Clinical Trial of Fluid Infusion Rates for Paediatric Diabetic Ketoacidosis

Guest Blogger Dr Jordan Evans

N Engl J Med 2018;378:2275-87.  
DOI: 10.1056/NEJMoa1716816

If there’s one thing we all know about manging diabetic ketoacidosis (DKA), it’s the importance of being extremely cautious with fluid management due to the risk of causing iatrogenic cerebral oedema right?...Wrong!  Once again, like John Snow, we unfortunately ‘know nothing!’.  When will the childhood lies end, Father Christmas isn’t real, the Easter bunny’s not real and now this, the most painful blow yet. 

In this PECARN (Pediatric Emergency Care Applied Research Network) study, published in the New England Journal of Medicine, Nathan Kuppermann et al investigated the influence of intravenous fluid administered on the rates of neurological injury in children with DKA.

What was the reason for the study?

Brain injury occurs in the region of 0.5% - 1% of DKA presentations.  It presents with sudden neurological deterioration. Patients without a marked neurological deterioration may have more mild neurological impairments e.g. memory / cognitive impairment.  As all of us were likely taught, brain injury in DKA has long been thought to be iatrogenic, secondary to fluid administration causing cerebral oedema due to osmotic gradients.  The evidence for this school of thought is however lacking and evidence has emerged actively disputing it.  Alternative explanations have been proposed that there may be something about being particularly unwell with DKA that leads to the neurological injury, possibly inflammatory or vascular changes.  The more unwell the patient is the more likely they are to require fluid resuscitation and therefore an association between severe DKA with brain injury and fluid administration could be mistaken as causation.  Remember that association is not proof of causation!  Oedema may develop secondary to the brain injury itself as it does in other mechanisms of injury such as trauma.

Where did the study take place?

The study was conducted across 13 centres in the United States.

Who did they include ?

Children aged 0 – 18 years with a diagnosis of DKA (pH < 7.25, glucose > 16.7 mmol/L.  Children with GCS <12 were excluded two years into study (due to concerns of treating clinicians). ​

What did the investigators do?

Children presenting to study centres with DKA were randomly assigned to one of the following four groups;
1)     0.9% saline fast administration
2)     0.9% saline slow administration
3)     0.45% saline fast administration
4)     0.45% saline slow administration
The fast group were given a 20ml/kg bolus which was then followed with replacement of a 10% fluid deficit with the first half of the deficit volume being replaced over 12hrs and the rest over the next 24 hrs.
The slow group were given a 10ml/kg bolus which was then followed by replacement volume for a 5% deficit which was given over 48hrs.
The primary outcome was a decline in mental status (GCS <15 on two occasions within first 24 hours of treatment.  Patients and parents were blinded but not the clinician.
Secondary outcomes; clinically apparent brain injury (neurological deterioration leading to clinical decision to treat for raised ICP, intubation or death), short term memory, memory & IQ at 2 months and 6 months. 

What were the results?

4912 patients met the inclusion criteria.  Due to the complexities of the study of these there were a total of 1389 episodes of DKA included in the study (from 1255 different children).  There was a fall in GCS in 3.5% of these epsiodes (48 episodes).  There was clinically apparent brain injury in 0.9% (12 episodes). There was no difference between the two groups for any of the outcomes.  (Some of the raw results favoured the fast fluid administration group although none of these results reached a statistically significant level). ​

Conclusions

​Kupperman et al. rightly concluded that ‘Neither the rate of administration nor the sodium chloride content of intravenous fluids significantly influenced neurologic outcomes in children with diabetic ketoacidosis’.

Take home message for practice in Wales

1. We no longer need to be as anxious about giving fluid too fast in DKA   

2. If you need to give a bolus for shock do so without fear of causing cerebral oedema, this study provides evidence that it’s not harmful.

3. With regards to the fluid deficit replacement although this study shows we could safely give it a little faster stick to current practice of the Wales DKA protocol as it doesn’t show any improvement in outcomes for the faster administration of IV fluids.

4. It’s worth remembering that there is good evidence for using 0.9% saline for maintenance IV fluids in children (to prevent hyponatraemia) so it’s not clear why they chose to have arms in this trial with both 0.9% saline and 0.45% saline.​