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The 40th Bubble Wrap


With millions upon millions of journal articles being published every year, it is impossible to keep up.  Every month we ask some of our friends from PERUKI (Paediatric Emergency Research in UK and Ireland) to point out something that has caught their eye.

Article 1: More Examinations, Fewer Antibiotics for neonates??

Vatne A, Klingenberg C, Øymar K, Rønnestad AE, Manzoni P, Rettedal, S. Reduced Antibiotic Exposure by Serial Physical Examinations in Term Neonates at Risk of Early-onset Sepsis. Pediatr Infect Dis J 2020;39(5):438–43

What’s it about? 

A single-centre population-based study in Stavanger, Norway investigated whether serial physical examinations (SPEs) of term neonates with suspected early-onset sepsis (EOS) could reduce unnecessary antibiotic exposure during the first three days of life without affecting their safety. Structured SPEs were conducted by nurses in the neonatal intensive care unit to observe vitals and other clinical signs suggestive of neonates with EOS. Outcomes relating to antibiotic exposure, time to initiating antibiotic use, and safety, were compared to a baseline period prior to SPE implementation.

In total, 17,242 term neonates were included in the study. There was a 57% relative reduction in neonates exposed to antibiotics (2.9% at baseline to 1.3% in the post-implementation period), a 60% relative reduction in mean antibiotic therapy-days per 1000 patient-days (320 to 129). The median time to initiate antibiotics in suspected EOS cases showed a 50% relative reduction (from 14 hours to 7 hours) and there were no post-discharge infection related-readmissions. 

Why does it matter? 

EOS within the first 72 hours of life is a leading contributor to neonatal morbidity and mortality. To prevent such consequences, many neonates with suspected EOS may be given empiric antibiotic therapy despite being uninfected. This can increase parental anxiety, health expenditure, and long-term development of antibiotic resistance. 

Clinically Relevant Bottom Line:

Implementing SPE can help to halve the burden of neonates being exposed to empiric antibiotic therapy with suspected EOS. Moreover, the study has shown that repeated, structured evaluation of clinical symptoms can help identify neonates in need of antibiotic therapy in a timelier manner, addressing EOS earlier on. While the study implemented hourly observations of neonates during their SPE implementation, it remains unclear what time interval remains safe and feasible. Some hospitals have shown that longer intervals of 4-7 hours remained safe, which may be an avenue for other hospitals that may not be as well-resourced as this tertiary obstetric and neonatal care centre. However, the study reported that no additional costs or staffing were involved in implementing SPE and rather, that it helped reduce the prospective workload for nurses as fewer neonates received antibiotic treatment.

I would have liked a more detailed description as to how the authors followed-up with patients to confirm there were no infection-related readmissions post-discharge, such as what duration from discharge when patients were re-contacted. It would also be interesting to know from further studies whether the inclusion of pre-term infants may alter these results. Finally, further studies should compare SPE implementation with the multivariate risk assessment EOS calculator, that is also identified in the EOS guidelines by the American Academy of Paediatrics, and has similarly shown a reduction (>40%) in antibiotic therapy use.

Reviewed by: Ivy Wei Jiang


Article 2: Medical management of a persistent ductus arteriosus

Kumar A, Gosavi RS, Sundaram V, Oleti TP, Krishnan A, Kiran S, Kumar J, Murki S, Sundaram M, Saini SS, Dutta S. Oral Paracetamol vs Oral Ibuprofen in Patent Ductus Arteriosus: A Randomized, Controlled, Noninferiority Trial. The Journal of Pediatrics. 2020 Apr 24.

What’s it about? 

This study investigated whether oral paracetamol is just as effective as oral ibuprofen in closing moderate-to-large patent ductus arteriosus (PDA) shunts in preterm neonate of <32 weeks of gestation in India between 2014 and 2017. The study randomised 161 preterm neonates who had haemodynamically significant PDA to receiving oral paracetamol (81 neonates) or oral ibuprofen (80 neonates). Interestingly, around 10% of patients in each arm discontinued the intervention and were excluded from the analysis. The primary outcome of PDA closure was similar in oral paracetamol and oral ibuprofen (95.4% vs 94%), with no difference in the time to closure of PDA between the oral paracetamol and oral ibuprofen (median, 66 hours [95% CI, 61-71 hours] vs 49 hours [95% CI, 44-54 hours]; P=0.71).

Why does it matter? 

Ductus arteriosus normally closes by end of first week in most preterm neonates >28 weeks of gestation. In preterm neonates with PDA, indomethacin and ibuprofen are commonly used to facilitate closure. Recent literature suggested that paracetamol can be just as effective as ibuprofen for closing PDA. With its safety profile, paracetamol can be an excellent alternative for treating PDA.

Clinically Relevant Bottom Line:

Oral paracetamol can be just as effective as oral ibuprofen in closing the PDA; for bonus reading, two authors produced a pair of Cochrane Reviews on their relative efficacy, published in January 2020. You can find them here:

Ohlsson  A, Shah  PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2020, Issue 1. Art. No.: CD010061. DOI: 10.1002/14651858.CD010061.pub4.

Ohlsson  A, Shah  SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2020, Issue 1. Art. No.: CD004213. DOI: 10.1002/14651858.CD004213.pub5.

Reviewed by: Jessica Win See Wong


Article 3: Are non-contact thermometers just random number generators?

Hayward G, Verbakel JY, Ismail FA, Edwards G, Wang K, Fleming S, Holtman GA, Glogowska M, Morris E, Curtis K, van den Bruel A. Non-contact infrared versus axillary and tympanic thermometers in children attending primary care: a mixed-methods study of accuracy and acceptability. British Journal of General Practice 2020 Mar 26;70(693):e236-e244.

What’s it all about?

The authors in this interesting study look into two main outcomes for children presenting to primary care with an acute illness: firstly, whether measurements taken with the non-contact infrared thermometers (NCITs) match those taken with the axillary and tympanic thermometers (current gold standard); and secondly, which one is preferred by parents. 

The authors recruited a total of 401 children (median age of 1.6 years). Two different brands of NCITs were used. The mean difference between each NCIT and axillary thermometers was found to be -0.14°C and -0.16°C respectively; however, the upper and lower limits of agreement between NCITs compared with tympanic and axillary thermometers were >1°C. This exceeds the commonly believed acceptable limits of agreement, which are ±0.5°C. Furthermore, NCITs had poor sensitivity for detecting temperature ≥38°C (29.3% and 4.9%).

On the other hand, from an acceptability point of view, parents liked the practicability and comfort of NCITs, while axillary thermometres were their least preferred device. But in the end, there was a willingness to adopt whichever device was medically recommended.

Why does it matter?

I was prompted to look further into the accuracy of NCITs when I came across this Letter to the Editor by J Aw, where the author raises concern for the use of NCITs when there is little data to support its accuracy and it may possibly give a false sense of security from the high number of false negatives. The letter is written in the context of the COVID-19 pandemic, although the use of NCITs likely extends into general clinical settings for paediatric patients.

This study’s findings seem to support this letter; however, the authors also found wide limits of agreement between the axillary and tympanic thermometers, making it difficult for us to draw definitive conclusions.

Clinically Relevant Bottom Line:

We need to be able to trust the devices on which we base our clinical decisions. There is clear scope for well-designed studies comparing NCITs, axillary and tympanic devices to those which measure core body temperatures, but in the meantime, clinicians should be aware of the limits of any peripheral temperature measurements and use them as part of a broader clinical assessment.

Reviewed by: Jennifer Moon


Article 4: An industry-sponsored trial comparing LAMA, LABA and LTRA in Paediatric Asthma 

Vogelnerg, C., Goldstein, S., Graham, L., Kaplan, A., de la Hoz, A., Hamelmann, E. (2020) A comparison of tiotropium, long acting B2 agonists and leukotriene receptor antagonists on lung function and exacerbations in paediatric patients with asthma, Respiratory Research, doi: 10.1186/s12931-020-1282-9

What’s it about?

In Australia, the current National Asthma Council recommends regular preventer treatment for children aged 6 years and above with frequent intermittent asthma. In line with other national guidelines, the stepwise approach recommends commencing inhaled corticosteroids (ICS) and then long-acting B2 agonists (LABA) or leukotriene receptor antagonists (LTRA). Long-acting muscarinic antagonists (LAMA) are generally reserved for patients with severe asthma. 

What did they do?

The main stated aim of the paper was to compare the efficacy and safety of three controller options (LAMA, LABA and LTRA) as add-on to ICS in adolescents and children aged 4–17 years with asthma. It’s important to note that the study was funded by Boheringer Ingelheim, who are the manufacturers of the dominant tiotropium inhaler in Australia. The extant literature was effectively compared with three tiotropium studies.

No studies were found which compared LABA, LAMA or LTRA directly; rather the emphasis was placed on ICS + placebo vs ICS + (one of the above). Children in the studies had a diagnosis of asthma and were aged 4 – 17 years. Each of LABA, LAMA & LTRA was stated to have broadly equivocal safety profiles.

The analyses of LAMA and LTRA studies found no difference in the frequency of asthma exacerbations when compared to placebo. The proportion of patients requiring oral corticosteroids in the LAMA studies was low, but there is no direct comparison to the placebo group. This outcome was difficult to assess as there were many confounding variables in the studies and limited statistics. 

Why does it matter?

The TGA’s 2016 Public Assessment Report (AusPAR), assessed Tiotropium (a long-acting muscarinic agonist) for a proposed extension of indications. In that report, the manufacturer objected to the addition of “risks of potential off label usage of Tiptropium in children.” Fast forward 3.5 years and, through this paper, the manufacturer is now trying to convince us of tiotropium’s valid use in children without any head to head trials with other ICS adjuvants, using this metaanalysis which is essentially a narrative review, given the obscure search strategy and exclusion criteria employed.

Clinically Relevant Bottom Line:

Based on the review’s meta-analyses, it appears LAMA and LABA are efficacious in regards to improving FEV1 however no conclusive statement can be made, given the methodology variability of the studies reviewed, lack of statistical information as well as the lack of direct comparison to LABA and LTRA. The use of tiotropium in children remains off label. We recommend following the current guidelines to optimise asthma management in children.

Reviewed by: Tina Abi Abdallah


Article 5: Heart rate neonatal resuscitation – does an app help assess it faster & more accurately?

What’s it about?

The objective was to investigate if a 6-second visual timer (VT) could improve heart rate (HR) assessment during simulated newborn resuscitation. This was a prospective observational study of newborn healthcare professionals using a three-phase developmental approach during newborn simulation. Phase I: auscultating the heart rate during newborn simulation using a standard clock timer (CT) or the visual timer (VT). Phase II: Repeating phase I using a bespoke training app called NeoRate (after appropriate application training). Phase III involved following the current new-born life support course; participants assessed random HRs using the VT or the CT. Outcome measures included: approximation of HR within 10+/- beats/min; correct HR category (60, 60-100, and >100 beats/min); assessment time and error-free rates). 1974 HR assessments were performed with participants more accurate using the VT for +/- 10 beats/ min (70% CT vs 86% VT, P<0.001) and correct HR category (78% CT vs 84% VT, P<0.01). The VT improved accuracy across all three phases. After training of the NeoRate app in phase II, accuracy of HR of both the CT and VT improved. The VT resulted in faster HR assessment times of 11 seconds compared with the CT at 15 seconds. Error-free scenarios increased from 24% using CT to 57% using the VT with a shorter assessment time (CT 116 seconds vs VT 53 second).

Why does it matter?

Heart rate assessment during neonatal resuscitation is an important indicator of a newborn’s condition and whether further resuscitation is required. A 2015 paper identified that pulse oximetry tends to underestimate heart rate by comparison to ECG, however, given the time taken attach leads, the most recent iteration of the ANZCOR Neonatal Resus guidelines only suggests the addition of ECG. The reported failure rate of auscultating the heart rate is said to be as high as 46%.  This study suggests a six-second visual timer improves the accuracy and reduces the time taken to make HR assessments during simulations.

Clinically Relevant Bottom Line:

This is a small trial which tested a potential alternative to improve heart rate assessments during neonatal resuscitation. The study trialled this in simulation settings with the suggestion to evaluate this in the clinical setting to determine potential real-life benefits. On balance, introducing increased complexity, devices & potential for misdirected task-focus needs to be weighed against the real-world outcomes, pragmatics and accuracy of existing resuscitation methods, timing and clinical information.

Reviewed by: Taryn Miller


That’s it for this month. Many thanks to all of our reviewers who have taken the time to scour the literature so you don’t have to. And, if you’d like to join our team of reviewers, or have an article that you think our readers would love to read, please send it through to



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