Skip to content

The 39th 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 the UK and Ireland) to point out something that has caught their eye.

Article 1: Saline nebs in acute viral bronchiolitis – more than just a placebo?

House SA, Gadomski AM, Ralston SL. Evaluating the Placebo Status of Nebulized Normal Saline in Patients with Acute Viral Bronchiolitis – A Systematic Review and Meta-analysis. JAMA Pediatrics 2020;174(3):250-259. Doi:10.1001/jamapediatrics.2019.5195

What’s it about?

The authors reviewed a total of 29 randomised clinical trials and 1583 patients (through March 2019). Trials comparing children 2 years or younger with bronchiolitis who were treated with nebulised normal saline (NS) as well as an alternative placebo were included for comparison. Standardised mean difference in respiratory scores for nebulised NS vs other placebo favoured nebulised NS by -0.9 points (95% CI, -1.2 to -0.6 points) at 60 minutes post treatment (P < .001). The weighted mean difference in respiratory scores using a consistent scale after nebulised NS was -1.6 points (95% CI, -1.9 to -1.3 points; I2 = 72%). There were no differences in respiratory rate or oxygen saturation comparing nebulised NS with other placebo.

Why does it matter?

In many randomised clinical trials, nebulised normal saline has been used as the placebo therapy against the active treatment (whether bronchodilators or sputum expectorants). However this systematic review and meta-analysis found that nebulised normal saline could actually act as an active treatment for acute viral bronchiolitis. Further studies should evaluate whether the improvements seen after nebulised normal saline therapy are just part of the natural fluctuations of bronchiolitis or true clinical outcomes.

Reviewed by: Jennifer Moon

Article 2: Should we consider azithromycin as a therapy option for severe RSV bronchiolitis?

Kong M, Zhang W, Sewell K, Gorman G, Kuo HC, Aban I, Ambalavanan N, Whitley. Should we consider Azithromycin as a therapy option for severe RSV bronchiolitis? JAMA Network Open 2020; 3(4):e203482. doi:10.1001/jamanetworkopen.2020.3482

What’s it about?

As we head into winter, and we continue to hear about the global impact of COVID-19, we should not forget about the burden of disease caused by RSV bronchiolitis. In 2018, the PREDICT network published Australia’s first bronchiolitis guidelines which do not currently recommend pharmaceutical treatment such as nebulisers, steroids or antibiotics. We continue to look for safe and effective therapies to help reduce disease severity and duration.

Azithromycin has been shown to have anti-inflammatory properties, by attenuating cytokine production, as well as anti-viral properties. This study looked at the safety of standard dose (SD = 10mg/kg) and high dose (HD = 20mg/kg) azithromycin, and whether azithromycin at SD or HD had any clinical benefits compared with placebo therapy.

What did they do?

This study was a double blind placebo controlled RCT which looked at 48 children aged 0 – 24 months who were admitted to a single centre PICU with RSV bronchiolitis, requiring non-invasive (HFNC, CPAP or BiPAP) or invasive respiratory support. The groups were randomised to receive an IV dose of placebo (0.9% NaCl), SD or HD Azithromycin q24 hourly for 3 days. Aside from this, they were managed as per the American Academy of Paediatrics for bronchiolitis. Baseline demographic characteristics were comparable among the 3 groups.

SD and HD Azithromycin were deemed safe, with no patients developing adverse side effects, specifically cardiac arrhythmia, gastrointestinal symptoms or abnormal laboratory values.

Patients who received HD Azithromycin had fewer days on ventilator support (p = 0.06), fewer days in PICU (p=0.09) and fewer hospital days (p=0.04). RSV replication was assessed using nasal and endotracheal samples which were collected at baseline, 24 hours and 48 hours after the start of treatment. There was no difference in viral load amongst nasal swabs taken in patients on NIV, however viral load in endotracheal aspirates in ventilated patients were lowest in the HD Azithromycin group (not statistically significant).

What the clinical bottom line?

Whilst this study was promising, showing a good safety profile of Azithromycin and potential clinical benefits in regards to reduction of disease severity and duration, further larger RCTs are needed to demonstrate more convincing benefits before recommending Azithromycin as part of the standard therapy for severe RSV bronchiolitis.

Reviewed by: Tina Abi Abdallah

Article 3: Six-Year Follow-up of a Trial of Antenatal Vitamin D for Asthma Reduction

Litonjua AA, Carey VJ, Laranjo N, Stubbs BJ, Mirzakhani H, O’Connor GT, Sandel M, Beigelman A, Bacharier LB, Zeiger RS, Schatz M. Six-year follow-up of a trial of antenatal vitamin D for asthma reduction. New England Journal of Medicine. 2020 Feb 6;382(6):525-33.

What’s it about?

The study followed children up to 6 years of age (from 2011 to 2018) to determine whether maternal Vitamin D has an effect on asthma and recurrent wheeze development in the United States. randomised 881 pregnant women – 439 assigned to receive 400 IU/day vitamin D3 (control group) and 442 assigned to receive 4400 IU/day vitamin D3 (vitamin D group). After excluding foetal/neonatal deaths and those lost to follow-up, the study analysed N=401 (control group) and N=405 (vitamin D group) mothers and their children.

By 6 years of age, 360 children (44.7%) – 176 (43.5%) in the vitamin D group and 184 (45.9%) in the control group – met the criteria for the outcome of asthma or recurrent wheeze. There was no significant effect of maternal vitamin D (4400IU/day) on the incidence of asthma or recurrent wheeze at the age of 6 years (interval-censored hazard ratio [control vs vitamin D], 1.12; P=0.25). There were no significant effects of maternal vitamin D supplementation on the secondary outcomes of eczema, allergic rhinitis, or lower respiratory tract infection. There was no association of maternal vitamin D supplementation with spirometric indexes. However, total airway resistance and lower peripheral airway resistance were lower in the vitamin D group than in the control group among children 5 to 6 years of age.

Why does it matter?

Vitamin D deficiency has been suggested to play a role in increasing asthma and allergies. Observational studies have suggested that higher maternal vitamin D is associated with a lower risk of asthma-related outcomes among children.

Clinically relevant bottom line

There was no effect of maternal vitamin D supplementation on asthma and recurrent wheezes development in children up to 6 years of age. Nevertheless, the effect of vitamin D supplementation on airway resistance suggests there may be prenatal programming of lung airways.

Reviewed by: Jessica Win See Wong

Article 4: Vitamin K Prophylaxis for Vitamin K Deficiency Bleeding

Zurynski Y, Grover CJ, Jalaludin B, et al. Vitamin K deficiency bleeding in Australian infants 1993–2017: an Australian Paediatric Surveillance Unit study.

Why does it matter and a bit of context

Vitamin K deficiency bleeding (VKDB) is an uncommon but potentially fatal disorder which is mostly preventable with vitamin K prophylaxis at birth. In Australia, Intramuscular vitamin K prophylaxis was introduced in 1961. During 1993-1995 the NHMRC favoured oral vitamin K due to requiring clarification of evidence around a reported association in 1992 where an association between IM Vitamin K and childhood cancer. However with further evidence this was found not to be true. From 1995, recommendations were made for the IM administration with an option for three oral doses (which were increased from 1mg to 2mg in 2010) if parents decline the injection.

What’s it about?

In this paper, the Australian Paediatric Surveillance Unit performed a study of all cases of VKDB in infants under 6 months of age in Australia from 1993-2017.  There was 76 notifications made, however after excluding incomplete data, errors and duplicate reports, 58 cases (47 definite and 11 probable) were identified. Cases were identified based on a history of spontaneous bruising, bleeding or intracranial haemorrhage with prolonged clotting time (including INR>4 or PT <4x upper limit) If available, correction following administration of vitamin K was also included. Cases with DIC or inherited coagulopathy as the cause identified were excluded. The overall incidence of VKDB was 0.84 per 100,000 lie births which is similar to rates in other countries which recommend intramuscular vitamin K.

The cases were divided into early (9%, first 24 hours), classic (19%, Days 1-7) and late (72%, 1 week-6 months). The majority of the infants were term and breast fed. Common sites of bleeding were cutaneous 45%, GI, 34% and intracranial 29%.

Out of the 58 cases, vitamin K had not been administered to 33(57%) of the infants. In all but 5 cases, this was because of refusal of parental consent. Of note four patients were missed whose parents had consented for vitamin K. For the 14 (24%) of infants who bled following IM prophylaxis, 3 had been given low dose (0.1mg) and 3 given unknown doses. Seven infants had oral prophylaxis and VKDB – with the majority (6 of 7) having only 1-2 doses. In the group there were six deaths, all from intracranial haemorrhage. Half were from home births with refusal of vitamin K. The remaining 3 had been delivered in hospital with IM prophylaxis.

In terms of progress over time, a peak in VKDB was noted in 1992, 2000 and 2013. The 1992 peak may be explained by the concerns around administration at that time. A corresponding drop in cases in 1994 following change of recommendation back to intramuscular form was also noticed

Clinically relevant bottom line

Intramuscular vitamin K 1mg is the recommended VKDB prophylaxis in infants. The incidence rate in australia is 0.84 per 100,000 live births. AIt is important to educate and encourage parents around the importance of vitamin K prophylaxis. Given 4 babies with VKDB had missed prophylaxis despite parental consent – we must remain vigilant in upholding standards of care to avoid preventable morbidity and mortality.

Reviewed by: Grace Leo


If we have missed out on something useful or you think other articles are absolutely worth sharing, please add them in the comments!

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.


  • Grace is a Registrar at Sydney Children's Hospital. She loves innovative medical education and paediatrics. She is on the organising committee for the DFTB18 and SMACC conference. Grace is a former internal director of the AMSJ. She enjoys board games, cooking and graphic design.

    View all posts


No data was found

Leave a Reply

Your email address will not be published. Required fields are marked *