JAMA Pediatrics Journal Club Slides: Insulin in Pediatric Diabetic Ketoacidosis Nallasamy K, Jayashree M, Singhi S, Bansal A. Low-dose vs standard-dose insulin in pediatric diabetic ketoacidosis: a randomized clinical trial. JAMA Pediatr. Published online September 29, 2014. doi:10.1001/jamapediatrics.2014.1211.

Introduction Background Standard recommended dose (0.1 U/kg/h) of insulin in diabetic ketoacidosis (DKA) guidelines is not backed by strong clinical evidence. Physiologic dose-effect studies have found that even lower doses could normalize ketonemia and acidosis. Lowering the insulin dose may be advantageous in the initial hours of therapy when a gradual decrease in glucose, electrolytes, and osmolality is desired. Study Objective To compare the efficacy and safety of low-dose insulin against the standard dose in children with DKA.

Methods Study Design: Prospective, open-label randomized clinical trial. Setting: Pediatric emergency department and intensive care unit of a tertiary care teaching hospital in northern India from November 1, 2011, through December 31, 2012. Patients: Fifty consecutive children 12 years or younger with a diagnosis of DKA were randomized to low-dose (0.05 U/kg/h; n = 25) and standard-dose (0.1 U/kg/h; n = 25) groups. Children were excluded if they had symptomatic cerebral edema, septic shock at presentation, anuria for longer than 6 hours, or insulin treatment before admission.

Methods Primary Outcome Rate of decrease in blood glucose (BG) until a level of 250 mg/dL or less is reached. Secondary Outcomes Time to resolution of acidosis. Episodes of treatment failures. Incidences of hypokalemia and hypoglycemia. Limitations Open-label design. Adolescent children not enrolled. A possibly stringent noninferiority margin of 18 mg/dL/h.

Results Trial Flow

Baseline Demographic and Biochemical Characteristics Results Baseline Demographic and Biochemical Characteristics Characteristic Low-Dose Group (n = 25) Standard-Dose Group Age, mean (SD), y 7.3 (3.8) 6.5 (3.6) Male/female, No. 9/16 11/14 Children with malnutrition, No. (%) 7 (28) 8 (32) New-onset DKA, No. (%) 13 (52) 16 (64) BG, mean (SD), mg/dL 485.3 (133) 524.4 (103) pH, mean (SD) 7.08 (0.12) 7.05 (0.11) Bicarbonate, mean (SD), mEq/L 6.2 (2.6) 7.0 (3.1) Sodium, mean (SD), mEq/L 133.0 (7.0) 134.5 (10.0) Potassium, mean (SD), mEq/L 4.8 (0.8) 4.7 (0.7) Effective osmolality, mean (SD), mOsm/kg 292.0 (13.8) 298.2 (21.2)

Primary Outcome for Low-Dose vs Standard-Dose Insulin Results Mean BG Decrease With Insulin Therapy Primary Outcome for Low-Dose vs Standard-Dose Insulin Mean (SD) rate of BG decrease until 250 mg/dL or less is reached: 45.1 (17.6) vs 52.2 (23.4) mg/dL/h. Mean (SD) time taken to achieve this target: 6.0 (3.3) vs 6.2 (2.2) hours. Mean (SD) BG decrease in the first hour of insulin: 39.2 (25.5) vs 61.3 (37.7) mg/dL/h.

Secondary Outcome Measures Results Secondary Outcome Measures

Comment Low-dose insulin achieved a clinically effective BG reduction that was comparable to the standard dose. Time to resolution of acidosis was similar in both groups, suggesting that the low dose could be as effective as the standard dose in suppressing lipolysis and ketogenesis. Gradual BG decrease in the initial hour and a tendency toward fewer episodes of hypokalemia suggest that the lower dose could be safer (higher insulin in the first few hours can cause a precipitous BG decrease and rapid electrolyte shifts, thus increasing the risk of cerebral edema).

Conclusions Low-dose insulin is noninferior to standard-dose insulin with respect to the rate of BG decrease and resolution of acidosis. This study opens the door for a subsequent superiority trial with a larger sample size to explore differences in the rate of BG decrease before 0.05 U/kg/h replaces 0.1 U/kg/h in the practice recommendations.

Conflict of Interest Disclosures Contact Information If you have questions, please contact the corresponding author: Muralidharan Jayashree, MD, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India 160012 (mjshree@hotmail.com). Conflict of Interest Disclosures None reported.