Effect of Early High-Flow Nasal Oxygen vs Standard Oxygen Therapy on Length of Hospital Stay in Hospitalized Children With Acute Hypoxemic Respiratory Failure: The PARIS-2 Randomized Clinical Trial.

Importance: Nasal high-flow oxygen therapy in infants with bronchiolitis and hypoxia has been shown to reduce the requirement to escalate care. The efficacy of high-flow oxygen therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure without bronchiolitis is unknown. Objective: To determine the effect of early high-flow oxygen therapy vs standard oxygen therapy in children with acute hypoxemic respiratory failure. Design, Setting, and Participants: A multicenter, randomized clinical trial was conducted at 14 metropolitan and tertiary hospitals in Australia and New Zealand, including 1567 children aged 1 to 4 years (randomized between December 18, 2017, and March 18, 2020) requiring hospital admission for acute hypoxemic respiratory failure. The last participant follow-up was completed on March 22, 2020. Interventions: Enrolled children were randomly allocated 1:1 to high-flow oxygen therapy (n = 753) or standard oxygen therapy (n = 764). The type of oxygen therapy could not be masked, but the investigators remained blinded until the outcome data were locked. Main Outcomes and Measures: The primary outcome was length of hospital stay with the hypothesis that high-flow oxygen therapy reduces length of stay. There were 9 secondary outcomes, including length of oxygen therapy and admission to the intensive care unit. Children were analyzed according to their randomization group. Results: Of the 1567 children who were randomized, 1517 (97%) were included in the primary analysis (median age, 1.9 years [IQR, 1.4-3.0 years]; 732 [46.7%] were female) and all children completed the trial. The length of hospital stay was significantly longer in the high-flow oxygen group with a median of 1.77 days (IQR, 1.03-2.80 days) vs 1.50 days (IQR, 0.85-2.44 days) in the standard oxygen group (adjusted hazard ratio, 0.83 [95% CI, 0.75-0.92]; P < .001). Of the 9 prespecified secondary outcomes, 4 showed no significant difference. The median length of oxygen therapy was 1.07 days (IQR, 0.50-2.06 days) in the high-flow oxygen group vs 0.75 days (IQR, 0.35-1.61 days) in the standard oxygen therapy group (adjusted hazard ratio, 0.78 [95% CI, 0.70-0.86]). In the high-flow oxygen group, there were 94 admissions (12.5%) to the intensive care unit compared with 53 admissions (6.9%) in the standard oxygen group (adjusted odds ratio, 1.93 [95% CI, 1.35-2.75]). There was only 1 death and it occurred in the high-flow oxygen group. Conclusions and Relevance: Nasal high-flow oxygen used as the initial primary therapy in children aged 1 to 4 years with acute hypoxemic respiratory failure did not significantly reduce the length of hospital stay compared with standard oxygen therapy. Trial Registration: anzctr.org.au Identifier: ACTRN12618000210279.

Impact of oral corticosteroids on respiratory outcomes in acute preschool wheeze: a randomised clinical trial.

OBJECTIVE: To determine if administration of oral prednisolone to preschool children with acute wheeze alters respiratory outcomes. DESIGN: Double-blind, randomised, placebo-controlled equivalence trial. SETTING: Three hospitals in New Zealand. PATIENTS: 477 children aged 24-59 months with acute wheeze associated with respiratory illness. INTERVENTIONS: 2 mg/kg (maximum 40 mg) oral prednisolone or similar placebo, once daily for 3 days. MAIN OUTCOME MEASURES: Primary outcome was change in Preschool Respiratory Assessment Measure (PRAM) score 24 hours after intervention. Secondary outcomes included PRAM score at 4 hours, length of emergency department and inpatient stays, admission and representation rates, time to return to normal activities and use of additional oral prednisolone or intravenous medications. Analysis was by intention-to-treat. RESULTS: There was no difference between groups for change in PRAM score at 24 hours (difference between means -0.39, 95% CI -0.84 to 0.06, p=0.09). Absolute PRAM score was lower in the prednisolone group at 4 hours (median (IQR) 1 (0-2) vs 2 (0-3), p=0.01) and 24 hours (0 (0-1) vs 0 (0-1), p=0.01), when symptoms had resolved for most children regardless of initial treatment. Admission rate, requirement for additional oral prednisolone and use of intravenous medication were lower in the prednisolone group, although there were no differences between groups for time taken to return to normal activities or rates of representation within 7 days. CONCLUSION: Oral prednisolone does not alter respiratory outcomes at 24 hours or beyond in preschool children presenting with acute wheeze.

Validation of the PredAHT-2 prediction tool for abusive head trauma.

OBJECTIVE: The validated Predicting Abusive Head Trauma (PredAHT) clinical prediction tool calculates the probability of abusive head trauma (AHT) in children <3 years of age who have sustained intracranial injuries (ICIs) identified on neuroimaging, based on combinations of six clinical features: head/neck bruising, seizures, apnoea, rib fracture, long bone fracture and retinal haemorrhages. PredAHT version 2 enables a probability calculation when information regarding any of the six features is absent. We aimed to externally validate PredAHT-2 in an Australian/New Zealand population. METHODS: This is a secondary analysis of a prospective multicentre study of paediatric head injuries conducted between April 2011 and November 2014. We extracted data on patients with possible AHT at five tertiary paediatric centres and included all children <3 years of age admitted to hospital who had sustained ICI identified on neuroimaging. We assigned cases as positive for AHT, negative for AHT or having indeterminate outcome following multidisciplinary review. The estimated probability of AHT for each case was calculated using PredAHT-2, blinded to outcome. Tool performance measures were calculated, with 95% CIs. RESULTS: Of 87 ICI cases, 27 (31%) were positive for AHT; 45 (52%) were negative for AHT and 15 (17%) had indeterminate outcome. Using a probability cut-off of 50%, excluding indeterminate cases, PredAHT-2 had a sensitivity of 74% (95% CI 54% t o89%) and a specificity of 87% (95% CI 73% to 95%) for AHT. Positive predictive value was 77% (95% CI 56% to 91%), negative predictive value was 85% (95% CI 71% to 94%) and the area under the curve was 0.80 (95% CI 0.68 to 0.92). CONCLUSION: PredAHT-2 demonstrated reasonably high point sensitivity and specificity when externally validated in an Australian/New Zealand population. Performance was similar to that in the original validation study. TRIAL REGISTRATION NUMBER: ACTRN12614000463673.

Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial.

BACKGROUND: Phenytoin is the current standard of care for second-line treatment of paediatric convulsive status epilepticus after failure of first-line benzodiazepines, but is only effective in 60% of cases and is associated with considerable adverse effects. A newer anticonvulsant, levetiracetam, can be given more quickly, is potentially more efficacious, and has a more tolerable adverse effect profile. We aimed to determine whether phenytoin or levetiracetam is the superior second-line treatment for paediatric convulsive status epilepticus. METHODS: ConSEPT was an open-label, multicentre, randomised controlled trial conducted in 13 emergency departments in Australia and New Zealand. Children aged between 3 months and 16 years, with convulsive status epilepticus that failed first-line benzodiazepine treatment, were randomly assigned (1:1) using a computer-generated permuted block (block sizes 2 and 4) randomisation sequence, stratified by site and age (≤5 years, >5 years), to receive 20 mg/kg phenytoin (intravenous or intraosseous infusion over 20 min) or 40 mg/kg levetiracetam (intravenous or intraosseous infusion over 5 min). The primary outcome was clinical cessation of seizure activity 5 min after the completion of infusion of the study drug. Analysis was by intention to treat. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12615000129583. FINDINGS: Between March 19, 2015, and Nov 29, 2017, 639 children presented to participating emergency departments with convulsive status epilepticus; 127 were missed, and 278 did not meet eligibility criteria. The parents of one child declined to give consent, leaving 233 children (114 assigned to phenytoin and 119 assigned to levetiracetam) in the intention-to-treat population. Clinical cessation of seizure activity 5 min after completion of infusion of study drug occurred in 68 (60%) patients in the phenytoin group and 60 (50%) patients in the levetiracetam group (risk difference -9·2% [95% CI -21·9 to 3·5]; p=0·16). One participant in the phenytoin group died at 27 days because of haemorrhagic encephalitis; this death was not thought to be due to the study drug. There were no other serious adverse events. INTERPRETATION: Levetiracetam is not superior to phenytoin for second-line management of paediatric convulsive status epilepticus. FUNDING: Health Research Council of New Zealand, A+ Trust, Emergency Medicine Foundation, Townsville Hospital Private Practice Fund, Eric Ormond Baker Charitable Fund, and Princess Margaret Hospital Foundation.

External Validation of the PediBIRN Clinical Prediction Rule for Abusive Head Trauma.

BACKGROUND AND OBJECTIVES: A 4-variable abusive head trauma (AHT) clinical prediction rule (CPR) for use in the PICU was derived and validated for children <3 years of age by the Pediatric Brain Injury Research Network (PediBIRN). We aimed to externally validate PediBIRN as designed (PICU only) as well as using broader inclusion criteria (admitted children with head injuries). METHODS: This was a secondary analysis of a prospective multicenter study of pediatric head injuries at 5 Australian and New Zealand tertiary pediatric centers. Possible AHT was identified by clinician suspicion, epidemiology codes, or a high-risk group (<3 years of age, admitted, abnormal neuroimaging results). At 1 center, we additionally reviewed head injuries in the forensic database. We designated patients as positive for AHT, negative for AHT, or having indeterminate outcome after multidisciplinary review and applied the PediBIRN CPR, blinded to outcome, to PICU admissions only, and any head injury admissions. CPR accuracy was calculated by using 95% confidence intervals. RESULTS: One hundred and forty-one patients were admitted with abnormal neuroimaging results. Twenty-eight (20%) were positive for AHT, 94 (67%) were negative for AHT, and 19 (13%) had indeterminate outcome. Excluding indeterminate cases, in the PICU (n = 28), the CPR was 100% (75%-100%) sensitive and 11% (0%-48%) specific; in all admitted patients (n = 141), sensitivity was 96% (82%-100%) and specificity of 43% (32%-53%). CONCLUSIONS: This validation revealed high sensitivity and low specificity for PICU patients. Specificity was improved but moderate in a broader group of admitted head injury patients.

A multicentre randomised controlled trial of levetiracetam versus phenytoin for convulsive status epilepticus in children (protocol): Convulsive Status Epilepticus Paediatric Trial (ConSEPT) - a PREDICT study.

BACKGROUND: Convulsive status epilepticus (CSE) is the most common life-threatening childhood neurological emergency. Despite this, there is a lack of high quality evidence supporting medication use after first line benzodiazepines, with current treatment protocols based solely on non-experimental evidence and expert opinion. The current standard of care, phenytoin, is only 60% effective, and associated with considerable adverse effects. A newer anti-convulsant, levetiracetam, can be given faster, is potentially more efficacious, with a more tolerable side effect profile. The primary aim of the study presented in this protocol is to determine whether intravenous (IV) levetiracetam or IV phenytoin is the better second line treatment for the emergency management of CSE in children. METHODS/DESIGN: 200 children aged between 3 months and 16 years presenting to 13 emergency departments in Australia and New Zealand with CSE, that has failed to stop with first line benzodiazepines, will be enrolled into this multicentre open randomised controlled trial. Participants will be randomised to 40 mg/kg IV levetiracetam infusion over 5 min or 20 mg/kg IV phenytoin infusion over 20 min. The primary outcome for the study is clinical cessation of seizure activity five minutes following the completion of the infusion of the study medication. Blinded confirmation of the primary outcome will occur with the primary outcome assessment being video recorded and assessed by a primary outcome assessment team blinded to treatment allocation. Secondary outcomes include: Clinical cessation of seizure activity at two hours; Time to clinical seizure cessation; Need for rapid sequence induction; Intensive care unit (ICU) admission; Serious adverse events; Length of Hospital/ICU stay; Health care costs; Seizure status/death at one-month post discharge. DISCUSSION: This paper presents the background, rationale, and design for a randomised controlled trial comparing levetiracetam to phenytoin in children presenting with CSE in whom benzodiazepines have failed. This study will provide the first high quality evidence for management of paediatric CSE post first-line benzodiazepines. TRIAL REGISTRATION: Prospectively registered with the Australian and New Zealand Clinical Trial Registry (ANZCTR): ACTRN12615000129583 (11/2/2015). UTN U1111-1144-5272. ConSEPT protocol version 4 (12/12/2014).