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The 68th Bubble Wrap


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.

Article 1: Saline vs other fluids on PICU- how does it affect outcomes?

Raman S, Gibbons KS, Mattke A, et al. Effect of Saline vs Gluconate/Acetate–Buffered Solution vs Lactate-Buffered Solution on Serum Chloride Among Children in the Pediatric Intensive Care Unit: The SPLYT-P Randomized Clinical Trial. JAMA Pediatr. Published online December 19, 2022. doi:10.1001/jamapediatrics.2022.4912

What’s it about? 

This study used biochemical and patient-orientated outcomes to investigate the effects of saline versus gluconate/acetate or buffered lactate solutions for maintenance fluid therapy in PICU. Authors employed a 3-arm open-label randomised control design within their centre where patients were allocated to receive a gluconate/acetate buffered solution, a lactate buffered solution or saline as their sole maintenance fluid after randomisation.

Patients were excluded if their diagnosis required a protocolised fluid regimen, such as DKA or burns, or if they had been admitted and randomised within the previous 28 days. The primary outcome measure was a plasma chloride rise greater than or equal to 5mEq/L (5mmol/L) within 48hr of randomisation. Secondary outcomes included new acute kidney injury (AKI) and PICU length of stay.

To detect a significant difference in plasma chloride between the groups, power calculations showed that 432 patients would need to be enrolled. However, the authors surpassed this and managed to randomise 583 patients, including 516, in their final analysis. Statistical methods included mixed effects modelling to account for impacts of random and fixed effects on the plasma chloride and Cox proportional hazard models to correct for factors affecting the length of stay other than plasma chloride level.

Of the included patients, 178, 171 and 167 were allocated to the gluconate/acetate buffered solution, lactate buffered solution or saline groups respectively. There was no significant difference between volumes of fluid received across these groups. The odds ratio for a rise of ≥ 5mmol/L plasma chloride was 0.5 in those receiving gluconate/acetate buffered solutions vs saline and 0.47 in those receiving lactate buffered solutions vs saline. This demonstrates a significantly lower risk of rises of ≥ 5mmol/L in plasma chloride when buffered solutions are used over saline. The secondary outcomes show more cases of new-onset AKI in patients receiving buffered solutions than saline but the study was not powered to determine whether these differences are significant.

Why does it matter?

The study showed that buffered solutions, when used as sole maintenance therapy within the PICU, have a lower risk of raising plasma chloride levels by 5mmol/L or more. This is significant as a wealth of evidence from adult ICU literature shows that rises in plasma chloride levels are associated with a higher risk of AKI and mortality.

See for the latest guidance on paediatric resuscitation fluids in addition to that goes through a case to highlight many valuable points, including fluid use.

Although there was not enough power or data within this study to link the plasma chloride rises to patient orientated outcomes such as AKI or mortality, and its single centre design prevents wider application, it forms a basis for further work looking at the patient orientated outcomes of different fluid types. 72.3% of patients received saline prior to randomisation and there were several instances of fluid contamination. In addition there were several deviations from the study protocol but it is unclear if these affected overall outcomes.

Clinically Relevant Bottom Line :

Based on this study’s data, buffered solutions, when used for maintenance fluid therapy within PICU, have a lower risk than saline of raising plasma chloride levels. This may help reduce renal dysfunction and mortality in this population, but further study is required to state this.

Reviewed by: Cameron Morrice

Article 2: Which is better, oral ibuprofen or ketorolac, in moderate to severe traumatic pain?

Ghirardo S. et al. Oral ibuprofen versus oral ketorolac for children with moderate to severe acute traumatic pain: a randomized comparative study. European Journal of Pediatrics. December 2022. doi: 10.1007/s00431-022-04759-3

What’s it about? 

Musculoskeletal injuries are a significant source of acute pain and a common reason for presentations to the pediatric emergency department (PED). Non-steroidal anti-inflammatory drugs (NSAIDs) are the analgesic of choice with an efficacy similar to opioids in this setting. Oral ibuprofen is the most commonly used NSAID, while ketorolac (another NSAID) is considered the best choice for severe acute pain. This multicenter randomised, double-blind trial aimed to compare the effectiveness of oral ibuprofen and ketorolac for acute traumatic moderate and severe pain in children and adolescents.

Patients aged 8 to 17 years presenting to two Italian centers complaining moderate to severe pain related to limb trauma. Pain was rated through NRS-11 scale (scores 4 to 6 were considered “moderate” and 7 to 10 “severe” pain). Eligible patients were divided in a “moderate pain” and “severe pain” groups and then randomly assigned to receive either 10 mg/kg of oral ibuprofen or 0.5 mg/kg oral ketorolac. Pain score was recorded every 30 min until 2 hours after drug administration. Primary outcome was the difference in NRS-11 reduction between ibuprofen and ketorolac after 60 min. Secondary outcomes were the difference in NRS-11 at 30-60-90-120 min, the number of patients achieving NRS-11 <4, the number of patients with a NRS-11 reduction >3 points at each time point and the number of those asking for rescue analgesic.

Two hundred twelve (212) patients were enrolled: 125 with severe pain (63 randomized to ibuprofen and 65 to ketorolac) and 87 with moderate pain (43 randomized to ibuprofen and 62 to ketorolac). No differences were found in the median pain score differences T0-T60 between those receiving ibuprofen or ketorolac (2.0 vs 1.0 respectively; p = 0.36) in patients with severe pain. At T60 and T90 the ibuprofen group revealed a lower median pain score and at 90 min a higher proportion of pain score decrease >3 points (p=0.01) and with pain scores <4 points (p=0.03) as compared to the ketorolac group. Regarding patients with moderate pain, no significant differences were recorded in the median pain score differences T0-T60.The mean change in score reduction between groups at T60 was 0.17 in ketorolac favor, no differences were observed for the other outcomes evaluated.

This study has limitations. First of all, ketorolac is administered orally and not sublingually (as it is often used) to avoid the possible bias of different absorption related to the route of administration (to maintain blinding of patients, nurses and clinicians). Secondly, despite being given at 0.5 mg/kg, the maximum dose allowed for ketorolac was only 10 mg which could be significantly underdosed in a proportion of the patients.

Why does it matter? 

Ibuprofen is currently the most widely used NSAID in children for acute pain, licensed from 6 months of age. This study demonstrated that oral ibuprofen was not inferior to oral ketorolac in managing children and adolescents presenting with acute severe traumatic pain. However, more is to be done to prove oral ibuprofen is not-inferiority to oral ketorolac in those with moderate acute traumatic pain.

Clinically Relevant Bottom Line:

Oral ibuprofen and ketorolac are similarly effective and thus can be used indifferently in managing children and adolescents presenting with acute traumatic musculoskeletal pain.

Reviewed by: Giacomo Stera

Article 3: Asking about fasting during Ramadan

Dabaja E, Haidous M, Shihan H, Haidar-El-Atrache S. Statewide Physician Survey Regarding Pediatric Muslim Fasting. Fam Community Health. 2023 Jan-Mar 01;46(1):51-57. doi: 10.1097/FCH.0000000000000351. PMID: 36383231.

What’s it about?

The paper is part of a longitudinal multiphase study in Michigan, USA, to assess how often Ramadan fasting intentions and behaviours are discussed with paediatric patients and how much comfort and/or confidence physicians have with the subject. They recruited 242 participants into the study, the vast majority of whom were specialist paediatrics trained, with just 5% being primary care and 8% being medical physicians with a particular interest in paediatrics.

Why does it matter?

Fasting during Ramadan is considered one of the primary pillars of the Muslim faith and an essential practice for Muslim families.  In previous studies, a majority of Muslim parents (84%) described paediatric fasting as either “moderately” or “very” important. However, there appear to be no published studies on either the long- or short-term health outcomes of paediatric fasting.  Other literature suggests that patients may take a lack of discussion of fasting as tacit approval to fast. This questionnaire demonstrates that the lack of a debate is likely due to physician discomfort and lack of knowledge.

Responses to the survey showed that most respondents had at least “a little” exposure to paediatric Muslim patients (97%), but that 60% of respondents had either no or minimal understanding of fasting practices. Only 11% described their knowledge as “advanced” despite 18% of respondents self-identifying as Muslim. 52% described themselves as either “extremely” or “somewhat” uncomfortable providing recommendations and so perhaps it is unsurprising that 44% of respondents “never” ask about fasting or intent to fast (this rises to 66% if including those that do not usually see Muslim patients or those that do not feel it is relevant to their practice). Convenience sampling in this study makes it unreliable to generalise the results of this to the population as a whole.

Have a look at this post to find out more about how paediatric presentations may differ more during Ramadan .

Clinically Relevant Bottom Line:

As a proportion of the world’s religions, Islam is expected to grow to 29.7% by 2050 (from 23.2% in 2010). The number of people practising Islam likely to be in contact with medical professionals in non-Muslim predominant countries is expected to grow. This means that understanding fasting practices and the best medical practices around them will only grow in importance.

Reviewed by: Andy Moriarty and Tara George

Article 4: Are the health and nutrition claims for infant formula accurate?

Cheung K Y, Petrou L, Helfer B, Porubayeva E, Dolgikh E, Ali S et al. Health and nutrition claims for infant formula: international cross sectional survey BMJ 2023; 380 :e071075 doi:10.1136/bmj-2022-071075

What’s it about?

This international cross sectional study aims to review available health and nutrition claims for infant formula products in across 15 countries (Australia, UK, Canada, Germany, India, Italy, Japan, Nigeria, Norway, Pakistan, Russia, Saudi Arabia, South Africa, Spain and USA) from 2020- 22. The countries were selected to provide a sampling from high-income and low, middle-income countries with a protocol used for data extraction. The primary outcome was to review the number and type of claims made for each product and ingredient. The references were cited and reviewed for the risk of bias using Cochrane risk of bias tool. As a result, 757 infant formulas were identified each with a median of 2 claims.

There were 31 types of claims across all products. 608 >1 claim the most common claims were: ” helps/supports development of brain and/or eyes and/or nervous system” (323 (53%) products, 13 ingredients), “strengthens/ supports a healthy immune system” (239 (39%) products, 12 ingredients), and “helps/supports growth and development” (224 (37%) products, 20 ingredients)”. Forty-one groups of ingredients were associated with >1 claim; however, many claims were made without any specific reference to a particular ingredient (50%).

The most cited ingredient associated with a claim was polyunsaturated fatty acids (46% of products- which totalled 9 different claims), probiotics, prebiotics or symbiotics (37% products 19 claims). 26% of products with >1 claim provided a reference. 90% of all claims referenced were clinical trials with a high risk of bias. All cited systematic reviews and pooled analyses also had an increased risk of bias- using the Cochrane risk of bias tool. There were multiple different claims for similar ingredients across competing formula products. In addition, there were various ingredients with the same category of claim attributed to them, and the evidence backing up these claims had a high risk of bias.

The data of this study was taken from multiple countries; however, with multiple researchers, there could have been differences in extraction processes across sites. With only 15 countries participating, it only partially represents the global situation.

Why does it matter?

Although human breast milk is the optimal source of infant nutrition, multiple families worldwide choose formula to feed their children. The choice of formula can be influenced by medical, socioeconomic, socio-political, psychosocial and economic factors. Recent research by WHO and UNICEF has highlighted how powerful the marketing of infant formula can be. The perceived benefits of the formula are controversial because they can be enhanced and sometimes even seen as superior to breastfeeding.

Clinically Relevant Bottom Line:

Despite attempts at a global level, unbiased data and transparency surrounding health claims for term infant formula are still lacking. There is a high prevalence of health claims in multiple formulas in multiple countries with little or no scientific backing. There needs to be more work done to ensure that customers are protected from biases when purchasing breast milk substitutes.

Reviewed by: Vicki Currie

Article 5: What’s the lactate?

Rocha, A.C., Chagas, J.B., Andrade, J.V., Pinto, C., Oliveira, G., Dias, A.S., Carvalho. (2022) The Prognostic value of delta-lactate in critically ill children. Journal of Paediatrics,Volume 59, pp328-334, doi: 10.1111/jpc.16294

What’s it about?

Hyperlactatemia is a sign of hypoperfusion and indicates a critically unwell child, but can it be used to predict outcomes?

This retrospective exploratory study reviewed four years’ worth of data (January 2016 to December 2019) for children aged one month – 18 years admitted to a PICU in Portugal. They excluded post-operative patients, those admitted for less than 48 hours, had less than two serum lactate measurements, or if the serum lactate measurements were less than 24 hours apart.

There were 1564 patients admitted during the time frame, and 249 patients met the inclusion criteria. The following information was retrieved from medical records: basic demographics (age, gender), duration of admission, diagnosis, paediatric index of mortality score 3 (PIM3), co-morbidities, need for invasive ventilation, ventilation free days, acute kidney injury +/- the need for renal replacement, the need for vasoactive drugs, procalcitonin level (at admission, peak level, time until normalisation), lactate levels (peak level on day 1 and day 2, time until normalisation) and death (during PICU admission or at 28 days). The authors determined the difference between the lactate levels on day 1 and day 2 would be delta lactate (DL), and used this value to create two groups for comparison:

  • Low mortality risk (LMR): decrease in lactate levels > 0.05mmol/L
  • High mortality risk (HMR): decrease in lactate levels < 0.05mmol/L

Patients who had elevated serum lactates (median of maximum lactate level) on day 1 and day 2 was associated with increased mortality, during PICU admission (p = 0.006) and at 28 days (0<0.001). However, there was no statistically significant association between DL and mortality. Those patients with an elevated lactate on day 1 and who also fell into the HMR group had longer admissions, higher PIM3 scores, fewer ventilation free days and were more likely to require renal replacement therapy. The median PIM3 scores was statistically significantly higher in the HMR group compared to the LMR group (p< 0.001).

Why does it matter?

They found those with higher elevated serum lactate levels over day one and day two had higher mortality and required more interventions during their PICU admission. They also identified an association between the lactate trend and mortality. Unfortunately, it could not determine a precise cut-off level for the trend to be able to use a set value as a prognostic marker. As we all know, lactate sampling can sometimes be an issue.

The authors acknowledged the sample’s heterogenicity as a potentially limiting factor. Because it was retrospective, insufficient lactate measurements or registrations on the blood gas analyser reduced the number of patients applicable. In addition, those patients with normal lactate on the first blood gas did not prompt a second reading- reducing the sample size further.

Clinically Relevant Bottom Line:

With a small sample size and retrospective study design, this study adds to the evidence that higher serum lactate levels on admission to PICU are associated with higher mortality and morbidity. However, further rigorous studies would be required to find an association between serial lactate measurements and mortality.

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.

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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