ENDOCRINOLOGY
Fluid Therapy in Diabetic Ketoacidosis
Source: Kuppermann N, Ghetti S, Schunk JE, et al. Clinical trial of fluid infu-
sion rates for pediatric diabetic ketoacidosis. N Engl J Med. 2018;378:2275–
2287; doi: 10.1056/NEJMoa1716816
Investigators from multiple institutions conducted a randomized
controlled trial to assess the effects of rate of administration of
IV fluids and sodium chloride (NaCl) content on neurologic out-
comes in children presenting with diabetic ketoacidosis (DKA).
The study was conducted at 13 ED sites in the Pediatric Emer-
gency Care Applied Research Network. Participants were children
0–18 years old presenting with DKA (defined as a blood glucose
>300 mg/dL and either a venous pH <7.25 or serum bicarbonate
level <15 mmol/L), and they were randomized using a 2 × 2 fac-
torial design to either fast or slow rehydration with IV fluid that
contained either 0.45% or 0.9% NaCl content. All participants re-
ceived an initial 10 mL/kg IV bolus of 0.9% NaCl fluid. Those ran-
domized to fast rehydration received a second bolus; fluid deficit
was calculated as 10% of body weight, which was replaced over
36 hours (one-half over the first 12 hours and the second one-
half over the next 24 hours). Children in the slow rehydration
group had no additional boluses, fluid deficit was calculated as
5% of body weight, and the deficit was corrected over 48 hours.
Glasgow Coma Scale (GCS) scores were assessed hourly over the
first 24 hours after admission. Short-term memory was assessed
every 4 hours by using forward and backward digit recall tests
with standardized scoring. The primary outcome was a GCS score
<14. The number of these episodes was calculated for each study
child who presented with an initial GCS score >14. Secondary out-
comes included scores on the digit recall tests. In addition, the
number of children with apparent brain injury, defined as need
for hyperosmolar therapy, intubation, or death, was determined.
Multiple statistical methods were used to compare outcomes
across groups.
A total of 1,255 children with 1,389 episodes of DKA were enrolled
in the trial. In 1,361 episodes of DKA in which the patient had an
initial GCS score >14, there were 48 episodes in which the GCS
score declined to <14 (3.5%), with no differences between groups
(slow vs fast rehydration, P=.34; 0.45% vs 0.9% NaCl content,
P=.43; interaction, P=.76). There were 12 episodes of clinically ap-
parent brain injury (0.9%); rates varied between 0.6% and 1.4% in
the 4 treatment groups, with no significant differences between
groups. There were also no statistically significant differences
between groups in digit recall scores except for a trend for high-
er forward recall scores for those randomized to fast rehydration
than for children randomized to slow rehydration (P=.06).
The authors conclude that neither IV fluid administration rates
nor NaCl content of the fluid influenced neurologic outcomes in
children treated for DKA.
• September 2018
TM
COMMENTARY BY
Patricia Y. Fechner, MD, FAAP, Seattle Children’s Hospital, Seattle,
WA
Dr Fechner has disclosed no financial relationship relevant to this commentary. This commentary
does not contain a discussion of an unapproved/investigative use of a commercial product/device.
DKA is the primary cause of complications, death, and cost in
children with type 1 diabetes mellitus.1 Thus, minimizing compli-
cations associated with DKA is paramount. The results of the cur-
rent study indicate that the rate of fluid and the sodium content
do not influence brain injury in a specialized center with a team
experienced in DKA management.
There are, however, several limitations of this study. Individuals
with GCS scores ≤11 were excluded after the first 2 years. Hence,
although the effect of rate of fluid and sodium content did not
play a role in a decline in mental status and apparent brain in-
jury, it may play a role in complications in individuals with lower
presenting GCS scores. In addition, because brain injury occurs
in <1% of DKA episodes, a trial adequately powered to identify a
difference in the different arms is almost impossible. Thus, the
investigators used alterations in mental status as a surrogate
marker. Risk factors for cerebral edema include greater acidosis,
lower carbon dioxide levels, higher blood urea nitrogen levels,
and younger age (AAP Grand Rounds, 2013;30[6]:70).2 Of those
individuals with more severe DKA and an initial GCS score >11,
there was no significant difference in the number who had a GCS
score that declined to <14 and who had clinically apparent brain
injury. Another study limitation was that there were 102 episodes
of DKA in children <3 years, but because of their age, digit recall
scores and assessment of memory function and IQ were not per-
formed. Thus, we do not know whether there were differences in
alterations in neurocognitive function in children aged 0–3 years
with DKA.
Despite these limitations, this is an important large prospective
randomized study that may result in new guidelines from the
International Society for Pediatric and Adolescent Diabetes.3
Bottom Line: Neither the rate of administration of fluid nor the
sodium content of fluid in children presenting with DKA appear
to be related to neurologic outcome.
References
1. Sperling MA. N Engl J Med. 2018;378(24):2336–2338; doi: 10.1056/NEJMe1806017
2. White PC, et al. J Pediatr. 2013;163(3):761–766; doi: 10.1016/j.jpeds.2013.02.005
3. Wolfsdorf JL, et al. Pediatr Diabetes. 2018 June 13 [published online ahead of print];
doi: 10.1111/pedi.12701
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