CPAP). We performed a pilot RCT to explore the feasibility, and inform the design and conduct, of a future large pragmatic RCT comparing HFNC and CPAP in paediatric critical care.MethodsIn this multi-centre pilot RCT, eligible patients were recruited to either Group A (step-up NRS) or Group B (step-down NRS). Participants were randomised (1:1) using sealed opaque envelopes to either CPAP or HFNC as their first-line mode of NRS. Consent was sought after randomisation in emergency situations. The primary study outcomes were related to feasibility (number of eligible patients in each group, proportion of eligible patients randomised, consent rate, and measures of adherence to study algorithms). Data were collected on safety and a range of patient outcomes in order to inform the choice of a primary outcome measure for the future RCT.ResultsOverall, 121/254 eligible patients (47.6%) were randomised (Group A 60%, Group B 44.2%) over a 10-month period (recruitment rate for Group A, 1 patient/site/month; Group B, 2.8 patients/site/month). In Group A, consent was obtained in 29/33 parents/guardians approached (87.9%), while in Group B 84/118 consented (71.2%). Intention-to-treat analysis included 113 patients (HFNC 59, CPAP 54). Most reported adverse events were mild/moderate (HFNC 8/59, CPAP 9/54). More patients switched treatment from HFNC to CPAP (Group A: 7/16, 44%; Group B: 9/43, 21%) than from CPAP to HFNC (Group A: 3/13, 23%; Group B: 5/41, 12%). Intubation occurred within 72 h in 15/59 (25.4%) of HFNC patients and 10/54 (18.5%) of CPAP patients (p = 0.38). HFNC patients experienced fewer ventilator-free days at day 28 (Group A: 19.6 vs. 23.5; Group B: 21.8 vs. 22.2).ConclusionsOur pilot trial confirms that, following minor changes to consent procedures and treatment algorithms, it is feasible to conduct a large national RCT of non-invasive respiratory support in the paediatric critical care setting in both step-up and step-down NRS patients.Trial registrationclinicaltrials.gov, NCT02612415. Registered on 23 November 2015.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2080-3) contains supplementary material, which is available to authorized users.

Aim-Therapeutic aerosols are routinely used in the management of infant obstructive airways disease. Infants often become distressed during administration. The aim of this study was to determine the influence of distress and disease severity on the absorption of aerosolised drug in this age group. Methods-Fifteen infants, eight with resolving chronic lung disease of prematurity (mean age, 13 months), and seven infants with normal birth histories (mean age, 11 months) were studied. Flow through small airways was assessed by measurement of partial forced expiratory flow volume curves. Each infant was then given a dose of 20 mg nebulised sodium cromoglicate via a Sidestream nebuliser and distress was graded as: 1, not distressed; 2, distressed. Infants were excluded if contact with the mask was lost for more than 10 seconds. Urine was collected for eight hours and analysed for excreted drug by radioimmunoassay. Results-Sodium cromoglicate is absorbed by the respiratory epithelium, and undergoes renal (43%) and hepatic (57%) excretion. A mean of 0.43% of the total nebulised drug dose was excreted in the urine of the non-distressed infants compared with 0.11% of total dose in the distressed infants. Flow through the small airways was significantly reduced in infants with chronic lung disease of prematurity. Maximum flow at functional residual capacity did not correlate with the amount of drug in the urine, but the degree of distress did. Conclusion-To maximise absorption, nebulised drugs should be given to settled infants. The degree of airways disease does not influence drug absorption in this age group.

Aims/hypothesisEndothelial cells (ECs) and smooth muscle cells (SMCs) play key roles in the development of intimal hyperplasia in saphenous vein (SV) bypass grafts. In diabetic patients, insulin administration controls hyperglycaemia but cardiovascular complications remain. Insulin is synthesised as a pro-peptide, from which C-peptide is cleaved and released into the circulation with insulin; exogenous insulin lacks C-peptide. Here we investigate modulation of human SV neointima formation and SV-EC and SV-SMC function by insulin and C-peptide.MethodsEffects of insulin and C-peptide on neointima formation (organ cultures), EC and SMC proliferation (cell counting), EC migration (scratch wound), SMC migration (Boyden chamber) and signalling (immunoblotting) were examined. A real-time RT–PCR array identified insulin-responsive genes, and results were confirmed by real-time RT–PCR. Targeted gene silencing (siRNA) was used to assess functional relevance.ResultsInsulin (100 nmol/l) augmented SV neointimal thickening (70% increase, 14 days), SMC proliferation (55% increase, 7 days) and migration (150% increase, 6 h); effects were abrogated by 10 nmol/l C-peptide. C-peptide did not affect insulin-induced Akt or extracellular signal-regulated kinase signalling (15 min), but array data and gene silencing implicated sterol regulatory element binding transcription factor 1 (SREBF1). Insulin (1–100 nmol/l) did not modify EC proliferation or migration, whereas 10 nmol/l C-peptide stimulated EC proliferation by 40% (5 days).Conclusions/interpretationOur data support a causative role for insulin in human SV neointima formation with a novel counter-regulatory effect of proinsulin C-peptide. Thus, C-peptide can limit the detrimental effects of insulin on SMC function. Co-supplementing insulin therapy with C-peptide could improve therapy in insulin-treated patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-010-1736-6) contains supplementary material, which is available to authorised users.

ObjectiveDescribe the course and outcomes in a UK national cohort of neonates with vein of Galen malformation identified before 28 days of life.MethodsNeonates with angiographically confirmed vein of Galen malformation presenting to 1 of 2 UK treatment centers (2006–2016) were included; those surviving were invited to participate in neurocognitive assessment. Results in each domain were dichotomized into “good” and “poor” categories. Cross‐sectional and angiographic brain imaging studies were systematically interrogated. Logistic regression was used to explore potential outcome predictors.ResultsOf 85 children with neonatal vein of Galen malformation, 51 had survived. Thirty‐four participated in neurocognitive assessment. Outcomes were approximately evenly split between “good” and “poor” categories across all domains, namely, neurological status, general cognition, neuromotor skills, adaptive behavior, and emotional and behavioral development. Important predictors of poor cognitive outcome were initial Bicêtre score ≤ 12 and presence of brain injury, specifically white matter injury, on initial imaging; in multivariate analysis, only Bicêtre score ≤ 12 remained significant.InterpretationDespite modern supportive and endovascular treatment, more than one‐third of unselected newborns with vein of Galen malformation did not survive. Outcome was good in around half of survivors. The importance of white matter injury suggests that abnormalities of venous as well as arterial circulation are important in the pathophysiology of brain injury. Ann Neurol 2018;84:547–555

Summary Background Sepsis bundles, promulgated by Surviving Sepsis Campaign have not been widely adopted because of variability in sepsis identification strategies, implementation challenges, concerns about excess antimicrobial use, and limited evidence of benefit. Methods A 1-hour septic shock and a 3-hour sepsis bundle were implemented using a Breakthrough Series Collaborative in 14 public hospitals in Queensland, Australia. A before (baseline) and after (post-intervention) study evaluated its impact on outcomes and antimicrobial prescription in patients with confirmed bacteremia and sepsis. Findings Between 01 July 2017 to 31 March 2020, of 6976 adults presenting to the Emergency Departments and had a blood culture taken, 1802 patients (732 baseline, 1070 post-intervention) met inclusion criteria. Time to antibiotics in 1-hour 73.7% vs 85.1% (OR 1.9 [95%CI 1.1-3.6]) and the 3-hour bundle compliance (48.2% to 63.3%, OR 1.7, [95%CI 1.4 to 2.1]) improved post-intervention, accompanied by a significant reduction in Intensive Care Unit (ICU) admission rates (26.5% vs 17.5% (OR 0.5, [95%CI 0.4 to 0.7]). There were no significant differences in-hospital and 30-day post discharge mortality between the two phases. In a post-hoc analysis of the post-intervention phase, sepsis pathway compliance was associated with lower in-hospital mortality (9.7% vs 14.9%, OR 0.6, 95%CI 0.4 to 0.8). The proportions of appropriate antimicrobial prescription at baseline and post-intervention respectively were 55.4% vs 64.1%, (OR 1.4 [95%CI 0.9 to 2.1]). Interpretation Implementing 1-hour and 3-hour sepsis bundles for patients presenting with bacteremia resulted in improved bundle compliance and a reduced need for ICU admission without adversely influencing antimicrobial prescription.

Infant botulism is a rare disease in the UK, with the first case being recognized in 1978 and only five subsequent cases being reported before 2007. This study reports two unlinked cases of infant botulism, caused by two distinct strains of Clostridium botulinum (toxin types A and B, respectively), that occurred within a single month in the south-east of England in October 2007. The use of real-time PCR to detect C. botulinum neurotoxin genes in clinical specimens to improve the diagnostic procedure and to follow carriage of the causative organism in the infant gut is described. The laboratory investigation of these two cases demonstrated that a combination of the mouse bioassay, real-time PCR assays and conventional microbiological culture can provide rapid confirmation of a clinical diagnosis and affect patient management. Both infants (aged 4 and 8 months) were previously healthy prior to the onset of symptoms, and in both cases, a diagnosis of infant botulism was delayed for at least 10 days after initial admission to hospital. Once diagnosed, one of the infants was the first in the UK to be treated with human-derived botulism immunoglobulin. Real-time PCR was used to demonstrate that C. botulinum was excreted in the infants' faeces for up to 68 and 81 days, respectively. Despite the infrequency of infant botulism in the UK, clinicians should be aware of this rare but serious condition and should seek microbiological advice when presented with young infants with compatible symptomologies.

The elevated sCD40L level in meningococcal sepsis implies release of sCD40L from platelets. However, there was no relationship between plasma sCD40L level and the degree of thrombocytopenia or disease severity. Furthermore, platelet surface bound CD40L was similar in controls and patients. Thus, further investigation is needed to determine whether platelet CD40L contributes to inflammation and thrombosis in MCS.