During our training in paediatric emergency medicine most of us will have been cautioned repeatedly of the dangers of over-zealous fluid administration in children with diabetic ketoacidosis. Cerebral oedema is the feared complication of this disease process and, as traditional wisdom would have it, either rapid fluid administration or the use of any hypotonic IV fluid would invite this situation upon your poor unsuspecting patient.
There was a plausible speculated physiological mechanism for this and some older literature linking cerebral oedema with large volume fluid resuscitation. The catch was that only association had been demonstrated, not causality and it is reasonable to suspect a confounder in that those with more severe DKA could be expected to be both at higher risk of cerebral oedema and more likely to receive large volumes of fluid resuscitation based on their clinical presentation.
Lead authors Nate Kupperman and Nicole Glaser suggested the causal effect of fluid resuscitation and cerebral oedema was a myth in a retrospective case-control study published 17 years ago. After building on this theory with both clinical and laboratory animal-based studies they have now published their randomized controlled trial showing no differences in brain injury rates in children treated with either 0.9% or 0.45% saline given either rapidly or at more conservative rates. This nine year long project should prompt us all to rethink our assumptions about fluid management in paediatric DKA.
Who did they study?
1389 episodes of DKA in 1255 children presenting to 13 US hospitals were included in the analysis. 4912 patients met inclusion criteria during the study period, the majority of exclusions were due the fact that the child had received too much management prior to contact with the study team. 631 were not approached for inclusion while 812 refused consent. More problematically for trial integrity, 289 were withdrawn by the treating physician and few further details are provided about these patients. 101 had been enrolled twice previously (no single patient was allowed to have more than 2 episodes of DKA included in the trial) and 90 had an underlying neurological condition. The median age of included patients was 11yrs with between 10 and 12% of those in each group being under the age of 6. Children with a GCS <12 were excluded from year 2 of the trial. These latter 2 points are relevant as younger and more clinically unwell children are traditionally thought to be at higher risk of brain injury.
What did they do?
Patients were randomised into 4 groups stratified by both geographical location and GCS at the time of randomization. The groups received:
- Fast rehydration with 0.45% sodium chloride
- Fast rehydration with 0.9% sodium chloride
- Slow rehydration with 0.45% sodium chloride
- Slow rehydration with 0.9% sodium chloride
Those in the fast groups received a 20ml/kg bolus followed by replacement of an assumed 10% fluid deficit, half of this deficit was replaced over 12hrs with the remainder replaced over the subsequent 24 hrs.
Those in the slow groups received a 10ml/kg bolus followed by replacement of an assumed deficit of 5% replaced evenly over 48hrs.
Maintenance fluid was provided throughout in addition to the deficit replacement in both groups and dextrose was added to the saline solution when blood glucose dropped to defined levels.
All patients in both groups received IV insulin at 0.1u/kg/hr.
What did they look for?
The primary outcome was deterioration of neurologic status as evidenced by two consecutive GCS scores of <14 during any hour within the first 24 hrs of treatment.
Secondary outcomes included short-term memory during treatment and IQ 2-6 months after the episode of DKA. Despite being the end point that many of us are most concerned about, clinically apparent brain injury (deterioration in neurological status requiring hyperosmolar therapy or endotracheal intubation or resulting in death) was a secondary outcome, presumably due to its rarity and hence difficulty in showing statistically significant differences between groups.
What did they find?
In a nutshell – no differences. Neither rapid fluid delivery nor the use of hypotonic 0.45% saline led to a worsening of any of the primary or secondary outcomes. There were a couple of trends towards benefit of the rapid fluid regimens but nothing that was statistically significant. Brain injury occurred in 0.9% of kids with DKA which is compatible with historically reported data.
Those receiving 0.9% saline were more likely to develop a hyperchloraemic acidosis than those receiving 0.45% saline, and this was more likely to occur in the group receiving fluid rapidly. This is entirely expected and of debatable clinical significance.
Study bottom line
Our traditionally cautious approach to fluid resuscitation in DKA is not supported. Though the very young and the very sick (generally our biggest causes for concern) may be lost in this cohort, the evidence that IV fluid administration is not the cause of brain injury in DKA is now stronger than anything that previously suggested it was. More interestingly it is perhaps now time to stop arguing over fluids and start trying to figure out what does cause brain injury in DKA.
A clinical bottom line by Damian Roland
With the reducing incidence of serious bacterial disease, diabetic ketoacidosis (DKA) is one of the few conditions that continues to result in children presenting extremely ill and often requiring ongoing high dependency, if not intensive, care. The challenge of DKA has previously been two-fold. First the children often look very unwell and have a substantial metabolic derangement to manage but added to this, there was the chance that your own interventions may cause fluid shifts resulting in cerebral oedema and potentially death. In relation to the incidence of DKA-mediated cerebral oedema, the risk has always been relatively low but it is difficult to find any guideline that doesn’t make clear that judicious use of fluids may result in substantial harm.
This PECARN study appears to turn that dogma around, whether it was fast or slow, isotonic or hypotonic, the type of fluid administration didn’t change the incidence of cerebral oedema or outcome. Certainly Dr. Kupperman should be congratulated on delivering a well-designed study (which ran against current guidance and expert opinion in some cases) and therefore must have involved significant challenges during its 5 years.
However I won’t be radically altering how I manage DKA in the immediate future, although I am sure changes to our maintenance regime will be discussed shortly. Our local practice doesn’t include any initial fluid boluses unless the clinician thinks that shock is present (in which case 10-20 mls/kg is recommended). I could I suppose use a fluid bolus more often in these patients, but with no evidence it reduces length of stay or patient comfort I don’t see the reason at the moment. The fast arm maintenance infusion rates are given over a shorter period than we use locally so this is something to dissect. As a quick aside it’s also important we remember hyponatraemic fluids are bad for long term maintenance and this study is not a recommendation for 0.45% in your general paediatric inpatient.
My key take away points are that cerebral oedema is rare but that clinical impairment of brain function in this study did seem to be more frequent in those with initially more severe acidosis. Sick patients with DKA will continue to need careful monitoring regardless of what fluid regime they are on.
For those of you who like their papers in small, easily digestible popcorn-sized nuggets…
Some other people’s thoughts