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The 43rd 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: Is ketamine the go-to for intubation in critically ill kids?

Conway JA, Kharayat P, Sanders RC Jr et al. Ketamine Use for Tracheal Intubation in Critically Ill Children Is Associated With a Lower Occurrence of Adverse Hemodynamic Events. Crit Care Med. 2020;48(6):e489‐e497.

What’s it about? 

Our adult colleagues have been wielding this debate for at least half a decade; but does it hold true in kids? This study investigated whether ketamine induction for tracheal intubation in critically ill children was associated with a reduced risk of adverse haemodynamic outcomes. Ketamine’s sympathomimetic effects are thought to cause hemodynamic preservation in acutely unwell patients, and thus has been previously recommended for induction in children with haemodynamic instability. 

This retrospective analysis of tracheal intubations performed January 2013 to June 2017 from forty PICUs worldwide, used data entered into the National Emergency Registry for Children database. Only the initial attempt at tracheal intubation was analysed. 

Adverse haemodynamic outcomes were defined as dysrhythmia, hypotension requiring intervention or cardiac arrest occurring within 20 minutes of tracheal intubation. Encounters in which ketamine was administered both with and without other medications were reviewed.

More than 10,000 primary tracheal intubations were performed, with about 1 in 3 using ketamine as an induction agent. Ketamine was used in 41.4% of children for whom haemodynamic instability was the primary indication for intubation, as opposed to only 35% of cases where a procedure was the indication, and 17.1% of neurological indications. The majority of children receiving ketamine were intubated for respiratory indications, reflective of respiratory compromise being the predominant cause for intubation in the paediatric population.

The mean dose of ketamine used for induction was 1.88mg/kg. Interestingly, the higher the dose per kilogram of ketamine used, the lower the odds of developing haemodynamic outcomes in children both with and without haemodynamic instability.

As a baseline, around 1 in 20 children had an adverse haemodynamic outcome in all children intubated either with or without ketamine. The most common adverse outcome was hypotension, occurring in 1 in 30 cases. The children who received ketamine were at significantly lower odds of developing poor haemodynamic outcomes (odds ratio 0.75 with a 95% confidence interval; p=0.002), irrespective of wheter they were intubated for haemodynamic instability versus other indications. 

Why does it matter? 

This large retrospective cohort study encompassing data from forty international PICUs is one of the first and largest studies illustrating a protective effect of ketamine against poor haemodynamic outcomes following tracheal intubation in a paediatric population. This protective effect spanned a range of indications including haemodynamic instability, sepsis and neurological indications. The protective effect was also consistent across patients both with and without haemodynamic instability.

Clinically Relevant Bottom Line:

These findings suggest that ketamine is an appropriate induction agent for children requiring tracheal intubation irrespective of the indication or haemodynamic status, in the PICU setting. Ketamine use is associated with a lower occurrence of adverse haemodynamic outcomes.

Interestingly, video laryngoscopy was used more in the ketamine intubations, and its use was also associated with lower odds of adverse haemodynamic outcomes. The protective effect of ketamine against haemodynamic adverse effects was also increased by concomitant use of midazolam. As the data analysed by this study was derived from intubation in PICU; care should be taken when applying the findings to other settings where tracheal intubation commonly occurs such as the emergency department, where there may less time to plan the intubation approach and lower availability of video laryngoscopy.

Reviewed by: Monica Parker

Article 2: Is amoxicillin superior to placebo in the treatment of mild pneumonia?

Jehan F, Nisar I, Kerai S, Balouch B, Brown N, Rahman N et al. Randomized Trial of Amoxicillin for Pneumonia in Pakistan. New England Journal of Medicine [Internet]. 2020;383(1):24-34.

What’s it about? 

This double-blind, randomised controlled study looked at the management of mild pneumonia in 3,856 children aged 2-59 months in Karachi, Pakistan. Mild pneumonia in the study was defined as children with a cough and/or difficulty breathing with tachypnoea (Children 2-11 months, RR >50 or children 12-59 months, RR>40). If wheeze was present, children were given three doses of inhaled bronchodilator therapy and these children were only included in the study if tachypnoea persisted post-bronchodilator delivery. Children were excluded if they had any ‘danger signs’ (not able to drink, persistent vomiting, convulsions, lethargic or unconscious, stridor in a calm child or severe malnutrition), had received antibiotics in the past 48 hours, had been hospitalised in the last 2 weeks or had any of; pedal oedema, TB, asthma, or other severe illness for which antibiotic therapy was warranted. 

The study assessed for non-inferiority between the current, WHO recommended treatment, a 3-day amoxicillin course (twice daily, weight-based dose) and a matched volume placebo. The primary outcome was treatment failure, assessed on day 0, 1, 2, and 3. Treatment failure was deemed to have occurred if the child developed danger signs, retraction of the lower chest wall, required hospitalisation, died, or if the treating physician changed the regime due to a new onset infection, or a serious adverse event. Treatment failure occurred in 95 children (4.9%) in the placebo group and 51 children (2.6%) in the amoxicillin group, with a percentage difference of 2.3%. The raw percentage margin required for non-inferiority was <1.75%, and thus the study did not show non-inferiority of placebo to amoxicillin (wow, that is confusing!) – suggesting amoxicillin is superior to placebo to treatment of children with mild pneumonia. The study assessed relapse by day 14 as a secondary outcome measure and found no difference between the two groups.

Why does it matter? 

Acute lower respiratory tract infections are a significant cause of mortality in children worldwide. Ensuring children receive adequate treatment is crucial, however in modern medicine where antibiotic resistance is becoming increasingly worrying, we must be vigilant and selective in our prescribing. This study found that to prevent 1 treatment failure, 44 children needed to be treated with antibiotics. It also noted that in the placebo group, treatment failure was more likely in children who had either a fever or wheeze. These findings suggest there are likely phenotypes of ‘mild pneumonia’ that do not require antibiotics – they just need classification.

Clinically Relevant Bottom Line:

With increasing antibiotic resistance it is essential to use antibiotics judiciously in a Paediatric population; in clinical settings dependent on the WHO definition of pneumonia, initiating antibiotics is a reasonable course of action. However, we acknowledge the broad phenotype and challenging differential diagnosis in preschoolers presenting with tachypnoea.

Reviewed by: Phoebe Campbell

Article 3: Neurodevelopmental outcomes after SSRI or SNRI exposure in utero…?

 Singal D, Chateau D, Struck S, Lee JB, Dahl M, Derksen S, Katz LY, Ruth C, Hanlon-Dearman A, Brownell M. In utero antidepressants and neurodevelopmental outcomes in kindergarteners. Pediatrics. 2020 May 1;145(5).

What’s it all about?

This study investigated whether in-utero exposure to selective serotonin reuptake inhibitor (SSRI) or selective serotonin norepinephrine inhibitor (SNRI) has an effect on neurodevelopmental outcomes in children.
The effects of maternal depression on the fetus, infant and preschool child has the potential to be an incredibly controversial topic. Acknowledging the significant complexity of this topic, we offer our brief review of this recent paper examining the impact of in utero SNRI on developmental outcomes in a Canadian population spanning 18 year and over 260,000 mother-child dyads.

The authors narrowed the population for study to mothers with a diagnosis of mood or anxiety disorder 90 days before conception until birth of the child; a population of 3050 children born in Manitoba, Canada between 1996 and 2014. 

Children were allocated to either the exposed group N=528 (mothers who had 2 or more SSRI or SNRI prescription dispensations during pregnancy) or the unexposed group N=2522 (mothers who did not have an SSRI or SNRI prescription during pregnancy).

The children had an Early Development Instrument (EDI), a 104-component questionnaire to assess the developmental health in kindergarten children in 5 domains:

  • 1) physical health and well-being,
  • 2) language and cognitive development,
  • 3) social competence,
  • 4) emotional maturity and
  • 5) communication skills and general knowledge.

Around 1 in 5 children in the exposed group were assessed as vulnerable on 2 or more domains on the EDI compared to 1 in 6 of children in the unexposed group (adjusted odds ratio=1.43; 95%CI 1.08-1.90).

Children in the exposed group had a significant risk of being vulnerable in the domain of language and cognitive development.

Why does it matter?

Children exposed in-utero to antidepressants (SSRIs or SNRIs) have higher rates of adverse outcomes in infancy such as neonatal abstinence syndrome, pulmonary hypertension and cardiac defects. However, few studies investigated the long-term neurodevelopmental effects in-utero exposure to these medications on child neurodevelopment, likely because of the complex relationship between maternal mental illness (treated or untreated), in utero exposures and other environmental factors. For a broader understanding of this topic, we recommend reading about Adverse Childhood Experiences .

Clinically Relevant Bottom Line:

The study identifies that children of mothers diagnosed with a mood/anxiety disorder who took antidepressants during pregnancy had an increased risk of developmental vulnerability and an increased risk of having language and cognitive difficulties in kindergarten, however this must be interpreted with some circumspection given the complexity of this area.

Reviewed by: Jessica Win See Wong

Article 4: Navigating the topic of COVID19 within pediatric palliative care consultations 

Ekberg, K., Weinglass, L., Ekberg, S., Danby, S., Herbert, A. (2020) The pervasive relevance of COVID-19 within routine paediatric palliative care consultations during the pandemic: A conversion analytic study, Palliative Medicine, doi: 10.1177/0269216320950089

What’s it about?

I think most would unanimously agree that COVID19 caused by the virus SARS-CoV2 has made a significant impact on lives across the globe. The lingering sense of uncertainty over our future way of life has caused unprecedented levels of fear and anxiety for many, and now more than ever is the time to protect our vulnerable population groups. Children with complex and serious medical conditions comprise our pediatric palliative care patients who rely on effective communication to coordinate all aspects of their care. Currently, there is minimal data on how the content and delivery of paediatric palliative care consultations has changed to adapt to the uncertain pandemic climate.

This conversation analysis study aimed to examine real-life paediatric palliative care consultations prior to, during and immediately following the first COVID19 pandemic wave in Brisbane, Australia to understand how clinicians and families address the pandemic in context of multi-disciplinary, chronic disease management. Twenty-five paediatric palliative care consultations – comprising 15 consultations pre-COVID19 and 10 consultations during and post-COVID19 – were video-recorded in a public children’s hospital. All pre-COVID19 consultations were face-to-face appointments, whereas the pandemic consultations comprised both telehealth and face-to-face appointments. Video-recorded data was transcribed to delineate how different conversational sequences related to COVID19 and its associated impact on daily life arose and were responded to in conversation. No children included in this study had a formal diagnosis of Coronavirus at the time of their recorded consultation.

Consultations lasted a mean duration of 41.5 minutes. Consultations recorded during the COVID19 pandemic revealed that relatively standard topics of discussion within pediatric palliative care discussions would often segue to discussions around COVID19 and occasionally elicit pandemic-specific issues of concern. Example conversations included concerns for simple analgesic use (ie ibuprofen) potentially aggravating symptoms of coronavirus or the perceived risks of hospital visits amidst the pandemic. The pandemic was discussed between 1 to 6 times for each of the 10 consultations, and was more often initiated by clinicians (55%) followed by parents (45%).

Why does it matter?

Effective communication between healthcare teams and families of paediatric palliative care patients is pivotal to achieving a holistic care model that encompasses the medical, psychosocial, cultural and spiritual aspects. COVID-19 has changed our world, including creating physical barriers to communication and management, and given rise to multiple topics of uncertainty that may complicate management. Clinicians should be well informed and equipped to navigate these new barriers and tricky conversations about COVID19 to help these families acclimate and make adjustments to the new ways of life amidst the global pandemic.

The bottom line

Given the enormity and pervasiveness of the COVID19 pandemic, this topic will inevitably be brought up in medical consultations. Clinicians and families of pediatric palliative care patients should be prepared to have an open conversation about COVID19 and its potential impacts on patient care. Clinicians will benefit from having a general approach to certain topics in the context of the pandemic, for example, medication choices, managing exacerbations of disease, school and social life, mental wellbeing, family dynamics. This will not only be largely beneficial in creating a safe management plan for the future, but may help soothe the emotional fears and uncertainty related to the pandemic amongst families and healthcare professionals.

Reviewed by: Emma Chan

Article 5: Another pharmaceutical company study or a promising therapy for RSV?

Griffin, M.P., Yuan, Y., Takas, T., Domachowske, J.B., Madhi, S.A., Manzoni, P., Simões, E.A., Esser, M.T., Khan, A.A., Dubovsky, F. and Villafana, T., 2020. Single-dose nirsevimab for prevention of RSV in preterm infants. New England Journal of Medicine383(5), pp.415-425.

What’s it about?

This RCT looked at the incidence of RSV-associated LRTI following nirsevimab injection, compared with placebo. Palavizumab was the first monoclonal antibody approved for this indication, more than a decade ago. The new mab on the block nirsevimab is a monoclonal antibody for an epitope on the RSV fusion protein, and appears to have enhanced neutralizing activity and a serum half-life of approximately 60 days.

Why does it matter?

RSV is a common cause of lower respiratory tract infection (LRTI) globally. It is responsible for the hospitalization of many children and is a leading cause of infant death in developing countries. Infants at risk include ex-premature babies, those with chronic lung disease or congenital cardiac disease. Given the impact of RSV-related disease, an effective and safe vaccine has been pursued for many years.

Healthy, ex-premature infants (born between 29 and 34+6 weeks) who met the stringent inclusion criteria were recruited from 23 countries, and analyzed as Northern vs Southern Hemisphere RSV seasons. Across the 23 countries, only ~1500 infants were entered in the study. Infants were randomized (unevenly at 2:1 in favour of the intervention!) to receive an intramuscular injection of nirsevimab 50mg or saline placebo. The primary outcome was the development of a RSV-associated LRTI which required medical review within 150 days of receiving the injection.

The results were promising, with a statistically significant difference between the intervention and placebo group. The incidence of RSV-associated LRTI requiring medical review was ~ 1 in 38 after nirsevimab and ~1 in 10 with placebo.

Clinically Relevant Bottom Line:

It almost sounds too good to be true, something amplified by a strongly positive trial funded by AstraZenca and Sanofi, the manufacturers of nirsevimab, including all authors being employed or owning shares in the companies. It is also worth noting that the paper did not go into great depths regarding the methodology or statistical analyses, and data was analysed by AstraZeneca employees. Other low hanging criticisms here include the threshold for presentation, the varied availability of healthcare, volunteer bias, frequency of respiratory virus testing and more. We’d recommend this paper as an interesting journal club article for further, robust critique! Further studies investigating nirsevimab are definitely warranted to ensure the results are reproducible, and then the unavoidable head to head with palivizumab.

Reviewed by: Tina Abi Abdallah

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.


  • The house-elves are still hard at work, copying, pasting, and occasionally weaving a little magic!



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