Which outcomes should be used in future bronchiolitis trials? Developing a bronchiolitis core outcome set using a systematic review, Delphi survey and a consensus workshop.

OBJECTIVES: The objective of this study was to develop a core outcome set (COS) for use in future clinical trials in bronchiolitis. We wanted to find out which outcomes are important to healthcare professionals (HCPs) and to parents and which outcomes should be prioritised for use in future clinical trials. DESIGN AND SETTING: The study used a systematic review, workshops and interviews, a Delphi survey and a final consensus workshop. RESULTS: Thirteen parents and 45 HCPs took part in 5 workshops; 15 other parents were also separately interviewed. Fifty-six items were identified from the systematic review, workshops and interviews. Rounds one and two of the Delphi survey involved 299 and 194 participants, respectively. Sixteen outcomes met the criteria for inclusion within the COS. The consensus meeting was attended by 10 participants, with representation from all three stakeholder groups. Nine outcomes were added, totalling 25 outcomes to be included in the COS. CONCLUSION: We have developed the first parent and HCP consensus on a COS for bronchiolitis in a hospital setting. The use of this COS will ensure outcomes in future bronchiolitis trials are important and relevant, and will enable the trial results to be compared and combined. TRIAL REGISTRATION NUMBER: ISRCTN75766048.

Establishing and augmenting views on the acceptability of a paediatric critical care randomised controlled trial (the FEVER trial): a mixed methods study.

OBJECTIVE: To explore parent and staff views on the acceptability of a randomised controlled trial investigating temperature thresholds for antipyretic intervention in critically ill children with fever and infection (the FEVER trial) during a multi-phase pilot study. DESIGN: Mixed methods study with data collected at three time points: (1) before, (2) during and (3) after a pilot trial. SETTING: English, Paediatric Intensive Care Units (PICUs). PARTICIPANTS: (1) Pre-pilot trial focus groups with pilot site staff (n=56) and interviews with parents (n=25) whose child had been admitted to PICU in the last 3 years with a fever and suspected infection, (2) Questionnaires with parents of randomised children following pilot trial recruitment (n=48 from 47 families) and (3) post-pilot trial interviews with parents (n=19), focus groups (n=50) and a survey (n=48) with site staff. Analysis drew on Sekhon et al's theoretical framework of acceptability. RESULTS: There was initial support for the trial, yet some held concerns regarding the proposed temperature thresholds and not using paracetamol for pain or discomfort. Pre-trial findings informed protocol changes and training, which influenced views on trial acceptability. Staff trained by the FEVER team found the trial more acceptable than those trained by colleagues. Parents and staff found the trial acceptable. Some concerns about pain or discomfort during weaning from ventilation remained. CONCLUSIONS: Pre-trial findings and pilot trial experience influenced acceptability, providing insight into how challenges may be overcome. We present an adapted theoretical framework of acceptability to inform future trial feasibility studies. TRIAL REGISTRATION NUMBERS: ISRCTN16022198 and NCT03028818.

Permissive versus restrictive temperature thresholds in critically ill children with fever and infection: a multicentre randomized clinical pilot trial.

BACKGROUND: Fever improves pathogen control at a significant metabolic cost. No randomized clinical trials (RCT) have compared fever treatment thresholds in critically ill children. We performed a pilot RCT to determine whether a definitive trial of a permissive approach to fever in comparison to current restrictive practice is feasible in critically ill children with suspected infection. METHODS: An open, parallel-group pilot RCT with embedded mixed methods perspectives study in four UK paediatric intensive care units (PICUs) and associated retrieval services. Participants were emergency PICU admissions aged > 28 days to < 16 years receiving respiratory support and supplemental oxygen. Subjects were randomly assigned to permissive (antipyretic interventions only at ≥ 39.5 °C) or restrictive groups (antipyretic interventions at ≥ 37.5 °C) whilst on respiratory support. Parents were invited to complete a questionnaire or take part in an interview. Focus groups were conducted with staff at each unit. Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between group separation of temperature and safety. RESULTS: One hundred thirty-eight children met eligibility criteria of whom 100 (72%) were randomized (11.1 patients per month per site) without prior consent (RWPC). Consent to continue in the trial was obtained in 87 cases (87%). The mean maximum temperature (95% confidence interval) over the first 48 h was 38.4 °C (38.2-38.6) in the restrictive group and 38.8 °C (38.6-39.1) in the permissive group, a mean difference of 0.5 °C (0.2-0.8). Protocol deviations were observed in 6.8% (99/1438) of 6-h time periods and largely related to patient comfort in the recovery phase. Length of stay, duration of organ support and mortality were similar between groups. No pre-specified serious adverse events occurred. Staff (n = 48) and parents (n = 60) were supportive of the trial, including RWPC. Suggestions were made to only include invasively ventilated children for the duration of intubation. CONCLUSION: Uncertainty around the optimal fever threshold for antipyretic intervention is relevant to many emergency PICU admissions. A more permissive approach was associated with a modest increase in mean maximum temperature. A definitive trial should focus on the most seriously ill cases in whom antipyretics are rarely used for their analgesic effects alone. TRIAL REGISTRATION: ISRCTN16022198 . Registered on 14 August 2017.

Potential impact of maternal vaccination on life-threatening respiratory syncytial virus infection during infancy.

BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of infant mortality. Here, we estimated the potential impact of maternal vaccination against RSV on life-threatening RSV infection in infants. METHODS: We developed a mathematical model for maternal vaccine-induced antibody dynamics and used characteristics of a maternal RSV vaccine currently in phase 3 of clinical development. The model was applied to data from two cohorts of children younger than 12 months with RSV-related paediatric intensive care unit (PICU) admission in the United Kingdom (n = 370) and the Netherlands (n = 167), and a cohort of 211 children younger than 12 months with RSV-related in-hospital death from 20 countries worldwide. RESULTS: Our model predicted that, depending on vaccine efficiency, maternal vaccination at 30 weeks' gestational age could have prevented 62-75% of RSV-related PICU admissions in the United Kingdom and 76-87% in the Netherlands. For the global mortality cohort, the model predicted that maternal vaccination could have prevented 29-48% of RSV-related in-hospital deaths. Preterm children and children with comorbidities were predicted to benefit less than (healthy) term children. CONCLUSIONS: Maternal vaccination against RSV may substantially decrease life-threatening RSV infections in infants.

Transaminase levels reflect disease severity in children ventilated for respiratory syncytial virus (RSV) bronchiolitis.

Bronchiolitis, often caused by respiratory syncytial virus (RSV), is the commonest cause of hospitalisation in infancy. Serum transaminases are sometimes raised in children with bronchiolitis. We tested the hypothesis that raised transaminases are associated with increased disease severity in children ventilated for bronchiolitis. Prospective observational cohort study of mechanically ventilated children with community-acquired RSV bronchiolitis. Alanine transaminase (ALT) and aspartate transaminase (AST) levels were measured daily. Children with normal transaminases were compared with those with elevated levels. Over 11 consecutive winters, 556 children with RSV bronchiolitis were mechanically ventilated - 226 had comorbidities and therefore excluded; 313 of remaining 330 were under 2 years age; 305 had early transaminase measurements. 57/305 (19%) had elevated transaminase (AST and/or ALT) levels. For the first time we show that duration of ventilation and length of admission were both significantly longer, and paediatric index of mortality and C-reactive protein higher, in those with elevated AST levels on admission (but not those with elevated ALT levels). Furthermore, transaminase elevations were transient, generally having normalised by seven days following admission. RSV bronchiolitis was more severe in children with early elevated AST levels and could be used early in the illness as a predictor for disease severity.

Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series.

BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of pneumonia mortality in young children. However, clinical data for fatal RSV infection are scarce. We aimed to identify clinical and socioeconomic characteristics of children aged younger than 5 years with RSV-related mortality using individual patient data. METHODS: In this retrospective case series, we developed an online questionnaire to obtain individual patient data for clinical and socioeconomic characteristics of children aged younger than 5 years who died with community-acquired RSV infection between Jan 1, 1995, and Oct 31, 2015, through leading research groups for child pneumonia identified through a comprehensive literature search and existing research networks. For the literature search, we searched PubMed for articles published up to Feb 3, 2015, using the key terms "RSV", "respiratory syncytial virus", or "respiratory syncytial viral" combined with "mortality", "fatality", "death", "died", "deaths", or "CFR" for articles published in English. We invited researchers and clinicians identified to participate between Nov 1, 2014, and Oct 31, 2015. We calculated descriptive statistics for all variables. FINDINGS: We studied 358 children with RSV-related in-hospital death from 23 countries across the world, with data contributed from 31 research groups. 117 (33%) children were from low-income or lower middle-income countries, 77 (22%) were from upper middle-income countries, and 164 (46%) were from high-income countries. 190 (53%) were male. Data for comorbidities were missing for some children in low-income and middle-income countries. Available data showed that comorbidities were present in at least 33 (28%) children from low-income or lower middle-income countries, 36 (47%) from upper middle-income countries, and 114 (70%) from high-income countries. Median age for RSV-related deaths was 5·0 months (IQR 2·3-11·0) in low-income or lower middle-income countries, 4·0 years (2·0-10·0) in upper middle-income countries, and 7·0 years (3·6-16·8) in high-income countries. INTERPRETATION: This study is the first large case series of children who died with community-acquired RSV infection. A substantial proportion of children with RSV-related death had comorbidities. Our results show that perinatal immunisation strategies for children aged younger than 6 months could have a substantial impact on RSV-related child mortality in low-income and middle-income countries. FUNDING: Bill & Melinda Gates Foundation.

Pulmonary bacterial coinfection in infants and children with viral respiratory infection.

The true incidence of pulmonary bacterial coinfection in infants and children hospitalized with a viral respiratory infection is difficult to ascertain but can vary widely from under 1 to 44%. For the same patient group admitted to pediatric intensive care units and/or requiring ventilatory support, the evidence is more convincing, with reported incidences of 17-39%. Studies covering influenza and respiratory syncytial virus infection dominate the recent literature. Whether treatment (or 'cover') with antibiotics is indicated/justified lies in the balance of risk of pulmonary bacterial coinfection (or risk of not diagnosing it), severity of disease and the patient setting. The balance between the overprescription of antibiotics and the possible sequelae associated with bacterial coinfection in infants and children continues to fuel debate.

Clinical course and outcome for critically ill children with Down syndrome: a retrospective cohort study.

PURPOSE: Children with Down syndrome (DS) have several genetic anomalies within chromosome 21 which may influence their response to critical illness. We compared the intensive care course and outcome of children with DS versus those without. METHODS: Retrospective cohort study in four English paediatric intensive care units (ICUs) (2003-2009, n = 33,485). We examined, via a competing risks model, whether risk (subhazard) for ICU mortality differed for children with DS, after adjusting for important confounders. RESULTS: DS patients exhibited lower disease severity at ICU admission but subsequently required a higher proportion of cardiovascular support, and similar renal support to non-DS patients. Children with DS (n = 1,278) had lower crude mortality than those without (4.2 versus 6.2 %, p = 0.003). This was not significant when expressed as standardized mortality ratio: 0.83 [95 % confidence interval (CI) 0.63-1.09] versus 0.90 (95 % CI 0.86-0.94). However, the competing risks model showed that mortality risk was influenced by length of ICU stay. At admission, DS patients exhibited a subhazard for mortality of 0.63 (95 % CI 0.46-0.85), which increased to 1.00 by day 10 of admission, and continued rising above that of non-DS children thereafter. CONCLUSIONS: Children with DS require a higher proportion of organ support than expected by disease severity at ICU admission. In addition, the mortality risk for children with DS is dependent upon length of ICU stay. These findings could reflect differences in case mix, but are also compatible with different response to critical illness in this group.

Death by acid rain: VAP or EXIT?

Ventilator-associated pneumonia (VAP) is a new (nosocomial) lower respiratory tract infection diagnosed in mechanically ventilated patients 48 or more hours after intubation. There is no gold standard for establishing the diagnosis and its pathogenesis is iatrogenic and multifactorial. Gastro-oesophageal reflux is common in mechanically ventilated children, but its role in VAP remains speculative. VAP is associated with increased mortality and morbidity, prolonged duration of ventilation and hospital stay, and escalated costs of hospitalisation. VAP 'bundles' are championed as the antidote.

Antibiotic-resistant bacteria and infection in children with cerebral palsy requiring mechanical ventilation.

INTRODUCTION: Severe and chronic illness can alter the bacterial flora carried in the oropharynx and gut. There are little data on the bacterial flora of children with chronic neurologic impairment. OBJECTIVES: To assess carriage of abnormal bacterial flora, antibiotic-resistant bacteria, infection, and mortality in children with cerebral palsy (CP) admitted for pediatric intensive care. DESIGN: Prospective observational single center cohort study. SETTING: Twenty-bed regional pediatric intensive care unit (PICU) in a university-affiliated tertiary referral children's hospital. PATIENTS: All children with an established diagnosis of CP admitted to PICU and ventilated for four or more days during a 6-yr period. MEASUREMENTS: Surveillance samples of throat and rectum were taken at admission to PICU and twice a week thereafter. Diagnostic samples were obtained on clinical indication. MAIN RESULTS: Fifty-three children with a total of 77 admissions were included. Most (90%) of the children with CP had moderate to severe functional limitations. Eighty-nine percent of the children with CP (47/53) carried abnormal bacterial flora/potential pathogens, most frequently Pseudomonas and Klebsiella species. Forty-seven percent (22/47) had antibiotic-resistant bacteria. Thirty-five children (66%) developed 86 infections during their PICU admission. Lower airways and blood were the two most commonly infected sites-Pseudomonas aeruginosa and coagulase-negative Staphylococci, the predominant infecting microorganisms. Sixty-five percent (56/86) of infections were primary endogenous infections, 21% (18/86) exogenous, and 9% (8/86) secondary endogenous. Carriage of abnormal bacterial flora, antibiotic-resistant bacteria, and infection rate was significantly higher than that of children of comparative age without CP ventilated for four or more days on PICU. Nine (17%) of the children with CP died in PICU and 4 of the deaths were infection related. CONCLUSIONS: In children with moderate to severe chronic neurologic impairment admitted to PICU, there is a high rate of carriage of abnormal bacteria/potential pathogens, antibiotic-resistant bacteria, and infection.

Think outside the box: extrapulmonary manifestations of severe respiratory syncytial virus infection.

Extrapulmonary effects of severe respiratory syncytial virus (RSV) infection are not uncommon. Dr Eisenhut's systematic review of extrapulmonary manifestations of severe RSV infection clearly demonstrates clinical consequences peripheral to the lung parenchyma. The extrapulmonary impact of RSV infection raises questions as to whether these are direct RSV effects (i.e., RSV infection of site-specific tissue), secondary to parenchymal lung disease and its causative respiratory failure, or the result of inflammatory mediators dispersed from the provoked respiratory epithelium.

The influence of hyperchloraemia on acid base interpretation in diabetic ketoacidosis.

OBJECTIVES: During the acute treatment of diabetic ketoacidosis we (a) determined the temporal incidence of hyperchloraemia, and (b) quantified the influence of hyperchloraemia on interpretation of common blood gas derived acid base parameters, namely base deficit and bicarbonate. DESIGN AND SETTING: Retrospective chart review in two regional paediatric intensive care units. MEASUREMENTS AND RESULTS: Stewart's physicochemical theory was used to develop regression equations quantifying the acidifying effect of hyperchloraemia on both base deficit and bicarbonate. These were then applied retrospectively to blood chemistry results from 18 children (median age 12.7 years, weight 43 kg) with diabetic ketoacidosis. Plasma ketonaemia was estimated using the albumin-corrected anion gap. The incidence of hyperchloraemia, as documented by a ratio of plasma chloride to sodium of greater than 0.79, increased from 6% at admission to 94% after 20 h of treatment. Correction for chloride produced a dramatic improvement in the relationship between changes in the anion gap vs. both base deficit (from R(2)=0.55 to R(2)=0.95) and bicarbonate (from R(2)=0.51 to R(2)=0.96) during treatment. After 20 h of treatment the mean base deficit had decreased from 24.7 mmol/l to 10.0 mmol/l however, the proportion that was due to hyperchloraemia increased from 2% to 98%. CONCLUSIONS: It is now possible using a simple correction factor to quantify the confounding effect of hyperchloraemia on both base deficit and bicarbonate in diabetic ketoacidosis. This bedside tool may be a useful adjunct to guide therapeutic interventions.

High mortality of invasive pneumococcal disease compared with meningococcal disease in critically ill children.

OBJECTIVE: To ascertain outcome, patterns of disease, incidence of concurrent infection, superinfection and penicillin resistance in children requiring intensive care for Streptococcus pneumoniae infection and compare it to a similar disease pattern, namely Neisseria meningitidis b infection. DESIGN AND SETTING: Prospective cohort study in a regional paediatric intensive care unit (PICU). PATIENTS AND PARTICIPANTS: Children with invasive pneumococcal and meningococcal disease requiring intensive care. MEASUREMENTS AND RESULTS: The study included 22 children with invasive pneumococcal disease (IPD), median age 14 months (interquartile range 3-52), median Paediatric Index of Mortality (PIM) 0.051 (0.028-0.066), median length of PICU stay 8.5 days (4-13). Four patients died, three (13.5%) attributable to IPD. Incidence of concurrent infection 27%. There were no superinfections. All S. pneumoniae were sensitive to cefotaxime; one isolate (3.7%) was resistant to penicillin. There were 186 children with meningococcal disease (MD), with a higher PIM (median 0.068, 0.033-0.108), older age (29 months, 10.7-77.9) and shorter length of PICU stay (median 3 days, 2-6). Eight (4.3%) children died from MD. Incidence of concurrent and superinfection was 18% and 6%, respectively in children with MD. All N. meningitidis cases were sensitive to cefotaxime and penicillin. The standardized mortality ratio was considerably higher with IPD (2.0) than with MD (0.52). CONCLUSIONS: In invasive pneumococcal disease preventative measures including early recognition, immediate antibiotic therapy and vaccination need to be taken in the community, similar to the control of meningococcal disease. Invasive pneumococcal disease should command the same respect as meningococcal disease.