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The 59th Bubble Wrap


With millions of journal articles published yearly, it is impossible to keep up.  So, 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: Septic shock is a race against the clock

Sankar, J., Garg, M., Ghimire, J.J, Sankar, J., Lodha, R., Kabra, S.K. (2021) Delayed Administration of Antibiotics Beyond the First Hour of Recognition Is Associated with Increased Mortality Rates in Children with Sepsis/Severe Sepsis and Septic Shock, Journal of Paediatrics, Volume 233, pp183-190, doi: 10.1016/j.jpeds.2020.12.035

What’s it about? 

This prospective observational study looked at children between 2 months and 17 years of age who were admitted to a paediatric tertiary care centre in New Delhi with either sepsis or septic shock (definitions as per Goldstein et al., 2005). The investigators did not intervene in management but asked staff to document times for the following – recognition of sepsis, time to the first dose of antibiotics and time to first fluid bolus. The authors then compared those who received empiric antibiotics in the first hour (early) and those who received them later (delayed). The primary outcome was mortality. Secondary outcomes were a validated paediatric organ dysfunction score, days in ICU, inotrope-free days, ventilator-free days and antibiotic-free days.

Over two years, 441 children were enrolled, 200 received antibiotics early, and 241 received delayed antibiotics. In each group, there was a higher proportion of patients with septic shock than sepsis (161 vs 39 in the early antibiotic group and 179 vs 62 in the delayed antibiotic group).

The significant finding, which supports other sepsis studies in both the adult and paediatric population, was that the odds ratio (OR) for mortality was higher in the delayed antibiotic group for children with septic shock (unadjusted OR 1.75, 95%CI 1.08 – 2.84, p=0.02). It was also higher, but not statistically significant, for the delayed antibiotic group for the children with sepsis (unadjusted OR 1.50, 95%CI 0.42 -5.35, p=0.92).

Why does it matter? 

Mortality and morbidity from paediatric sepsis vary from country to country. Still, it is higher in low- or middle-income countries where there is a greater burden of illness, limited resources, variable paediatric training and reduced access to intensive care units. Studies like this could help guide the development of sepsis guidelines and also help design parental education programs to recognise the unwell child to encourage timely presentations to the hospital.

Clinically Relevant Bottom Line:

This study reiterates the importance of early administration of empiric antibiotics, particularly for children with severe sepsis and septic shock; the authors found the odds ratio for mortality was higher in those who had delayed administration. Therefore, hospitals should continue educating staff and promoting early empiric antibiotics’ importance in their sepsis guidelines.

Reviewed by: Tina Abi Abdallah

Article 2: Do inhaled antibiotics improve respiratory function in children with bronchiectasis?

Twiss J, Stewart A, Gilchrist CA, Keelan JA, Metcalfe R, Byrnes CA. Randomised controlled trial of nebulised gentamicin in children with bronchiectasis. Journal of Paediatrics and Child Health. 2022 Feb 16. doi: 10.1111/jpc.15899

What’s it about? 

This study examined whether nebulised gentamicin improved respiratory function in children with non-cystic fibrosis (non-CF) bronchiectasis. This was a randomised, double-blind, placebo-controlled, crossover trial of 12-week nebulised placebo/ gentamicin, 6-week washout, then 12-week gentamicin/ placebo. They recruited 15 children aged 5-15 with non-CF bronchiectasis, chronic infection (any pathogen) and who could perform spirometry in a hospital bronchiectasis clinic over 2.5 years. The two (!) primary outcomes were change in FEV1 and rate of hospitalisation for exacerbations. Secondary outcomes included sputum bacterial density, inflammatory markers, total antibiotics required and symptom severity.

With respect to primary outcomes, there was no significant change in mean FEV1 (56% vs 55%) or the annual rate of hospitalisation (1.1 vs 0) between gentamicin and placebo, respectively. There was a statistically significant reduction in Haemophilus influenzae sputum bacterial growth (27% vs 80%) and bacterial density as well as sputum inflammatory markers (interleukin-1β, interleukin-8 and tumour necrosis factor-α) following inhaled antibiotic administration. Children were less likely to receive additional antibiotics for respiratory exacerbation and had reduced symptom severity when receiving gentamicin. Treatment adherence was poor, like other studies on inhaled antibiotics in the paediatric cohort.

Why does it matter? 

Non-CF bronchiectasis is an obstructive respiratory disease manifesting as a chronic productive cough, recurrent bacterial infections and progressive lung damage. Childhood-onset bronchiectasis differs from adult-onset bronchiectasis in that early detection and treatment can halt, and possibly even reverse, disease progression in children.

Haemophilus influenza is the most common organism causing infection, with several oral antibiotic treatments available for children. However, inhaled antibiotics may be better for highly concentrated, localized antibiotic delivery with fewer systemic effects. Trials in adults have shown a reduction in sputum bacterial density, frequency of exacerbation, and increased bacterial eradication with inhaled antibiotics; however, there is no consistent improvement in quality of life or FEV1. The efficacy of inhaled antibiotics in children with non-CF bronchiectasis has not been clinically determined, hence the importance of this clinical trial. 

Clinically Relevant Bottom Line:

Treatment of children with non-CF bronchiectasis with inhaled gentamicin significantly reduces sputum bacterial density and inflammation. However, there were no overall significant improvements in the hospitalisation rate or FEV1. Adherence to the treatment regime was a substantial hindrance for this paediatric cohort.

Reviewed by: Emma Chan

Article 3: Does HIE work in LMICs?

Thayyil, S. et al 2021. Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh. The Lancet Global Health, 9(9), pp.e1273-e1285.

What’s it all about?

HELIX is a multi-country randomised control trial in 7 large neonatal intensive care units across India, Sri Lanka and Bangladesh looking at therapeutic hypothermia (‘cooling’) in neonatal encephalopathy. A team at Imperial College London oversaw the trial. The units used the same cooling device used in Imperial and high-level neonatal intensive care including 3t MRI scanning, facilities for intubation and invasive cardiovascular monitoring overseen by experienced neonatal consultants. 408 infants were enrolled, 202 in the treatment group and 206 in the control group. Survival analysis showed a significant difference between groups, with hypothermia increasing the risk of death at any time by 47%. This means for every 9 infants treated, one additional infant will die.

Why does it matter?

Neonatal encephalopathy causes 1 million deaths yearly, 96-99% of which are in low and middle-income countries (LMICs). Therapeutic hypothermia is a well-established intervention worldwide, and since 2015, low-cost cooling devices have been used in LMICs.

The Bottom Line:

The paper’s authors would argue that therapeutic hypothermia should not be offered for neonatal encephalopathy in LMICs, even when tertiary neonatal facilities are available.

Reviewed by: Freya Guinness

Article 4: Does the shock index help diagnose serious illness in febrile children?

Hagedoorn NN, Zachariasse JM,Borensztajn D, et al. Arch Dis Child 2022;107:116–122.Shock Index in the Early Assessment of febrile children at the emergency department – a prospective multicentre trial.

What’s it about?

Predicting serious illness in febrile children is difficult. This multi-centre trial looks at the reference ranges for shock index (heart rate/systolic BP) to determine the diagnostic value of the shock index in serious illness in febrile children. As with everything in paediatrics, the shock index values are age-dependent. In adults, a shock index of > 1.3 is associated with an increased risk of admission and mortality. The caveat is that hypotension is generally a late sign of serious illness in children.

Why does it matter?

We have all been in that difficult situation looking after a child with a fever and tachycardia that looks unwell.  This study revealed low numbers of serious bacterial infections in this group (8.2%). 0.8% needed immediate life-saving interventions, with only 1.2% requiring admission to PICU from the ED. They had robust criteria for a ‘presumed bacterial infection’ and excluded units that did not have complete data sets. 

The bottom line

This is the first study to examine validated, age-appropriate shock index values. A high shock index in a child with a fever appears to be associated with serious bacterial infections. It also may be used to predict PICU admission and the need for fluid resuscitation and treatment escalation alongside other clinical markers.   Its low sensitivity suggests it is not the early screening tool everyone hoped it would be.

Reviewed by: Sam Danaher

Article 5: Can we be better at triaging patients with comorbidities?

Zachariasse JM, Espina PR, Borensztajn DM, et al. Improving triage for children with comorbidity using the ED-PEWS: an observational study. Arch Dis Child 2022;107:229–233.

What’s it about?

Paediatric patients with chronic underlying conditions represent a vulnerable population presenting in the ED. Failure to identify serious illness during triage may lead to misdiagnosis and worse outcomes for this patient cohort.

This study looked to see if the ED-PEWS triage system could improve the triage of paediatric patients with comorbidities presenting to the Paediatric ED.

This was a secondary analysis of a prospective cohort that included 53,829 consecutive paediatric ED visits of children <16 years in three European hospitals (Netherlands, UK, and Austria). They participated in the TrIAGE (Triage Improvements Across General Emergency departments) project between 2012 and 2015. The presence of comorbidities was assessed using ICD-9 codes. 5053 (9%) paediatric patients had non-complex morbidity, and 5537 (10%) had complex issues.

The c-statistic for the identification of high-urgency patients was 0.86 (95% CI 0.84–0.88) for children without comorbidities, 0.87 (0.82–0.92) for non-complex comorbidities and 0.86 (0.84–0.88) for complex issues.

ED-PEWS showed comparable performance in identifying children with underlying chronic conditions compared with previously healthy children.

There is no gold standard to evaluate triage and early warning scores. The authors chose a three-category reference based on TriAGE trial methods and expert opinion.

Why does it matter?

This is one of the first studies explicitly targeting the triage of paediatric patients with chronic medical conditions.

Clinically Relevant Bottom Line:

Combining ED-PEWS with the Manchester Triage System improved the triage and correct identification of high-urgency paediatric patients with comorbidities.

Reviewed by: Spyridon Karageorgos

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.

All articles reviewed and edited by Vicki Currie.


  • Vicki is a Paediatric Registrar in the West Midlands in the UK , starting PEM in September 2021. Vicki is passionate about good communication in teams and with patients along with teaching at undergraduate and postgraduate level. When not editing Bubble wrap Vicki can be found running with her cocker spaniel Scramble or endlessly chatting with friends.


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