Bilateral remote ischemic conditioning in children: A two-center, double-blind, randomized controlled trial in young children undergoing cardiac surgery.

Objective: The study objective was to determine whether adequately delivered bilateral remote ischemic preconditioning is cardioprotective in young children undergoing surgery for 2 common congenital heart defects with or without cyanosis. Methods: We performed a prospective, double-blind, randomized controlled trial at 2 centers in the United Kingdom. Children aged 3 to 36 months undergoing tetralogy of Fallot repair or ventricular septal defect closure were randomized 1:1 to receive bilateral preconditioning or sham intervention. Participants were followed up until hospital discharge or 30 days. The primary outcome was area under the curve for high-sensitivity troponin-T in the first 24 hours after surgery, analyzed by intention-to-treat. Right atrial biopsies were obtained in selected participants. Results: Between October 2016 and December 2020, 120 eligible children were randomized to receive bilateral preconditioning (n = 60) or sham intervention (n = 60). The primary outcome, area under the curve for high-sensitivity troponin-T, was higher in the preconditioning group (mean: 70.0 ± 50.9 µg/L/h, n = 56) than in controls (mean: 55.6 ± 30.1 µg/L/h, n = 58) (mean difference, 13.2 µg/L/h; 95% CI, 0.5-25.8; P = .04). Subgroup analyses did not show a differential treatment effect by oxygen saturations (pinteraction = .25), but there was evidence of a differential effect by underlying defect (pinteraction = .04). Secondary outcomes and myocardial metabolism, quantified in atrial biopsies, were not different between randomized groups. Conclusions: Bilateral remote ischemic preconditioning does not attenuate myocardial injury in children undergoing surgical repair for congenital heart defects, and there was evidence of potential harm in unstented tetralogy of Fallot. The routine use of remote ischemic preconditioning cannot be recommended for myocardial protection during pediatric cardiac surgery.

Implementing early rehabilitation and mobilisation for children in UK paediatric intensive care units: the PERMIT feasibility study.

Background: Early rehabilitation and mobilisation encompass patient-tailored interventions, delivered within intensive care, but there are few studies in children and young people within paediatric intensive care units. Objectives: To explore how healthcare professionals currently practise early rehabilitation and mobilisation using qualitative and quantitative approaches; co-design the Paediatric Early Rehabilitation and Mobilisation during InTensive care manual of early rehabilitation and mobilisation interventions, with primary and secondary patient-centred outcomes; explore feasibility and acceptability of implementing the Paediatric Early Rehabilitation and Mobilisation during InTensive care manual within three paediatric intensive care units. Design: Mixed-methods feasibility with five interlinked studies (scoping review, survey, observational study, codesign workshops, feasibility study) in three phases. Setting: United Kingdom paediatric intensive care units. Participants: Children and young people aged 0-16 years remaining within paediatric intensive care on day 3, their parents/guardians and healthcare professionals. Interventions: In Phase 3, unit-wide implementation of manualised early rehabilitation and mobilisation. Main outcome measures: Phase 1 observational study: prevalence of any early rehabilitation and mobilisation on day 3. Phase 3 feasibility study: acceptability of early rehabilitation and mobilisation intervention; adverse events; acceptability of study design; acceptability of outcome measures. Data sources: Searched Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature, MEDLINE, PEDro, Open grey and Cochrane CENTRAL databases. Review methods: Narrative synthesis. Results: In the scoping review we identified 36 full-text reports evaluating rehabilitation initiated within 7 days of paediatric intensive care unit admission, outlining non-mobility and mobility early rehabilitation and mobilisation interventions from 24 to 72 hours and delivered twice daily. With the survey, 124/191 (65%) responded from 26/29 (90%) United Kingdom paediatric intensive care units; the majority considered early rehabilitation and mobilisation a priority. The observational study followed 169 patients from 15 units; prevalence of any early rehabilitation and mobilisation on day 3 was 95.3%. We then developed a manualised early rehabilitation and mobilisation intervention informed by current evidence, experience and theory. All three sites implemented the Paediatric Early Rehabilitation and Mobilisation during InTensive care manual successfully, recruited to target (30 patients recruited) and followed up the patients until day 30 or discharge; 21/30 parents consented to complete additional outcome measures. Limitations: The findings represent the views of National Health Service staff but may not be generalisable. We were unable to conduct workshops and interviews with children, young people and parents to support the Paediatric Early Rehabilitation and Mobilisation during InTensive care manual development due to pandemic restrictions. Conclusions: A randomised controlled trial is recommended to assess the effectiveness of the manualised early rehabilitation and mobilisation intervention. Future work: A definitive cluster randomised trial of early rehabilitation and mobilisation in paediatric intensive care requires selection of outcome measure and health economic evaluation. Study registration: The study is registered as PROSPERO CRD42019151050. The Phase 1 observational study is registered Clinicaltrials.gov NCT04110938 (Phase 1) (registered 1 October 2019) and the Phase 3 feasibility study is registered NCT04909762 (Phase 3) (registered 2 June 2021). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/21/06) and is published in full in Health Technology Assessment; Vol. 27, No. 27. See the NIHR Funding and Awards website for further award information.

Early rehabilitation and mobilisation, within the first week of intensive care admission, can improve the speed of recovery from illness or injury in adults. However, there is a lack of evidence about whether critically unwell children benefit from early rehabilitation and mobilisation. We aimed to identify which patients may benefit from early rehabilitation and mobilisation. Also, to develop and test a manual of early rehabilitation and mobilisation using the best evidence and expertise ­ called the Paediatric Early Rehabilitation and Mobilisation during InTensive care manual. Then evaluate whether the manual could be implemented safely in paediatric intensive care units and was acceptable to staff and families. We undertook in respect of early rehabilitation and mobilisation: review of existing research; national survey of practice (124 staff); gathered information about current conduct (15 paediatric intensive care units, 169 patients); spoke to experts (18 people); developed the Paediatric Early Rehabilitation and Mobilisation during InTensive care manual to guide paediatric intensive care unit staff; Tested the Paediatric Early Rehabilitation and Mobilisation during InTensive care manual in three paediatric intensive care units with 30 patients; gathered feedback from healthcare professionals via weekly 'debriefs' (47), interviews (13) and surveys (118), and from parents via parent-completed questionnaires (21) and interviews (14). Despite being regarded as important, currently early rehabilitation and mobilisation practice is inconsistent, not considered 'early' enough and often focuses on low-risk activities conducted on the bed. Introducing the Paediatric Early Rehabilitation and Mobilisation during InTensive care manual as part of a trial was acceptable and feasible and helps standardise delivery to unwell children. Measuring child and parent reported outcomes was acceptable but follow-up at 30 days was incomplete. A larger trial of early rehabilitation and mobilisation, involving more paediatric intensive care units, is feasible and required to demonstrate benefit to children.

Feasibility of non-invasive neuro-monitoring during extracorporeal membrane oxygenation in children.

INTRODUCTION: Detection of neurological complications during extracorporeal membrane oxygenation (ECMO) may be enhanced with non-invasive neuro-monitoring. We investigated the feasibility of non-invasive neuro-monitoring in a paediatric intensive care (PIC) setting. METHODS: In a single centre, prospective cohort study we assessed feasibility of recruitment, and neuro-monitoring via somatosensory evoked potentials (SSEP), electroencephalography (EEG) and near infrared spectroscopy (NIRS) during venoarterial (VA) ECMO in paediatric patients (0-15 years). Measures were obtained within 24h of cannulation, during an intermediate period, and finally at decannulation or echo stress testing. SSEP/EEG/NIRS measures were correlated with neuro-radiology findings, and clinical outcome assessed via the Pediatric cerebral performance category (PCPC) scale 30 days post ECMO cannulation. RESULTS: We recruited 14/20 (70%) eligible patients (median age: 9 months; IQR:4-54, 57% male) over an 18-month period, resulting in a total of 42 possible SSEP/EEG/NIRS measurements. Of these, 32/42 (76%) were completed. Missed recordings were due to lack of access/consent within 24 h of cannulation (5/42, 12%) or PIC death/discharge (5/42, 12%). In each patient, the majority of SSEP (8/14, 57%), EEG (8/14, 57%) and NIRS (11/14, 79%) test results were within normal limits. All patients with abnormal neuroradiology (4/10, 40%), and 6/7 (86%) with poor outcome (PCPC ≥4) developed indirect SSEP, EEG or NIRS measures of neurological complications prior to decannulation. No study-related adverse events or neuro-monitoring data interpreting issues were experienced. CONCLUSION: Non-invasive neuro-monitoring (SSEP/EEG/NIRS) during ECMO is feasible and may provide early indication of neurological complications in this high-risk population.

Early mobilisation and rehabilitation in the PICU: a UK survey.

OBJECTIVE: To understand the context and professional perspectives of delivering early rehabilitation and mobilisation (ERM) within UK paediatric intensive care units (PICUs). DESIGN: A web-based survey administered from May 2019 to August 2019. SETTING: UK PICUs. PARTICIPANTS: A total of 124 staff from 26 PICUs participated, including 22 (18%) doctors, 34 (27%) nurses, 28 (23%) physiotherapists, 19 (15%) occupational therapists and 21 (17%) were other professionals. RESULTS: Key components of participants' definitions of ERM included tailored, multidisciplinary rehabilitation packages focused on promoting recovery. Multidisciplinary involvement in initiating ERM was commonly reported. Over half of respondents favoured delivering ERM after achieving physiological stability (n=69, 56%). All age groups were considered for ERM by relevant health professionals. However, responses differed concerning the timing of initiation. Interventions considered for ERM were more likely to be delivered to patients when PICU length of stay exceeded 28 days and among patients with acquired brain injury or severe developmental delay. The most commonly identified barriers were physiological instability (81%), limited staffing (79%), sedation requirement (73%), insufficient resources and equipment (69%), lack of recognition of patient readiness (67%), patient suitability (63%), inadequate training (61%) and inadequate funding (60%). Respondents ranked reduction in PICU length of stay (74%) and improvement in psychological outcomes (73%) as the most important benefits of ERM. CONCLUSION: ERM is gaining familiarity and endorsement in UK PICUs, but significant barriers to implementation due to limited resources and variation in content and delivery of ERM persist. A standardised protocol that sets out defined ERM interventions, along with implementation support to tackle modifiable barriers, is required to ensure the delivery of high-quality ERM.

Comparative Effectiveness of Diversion of Cerebrospinal Fluid for Children With Severe Traumatic Brain Injury.

Importance: Diversion of cerebrospinal fluid (CSF) has been used for decades as a treatment for children with severe traumatic brain injury (TBI) and is recommended by evidenced-based guidelines. However, these recommendations are based on limited studies. Objective: To determine whether CSF diversion is associated with improved Glasgow Outcome Score-Extended for Pediatrics (GOS-EP) and decreased intracranial pressure (ICP) in children with severe TBI. Design, Setting, and Participants: This observational comparative effectiveness study was performed at 51 clinical centers that routinely care for children with severe TBI in 8 countries (US, United Kingdom, Spain, the Netherlands, Australia, New Zealand, South Africa, and India) from February 2014 to September 2017, with follow-up at 6 months after injury (final follow-up, October 22, 2021). Children with severe TBI were included if they had Glasgow Coma Scale (GCS) scores of 8 or lower, had intracranial pressure (ICP) monitor placed on-site, and were aged younger than 18 years. Children were excluded if they were pregnant or an ICP monitor was not placed at the study site. Consecutive children were screened and enrolled, data regarding treatments were collected, and at discharge, consent was obtained for outcomes testing. Propensity matching for pretreatment characteristics was performed to develop matched pairs for primary analysis. Data analyses were completed on April 18, 2022. Exposures: Clinical care followed local standards, including the use of CSF diversion (or not), with patients stratified at the time of ICP monitor placement (CSF group vs no CSF group). Main Outcomes and Measures: The primary outcome was GOS-EP at 6 months, while ICP was considered as a secondary outcome. CSF vs no CSF was treated as an intention-to-treat analysis, and a sensitivity analysis was performed for children who received delayed CSF diversion. Results: A total of 1000 children with TBI were enrolled, including 314 who received CSF diversion (mean [SD] age, 7.18 [5.45] years; 208 [66.2%] boys) and 686 who did not (mean [SD] age, 7.79 [5.33] years; 437 [63.7%] boys). The propensity-matched analysis included 98 pairs. In propensity score-matched analyses, there was no difference between groups in GOS-EP (median [IQR] difference, 0 [-3 to 1]; P = .08), but there was a decrease in overall ICP in the CSF group (mean [SD] difference, 3.97 [0.12] mm Hg; P < .001). Conclusions and Relevance: In this comparative effectiveness study, CSF diversion was not associated with improved outcome at 6 months after TBI, but a decrease in ICP was observed. Given the higher quality of evidence generated by this study, current evidence-based guidelines related to CSF diversion should be reconsidered.

Effect of High-Flow Nasal Cannula Therapy vs Continuous Positive Airway Pressure Therapy on Liberation From Respiratory Support in Acutely Ill Children Admitted to Pediatric Critical Care Units: A Randomized Clinical Trial.

Importance: The optimal first-line mode of noninvasive respiratory support for acutely ill children is not known. Objective: To evaluate the noninferiority of high-flow nasal cannula therapy (HFNC) as the first-line mode of noninvasive respiratory support for acute illness, compared with continuous positive airway pressure (CPAP), for time to liberation from all forms of respiratory support. Design, Setting, and Participants: Pragmatic, multicenter, randomized noninferiority clinical trial conducted in 24 pediatric critical care units in the United Kingdom among 600 acutely ill children aged 0 to 15 years who were clinically assessed to require noninvasive respiratory support, recruited between August 2019 and November 2021, with last follow-up completed in March 2022. Interventions: Patients were randomized 1:1 to commence either HFNC at a flow rate based on patient weight (n = 301) or CPAP of 7 to 8 cm H2O (n = 299). Main Outcomes and Measures: The primary outcome was time from randomization to liberation from respiratory support, defined as the start of a 48-hour period during which a participant was free from all forms of respiratory support (invasive or noninvasive), assessed against a noninferiority margin of an adjusted hazard ratio of 0.75. Seven secondary outcomes were assessed, including mortality at critical care unit discharge, intubation within 48 hours, and use of sedation. Results: Of the 600 randomized children, consent was not obtained for 5 (HFNC: 1; CPAP: 4) and respiratory support was not started in 22 (HFNC: 5; CPAP: 17); 573 children (HFNC: 295; CPAP: 278) were included in the primary analysis (median age, 9 months; 226 girls [39%]). The median time to liberation in the HFNC group was 52.9 hours (95% CI, 46.0-60.9 hours) vs 47.9 hours (95% CI, 40.5-55.7 hours) in the CPAP group (absolute difference, 5.0 hours [95% CI -10.1 to 17.4 hours]; adjusted hazard ratio 1.03 [1-sided 97.5% CI, 0.86-∞]). This met the criterion for noninferiority. Of the 7 prespecified secondary outcomes, 3 were significantly lower in the HFNC group: use of sedation (27.7% vs 37%; adjusted odds ratio, 0.59 [95% CI, 0.39-0.88]); mean duration of critical care stay (5 days vs 7.4 days; adjusted mean difference, -3 days [95% CI, -5.1 to -1 days]); and mean duration of acute hospital stay (13.8 days vs 19.5 days; adjusted mean difference, -7.6 days [95% CI, -13.2 to -1.9 days]). The most common adverse event was nasal trauma (HFNC: 6/295 [2.0%]; CPAP: 18/278 [6.5%]). Conclusions and Relevance: Among acutely ill children clinically assessed to require noninvasive respiratory support in a pediatric critical care unit, HFNC compared with CPAP met the criterion for noninferiority for time to liberation from respiratory support. Trial Registration: ISRCTN.org Identifier: ISRCTN60048867.

Effect of High-Flow Nasal Cannula Therapy vs Continuous Positive Airway Pressure Following Extubation on Liberation From Respiratory Support in Critically Ill Children: A Randomized Clinical Trial.

Importance: The optimal first-line mode of noninvasive respiratory support following extubation of critically ill children is not known. Objective: To evaluate the noninferiority of high-flow nasal cannula (HFNC) therapy as the first-line mode of noninvasive respiratory support following extubation, compared with continuous positive airway pressure (CPAP), on time to liberation from respiratory support. Design, Setting, and Participants: This was a pragmatic, multicenter, randomized, noninferiority trial conducted at 22 pediatric intensive care units in the United Kingdom. Six hundred children aged 0 to 15 years clinically assessed to require noninvasive respiratory support within 72 hours of extubation were recruited between August 8, 2019, and May 18, 2020, with last follow-up completed on November 22, 2020. Interventions: Patients were randomized 1:1 to start either HFNC at a flow rate based on patient weight (n = 299) or CPAP of 7 to 8 cm H2O (n = 301). Main Outcomes and Measures: The primary outcome was time from randomization to liberation from respiratory support, defined as the start of a 48-hour period during which the child was free from all forms of respiratory support (invasive or noninvasive), assessed against a noninferiority margin of an adjusted hazard ratio (HR) of 0.75. There were 6 secondary outcomes, including mortality at day 180 and reintubation within 48 hours. Results: Of the 600 children who were randomized, 553 children (HFNC, 281; CPAP, 272) were included in the primary analysis (median age, 3 months; 241 girls [44%]). HFNC failed to meet noninferiority, with a median time to liberation of 50.5 hours (95% CI, 43.0-67.9) vs 42.9 hours (95% CI, 30.5-48.2) for CPAP (adjusted HR, 0.83; 1-sided 97.5% CI, 0.70-∞). Similar results were seen across prespecified subgroups. Of the 6 prespecified secondary outcomes, 5 showed no significant difference, including the rate of reintubation within 48 hours (13.3% for HFNC vs 11.5 % for CPAP). Mortality at day 180 was significantly higher for HFNC (5.6% vs 2.4% for CPAP; adjusted odds ratio, 3.07 [95% CI, 1.1-8.8]). The most common adverse events were abdominal distension (HFNC: 8/281 [2.8%] vs CPAP: 7/272 [2.6%]) and nasal/facial trauma (HFNC: 14/281 [5.0%] vs CPAP: 15/272 [5.5%]). Conclusions and Relevance: Among critically ill children requiring noninvasive respiratory support following extubation, HFNC compared with CPAP following extubation failed to meet the criterion for noninferiority for time to liberation from respiratory support. Trial Registration: isrctn.org Identifier: ISRCTN60048867.

Co-ordinated multidisciplinary intervention to reduce time to successful extubation for children on mechanical ventilation: the SANDWICH cluster stepped-wedge RCT.

BACKGROUND: Daily assessment of patient readiness for liberation from invasive mechanical ventilation can reduce the duration of ventilation. However, there is uncertainty about the effectiveness of this in a paediatric population. OBJECTIVES: To determine the effect of a ventilation liberation intervention in critically ill children who are anticipated to have a prolonged duration of mechanical ventilation (primary objective) and in all children (secondary objective). DESIGN: A pragmatic, stepped-wedge, cluster randomised trial with economic and process evaluations. SETTING: Paediatric intensive care units in the UK. PARTICIPANTS: Invasively mechanically ventilated children (aged < 16 years). INTERVENTIONS: The intervention incorporated co-ordinated multidisciplinary care, patient-relevant sedation plans linked to sedation assessment, assessment of ventilation parameters with a higher than usual trigger for undertaking an extubation readiness test and a spontaneous breathing trial on low levels of respiratory support to test extubation readiness. The comparator was usual care. Hospital sites were randomised sequentially to transition from control to intervention and were non-blinded. MAIN OUTCOME MEASURES: The primary outcome measure was the duration of invasive mechanical ventilation until the first successful extubation. The secondary outcome measures were successful extubation, unplanned extubation and reintubation, post-extubation use of non-invasive ventilation, tracheostomy, post-extubation stridor, adverse events, length of intensive care and hospital stay, mortality and cost per respiratory complication avoided at 28 days. RESULTS: The trial included 10,495 patient admissions from 18 paediatric intensive care units from 5 February 2018 to 14 October 2019. In children with anticipated prolonged ventilation (n = 8843 admissions: control, n = 4155; intervention, n = 4688), the intervention resulted in a significantly shorter time to successful extubation [cluster and time-adjusted median difference -6.1 hours (interquartile range -8.2 to -5.3 hours); adjusted hazard ratio 1.11, 95% confidence interval 1.02 to 1.20; p = 0.02] and a higher incidence of successful extubation (adjusted relative risk 1.01, 95% confidence interval 1.00 to 1.02; p = 0.03) and unplanned extubation (adjusted relative risk 1.62, 95% confidence interval 1.05 to 2.51; p = 0.03), but not reintubation (adjusted relative risk 1.10, 95% confidence interval 0.89 to 1.36; p = 0.38). In the intervention period, the use of post-extubation non-invasive ventilation was significantly higher (adjusted relative risk 1.22, 95% confidence interval 1.01 to 1.49; p = 0.04), with no evidence of a difference in intensive care length of stay or other harms, but hospital length of stay was longer (adjusted hazard ratio 0.89, 95% confidence interval 0.81 to 0.97; p = 0.01). Findings for all children were broadly similar. The control period was associated with lower, but not statistically significantly lower, total costs (cost difference, mean £929.05, 95% confidence interval -£516.54 to £2374.64) and significantly fewer respiratory complications avoided (mean difference -0.10, 95% confidence interval -0.16 to -0.03). LIMITATIONS: The unblinded intervention assignment may have resulted in performance or detection bias. It was not possible to determine which components were primarily responsible for the observed effect. Treatment effect in a more homogeneous group remains to be determined. CONCLUSIONS: The intervention resulted in a statistically significant small reduction in time to first successful extubation; thus, the clinical importance of the effect size is uncertain. FUTURE WORK: Future work should explore intervention sustainability and effects of the intervention in other paediatric populations. TRIAL REGISTRATION: This trial is registered as ISRCTN16998143. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 18. See the NIHR Journals Library website for further project information.

Mechanical ventilation is a life-saving therapy, but may involve related risks because of the breathing tube in the mouth and throat, the sedative drugs required to reduce anxiety and remaining confined to bed. Therefore, getting off the ventilator (called weaning) is an important patient outcome. Previous studies have shown that an organised approach involving nurses, doctors and physiotherapists reduces the time that patients spend on the ventilator. Our study involved more than 10,000 patients admitted to 18 children's intensive care units. We tested a co-ordinated staff approach for managing a child's sedation and ventilator needs against usual care, which was mainly consultant led and did not involve bedside nurses. We wanted to find out if this approach improved the outcomes for children and did not cause additional harm. We first collected information in the intensive care units when children were weaned from the ventilator using usual care. Following staff training in the new approach, we compared children's outcomes between the two approaches. Compared with usual care, the new approach reduced the time that children spent on the ventilator by between 5 and 9 hours, and increased children's chances of having their breathing tube removed successfully. Some children pulled out their breathing tubes themselves before it was medically planned to do so. This happened more with the new approach, but the chance of needing the breathing tube put back in was not different from usual care. With the new approach, more children needed to use a mask ventilator than those receiving usual care, although the length of time that this was required was not different from usual care. The intensive care length of stay was the same for children receiving the new approach and usual care. However, with the new approach, children stayed in hospital 1 day longer, which resulted in higher costs (£715 per child); thus, the clinical relevance is uncertain.

Lactate, Base Excess, and the Pediatric Index of Mortality: Exploratory Study of an International, Multicenter Dataset.

OBJECTIVES: To investigate the relationship between ICU admission blood lactate, base excess, and ICU mortality and to explore the effect of incorporating blood lactate into the Pediatric Index of Mortality. DESIGN: Retrospective cohort study based on data prospectively collected on every PICU admission submitted to the U.K. Pediatric Intensive Care Audit Network and to the Australia and New Zealand Pediatric Intensive Care Registry. SETTING: Thirty-three PICUs in the United Kingdom/Republic of Ireland and nine PICUs and 20 general ICUs in Australia and New Zealand. PATIENTS: All ICU admissions between January 1, 2012, and December 31, 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred twenty-three thousand two hundred fifty-two admissions were recorded in both datasets; 81,576 (66.2%) in the United Kingdom/Republic of Ireland and 41,676 (33.8%) in Australia and New Zealand. Of these 75,070 (61%) had a base excess recorded, 63,316 (51%) had a lactate recorded, and 60,876 (49%) had both base excess and lactate recorded. Median lactate value was 1.5 mmol/L (interquartile range, 1-2.4 mmol/L) (United Kingdom/Republic of Ireland: 1.5 [1-2.5]; Australia and New Zealand: 1.4 [1-2.3]). Children with a lactate recorded had a higher illness severity, were more likely to be invasively ventilated, admitted after cardiac surgery, and had a higher mortality rate, compared with admissions with no lactate recorded (p < 0.001). The relationship between lactate and mortality was stronger (odds ratio, 1.32; 95% CI, 1.31-1.34) than between absolute base excess and mortality (odds ratio, 1.13; 95% CI, 1.12-1.14). Addition of lactate to the Pediatric Index of Mortality score led to a small improvement in performance over addition of absolute base excess, whereas adding both lactate and absolute base excess achieved the best performance. CONCLUSIONS: At PICU admission, blood lactate is more strongly associated with ICU mortality than absolute base excess. Adding lactate into the Pediatric Index of Mortality model may result in a small improvement in performance. Any improvement in Pediatric Index of Mortality performance must be balanced against the added burden of data capture when considering potential incorporation into the Pediatric Index of Mortality model.

Effect of a Sedation and Ventilator Liberation Protocol vs Usual Care on Duration of Invasive Mechanical Ventilation in Pediatric Intensive Care Units: A Randomized Clinical Trial.

Importance: There is limited evidence on the optimal strategy for liberating infants and children from invasive mechanical ventilation in the pediatric intensive care unit. Objective: To determine if a sedation and ventilator liberation protocol intervention reduces the duration of invasive mechanical ventilation in infants and children anticipated to require prolonged mechanical ventilation. Design, Setting, and Participants: A pragmatic multicenter, stepped-wedge, cluster randomized clinical trial was conducted that included 17 hospital sites (18 pediatric intensive care units) in the UK sequentially randomized from usual care to the protocol intervention. From February 2018 to October 2019, 8843 critically ill infants and children anticipated to require prolonged mechanical ventilation were recruited. The last date of follow-up was November 11, 2019. Interventions: Pediatric intensive care units provided usual care (n = 4155 infants and children) or a sedation and ventilator liberation protocol intervention (n = 4688 infants and children) that consisted of assessment of sedation level, daily screening for readiness to undertake a spontaneous breathing trial, a spontaneous breathing trial to test ventilator liberation potential, and daily rounds to review sedation and readiness screening and set patient-relevant targets. Main Outcomes and Measures: The primary outcome was the duration of invasive mechanical ventilation from initiation of ventilation until the first successful extubation. The primary estimate of the treatment effect was a hazard ratio (with a 95% CI) adjusted for calendar time and cluster (hospital site) for infants and children anticipated to require prolonged mechanical ventilation. Results: There were a total of 8843 infants and children (median age, 8 months [interquartile range, 1 to 46 months]; 42% were female) who completed the trial. There was a significantly shorter median time to successful extubation for the protocol intervention compared with usual care (64.8 hours vs 66.2 hours, respectively; adjusted median difference, -6.1 hours [interquartile range, -8.2 to -5.3 hours]; adjusted hazard ratio, 1.11 [95% CI, 1.02 to 1.20], P = .02). The serious adverse event of hypoxia occurred in 9 (0.2%) infants and children for the protocol intervention vs 11 (0.3%) for usual care; nonvascular device dislodgement occurred in 2 (0.04%) vs 7 (0.1%), respectively. Conclusions and Relevance: Among infants and children anticipated to require prolonged mechanical ventilation, a sedation and ventilator liberation protocol intervention compared with usual care resulted in a statistically significant reduction in time to first successful extubation. However, the clinical importance of the effect size is uncertain. Trial Registration: isrctn.org Identifier: ISRCTN16998143.

Reliability in the assessment of paediatric somatosensory evoked potentials post cardiac arrest.

OBJECTIVE: To measure inter- and intra-rater agreement in the interpretation of cortical somatosensory evoked potential (SSEP) components following paediatric cardiac arrest (CA) in multi-professional neurophysiology teams. METHODS: Thirteen professionals blinded to patient outcome interpreted 96 SSEPs in paediatric patients 24-/48-/72-hours following CA. Of these, 34 were duplicates used to assess intra-rater agreement. Consistent interpretations (absent/present/indeterminate) between scientists (who record/identify SSEP components) and neurophysiologists (who provide prognostic SSEP interpretation) were expressed as percentages. Rates of agreement were calculated using Fleiss' kappa coefficient (K). RESULTS: Unanimous agreement between professionals was present in 40% (95%CI: 28-54%) of the interpreted SSEPs, with a K value of 0.62 (95%CI: 0.55-0.70) based on average agreement. Agreement was similar between neurophysiologists (K = 0.67; 95%CI: 0.57-0.77) and scientists (K = 0.62; 95%CI: 0.54-0.70) but lower in patients < 2 years old (K = 0.23; 95%CI: 0.14-0.33) and in those with poor outcome (K = 0.21; 95%CI: 0.07-0.35). No SSEP was unanimously interpreted as absent and 92% (95%CI: 89-95%) of duplicate SSEPs were interpreted consistently. CONCLUSION: Despite substantial agreement when interpreting prognostic SSEPs, this was significantly lower in children with poor outcome and of younger age. SIGNIFICANCE: Clinicians using SSEPs in the intensive care unit should be aware of the inter-rater variability when interpreting SSEPs as absent.

The Prognostic Value of Somatosensory Evoked Potentials in Children After Cardiac Arrest: The SEPIA Study.

PURPOSE: Absent cortical somatosensory evoked potentials (SSEPs) reliably predict poor neurologic outcome in adults after cardiac arrest (CA). However, there is less evidence to support this in children. In addition, targeted temperature management, test timing, and a lack of blinding may affect test accuracy. METHODS: A single-center, prospective cohort study of pediatric (aged 24 hours to 15 years) patients in which prognostic value of SSEPs were assessed 24, 48, and 72 hours after CA. Targeted temperature management (33-34°C for 24 hours) followed by gradual rewarming to 37°C was used. Somatosensory evoked potentials were graded as present, absent, or indeterminate, and results were blinded to clinicians. Neurologic outcome was graded as "good" (score 1-3) or "poor" (4-6) using the Pediatric Cerebral Performance Category scale 30 days after CA and blinded to SSEP interpreter. RESULTS: Twelve patients (median age, 12 months; interquartile range, 2-150; 92% male) had SSEPs interpreted as absent (6/12) or present (6/12) <72 hours after CA. Outcome was good in 7 of 12 patients (58%) and poor in 5 of 12 patients (42%). Absent SSEPs predicted poor outcome with 88% specificity (95% confidence interval, 53% to 98%). One patient with an absent SSEP had good outcome (Pediatric Cerebral Performance Category 3), and all patients with present SSEPs had good outcome (specificity 100%; 95% confidence interval, 51% to 100%). Absence or presence of SSEP was consistent across 24-hour (temperature = 34°C), 48-hour (t = 36°C), and 72-hour (t = 36°C) recordings after CA. CONCLUSIONS: Results support SSEP utility when predicting favorable outcome; however, predictions resulting in withdrawal of life support should be made with caution and never in isolation because in this very small sample there was a false prediction of unfavorable outcome. Further prospective, blinded studies are needed and encouraged.

Traumatic Brain Injury Practice Guidelines: Variability in U.K. PICUs.

OBJECTIVES: Traumatic brain injury in children is a leading cause of morbidity and mortality. Lack of high-quality evidence may lead to variation in management within and between PICUs. We examined U.K. pediatric traumatic brain injury management guidelines for extent of variability. DESIGN: Analysis of U.K. PICU traumatic brain injury guidelines for areas of consistency and variation among each other and against the second edition of Brain Trauma Foundation pediatric traumatic brain injury guidelines. SETTING: Not applicable. SUBJECTS: Not applicable. INTERVENTIONS: Textual analysis of U.K. PICU guidelines. MEASUREMENTS AND MAIN RESULTS: Twelve key clinical topics in three traumatic brain injury management domains were identified. We performed textual analysis of recommendations from anonymized local guidelines and compared them against each other and the Brain Trauma Foundation pediatric traumatic brain injury guidelines. Fifteen guidelines used by 16 of the 20 U.K. PICUs that manage traumatic brain injury were analyzed. Relatively better consistency was observed for intracranial pressure treatment thresholds (10/15), avoiding prophylactic hyperventilation (15/15), cerebrospinal fluid drainage (13/15), barbiturate (14/15), and decompressive craniectomy (12/15) for intracranial hypertension. There was less consistency in indications for intracranial pressure monitoring (3/15), cerebral perfusion pressure targets (2/15), target osmolarities (7/15), and hyperventilation for intracranial hypertension (2/15). Variability in choice and hierarchy of the interventions for intracranial hypertension were observed, albeit with some points of consistency. CONCLUSIONS: Significant variability in pediatric traumatic brain injury management guidelines exists. Despite the heterogeneity, we have highlighted a few points of consistency within the key topic areas of pediatric traumatic brain injury management. We anticipate that this provides impetus for further work around standardization.

First-line support for assistance in breathing in children: statistical and health economic analysis plan for the FIRST-ABC trial.

BACKGROUND: The FIRST-ABC trial comprises of two pragmatic, multicentre, parallel groups, non-inferiority randomised clinical trials designed to evaluate the clinical non-inferiority of first-line use of high flow nasal cannula (HFNC) to continuous positive airway pressure (CPAP) in critically ill children who require non-invasive respiratory support (NRS). OBJECTIVES: To describe the pre-specified statistical and health economic analysis for the FIRST-ABC trial before completion of patient recruitment and data collection. METHODS: The statistical analysis plan was designed by the chief investigators and statisticians. We define the primary and secondary outcomes, summarise methods for data collection and safety monitoring, and present a detailed description of the planned statistical and health economic analysis. RESULTS: The primary clinical outcome is time to liberation from respiratory support. The primary effect estimate will be the adjusted hazard ratio, reported with a 95% confidence interval. As a sensitivity analysis, the primary analysis will be repeated using time to start weaning of NRS. Subgroup analyses will be performed to test for interactions between the effect of allocated treatment group and pre-specified baseline covariates. The health economic analysis will follow the intention-to-treat principle and report the mean (95% confidence interval) incremental costs, quality-adjusted life years (QALYs) and cost-effectiveness up to 6 months. All analyses will be performed separately for each of the two trials, and any results will not be combined. CONCLUSION: The FIRST-ABC trial will assess the non-inferiority of HFNC compared to CPAP in two parallel trials with shared infrastructure (step-up RCT and step-down RCT). We have developed a pre-specified statistical and health economics analysis plan for the FIRST-ABC study before trial completion to minimise analytical bias. TRIAL REGISTRATION: ISRCTN ISRCTN60048867 . Registered on 19 June 2019.

Bilateral Remote Ischaemic Conditioning in Children (BRICC) trial: protocol for a two-centre, double-blind, randomised controlled trial in young children undergoing cardiac surgery.

INTRODUCTION: Myocardial protection against ischaemic-reperfusion injury is a key determinant of heart function and outcome following cardiac surgery in children. However, with current strategies, myocardial injury occurs routinely following aortic cross-clamping, as demonstrated by the ubiquitous rise in circulating troponin. Remote ischaemic preconditioning, the application of brief, non-lethal cycles of ischaemia and reperfusion to a distant organ or tissue, is a simple, low-risk and readily available technique which may improve myocardial protection. The Bilateral Remote Ischaemic Conditioning in Children (BRICC) trial will assess whether remote ischaemic preconditioning, applied to both lower limbs immediately prior to surgery, reduces myocardial injury in cyanotic and acyanotic young children. METHODS AND ANALYSIS: The BRICC trial is a two-centre, double-blind, randomised controlled trial recruiting up to 120 young children (age 3 months to 3 years) undergoing primary repair of tetralogy of Fallot or surgical closure of an isolated ventricular septal defect. Participants will be randomised in a 1:1 ratio to either bilateral remote ischaemic preconditioning (3×5 min cycles) or sham immediately prior to surgery, with follow-up until discharge from hospital or 30 days, whichever is sooner. The primary outcome is reduction in area under the time-concentration curve for high-sensitivity (hs) troponin-T release in the first 24 hours after aortic cross-clamp release. Secondary outcome measures include peak hs-troponin-T, vasoactive inotrope score, arterial lactate and central venous oxygen saturations in the first 12 hours, and lengths of stay in the paediatric intensive care unit and the hospital. ETHICS AND DISSEMINATION: The trial was approved by the West Midlands-Solihull National Health Service Research Ethics Committee (16/WM/0309) on 5 August 2016. Findings will be disseminated to the academic community through peer-reviewed publications and presentation at national and international meetings. Parents will be informed of the results through a newsletter in conjunction with a local charity. TRIAL REGISTRATION NUMBER: ISRCTN12923441.

NEUROlogical Prognosis After Cardiac Arrest in Kids (NEUROPACK) study: protocol for a prospective multicentre clinical prediction model derivation and validation study in children after cardiac arrest.

INTRODUCTION: Currently, we are unable to accurately predict mortality or neurological morbidity following resuscitation after paediatric out of hospital (OHCA) or in-hospital (IHCA) cardiac arrest. A clinical prediction model may improve communication with parents and families and risk stratification of patients for appropriate postcardiac arrest care. This study aims to the derive and validate a clinical prediction model to predict, within 1 hour of admission to the paediatric intensive care unit (PICU), neurodevelopmental outcome at 3 months after paediatric cardiac arrest. METHODS AND ANALYSIS: A prospective study of children (age: >24 hours and <16 years), admitted to 1 of the 24 participating PICUs in the UK and Ireland, following an OHCA or IHCA. Patients are included if requiring more than 1 min of cardiopulmonary resuscitation and mechanical ventilation at PICU admission Children who had cardiac arrests in PICU or neonatal intensive care unit will be excluded. Candidate variables will be identified from data submitted to the Paediatric Intensive Care Audit Network registry. Primary outcome is neurodevelopmental status, assessed at 3 months by telephone interview using the Vineland Adaptive Behavioural Score II questionnaire. A clinical prediction model will be derived using logistic regression with model performance and accuracy assessment. External validation will be performed using the Therapeutic Hypothermia After Paediatric Cardiac Arrest trial dataset. We aim to identify 370 patients, with successful consent and follow-up of 150 patients. Patient inclusion started 1 January 2018 and inclusion will continue over 18 months. ETHICS AND DISSEMINATION: Ethical review of this protocol was completed by 27 September 2017 at the Wales Research Ethics Committee 5, 17/WA/0306. The results of this study will be published in peer-reviewed journals and presented in conferences. TRIAL REGISTRATION NUMBER: NCT03574025.

FIRST-line support for assistance in breathing in children (FIRST-ABC): a master protocol of two randomised trials to evaluate the non-inferiority of high-flow nasal cannula (HFNC) versus continuous positive airway pressure (CPAP) for non-invasive respiratory support in paediatric critical care.

INTRODUCTION: Even though respiratory support is a common intervention in paediatric critical care, there is no randomised controlled trial (RCT) evidence regarding the effectiveness of two commonly used modes of non-invasive respiratory support (NRS), continuous positive airway pressure (CPAP) and high-flow nasal cannula therapy (HFNC). FIRST-line support for assistance in breathing in children is a master protocol of two pragmatic non-inferiority RCTs to evaluate the clinical and cost-effectiveness of HFNC (compared with CPAP) as the first-line mode of support in critically ill children. METHODS AND ANALYSIS: We will recruit participants over a 30-month period at 25 UK paediatric critical care units (paediatric intensive care units/high-dependency units). Patients are eligible if admitted/accepted for admission, aged >36 weeks corrected gestational age and <16 years, and assessed by the treating clinician to require NRS for an acute illness (step-up RCT) or within 72 hours of extubation following a period of invasive ventilation (step-down RCT). Due to the emergency nature of the treatment, written informed consent will be deferred to after randomisation. Randomisation will occur 1:1 to CPAP or HFNC, stratified by site and age (<12 vs ≥12 months). The primary outcome is time to liberation from respiratory support for a continuous period of 48 hours. A total sample size of 600 patients in each RCT will provide 90% power with a type I error rate of 2.5% (one sided) to exclude the prespecified non-inferiority margin of HR of 0.75. Primary analyses will be undertaken separately in each RCT in both the intention-to-treat and per-protocol populations. ETHICS AND DISSEMINATION: This master protocol received favourable ethical opinion from National Health Service East of England-Cambridge South Research Ethics Committee (reference: 19/EE/0185) and approval from the Health Research Authority (reference: 260536). Results will be disseminated via publications in peer-reviewed medical journals and presentations at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN60048867.

Implementation and Early Evaluation of a Quantitative Electroencephalography Program for Seizure Detection in the PICU.

OBJECTIVES: To describe implementation and early evaluation of using quantitative electroencephalography for electrographic seizure detection by PICU clinician staff. DESIGN: Prospective observational study of electrographic seizure detection by PICU clinicians in patients monitored with quantitative electroencephalography. Quantitative electroencephalography program implementation included a continuous education and training package. Continuous quantitative electroencephalography monitoring consisted of two-channel amplitude-integrated electroencephalography, color density spectral array, and raw-electroencephalography. SETTING: PICU. PATIENTS: Children less than 18 years old admitted to the PICU during the 14-month study period and deemed at risk of electrographic seizure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Real time electrographic seizure detection by a PICU team was analyzed for diagnostic accuracy and promptness, against electrographic seizure identification by a trained neurophysiologist, retrospectively reading the same quantitative electroencephalography and blinded to patient details. One-hundred one of 1,510 consecutive admissions (6.7%) during the study period underwent quantitative electroencephalography monitoring. Status epilepticus (35%) and suspected hypoxic-ischemic injury (32%) were the most common indications for quantitative electroencephalography. Electrographic seizure was diagnosed by the neurophysiologist in 12% (n = 12) of the cohort. PICU clinicians correctly diagnosed all 12 patients (100% sensitivity and negative predictive value). An additional eleven patients had a false-positive diagnosis of electrographic seizure (false-positive rate = 52% [31-73%]) leading to a specificity of 88% (79-94%). Median time to detect seizures was 25 minutes (5-218 min). Delayed recognition of electrographic seizure (> 1 hr from onset) occurred in five patients (5/12, 42%). CONCLUSIONS: Early evaluation of quantitative electroencephalography program to detect electrographic seizure by PICU clinicians suggested good sensitivity for electrographic seizure detection. However, the high false-positive rate is a challenge. Ongoing work is needed to reduce the false positive diagnoses and avoid electrographic seizure detection delays. A comprehensive training program and regular refresher updates for clinical staff are key components of the program.

Characteristics of a Brisk or Sluggish Pupillary Light Reflex: A Nursing Perspective.

BACKGROUND: Pupillary light reflex (PLR) has traditionally been assessed using a pen torch (light). Although the terms "brisk" or "sluggish" are often used, it is unclear what characteristics of the PLR result in this description. More recently, automated infrared pupillometry has enabled us to quantify the different components of a PLR. METHODS: We conducted a 2-part questionnaire survey of pediatric intensive care unit (PICU) nurses. In part 1, nurses were requested to describe the key characteristics that they associate with a brisk or sluggish PLR in free-text responses. In part 2, after an introduction to pupillometry and the different components of a PLR, nurses were asked to rank the relative importance of latency (time taken for pupil to start reacting to light), percentage change (in pupil size after light stimulus), and constriction velocity (rate of constriction after light stimulus) in relation to a pupil being described as "brisk" and "sluggish. RESULTS: Fifty nurses responded. In part 1, "Quick" was the commonest term used (36% of respondents) to describe a brisk PLR, and 72% used "slow" for a sluggish PLR. Most descriptions most closely mapped to features of latency and/or constriction velocity. In part 2, latency was ranked the most important component on pupillometry for describing brisk (32%) and sluggish (34%) PLRs. Constriction velocity was ranked as the most important by 18% (brisk) and 20% (sluggish), whereas 44% (brisk) and 46% (sluggish) ranked percentage change behind the other 2 characteristics. CONCLUSION: Latency, followed by the constriction velocity, was felt by PICU nurses to be the most important characteristic of the PLR that results in terms "brisk" or "sluggish" being used at the bedside to describe a PLR. We plan to compare these subjective opinions with objective findings from pupillometry.

Trends in long-stay admissions to a UK paediatric intensive care unit.

OBJECTIVE: Prolonged admission to a paediatric intensive care unit (PICU) consumes significant healthcare resource. An increase in the number of long-stay admissions and bed utilisation has been reported elsewhere in the world but not in the UK. If an increasing trend of long-stay admissions is evident, this may have significant implications for provision of paediatric intensive care in the future. DESIGN/SETTING/PATIENTS: We retrospectively analysed prospectively collected data from Birmingham Children's Hospital, UK, over a 20-year period from 1998 to 2017. PICU admissions, bed-days, length of stay and mortality trends were analysed and reported over four different epochs (1998-2002, 2003-2007, 2008-2012 and 2013-2017) for long-stay admissions (PICU length of stay ≥28 days) and others. Differences in patient demographics, diagnostic categorisation and hospital utilisation were also analysed. RESULTS: In total, 24 203 admissions accounted for 131 553 bed-days over the 20-year period. 705 (2.9%) long-stay admissions accounted for 42 312 (32%) bed-days. Proportion of long-stay admissions and corresponding bed-days increased from 1.6% and 20.5% in 1998-2002 to 4.5% and 42.6%, respectively, in 2013-2017 (p<0.001). Long-stay patients had a significantly higher number of hospital admissions (median: 4 vs 2, p<0.001) per patient and overall hospital length of stay (median: 98 vs 15, p<0.001) bed-days compared with other patients. Long-stay admissions were associated with significantly higher crude mortality (23% vs 6%, p<0.001) compared with other admissions. CONCLUSIONS: A significant increase in the proportion of prolonged PICU admissions with disproportionately high resource utilisation and mortality is evident over two decades.