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

Abstract

Importance: Saline (0.9% sodium chloride), the fluid most commonly used to treat diabetic ketoacidosis (DKA), can cause hyperchloremic metabolic acidosis. Balanced crystalloids, an alternative class of fluids for volume expansion, do not cause acidosis and, therefore, may lead to faster resolution of DKA than saline.

Objective: To compare the clinical effects of balanced crystalloids with the clinical effects of saline for the acute treatment of adults with DKA.

Design, setting, and participants: This study was a subgroup analysis of adults with DKA in 2 previously reported companion trials-Saline Against Lactated Ringer's or Plasma-Lyte in the Emergency Department (SALT-ED) and the Isotonic Solutions and Major Adverse Renal Events Trial (SMART). These trials, conducted between January 2016 and March 2017 in an academic medical center in the US, were pragmatic, multiple-crossover, cluster, randomized clinical trials comparing balanced crystalloids vs saline in emergency department (ED) and intensive care unit (ICU) patients. This study included adults who presented to the ED with DKA, defined as a clinical diagnosis of DKA, plasma glucose greater than 250 mg/dL, plasma bicarbonate less than or equal to 18 mmol/L, and anion gap greater than 10 mmol/L. Data analysis was performed from January to April 2020.

Interventions: Balanced crystalloids (clinician's choice of Ringer lactate solution or Plasma-Lyte A solution) vs saline for fluid administration in the ED and ICU according to the same cluster-randomized multiple-crossover schedule.

Main outcomes and measures: The primary outcome was time between ED presentation and DKA resolution, as defined by American Diabetes Association criteria. The secondary outcome was time between initiation and discontinuation of continuous insulin infusion.

Results: Among 172 adults included in this secondary analysis of cluster trials, 94 were assigned to balanced crystalloids and 78 to saline. The median (interquartile range [IQR]) age was 29 (24-45) years, and 90 (52.3%) were women. The median (IQR) volume of isotonic fluid administered in the ED and ICU was 4478 (3000-6372) mL. Cumulative incidence analysis revealed shorter time to DKA resolution in the balanced crystalloids group (median time to resolution: 13.0 hours; IQR: 9.5-18.8 hours) than the saline group (median: 16.9 hours; IQR: 11.9-34.5 hours) (adjusted hazard ratio [aHR] = 1.68; 95% CI, 1.18-2.38; P = .004). Cumulative incidence analysis also revealed shorter time to insulin infusion discontinuation in the balanced crystalloids group (median: 9.8 hours; IQR: 5.1-17.0 hours) than the saline group (median: 13.4 hours; IQR: 11.0-17.9 hours) (aHR = 1.45; 95% CI, 1.03-2.03; P = .03).

Conclusions and relevance: In this secondary analysis of 2 cluster randomized clinical trials, compared with saline, treatment with balanced crystalloids resulted in more rapid resolution of DKA, suggesting that balanced crystalloids may be preferred over saline for acute management of adults with DKA.

Trial registration: ClinicalTrials.gov Identifiers: NCT02614040; NCT02444988.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Self reported receiving personal fees from Baxter for educational presentations on resuscitation. Dr Rice reported serving as the director of medical affairs for Cumberland Pharmaceuticals, Inc, and receiving personal fees from Avisa Pharmaceutical outside the submitted work. Dr Collins reported personal fees from Vir Biotech outside the submitted work. Dr Lindsell reported grants from the National Center for Advancing Translational Sciences (NCATS) during the conduct of the study; grants from the National Institute of General Medical Sciences, grants from the US Department of Defense, other from the Centers for Disease Control and Prevention, grants from the National Institute of Diabetes and Digestive and Kidney Diseases, grants from the National Heart, Lung, and Blood Institute, grants from Marcus Foundation, and research funding to conduct research outside the submitted work from the Centers for Disease Control and Prevention, Endpoint Health, and Entegrion; in addition, Dr Lindsell had a patent to risk stratify adults and children with sepsis and septic shock issued; and stock options in Bioscape Digital outside the current work. No other disclosures were reported.

Figures

Figure 1.. Plasma Electrolyte Concentrations in the First 72 Hours After Arrival in the Emergency Department by Assigned Treatment Group (Balanced Crystalloids vs Saline)

Graphs show concentrations of sodium (A), potassium (B), chloride (C), bicarbonate (D), creatinine (E), and glucose (F). Lines denote means, and shaded bands denote 95% CIs. Plots were created with locally weighted scatterplot smoothing. Patients were censored at the time of hospital discharge or death. Separation of 95% CIs for chloride and bicarbonate suggest significant differences between the balanced crystalloids and saline groups. SI conversions: To convert bicarbonate to millimoles per liter, multiply by 1.0; chloride to millimoles per liter, multiply by 1.0; creatinine to micromoles per liter, multiply by 88.4; glucose to millimoles per liter, multiply by 0.0555; sodium to millimoles per liter, multiply by 1.0; potassium to millimoles per liter, multiply by 1.0.

Figure 2.. Cumulative Incidence by Assigned Treatment Group (Balanced Crystalloids vs Saline) of Resolution of Diabetic Ketoacidosis (DKA) and Discontinuation of Insulin Infusion Therapy

Graphs show cumulative incidence of resolution of DKA (A) and discontinuation of insulin infusion therapy (B), with time 0 defined as emergency department (ED) presentation and initiation of insulin infusion, respectively. The cumulative incidence probabilities for DKA resolution were calculated using the Turnbull nonparametric method. Displayed P values were calculated with a log-rank test. Twenty-six patients (15 in the balanced crystalloids group and 11 in the saline group) were discharged from the hospital without meeting the laboratory definition of DKA resolution; these patients were considered to have DKA resolution at the time of hospital discharge.