FIRST-line support for Assistance in Breathing in Children (FIRST-ABC): a multicentre pilot randomised controlled trial of high-flow nasal cannula therapy versus continuous positive airway pressure in paediatric critical care.

BACKGROUND: Although 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. METHODS: In 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. RESULTS: Overall, 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). CONCLUSIONS: Our 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 REGISTRATION: clinicaltrials.gov, NCT02612415 . Registered on 23 November 2015.

FIRST-line support for Assistance in Breathing in Children (FIRST-ABC): protocol for a multicentre randomised feasibility trial of non-invasive respiratory support in critically ill children.

INTRODUCTION: Over 18 000 children are admitted annually to UK paediatric intensive care units (PICUs), of whom nearly 75% receive respiratory support (invasive and/or non-invasive). Continuous positive airway pressure (CPAP) has traditionally been used to provide first-line non-invasive respiratory support (NRS) in PICUs; however, high-flow nasal cannula therapy (HFNC), a novel mode of NRS, has recently gained popularity despite the lack of high-quality trial evidence to support its effectiveness. This feasibility study aims to inform the design and conduct of a future definitive randomised clinical trial (RCT) comparing the two modes of respiratory support. METHODS AND ANALYSIS: We will conduct a three-centre randomised feasibility study over 12 months. Patients admitted to participating PICUs who satisfy eligibility criteria will be recruited to either group A (primary respiratory failure) or group B (postextubation). Consent will be obtained from parents/guardians prior to randomisation in 'planned' group B, and deferred in emergency situations (group A and 'rescue' group B). Participants will be randomised (1:1) to either CPAP or HFNC using sealed, opaque envelopes, from a computer-generated randomisation sequence with variable block sizes. The study protocol specifies algorithms for the initiation, maintenance and weaning of HFNC and CPAP. The primary outcomes are related to feasibility, including the number of eligible patients in each group, feasibility of randomising >50% of eligible patients and measures of adherence to the treatment protocols. Data will also be collected on patient outcomes (eg, mortality and length of PICU stay) to inform the selection of an appropriate outcome measure in a future RCT. We aim to recruit 120 patients to the study. ETHICS AND DISSEMINATION: Ethical approval was granted by the National Research Ethics Service Committee North East-Tyne&Wear South (15/NE/0296). Study findings will be disseminated through peer-reviewed journals, national and international conferences. TRIALS REGISTRATION NUMBER: NCT02612415; pre-results.

An in vitro model to consider the effect of 2 mM glutamine and KNK437 on endotoxin-stimulated release of heat shock protein 70 and inflammatory mediators.

OBJECTIVE: Glutamine has been shown to promote the release of heat shock protein 70 (HSP70) both within experimental in vitro models of sepsis and in adults with septic shock. This study aimed to investigate the effects of 2 mM glutamine and an inhibitor of HSP70 (KNK437) on the release of HSP70 and inflammatory mediators in healthy adult volunteers. METHODS: An in vitro whole blood endotoxin stimulation assay was used. RESULTS: The addition of 2 mM glutamine significantly increased HSP70 levels over time (P < 0.05). HSP70 release had a positive correlation at 4 h with IL-1 ß (r = 0.51, P = 0.03) and an inverse correlation with TNF-α (r = -0.56, P = 0.02) and IL-8 levels (r = -0.52, P = 0.03), and there were no significant correlations between HSP70 and IL6 or IL-10 or glutamine. Glutamine supplementation significantly (P < 0.05) attenuated the release of IL-10 at 4 h and IL-8 at 24 h, compared with conditions without glutamine. In endotoxin-stimulated blood there were no significant differences in the release of IL-6, TNF-α, and IL-1 ß with glutamine supplementation at 4 and 24 h. However, glutamine supplementation (2 mM) appeared to attenuate the release of inflammatory mediators (IL-1 ß, IL-6, TNF-α), although this effect was not statistically significant. The addition of KNK437, a HSP70 inhibitor, significantly diminished HSP70 release, which resulted in lower levels of inflammatory mediators (P < 0.05). CONCLUSION: Glutamine supplementation promotes HSP70 release in an experimental model of sepsis. After the addition of KNK437, the effects of glutamine on HSP70 and inflammatory mediator release appear to be lost, suggesting that HSP70 in part orchestrates the inflammatory mediator response to sepsis. The clinical implications require further investigation.

Early application of generic mortality risk scores in presumed meningococcal disease.

OBJECTIVE: Mortality from meningococcal disease typically occurs within 24 hrs of intensive care unit (ICU) admission. An early, accurate mortality-risk tool may aid in trial design for novel therapies. We assessed the performance of two generic scores that assign mortality risk within 1 hr of ICU admission: the Preintensive Care Pediatric Risk of Mortality (Pre-ICU PRISM) and Pediatric Index of Mortality (PIM). DESIGN: Prospective, observational study over 21 months. SETTING: Two tertiary pediatric ICUs accepting referrals from southeast England. PATIENTS: Patients were 165 consecutive children with meningococcal disease. Ages ranged from 0.1 to 17 yrs (median 2.3 yrs). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: PIM demonstrated greater sensibility, with complete data collected in 93% of cases, compared with 35% for the pre-ICU PRISM. Both scores discriminated well. The area under the receiver operating characteristic curve was 0.90 (95% confidence interval, 0.81-1.00) for PIM and 0.94 (95% confidence interval, 0.88-0.98) for Pre-ICU PRISM; this did not change when applied to the subgroup of patients with complete data. Both scores calibrated poorly, overestimating mortality in the medium-risk strata (and also in the high-risk stratum in the case of Pre-ICU PRISM). When used as a stratification tool for a hypothetical trial (60% reduction in mortality, 80% power), the scores allowed for a reduction in study size by 50% (PIM) and 43% (pre-ICU PRISM). CONCLUSIONS: Pre-ICU PRISM and PIM both discriminate well but calibrate poorly when applied to a cohort of children with meningococcal sepsis. Both scores provide an effective means of stratification for clinical trial purposes. The main advantage for PIM appears to be ease of data collection.

Unattended home sleep studies for the evaluation of suspected obstructive sleep apnoea syndrome in children.

Children suspected of obstructive sleep apnoea syndrome (OSAS) are traditionally investigated in hospital with overnight sleep studies, and single-channel pulse oximetry is the commonest form of initial study. A prospective study was conducted comparing unsupervised sleep studies, using a Nellcor N-395 pulse oximeter, performed in hospital and at home. Two hundred and eleven patient studies were completed in 18 months, 158 in hospital and 53 at home. The median age of patients was four years in both groups. The mean study duration was 9 h 5 min in hospital and 9 h 12 min at home (P = 0.75). The mean time in pulse search was 0.4% (SD = 0.7) in hospital and 0.2% (SD = 0.4) at home (P = 0.008). The number of failed studies was 96 of 254 (38%) in hospital and three of 56 (5%) at home (P < 0.001). Overall, 149 hospital bed days were saved (at pounds 690 per bed day), representing pounds 68,540 saved annually. The results show that unattended home sleep studies in the form of overnight pulse oximetry can be performed to a standard better than hospital studies, where local community nursing facilities exist.

Children with human immunodeficiency virus admitted to a paediatric intensive care unit in the United Kingdom over a 10-year period.

OBJECTIVE: There is little published experience regarding the outcome of children with human immunodeficiency virus (HIV) infection treated on a paediatric intensive care unit (PICU). We describe the outcome of children with HIV infection in our hospital over a 10-year period. METHOD: We performed a retrospective analysis of all children with HIV infection admitted to our PICU between August 1992 and July 2002. Their ages ranged from 2 months to 11 years (median 4 months). Information collected included demographic data, clinical presentation, investigations, treatment and outcome. RESULTS: There were 42 children with HIV infection admitted to PICU during the study period, with 66 admission episodes. Sixteen (38%) children died in PICU, and 26 (62%) survived their last PICU admission. Of these, 5 died at a later date (between 1 and 32 months after discharge from PICU) and 21 survived to the time of reporting. The most frequent reason for PICU admission was respiratory failure, due either to Pneumocystis carinii pneumonia (45% of admissions) or to other respiratory pathogens (32%). Over 80% of current survivors had good outcomes in terms of growth and development; 6 children had evidence of spastic diplegia. CONCLUSIONS: Although there is significant mortality among children with HIV infection admitted to PICU, many of them survive their admission, and over 80% of the survivors have good outcomes with the currently available highly active anti-retroviral therapy. This provides evidence that intensive care treatment is appropriate for this group of patients in the United Kingdom.

Heliox therapy in bronchiolitis: phase III multicenter double-blind randomized controlled trial.

BACKGROUND AND OBJECTIVE: Supportive care remains the mainstay of therapy in bronchiolitis. Earlier studies suggest that helium-oxygen therapy may be beneficial, but evidence is limited. We aimed to compare efficacy of 2 treatment gases, Heliox and Airox (21% oxygen + 79% helium or nitrogen, respectively), on length of hospital treatment for bronchiolitis. METHODS: This was a multicenter randomized blinded controlled trial of 319 bronchiolitic infant subjects randomly assigned to either gas; 281 subjects completed the study (140 Heliox, 141 Airox), whose data was analyzed. Treatment was delivered via facemask (nasal cannula, if the facemask intolerant) ± continuous positive airway pressure (CPAP). Severe bronchiolitics received CPAP from the start. Primary end point was length of treatment (LoT) required to alleviate hypoxia and respiratory distress. Secondary end-points were proportion of subjects needing CPAP; CPAP (LoT); and change in respiratory distress score. RESULTS: Analysis by intention to treat (all subjects); median LoT (inter-quartile range, days): Heliox 1.90 (1.08-3.17), Airox 1.87 (1.11-3.34), P = .41. Facemask tolerant subgroup: Heliox 1.46 (0.85-1.95), Airox 2.01 (0.93-2.86), P = .03. Nasal cannula subgroup: Heliox 2.51 (1.21-4.32), Airox 2.81 (1.45-4.78), P = .53. Subgroup started on CPAP: Heliox 1.55 (1.38-2.01), Airox 2.26 (1.84-2.73), P = .02. Proportion of subjects needing CPAP: Heliox 17%, Airox 19%, O.R. 0.87 (0.47-1.60), P = .76. Heliox reduced respiratory distress score after 8 hours (mixed models estimate, -0.1298; P < .001). The effect was greater for facemask compared with nasal cannula (mixed models estimate, 0.093; P = .04). CONCLUSIONS: Heliox therapy does not reduce LoT unless given via a tight-fitting facemask or CPAP. Nasal cannula heliox therapy is ineffective.

The challenge of developing a new predictive formula to estimate energy requirements in ventilated critically ill children.

BACKGROUND: Traditionally, energy requirements have been calculated using predictive equations. These methods have failed to calculate energy expenditure accurately. Routine indirect calorimetry has been suggested, but this method is technically demanding and costly. This study aimed to develop a new predictive equation to estimate energy requirements for critically ill children. METHODS: This prospective, observational study on ventilated children included patients with an endotracheal tube leak of < 10% and fractional inspired oxygen of < 60%. An indirect calorimetry energy expenditure measurement was performed and polynomial regression analysis was used to develop new predictive equations. The new formulas were then compared with existing prediction equations. RESULTS: Data from 369 measurements were included in the formula design. Only weight and diagnosis influenced energy expenditure significantly. Three formulas (A, B, C) with an R² > 0.8 were developed. When we compared the new formulas with commonly used equations (Schofield, Food and Agriculture Organization/World Health Organization/United Nations University, and White equation), all formulas performed very similar, but the Schofield equation seemed to have the lowest SD. CONCLUSIONS: All 3 new pediatric intensive care unit equations have R² values of > 0.8; however, the Schofield equation still performed better than other predictive methods in predicting energy expenditure in these patients. Still, none of the predictive equations, including the new equations, predicted energy expenditure within a clinically accepted range, and further research is required, particularly for patients outside the technical scope of indirect calorimetry.

Successful blind placement of nasojejunal tubes in paediatric intensive care: impact of training and audit.

AIM: This paper is a report of a study to monitor continuing nasojejunal tube placement success rate and to evaluate a training programme for staff placing these tubes at the bedside. BACKGROUND: Gastric delivery of enteral feeds is frequently poorly tolerated due to impaired gastric motility in critically ill children. Consequently, there has been an increased interest in the use of the nasojejunal feeding route. Nasojejunal tubes are both safe and well-tolerated, but placements of these tubes are notoriously difficult and therefore often avoided. Consequently, a blind bedside technique was developed, with a placement success of 96%. METHOD: A training programme using this technique was developed for nursing staff on the unit. This included one-to-one training of key nurses of the nasojejunal tube placement technique and a supervised nasojejunal placement with either the senior nurse or dietitian. This practice was audited in 100 consecutive patients in 2001 and 2004. Patient demographics, diagnosis, time taken for placement and reasons for unsuccessful placements were documented. RESULTS: The 2001 audit (n = 100) indicated that the nasojejunal route was used in 19% of all cases, with 1% and 80% of patients fed via the parenteral and nasogastric route respectively. In 2004 (n = 94), 18% of patients were fed via the nasojejunal route, 3% parenterally and 79% via the gastric route. Placement success continued to be between 94.5-95% in 2001 and 2004. CONCLUSION: Continued successful placement of blind nasojejunal feeding tubes can be achieved through a well-monitored education programme, regular audit cycles and multidisciplinary team support.

Food allergy as a risk factor for life-threatening asthma in childhood: a case-controlled study.

BACKGROUND: No objective clinical risk factors exist for pediatric life-threatening asthma. OBJECTIVES: In this study, we address whether persistent food allergy and degree of atopy are risk factors for life-threatening asthma. METHODS: By use of a case-controlled design, children (1-16 years) ventilated for an exacerbation of asthma were enrolled. Each case was matched by sex, age, and ethnicity, with 2 controls who had attended with a non-life-threatening exacerbation. All subjects were assessed by means of a questionnaire, spirometry, and skin prick or RAST testing. The data were analyzed by conditional logistic regression. RESULTS: Nineteen cases and 38 controls were enrolled. Compared with controls, cases were found to have the following risk factors: food allergy (odds ratio, 8.58; 95% CI, 1.85-39.71), multiple allergic diagnoses (4.42; 1.17-16.71), early onset of asthma (6.48; 1.36-30.85), and frequent admissions (14.2; 1.77-113.59). After regression analysis, only frequent admission with asthma (9.85; 1.04-93.27) and food allergy (5.89; 1.06-32.61) were independently associated with life-threatening asthma. Half the cases had food allergy compared with only 10% of controls. CONCLUSION: This study demonstrates that poorly controlled asthma and food allergy are significant risk factors for life-threatening asthma. More intensive management of this high-risk group of children might help to reduce future morbidity and mortality.