2018 was a pivotal year for the management of paediatric diabetic ketoacidosis (DKA) when our understanding of the role of intravenous fluids in DKA-related cerebral oedema was questioned by Kuppermann et al.’s seminal paper published in NEJM.
What’s the big deal?
One of the concerns about DKA treatment is a change in neurological status that could indicate cerebral oedema. Clinical brain swelling complicates 0.5% to 1% of paediatric DKA episodes, and when it occurs permanent morbidity and mortality are common. Factors leading to this are unclear, but previous retrospective studies have found associations between declining sodium concentration during DKA and cerebral injury. So, does hyponatraemia during treatment impact the risk of cerebral oedema?
2018’s PECARN Fluid Therapies Under Investigation in Diabetic Ketoacidosis (FLUID) Trial assessed the impact of variations in intravenous fluid protocols on the risk of mental status changes during treatment and cognitive outcomes after recovery in children with DKA.
Glaser et al. analysed the data from this original study to identify factors influencing changes in serum sodium concentrations during DKA treatment and whether these changes are associated with mental status changes and the risk of cerebral injury.
What was the study design?
The PECARN FLUID trial was a randomised controlled trial conducted at 13 US hospitals over five years. 1389 episodes of DKA in 1255 children were included in the original analysis. Disorders that could affect neurocognitive evaluation were excluded (including drug and alcohol use, head trauma and underlying neurological condition) alongside substantial treatment for DKA before arrival at the study site. The median age of patients was 11 years. Between 10 to 12% of those in each group were under 6. Children with a GCS <12 were excluded from year 2 of the trial.
Who did they study?
Of the 1389 episodes in the PECARN FLUID Trial, there were 1251 episodes that recorded glucose and sodium concentrations at the start of treatment and at least 3 hours after initiation of IV insulin following study fluid administration. Exclusions included those who did not receive treatment or received a bolus only. 85 episodes were excluded as intravenous fluid sodium concentration had been altered from the protocol for clinical reasons.
What did they do?
A quick reminder of the randomisation groups:
- Fast rehydration (20ml/kg bolus and 10% fluid deficit with half replaced over 12 hours and the remainder over the subsequent 24 hours) with 0.45% sodium chloride
- Fast rehydration (20ml/kg bolus and 10% fluid deficit with half replaced over 12 hours and the remainder over the subsequent 24 hours) with 0.9% sodium chloride
- Slow rehydration (10ml/kg bolus and 5% fluid deficit replaced evenly over 48 hours) with 0.45% sodium chloride
- Slow rehydration (10ml/kg bolus and 5% fluid deficit replaced evenly over 48 hours) with 0.9% sodium chloride
All patients in both groups received IV insulin at 0.1units/kg/hr. For the purpose of this 2021 study, data from the first 4, 8 and 12 hours of treatment were analysed for glucose-corrected sodium concentrations and mental status. Due to the resolution of DKA during treatment, this equated to 1251, 1086 and 877 episodes at each time point respectively.
Why ‘glucose-corrected’ sodium?
Remember, glucose draws water into the intravascular space via osmotic pressure, diluting extracellular sodium and causing low serum sodium. As the glucose normalises, so too should hyponatraemia with appropriate rehydration. If glucose-corrected sodium falls during treatment, this may indicate an excess of free water. Traditionally, this has been thought to be a potential risk factor for cerebral oedema. We, therefore, monitor the trend in sodium corrected for the change in glucose.
How did they compare?
Patients whose glucose-corrected sodium declined between baseline and the three time points were compared with those whose glucose-corrected sodium remained stable or increased. The mental status of the two groups during treatment was also compared, including GCS scoring and digit span scores (a test of short-term memory used in participants aged 3 years and older).
What did they find?
They found that a decline in glucose-corrected sodium concentration was not associated with altered mental status during DKA treatment or clinically apparent cerebral injury.
Factors that impacted sodium trends were sodium and chloride concentrations at presentation and sodium content of intravenous fluids (greater decline with 0.45%). Interestingly, older patients and patients with previously diagnosed diabetes were more likely to have a greater decline in glucose-corrected sodium concentrations during treatment, although the reason remains unclear.
The fluid infusion rate had minimal impact on sodium concentrations at the 12-hour time point only. This data has some limitations.
Clinically apparent brain injury only occurred in <1% of DKA episodes. This makes interpretation of this outcome relative to any specific factor difficult. Perhaps early recognition due to the trial protocol played a part in this. Only a small percentage of patients were under six years old; these children may be the group most at risk of cerebral oedema. However, after adjusting for other risk factors, the FLUID team has not found an increased risk of cerebral injury or oedema in younger patients. Finally, changes to fluid treatment outside the protocol were not investigated for their impact on serum sodium concentrations and associated mental status changes.
Bottom Line
What will this study change? Current BSPED guidance for paediatric DKA management advises baseline and hourly neurological observations (half-hourly in severe DKA or those under two years old) and four hourly serum sodium monitoring. The overall findings of this study show that in contrast to data from previous retrospective studies, the risk of cerebral injury during DKA treatment is not increased in episodes with declining sodium concentrations, but this is unlikely to impact on current monitoring established during DKA treatment.
A note from the author, Nicole Glaser
For the past several decades, DKA protocols have recommended monitoring trends in serum sodium levels during DKA treatment and adjusting fluid infusions to ensure a rise in the serum sodium level during treatment. These recommendations were based on data from retrospective studies showing associations between DKA-related cerebral injury in children and declines in serum sodium during treatment. However, no prospective studies have investigated associations between sodium decline and cerebral injury.
Furthermore, factors influencing sodium changes during DKA treatment have not been explored.  In this study, we prospectively monitored serum sodium levels in children treated with fluids varying in sodium content and infused at varying rates. We carefully assessed mental status during DKA treatment using Glasgow Coma Scale scores.
We found that serum sodium trends during DKA were mainly influenced by the balance of free water versus sodium losses at presentation and by intravenous fluid sodium content.
The rate of infusion played very little role in determining sodium trends. Importantly, contrary to previous beliefs, declines in serum sodium were not associated with altered mental status or clinical diagnoses of cerebral injury. These data suggest that sodium declines documented in retrospective studies of children with DKA-related cerebral injury might have reflected late effects of the cerebral injury itself (SIADH or cerebral salt wasting), rather than playing a role in causation.
Promoting an increase in the serum sodium level during DKA treatment should therefore be deemphasized. Furthermore, fluid infusion rates should not be restricted based on concerns about serum sodium trends. If changes in serum sodium are desired, the fluid sodium content should be adjusted.
