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The 69th Bubble Wrap – DFTB x CHEERI


With millions of journal articles published yearly, 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. This time CHEERI (Child Health East of England Research Initiative) are helping us out.

Article 1: Can hyperchloraemia cause AKI in critically unwell children?

Dylan Ginter, Elaine Gilfoyle, et al. Hyperchloremia and association with acute kidney injury in critically ill children. Paediatric nephrology. Published 21 November 2022.

What’s it about? 

There is robust evidence in the adult population to suggest an association of hyperchloremia with AKI in critically unwell patients, but it is limited in paediatric patients.

This is a single-centre retrospective cohort study of patients admitted to PICU between January to December 2017 in Alberta, Calgary. Patients admitted to PICU for more than 24 hours and who received intravenous fluids were included in the study. Patients were excluded if they had pre-existing kidney disease or required kidney replacement therapy within 6 hours of admission.

A total of 407 patients were recruited, of which 209 had hyperchloremia and 198 did not. Hyperchloremia was defined as a serum chloride value equal to or greater than 110 mmol/L within the first seven days of admission to PICU. Other chloride values were also collected. A decline in eGFR was calculated based on the first admission creatinine value compared to the lowest.

Results showed that 51% with hyperchloremia developed AKI compared to only 27% without hyperchloremia. The two groups were statistically different in the diagnosis category. The most common diagnosis in the hyperchloremic group was neurologic illness compared to a respiratory diagnosis in the non-hyperchloremic group. The disease severity between the two groups varied significantly but was similar for per cent fluid overload.

However, there was no significant difference in both groups regarding the length of PICU stay, mortality, need for KRT, time on mechanical ventilation or mortality.

For more discussion on high chloride-containing fluids, please take a look at this post.

Why does it matter?

After controlling for multiple confounding variables, this study had a significant association between hyperchloremia and AKI in critically unwell children. The results suggest that the association of IV fluid type with AKI development is only important if hyperchloremia develops in the patients.

However, the total amount of chloride administered was calculated only from IV fluids in the unit. It did not include specific electrolyte replacement solutions or details and type of fluids administered before transfer to the unit or hyperchloremia as a result of renal tubular acidosis thus possibly underestimating the total chloride load. In addition, The temporal relationship between hyperchloremia and AKI was evaluated at the time of admission to PICU, and any relationship between the two variables before this was not reviewed.  As this is a retrospective study, we can only conclude associations, not causations.

Clinically Relevant Bottom Line :

We need further studies looking at hyperchloremia and long-standing kidney dysfunction and those comparing the risk of AKI in balanced and unbalanced salt solutions. However, watch the chloride level as a risk for developing AKI!

Reviewed by: Rachana Varma

Article 2: Is newborn screening for spinal muscular atrophy with next-generation DNA sequencing feasible?

Shum, Bennett O V et al. “Technical feasibility of newborn screening for spinal muscular atrophy by next-generation DNA sequencing.” Frontiers in genetics vol. 14 1095600. 12 Jan. 2023, doi:10.3389/fgene.2023.1095600

What’s it about? 

For this study, a next-generation sequencing (NGS) assay was developed and used to test dried blood spot (DBS) samples from 2552 newborns (with no clinical diagnosis) for spinal muscular atrophy (SMA) to assess whether this technique is feasible for high-throughput screening.

The responsible mutation in >95% of SMA cases is an exon seven deletion in the SMN1 gene, which is the basis of detection for this NGS assay and current PCR-based tests.

The DBS samples were collected over two weeks across 80 maternity units in Queensland, Australia. Additionally, 12 positive controls were detected with 100% sensitivity. The test also had 100% specificity (no false positives), an improvement from current PCR-based assays. The new assay uses three genetic loci to discriminate between SMN1 and SMN2, whereas the previous only used one locus.

>200 DBS samples in a day were processed, with a sample failure rate of zero (no retesting needed). Therefore, it’s a robust, accurate and high-throughput test.

Why does it matter? 

SMA is an autosomal recessive disorder that causes alpha motor neuron degeneration that leads to progressive muscular weakness and sometimes death and has an incidence of approximately 1 in 10,000 live births. The affected individuals inherit an affected gene from each biological parent.

The UK currently does not do newborn screening for SMA, but screening is approved in six European countries, with all newborns being screened in Norway and Germany. This study demonstrates the technical feasibility of implementing newborn screening of SMA using NGS in the UK, which would improve clinical outcomes through earlier diagnosis and treatment. NGS testing would be more expensive to implement than PCR testing but is felt by the authors to be more cost effective due to cost-effective the ability to screen for more than one condition in the assay.

See this post for an approach to assessing the ‘floppy infant’.

Clinically Relevant Bottom Line:

This NGS test for SMA is as effective as current techniques and offers the potential for future newborn screening alongside hundreds of other conditions simultaneously.

Reviewed by: Jenny Yang

Article 3: Does the use of high flow nasal oxygen during neonatal intubation affect the success rate?

Hodgson KA, Owen LS, Kamlin COF, Roberts CT, Newman SE, Francis KL, Donath SM, Davis PG, Manley BJ. Nasal High-Flow Therapy during Neonatal Endotracheal Intubation. N Engl J Med. 2022 Apr 28;386(17):1627-1637. doi: 10.1056/NEJMoa2116735. PMID: 35476651

What’s it about?

This was a multicentre RCT looking at whether the use of high-flow nasal oxygen (HFNO) during endotracheal intubation would increase the rate of successful first-attempt intubation without physiological instability (desaturations >20% from baseline or bradycardia with heart rate <100). Secondary outcomes were the median oxygen saturation during the intubation attempt, the time to and duration of desaturation (if applicable), and the duration and number of intubation attempts. All intubations were recorded, and data was documented in a case report form and verified against the video.

It took place in two tertiary units in Australia. However, exclusion criteria did include urgent intubation as determined by the clinician and HR <120 before intubation- which is important as it does not tell us about intubation of critically unwell infants.

251 intubations were included in the study (124 in the HFNO group and 127 in the control group which was standard care). The median age was around 27 weeks, and weight was 920g.  In the HFNO group, successful first-attempt intubation without physiological instability was achieved in 50% of the intubations and 31.5% in the control group (adjusted risk difference 17.6%, 95% CI:  6% to 29.2%). This effect was more prominent when the experience of the operator was considered. In less experienced operators (<20 previous intubations), the success rate was significantly higher in the HFNO group (49.2%) compared to the control group (15.7%).

Desaturation beyond the pre-defined threshold occurred less frequently in the HFNO group.

There was no difference in the occurrence of serious adverse events (cardiac compressions or adrenaline administration within 1 hour and pneumothorax or death within 72 hours).

Some limitations of the study were that the treatments were not concealed- however, this was mitigated by the intubations being videoed- resulting in an independent verifier.

Why does it matter?

With the use of non-invasive ventilation and the adoption of less-invasive surfactant administration (LISA), trainees have fewer opportunities to become proficient in intubation. Additionally, the rate of successful first-attempt intubation is low, and attempts are often abandoned due to physiological instability in the infant.

It is important to identify interventions to improve rates of safe and successful intubations in neonates, which remains an essential skill for clinicians looking after sick neonates.

Check out this talk on neonatal intubation from DFTB18.

Clinically Relevant Bottom Line:

Using high-flow nasal oxygen during neonatal intubation improves the rate of successful first-attempt intubation without physiological instability. This seems especially beneficial for inexperienced operators.

Reviewed by: Haoxin Chen

Article 4: The hidden burden of severe myalgic encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS) in the UK.

Royston AP, Rai M, Brigden A, Burge S, Segal TY, Crawley EM. Severe myalgic encephalomyelitis/chronic fatigue syndrome in children and young people: a British Paediatric Surveillance Unit study. Arch Dis Child. 2023 Mar;108(3):230-235. doi: 10.1136/archdischild-2022-324319. Epub 2022 Dec 1. PMID: 36456114; PMCID: PMC9985735.

What’s it about?

Severe ME/CFS in the UK by the 2007 NICE guidance as fatigue so extreme that people cannot do any activity for themselves or can carry out a minimal daily task only (such as face washing and cleaning teeth). They have severe cognitive difficulties and depend on a wheelchair for mobility. They are often unable to leave the house or have severe and prolonged after-effects if they do so.

This paper summarises data on the prevalence and incidence of severe ME/CFS in children aged 5-16, obtained through a prospective surveillance study conducted by the BPSU (British Paediatric Surveillance Unit) between February 2018 and February 2019. In addition, an additional method of reporting was used by collecting data on children and young people referred to the two largest specialist ME/CFS centres at Royal United Hospitals, Bath and University College London Hospitals, London.

A total of 285 cases of ME / CFS were reported, of which 33 were severe, four probable severe and 55 possible severe. The estimated prevalence of severe ME/CFS was 3.2 per million children. Including possible/probable severe ME/CFS gave 8.9 per million children. The incidence rate was 0.9 per million children years. The median age was 13, and 58% of cases were female. The median time to diagnosis was 0.47 years.

The paper also determined that 42% of Children and Young People (CYP) with confirmed and possible/probable severe ME/CFS were not receiving any education or tuition.

Why does it matter?

The most severely unwell CYP with ME/CFS are an extremely vulnerable and, sadly, generally invisible group of patients. Although rare, their symptoms are devastating, resulting in a lack of ability to attend school or college and interact socially with their peers.

This paper reports that the incidence and prevalence of severe ME/CFS in CYP is much less than previous literature on the subject, which were estimations of paediatric ME/CFS of all degrees of severity.

Although this study reports a lower-than-expected incidence of CYP with severe ME/CFS in the UK (0.9 per million children years), many of those in this category are unable to access education or tuition, which will have significant consequences on their quality of life in both the short-term, medium-term and long-term.

Limitations to the study include a lower response rate than anticipated and a 12-month follow-up that could not be conducted due to the pandemic. In addition, the requirement for an FBC may have excluded some children and young people.

Clinically Relevant Bottom Line:

The epidemiological knowledge obtained from this study of severe paediatric ME/CFS is essential for commissioning services in the UK. Services include those provided by health and social care and the provision of tuition/homeschooling by local authorities. However, we need to do much more to understand the experience and improve treatments for children and young people most severely affected by ME/CFS, such as those bed-bound and requiring inpatient rehabilitation.

Reviewed by: Alison Skippen

Article 5: Does the use of prophylactic surfactant in preterm neonates improve outcome?

Gaertner VD, Minocchieri S, Waldmann AD et al Prophylactic surfactant nebulisation for the early aeration of preterm lung: a randomised clinical trial. Arch Dis Child Fetal Neonatal Ed Epub ahead of print: 23/3/2022. doi: 10.1136/archdischild-2022-324519.

What’s it about?

This parallel randomised controlled study conducted at the University Hospital Zurich compares nebulised surfactant administered immediately after birth to positive distending pressure alone. This was a masked trial with the blinding of parents and healthcare providers. Nebulisation was provided by a customised vibrating membrane nebuliser simultaneously with the first application of PEEP after birth.

The primary outcome was the difference in end-expiratory lung impedance from birth to 30 min after birth. All infants born between 26 0/7 and 31 6/7 weeks’ gestation were eligible, excluding those with severe congenital anomalies of the lung or genetic syndromes.

Data were analysed from 32 infants. end-­expiratory lung impedance was slightly higher in the intervention group (25 vs 10) at 6 and 12 hours after birth, particularly in the central areas of the lung. There were no differences in cardiorespiratory and clinical parameters. End Expiratory lung impedance correlates well with functional residual capacity. Two adverse events: one infant developed a pneumothorax, and the other had an airway obstruction with associated bradycardia requiring suctioning and intubation.

Prophylactic nebulised surfactant was feasible but showed minimal effects on lung physiology with no differences in clinical outcomes.

This was a single-centre study; therefore may not be generalisable. In addition, infants were only included between 26- 32 weeks- hence, results cannot be extrapolated outside of this.

Why does it matter?

Using nebulised surfactant might help deliver the surfactant directly to the baby’s lungs, thus avoiding the need and reducing the risks associated with intubation, such as vasovagal reaction or intraventricular haemorrhage.

Check out DFTB post on bronchopulmonary dysplasia.

Electrical impedance tomography is a radiation-free imaging technique that allows researchers to monitor air distribution within the baby’s lungs, which can help guide ventilation strategies and optimise lung function.

Clinically Relevant Bottom Line:

Prophylactic nebulised surfactant cannot be recommended for clinical practice, as further research is needed to evaluate its safety, efficacy and potential limitations fully. In addition, different interfaces, nebuliser types and surfactant concentrations should also be researched.

Reviewed by: Heba Hassan

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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