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Long B, Gottlieb M. Liberal versus conservative intravenous fluid administration in pediatric diabetic ketoacidosis. Academic Emergency Medicine. Published online November 3, 2022:acem.14596.

Study Population: Three trials of 1323 children aged 0–18 years presenting to emergency departments with diabetic ketoacidosis

Efficacy Endpoints

Reduction in GSC (primary), cerebral edema, hospital length of stay

Harm Endpoints

Adverse events such as pulmonary edema, thrombosis, alteration in mental status, kidney injury, electrolyte imbalances

Narrative

Diabetic ketoacidosis (DKA), a dangerous condition of elevated blood glucose, dehydration, and acidosis, is associated with morbidity and mortality in children.1 Much of this is due to neurologic damage and deaths from DKA-related brain injury, a condition occurring in 0.3%–0.9% of children with DKA.2^, 3^, 4 Unfortunately, the cause of cerebral edema in DKA is unknown, and there is controversy about whether rate, volume, or type of intravenous (IV) fluid therapy plays a role.5^, 6^, 7

The systematic review summarized here included randomized controlled trials (RCTs) comparing liberal (fast) versus conservative (slow) IV fluid infusion during management of children with DKA.8 Participants were under 18 years of age and required IV fluid and insulin infusion. The primary outcome in the systematic review was reduction in Glasgow Coma Scale (GCS). Secondary outcomes included development of cerebral edema and hospital length of stay (LOS). Adverse events included pulmonary edema, development of kidney injury, and electrolyte imbalances.

The meta-analysis identified three RCTs conducted in the emergency department, one of which contributed 1389 out of 1457 (95%) of the total DKA episodes analyzed.9 Concentrations of saline infusion were mostly either 0.45% or 0.9%. All three trials compared 20 mL/kg (liberal) with 10 mL/kg administered as IV bolus or over 1 h; however, the definition of “liberal” and “conservative” differed among the three trials. The largest trial used a two-by-two factorial design also comparing 0.45% to 0.9% saline solution.9 No study reported DKA severity, mortality, PICU admission, or development of kidney injury.

There was no difference in reduction in GCS (n = 1361), development of cerebral edema (n = 1439), or hospital LOS (n = 1439). There were no cases of pulmonary edema or thrombosis reported. Three percent of the total study population experienced a serious adverse event, most commonly an alteration in mental status. Hyperchloremic metabolic acidosis and hypocalcemia were more common in the liberal infusion group, but rates of hypoglycemia and hypokalemia were similar.9 Subgroup analysis evaluating <0.9% saline compared with 0.9% saline found no difference in outcomes.

Caveats

No significant differences in outcomes between fluid rate or fluid choice were identified in this meta-analysis. However, the presented data have several limitations. The most significant limitation is that one trial accounts for 95% of patients and episodes in the analysis, and this trial's results have not been reproduced or externally validated.9 This trial incorporated a two-by-two factorial design based on fluid infusion amount and saline concentration.9 There was also important heterogeneity in study designs and primary outcomes among the included trials. While all studies used saline, they differed in maintenance infusions and concentrations. Moreover, “evidence certainty” was rated as low to very low because all trials were at high risk of bias due to a lack of blinding of participants, providers, or outcome assessors. The wide confidence intervals for the effect sizes are likely due to small sample sizes and heterogeneity, suggesting the need for trials with larger sample sizes with more homogenous populations. Finally, no trial used “balanced” electrolyte solutions (e.g., Ringer's lactate).

Based on the available evidence, we have assigned a color recommendation of yellow (unclear if benefit) for liberal versus conservative IV fluid regimens. The high risk of bias and lack of any trials reproducing the findings of the lone large study suggest larger, more rigorous trials will be critical. Future studies evaluating IV fluid administration and IV fluid type with clear, patient-centered outcomes are necessary. It is reassuring that the overall conclusion of the systematic review is in line with the rigorous randomized trial published in 2018, which was included in the systematic review and demonstrates no evidence that fluid rate or fluid choice has an important impact on cerebral edema or adverse outcomes in children with DKA.9

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

Author

Brit Long, MD; Michael Gottlieb, MD
Supervising Editors: Shahriar Zehtabchi, MD

Published/Updated

October 25, 2022