Colin Powell

Importance Asthma is a common chronic disease with significant morbidity and mortality. Objectives To assess the safety and efficacy of subcutaneous epinephrine in addition to the standard first-line treatment of acute asthma in children. Data source and study selection The following databases were inspected from 1966 to 22 June 2025: MEDLINE, EMBASE, CINAHL and the Cochrane Central Register of Controlled Trials. Only randomised controlled trials were included. Data extraction and synthesis One study out of 197 citations was included in this review. Main outcomes The outcome measures were morbidity, escalation of care, length of hospital stay, adverse events, mortality due to exacerbation and change in lung function. Results We included one study with a total number of participants (n)=43. Participants who received subcutaneous epinephrine showed no significant difference in the asthma clinical score postintervention (3.3 compared with 4.0, respectively), as well as in the hospitalisation rate (risk ratio (RR) 0.38, 95% CI 0.04 to 3.40, p=0.39, n=43) and the need for additional intravenous medications (RR 0.23, 95% CI 0.03 to 1.81, p=0.16, n=43), or predicted increase in peak expiratory flow (PEF) percentage at 2 hours (mean difference −1.00, 95% CI −8.21 to 6.21, p=0.79, n=31). Conclusion This review demonstrated very low certainty of evidence based on a single paper indicating that subcutaneous epinephrine does not benefit children with acute asthma in terms of asthma clinical score, hospitalisation rate and the need for additional intravenous medications. No significant improvement in PEF percentage was observed after the intervention. PROSPERO registration number CRD42023405407.

Background: The role of inhaled/nebulised ipratropium bromide (IB) in asthma is unclear. Aims: To assess the efficacy and safety of inhaled/nebulised IB for asthma management in children. Methods: We searched MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials and the Web of Science until July 2024. We included randomised controlled trials (RCTs) and followed international guidelines for reporting systematic reviews. Outcomes included morbidity, escalation of care, length of hospital stay, mortality, adverse events and lung function. Results: We included 24 studies (total participants n=3238). The hospitalisation rate (risk ratio (RR) 0.84, 95% CI 0.70 to 1.00, I ^² 30%), hospital stay in hours (MD 1.75, 95% CI −0.87 to 4.36, I ^² 15%) and paediatric intensive care (PICU) admission (RR 0.91, 95% CI 0.35 to 2.32, I ^² 0%) were similar. The hospitalisation rate was lower in patients who received IB nebuliser (RR 0.76, 95% CI 0.64 to 0.90, I ^² 0%). The asthma severity score was significantly better in the IB group (MD −0.38, 95% CI −0.63 to −0.12, I ² 59%). No serious adverse events were reported. Conclusion: This review found high-certainty evidence that the IB nebuliser leads to a lower hospitalisation rate. However, when inhaled/nebulised IBs were analysed together, the hospitalisation rate was similar, with moderate certainty evidence. IB improved asthma clinical scores, with low certainty evidence. No difference was reported in other prespecified outcomes. Considering the current evidence and safety profile, inhaled/nebulised IB needs to be considered as an additional treatment for acute asthma exacerbation. PROSPERO registration number: CRD42023405023.

Importance: The role of intravenous short-acting beta-2 agonist (SABA) in acute asthma in childhood is unclear. Objectives: To assess the safety and efficacy of intravenous SABA versus placebo for acute asthma. Data selection and extraction: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Web of Science and the Cumulative Index to Nursing and Allied Health Literature up to May 2024. We included only randomised controlled trials (RCTs) and followed the international guidelines for conducting systematic reviews. Outcomes measured were morbidity, escalation of care, length of hospital stay, adverse events, mortality and changes in lung functions. Results: Four RCTs were included (total participants=183). Intravenous SABA group had better asthma severity scores (risk ratio (RR)=0.38, 95 % CI 0.19 to 0.78, p=0.009), similar need for mechanical ventilation (RR=0.13, 95 % CI 0.01 to 2.42, p=0.17), similar escalation of intravenous treatment (RR=1.51, 95 % CI 0.60 to 3.82, p=0.38), shorter duration of hospital stay (hours) (mean difference (MD)=−18.68, 95 % CI −36.76 to −0.61) and less duration of oxygen supplementation (days) (MD=−1.73, 95% CI −3.01 to −0.45, p=0.008). Adverse events were tachycardia, hypotension and hypokalaemia. One study reported a single participant with arrhythmia and a non-significant increase in troponin I among the intravenous SABA group. Conclusion: This review found low-to-moderate certainty evidence that intravenous SABA would improve acute asthma severity with infrequent adverse events reported. However, this evidence is limited due to the limited number of included studies. PROSPERO registration number: CRD42023405119.

Importance: Evidence regarding second-line treatment for severe asthma is limited. Objectives: To evaluate the safety and efficacy of intravenous aminophylline, intravenous short-acting beta agonist (SABA), intravenous magnesium sulphate, intravenous ketamine or subcutaneous adrenaline as a second-line treatment for severe asthma. Methods: We included only randomised controlled trials (RCTs) and followed the international guidelines for conducting systematic reviews. We performed a comprehensive literature search up to May 2024. Outcomes included morbidity, escalation of care, length of hospital stay, adverse events, mortality and changes in lung functions. Results: Nine RCTs were included (total participants=546). Compared with other treatments, intravenous aminophylline showed no significant difference in the duration of hospital stay in hours, except for critically ill ventilated patients who had a shorter stay (mean difference (MD)=−12.99, 95 % CI −33.13 to 7.15). The need for additional intravenous medications (RR=2.17, 95 % CI 0.48 to 9.71) and asthma severity scores postinterventions (MD=0.97, 95 % CI −0.91 to 2.85) was similar. More nausea and emesis were observed in the intravenous aminophylline group. The intravenous SABA group showed no difference in hospital stay (MD=−10.12, 95 % CI −45.74 to 25.49) or need for ventilation (RR=0.25, 95 % CI 0.03 to 2.21). There were no frequent serious adverse events. The intravenous magnesium sulphate group had a lower hospitalisation rate (RR=1.52, 95 % CI 1.26 to 1.84), reduced need for additional intravenous medication (RR=6.30, 95 % CI 2.62 to 15.17) and a rapid improvement in asthma severity scores (p<0.05). Conclusion: There is low-to-very-low certainty evidence demonstrating the superiority of any intravenous second-line treatment options for acute asthma. PROSPERO registration number: CRD42023405226.

Importance: The role of intravenous aminophylline in acute asthma in childhood is unclear. Objectives: To assess the safety and efficacy of intravenous aminophylline for asthma in children. Methods: From 1966 to May 2024, we searched MEDLINE, Embase, CINAHL, Web of Science and the Cochrane Central Register of Controlled Trials. We included only randomised controlled trials testing standard treatment in combination with aminophylline and followed the international guidelines for conducting systematic reviews. The outcomes measured were morbidity, escalation of care, length of hospital stay, adverse events, mortality and lung functions. We used the random-effects model for data analysis and the fixed-effects model to evaluate heterogeneity. Results: Nine studies (466 participants) fulfilled our a priori eligibility criteria. No significant difference was found in post-treatment asthma severity score (mean difference (MD)=0.13, 95% CI −0.79 to 1.06, I ² =0 %), hospitalisation rate (risk ratio (RR)=0.66, 95% CI 0.27 to 1.59, I ² =0 % ), paediatric intensive care unit admission (RR=0.73, 95% CI 0.51 to 1.05, I ² =0%), intubation rate (RR=0.09, 95% CI 0.01 to 1.64, p=0.1) or length of hospital stay (MD=−3.62, 95% CI −13.05 to 5.82, I ² =31%). Emesis (RR=3.52, 95% CI 2.04 to 6.06, I ² =0%) and nausea (RR=4.92, 95% CI 2.41 to 10.06, I ² =0%) occurred more in the aminophylline group. One study showed improved lung function in the aminophylline group, while others showed no difference. Conclusion: This review showed limited evidence of the benefit of intravenous aminophylline in managing asthma in most preventilation severity parameters. However, lowering the intubation rate and improving lung function deserve more attention. PROSPERO registration number: CRD42023405234.

Background: The role of intravenous magnesium sulfate in asthma exacerbation is unclear. Aims: To determine the efficacy and safety of intravenous magnesium sulfate in managing asthma exacerbation in children. Methods: We searched MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials and the Web of Science up to May 2024. We included randomised controlled trials and followed the international guidelines for conducting systematic reviews. Outcomes included morbidity, escalation of care, length of hospital stay, lung functions, adverse events, and mortality. Results: Nine studies (total participants=473) were included. Hospitalisation rate and the need for non-invasive ventilation were less among the intravenous magnesium sulfate group (mean difference (MD)=0.70, 95% CI 0.54 to 0.90, I ² 7%, n=115) and (risk ratio (RR)=0.17, 95% CI 0.15 to 0.54, p=0.003, n=143), respectively. Asthma severity scores (MD=−0.18, 95% CI −1.35 to 0.98, I ² 2%, n=115), length of hospital stay (MD=−78.86, 95% CI −200.37 to 42.66, I ² 99%, n=284) and the need for invasive ventilation (RR=0.35, 95% CI 0.11 to 1.17, I ² 0%, n=237) were similar. There was no difference in the Paediatric Intensive Care Unit (PICU) admission rate (p=0.43 n=61). Peak expiratory flow improved in the intravenous magnesium group (p<0.001, n=20). No serious adverse events were reported. Conclusion: We found low-certainty evidence that intravenous magnesium sulfate results in a lower hospitalisation rate and less need for non-invasive ventilation. Asthma scores, PICU admission, invasive ventilation and length of hospital stay were similar. While the evidence base is weak, the favourable safety profile suggests that intravenous magnesium sulfate can be considered a treatment for asthma exacerbations. PROSPERO registration number: CRD42023405261.

Background: Procalcitonin is a biomarker specific for bacterial infection, with a more rapid response than other commonly used biomarkers, such as C-reactive protein, but it is not routinely used in the National Health Service. Objective: To determine if using a procalcitonin-guided algorithm may safely reduce duration of antibiotic therapy compared to standard of care in hospitalised children with suspected or confirmed infection. Design: A pragmatic, multicentre, open-label, parallel two-arm, individually randomised controlled trial with internal pilot phase, qualitative study and health economic evaluations. Setting: Paediatric wards or paediatric intensive care units within children’s hospitals (n = 6) and district general hospitals (n = 9) in the United Kingdom. Participants: Children aged between 72 hours and 18 years admitted to hospital and being treated with intravenous antibiotics for suspected or confirmed bacterial infection. Interventions: Procalcitonin-guided algorithm versus usual standard care alone. Main outcome measures: Coprimary outcomes were duration of intravenous antibiotic use and a composite safety measure. Results: Between 11 June 2018 and 12 October 2022, 1949 children were recruited: 977 to the procalcitonin group [427 female (43.7%), 550 male (56.3%)], and 972 to the usual care group [478 female (49.2%), 494 male (50.8%)]. Duration of intravenous antibiotics was not significantly different between the procalcitonin group (median 96.0 hours) and the usual care group (median 99.7 hours) [hazard ratio = 0.96 (0.87, 1.05)], and the procalcitonin-guided algorithm was non-inferior to usual care [risk difference = −0.81% (95% confidence interval upper bound 1.11%)]. At clinical review, a procalcitonin result was available for 81.8% of the time, which was considered as part of clinical decision-making 66.6% of the time, and the algorithm was adhered to 57.2% of the time. Incremental cost-effectiveness ratio per duration of intravenous antibiotics hour avoided from bootstrapped samples was £467.62 per intravenous antibiotic hour avoided. Cost analysis of complete cases was also higher in the procalcitonin arm for all age groups, and for children aged 5 years and over. The intervention is not cost-effective as it is more expensive with no significant improvement in intravenous antibiotic duration. Limitations: Robust antimicrobial stewardship programmes were already implemented in the lead recruiting sites, and adherence to the algorithm was poor. Clinicians may be reluctant to adhere to biomarker-guided algorithms, due to unfamiliarity with interpreting the test result. Conclusions: In children hospitalised with confirmed or suspected bacterial infection, the addition of a procalcitonin-guided algorithm to usual care is non-inferior in terms of safety, but does not reduce duration of intravenous antibiotics, and is not cost-effective. In the presence of robust antimicrobial stewardship programmes to reduce antibiotic use, a procalcitonin-guided algorithm may offer little added value. Future work: Future trials must include an implementation framework to improve trial intervention fidelity, and repeated cycles of education and training to facilitate implementation of biomarker-guided algorithms into routine clinical care. Trial registration: This trial is registered as ISRCTN11369832. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/188/42) and is published in full in Health Technology Assessment; Vol. 29, No. 16. See the NIHR Funding and Awards website for further award information.

Rationale While there are numerous published paediatric asthma scores, it is unknown how commonly scores are recommended in asthma guidelines across different geographical regions globally, and what their validation status is. Objectives (1) To describe which clinical guidelines recommend asthma scores across different geographical regions. (2) To describe the initial and subsequent validation of the commonly recommended asthma scores. Methods Observational study of asthma scores recommended in guidelines for the management of acute paediatric asthma from institutions across the Pediatric Emergency Medicine Network; global paediatric emergency medicine research network comprising all eight local and regional paediatric emergency medicine research networks. Main results 158 guidelines were identified. Overall, 83/158 (53%) guidelines recommend a bedside clinical score for assessment of asthma severity. While a single country-specific clinical score was recommended in all guidelines from Spain and Canada, 27/28 (96%) of the USA guidelines recommend a wide variety of scores, and scores are rarely recommended in guidelines from other research networks (PERUKI, Paediatric Emergency Research in the UK and Ireland and PREDICT, Paediatric Research in Emergency Departments International Collaborative in Australia and New Zealand) and other countries (Costa Rica, South Africa, Nigeria, Singapore, India). The Pediatric Respiratory Assessment Measure (PRAM) and the pulmonary score (PS) were the most frequently used scoring instruments. While the PRAM has undergone the most extensive validation, including construct validity, validation studies for the PS are limited. Inter-rater reliability, as well as the criterion, responsiveness and discriminative validity aspects represent the most common limitations in many of the scores. Conclusions There are marked geographical differences in both the recommendation for and the type of clinical asthma score in clinical practice guidelines. While many asthma scores are recommended, most have insufficient validation.