Copyright restrictions may apply

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.

Copyright restrictions may apply

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.

Introduction

Copyright restrictions may apply

• 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

Copyright restrictions may apply

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.

Copyright restrictions may apply

ResultsTrial Flow

Copyright restrictions may apply

ResultsBaseline Demographic and Biochemical Characteristics

Characteristic Low-Dose Group

(n = 25)

Standard-Dose Group

(n = 25)

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)

Copyright restrictions may apply

Results

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.

Mean BG Decrease WithInsulin Therapy

Copyright restrictions may apply

Results

Secondary Outcome Measures

Copyright restrictions may apply

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).

Copyright restrictions may apply

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.

Copyright restrictions may apply

• 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.

Contact Information