Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis

incomplete Journal Club Article
Kupperman, et. al.. "Clinical Trial of Fluid Infusion Rates for Pediatric Diabetic Ketoacidosis". New England Journal of Medicine. 2018. 378(24):2275-2287.
PubMed Full text


Brain injuries in the pediatric DKA patient are a significant contributor to morbidity and mortality in this population. They occur in .5%-.9% of all cases[1]. For decades it had been thought that rapid administration of IVF (a mainstay of treatment) was leading to cerebral edema and therefore was the priniciple cause of these brain injuries. Nationally, many treatment protocols were changed to reflect the belief that slower infusions might decrease the rate of this serious outcome. Even so, the occurence of clinically significant brain injury in the pediatric DKA population has not changed over time.

Graphical Abstract

DKA Infusion.png

Clinical Question

Does the rate of infusion or NaCl content (.45% or .9%) of IVF’s have an effect on neurologic outcomes in pediatric DKA?


Neither the rate nor NaCl content of the IVF has a significant effect on development of measurable adverse neurologic outcomes in pediatric DKA.

Major Points

Pediatric centers may consider reassessing guideline for IVF resuscitation in DKA patients in the face of this evidence that contradicts the existing dogma.

Study Design

  • Multicenter randomized control trial.
    • Randomization occurred by variable length blocks per center, and randomization was stratified by GCS and center.
  • Occurred at 13 PECARN centers


Patient Demographics

0 to 18 years of age, 1255 children, some randomized twice during study period giving 1361 encounters for the primary analysis

Inclusion Criteria

Diagnosis of DKA (glucose >300, pH <7.25, bicarb <15)

Exclusion Criteria

Underlying disorders that affect cognition, alcohol/narcotic use, head trauma, DKA having already received substantial treatment, pregnant, condition for which treating physician wanted specific fluid and electrolyte replacement. GCS 11 or lower excluded after year 2 of study given investigators did not think it appropriate to randomize treatment for patients with exisiting signs of neurologic compromise.


  • Rapid or slow infusion of IVF's
    • rapid = replace 1/2 fluid deficit during initial 12 hours + maintenance fluids
    • slow = replace deficit + maintenance evenly during 48 hour period
  • 0.45% NaCl or 0.9% NaCl
  • All patients received an initial 10 cc/kg fluid bolus
  • Rapid group could receive additional 10 cc/kg fluid bolus


Primary Outcome

  • 2 consecutive GCS scores <14 in any hour during first 24h of treatment
    • 3.5% developed GCS <14, no difference among groups

Secondary Outcomes

Clinically apparent brain injury (initiation of hyperosmolar therapy, intubation, death), short term memory, and memory and IQ 2-6 months after recovery

  • 1.6% required hyperosmolar therapy, no difference among groups
    • 0.9% (12 patients) had clinically apparent brain injury, one death with remaining recovering without overt neurologic deficit, no difference among groups

Neurocognitive assessment

  • 30% of patients lost to follow-up or declined to return
  • no difference in treatment groups with >60% that did follow-up

Subgroup analysis

8 different subgroups

  • Relative risk of decline in GCS didn’t differ among subgroups
  • Forward digit span scores improved quicker in rapid rehydration subgroup with lowest PCO2
  • Backward digit span scores improved quicker in rapid rehydration subgroup with lowest pH

Criticisms & Further Discussion

  • Clinicians not blinded to intervention
  • Low incidence of clinically apparent brain injury (<1%) makes hard to study
  • GCS is a classification tool developed to study outcomes in traumatic injury to the head. It is unclear whether it is an adequate proxy for neurologic damage (particularly more subtle findings).
  • Exclusion of patients with GCS <12 may have eliminated an important population in which rate of infusion or concentration of fluids has a measurable effect
  • Repeat episodes of DKA in same patients (decreases power)
  • Despite 10 cc/kg being the "fast" group, it's still fairly conservative when considering 20 cc/kg is the standard pediatric bolus
  • During the creation of the protocol and powering of the study, they estimated a 20% incidence rate of drop in GCS to <14, however primary outcome only occurred in 3.5%
  • No evaluation of balanced crystalloids
  • Did an analysis of both per-protocol and per-treatment received
    • No significant difference

External Links

See Also


Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant U01HD062417) and the Emergency Medical Services for Children Network Development Demonstration Program of the Maternal and Child Health Bureau, Health Resources and Services Administration, under cooperative agreement (awards U03MC00008, U03MC00001, U03MC00003, U03MC00006, U03MC00007, U03MC22684, and U03MC22685).


  1. Edge JA, Hawkins MM, Winter DL, Dunger DB. The risk and outcome of cerebral oedema developing during diabetic ketoacidosis. Arch Dis Child 2001;85:16-22.