Infusion Type Doesn't Affect Brain Outcomes in Pediatric DKA

Miriam E. Tucker

June 13, 2018

In children presenting to the emergency department with diabetic ketoacidosis (DKA), neither the rate of administration nor the sodium chloride content of intravenous fluids appears to significantly influence neurologic outcomes, new research suggests.

The study was conducted to fill the gaps in research that inform current DKA treatment guidelines, which typically call for slow rehydration with isotonic fluids in order to avoid brain swelling, Nathan Kuppermann, MD, of the Department of Emergency Medicine, University of California, Davis, Sacramento, and colleagues explain in their article published online June 13 in the New England Journal of Medicine.

Kuppermann and colleagues point out that this approach is generally supported by retrospective reviews but those studies have been subject to bias, given that higher rates of brain injury have been seen in children who are more dehydrated and therefore received larger fluid volumes.

Also, children included in those studies were often referred from nonpediatric centers that used different protocols. 

In contrast, "in the current study, which was performed at specialized centers with specialized staff, DKA–related brain injury appears unlikely to have been caused by the composition or rate of intravenous therapy...These conclusions are likely to generate discussion and lead to revision of current recommendations,"  writes Mark A. Sperling, MD, of the Department of Pediatrics, Division of Endocrinology and Diabetes, Icahn School of Medicine at Mount Sinai, New York City, in an accompanying editorial.

No Difference in Mental Status by DKA Treatment

As Sperling explains in his editorial, DKA constitutes a profound metabolic disturbance of energy homeostasis with a distinct biochemical profile that is characterized by hyperglycemia, ketonemia, metabolic acidosis, and electrolyte abnormalities. It is caused by insulin deficiency, the hallmark of type 1 diabetes.

The typical signs and symptoms — polyuria, ketotic breath, and Kussmaul respirations — reflect biochemical and molecular processes caused by insulin deficiency and counter-regulatory hormones. Despite such knowledge, 30% to 50% of all children with new-onset type 1 diabetes have DKA at time of diagnosis, even in highly developed countries.

"DKA remains the leading cause of complications, death, and excessive healthcare utilization and costs in patients with type 1 diabetes," he stresses.

In this prospective, randomized trial of 13 different emergency departments in urban areas, conducted from February 2011 through September 2016, a total of 1255 children (about half with previously diagnosed diabetes) with 1389 DKA episodes were randomized to one of four treatment regimens: fluid with 0.9% or 0.45% sodium chloride content, or rapid or slow rate of administration.

All children were also given insulin infusions with added dextrose as needed.

The primary outcome, a decline in mental status as indicated by two consecutive Glasgow Coma Scale scores of less than 14 (on a scale of 3 to 15), occurred in 3.5% of children overall, with no significant differences by treatment group. The relative risks (RR) were 0.76 for fast versus slow administration (P = .34) and 0.80 for 0.45% versus 0.9% sodium chloride solution (P = .43). 

Clinically apparent and adjudicated brain injury occurred in 12 episodes of DKA (0.9%), a rate similar to previous reports. That incidence was somewhat higher with slow versus fast hydration, although the difference wasn't significant (RR, 0.49; P = .24). There was no significant difference by sodium chloride concentration (RR, 1.43; P = .53).

Refer Children With DKA to Specialist Centers

Overall, most of those 12 children presented with severe acidosis and hypocapnia.

One died, and the rest recovered without overt neurologic deficits. These outcomes, Sperling writes, "are consistent with findings in another report and attest to the need to refer children with DKA to specialized centers."  

Short-term memory, assessed by the digit-span recall test, also didn't significantly differ among groups (P > .05).

Children older than 3 years who had experienced DKA (855 episodes in total) returned within 2 to 6 months for neurocognitive testing. Again, there were no significant differences following recovery among the treatment groups.

Differences Seen in Some Non-Neurologic Outcomes

There were some significant differences in non-neurological adverse events. Hyperchloremic acidosis was more common among patients who received the higher sodium chloride concentration (P = .04) or faster infusion (P < .001).

Hypocalcemia was also more common in the groups that received the higher sodium chloride concentration or faster infusion (P < .001 for both). Hypophosphatemia was more common with 0.9% versus 0.45% sodium chloride solution (P = .03), but didn't differ by infusion rate (P = .26). 

Hypoglycemia and hypokalemia rates were similar among groups. Serious adverse events occurred in less than 3% of patients overall and didn't differ by treatment groups. Time to DKA resolution and duration of hospital stay also didn't differ.

According to Sperling, "Better understanding of the blood–brain barrier and its alterations in DKA may provide new targets for therapy in patients with cerebral edema, and campaigns to educate and heighten awareness of diabetes in the medical and lay communities should reduce the incidence of DKA at initial diagnosis."

Kuppermann reports grants from the National Institutes of Health and US Health Resources & Services Administration. Sperling reports personal fees from Novo Nordisk outside the submitted work.

N Engl J Med. Published online June 13, 2018. Article, Editorial

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