Balanced Crystalloid for DKA

Clinical Effects of Balanced Crystalloids vs Saline in Adults With Diabetic Ketoacidosis: A Subgroup Analysis of Cluster Randomized Clinical Trials.

Self WH, Evans CS, Jenkins CA, et al.; Pragmatic Critical Care Research Group.

JAMA Netw Open. 2020 Nov 2;3(11):e2024596. [Full text]

Intravenous fluids, like all medical interventions, have risks and benefits. There has been a growing association of harms with both the total volume [1] and type of fluid administered. For example, the use of saline (with is not “normal” [2] ) is associated with acute kidney injury [3] and with mortality in critically ill septic patients [4].

Two large trials, SALT-ED (non-critically ill) [5] and SMART (critically ill) [6] aimed to prospectively asses outcome differences between balanced cystalloids and saline. Neither SALT-ED (non-critically ill) or SMART (critically ill) found a difference in hospital free days or inpatient mortality, respectively, but both did note more major adverse kidney events associated with saline.

The harms of saline are partly attributed to its chloride concentration (154 mEq/L), which is higher than that in human plasma (94-111 mEq/L). Chloride can induce a metabolic acidosis (MA) amongst other consequences. In patients presenting with MA, such as those with diabetic ketoacidosis (DKA), saline could theoretically delay improvement in acidosis, while balanced crystalloids such as lactated ringers (LR) could hasten the resolution of MA. The SALT-ED and SMART trials included patients with DKA and this is a subset analysis of that cluster randomized trial looking only at those patients with DKA.


The subset of adults with DKA on presentation from the SALT-ED (non-ICU) and SMART (ICU) trials were included. SALT-ED patients were those that presented to the Vanderbilt emergency department (ED), received at least 500mL and subsequently were admitted to a non-ICU location. SMART included all ICU admissions to the five Vanderbilt medical center ICUs.

Patients with DKA were identified by documented ICD-10 codes with the diagnosis confirmed by chart review. Furthermore, patients required admission blood glucose (BG) > 250 mg/dL, a bicarbonate (HCO3) level <18 and an anion gap (AG) > 10. No transfers from other hospitals could be considered and the cardiac and neurologic ICUs were not included as they used an alternate fluid protocol in the original SMART trial.

Consistent with the concept of a pragmatic clinical trial, the timing and volume of fluid was determined by the treating team, the treating team was aware of the fluid type and could use an alternate fluid based on the team’s discretion.


The primary outcome was the time to DKA resolution, defined as the time from ED presentation, until the following were met: BG < 200, HCO3 ≥ 15, venous blood gas pH > 7.3 and AG ≥ 12.

The major secondary outcome was time to discontinuation of the insulin infusion, defined as the time between initiation and final discontinuation of that infusion during the hospitalization for DKA. Other outcomes included hyper- and hypo-kalemia and adverse kidney events (new renal replacement or an ↑Cr > 200% from baseline).


During the 15-month study period, 172 patients met eligibility criteria, with 94 assigned to balanced crystalloids and 78 patients assigned to saline. The median age was 29, 52% were women, 83% had type I diabetes, and the median hemoglobin A1c was 10.9%.

Adherence to assigned crystalloid was high with 85.3% administered in the balanced crystalloids group was per protocol and 96.7% in the saline group was saline. LR was the balanced crystalloids used 96.9% of the time, with Plasma-Lyte only used in 3.1%.

The time to DKA resolution was shorter in the balanced crystalloid group, 13 hrs versus 16.9 hours (aHR = 1.68, 95% CI 1.18-2.38, P = 0.004). Time to discontinuation of the insulin infusion was also shorter in the in the balanced crystalloid group, 9.8 hrs versus 13.4 hours (aHR = 1.45, 95% CI 1.03-2.03, P = 0.03).

There was no difference in the frequency of hyperkalemia but there was more hypokalemia in the saline group (10 vs 19%, aHR = 0.35, 95% CI 0.13-0.91, P = 0.03). The rate of adverse kidney events was similar.


This was a secondary analysis of two open label, pragmatic trials with a primary outcome that was not a “hard” outcome such as mortality. Yet, the finding of more rapid resolution of DKA and secondarily less time on an insulin drip still are compelling. With the mounting evidence associating saline with renal injury, one could at least consider more use of, if not exclusive use of, balanced crystalloids in DKA. Any concerns related to electrolyte derangement, often cited as a barrier to LR adoption, but which were not observed in or supported by this analysis, would be mitigated via the frequent reassessment and monitoring required in appropriate DKA management. In the end, thoughtful use of fluids is always warranted, rather than a purely algorithmic approach. In other words, we must move away from “maintenance”… …of the status quo.

F: Follow upDuration of hospital stay, up to 30d
R: RandomizationYes, clustered Q month
I: Intention to treatYes
S: Similar at baselineYes
B: BlindingNo, pragmatic design
E: Equal treatmentYes, ADA DKA protocol otherwise recommended throughout
S: Source (funding)Vanderbilt Clinical and Translational Science Awards (CTSA) grant

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