Randomized Control Trial of Fluid Therapy for Pediatric Diabetic Ketoacidosis

Fluid Therapy and Cerebral Injury in Pediatric Diabetic Ketoacidosis

The investigators will conduct a randomized controlled trial comparing four different intravenous (IV) fluid treatment protocols for pediatric diabetic ketoacidosis (DKA). Two rates of rehydration will be compared; a more rapid rate and a slower rate. Within each of these two basic rehydration protocols, the investigators will vary the type of rehydration fluid used (0.9% saline or 0.45% saline). The investigators will compare the different treatments by conducting assessments of neurological injury, by measuring the frequency of significant cerebral edema, and by measuring long-term neurocognitive function.

These studies will allow us to determine whether variations in IV fluid treatment protocols affect acute neurological outcomes of DKA. Additionally, they will provide important data regarding the impact of DKA and DKA treatment on long-term neurocognitive function in children. In this way, the investigators hope to identify a more ideal fluid management strategy for children with DKA.

Previous studies have suggested that DKA may cause blood flow to the brain to be reduced and that brain injury might result from this reduction in blood flow and/or the effects of re-establishment of normal blood flow during DKA treatment with insulin and iv fluids. The investigators hypothesize that more rapidly re-establishing normal blood flow to the brain during DKA, by giving fluids more rapidly and using fluids with a higher sodium (salt) content, will help to minimize brain injury caused by DKA.

Study Overview

• Status: Completed
• Conditions: Diabetic Ketoacidosis; Cerebral Edema
• Intervention / Treatment: Drug: 0.45% saline replacement fluid; Drug: 0.9% saline replacement fluid; Drug: 0.45% saline intravenous fluid; Drug: 0.9% saline Intravenous fluid

Detailed Description

These data will be compared to observational data from children with type 1 diabetes without DKA.

• Study Type: Interventional
• Enrollment (Actual): 1389
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • University of California, Davis
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I. DuPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Ann & Robert Lurie Children's Hospital of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University & St. Louis Children's Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Hasbro Children's Hospital/Rhode Island Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84158
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• must present or be transferred to a participating emergency department
• age less than 18 years

• diagnosis of DKA

  • serum glucose or fingerstick glucose concentration >300 mg/dL
  • venous pH < 7.25 OR serum bicarbonate concentration < 15 mmol/L.

Exclusion Criteria:

• patients with underlying neurological disorders or neurocognitive deficits which would affect either mental status testing during treatment or subsequent neurocognitive testing after recovery
• patients who present with concomitant alcohol or drug use, head trauma, meningitis or other conditions which might affect neurological function
• patients transferred to one of the participating emergency departments after initiation of DKA treatment other than one 10cc/kg intravenous bolus of 0.9% saline
• patients who are known to be pregnant at time of ED evaluation
• patients who have been enrolled in this study twice previously
• patients for whom the treating physician believed a specific fluid and electrolyte regimen was warranted
• patients for whom informed consent could not be obtained within 1 hour after completion of the initial fluid bolus, or within 2 hours from initiation of fluids, whichever is longer
• Patients who have been receiving IV fluids at a maintenance rate or greater (defined by the 4-2-1 rule) for more than two hours; OR
• Patients for whom it has been more than four hours since DKA therapy (IV fluids, IV bolus, or IV insulin) began; OR
• Patients who have been given hyperosmolar therapy (i.e. mannitol or 3% normal saline) prior to or since arriving at one of the participating PECARN emergency departments; OR
• Patients for whom the treating physician intends to immediately administer hyperosmolar therapy (i.e. mannitol or 3% normal saline); OR
• Patients whose baseline GCS is 11 or less.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rapid rehydration using 0.45% saline replacement fluid; This arm will involve more rapid intravenous fluid treatment which will include a second 10cc/Kg bolus of 0.9% saline and assume a 10% fluid deficit. 0.45% saline will be used as the replacement fluid for this arm.	Drug: 0.45% saline replacement fluid; 10cc/Kg bolus of 0.9% saline followed by 0.45% saline used as the replacement fluid
Experimental: Rapid rehydration using 0.9% saline replacement fluid; This arm will involve more rapid intravenous fluid treatment which will include a second 10cc/Kg bolus of 0.9% saline and assume a 10% fluid deficit. 0.9% saline will be used as the replacement fluid.	Drug: 0.9% saline replacement fluid; 10cc/Kg bolus of 0.9% saline followed by 0.9% saline used as the replacement fluid.
Experimental: Slower rehydration using 0.45% saline intravenous fluid; This arm will involve slower rehydration (assumed 5% fluid deficit and no additional fluid bolus) with 0.45% saline used as the replacement fluid.	Drug: 0.45% saline intravenous fluid; 0.45% saline fluid
Experimental: Slower rehydration using 0.9% saline intravenous fluid; This arm will involve slower rehydration (assumed 5% fluid deficit and no additional fuid bolus) with 0.9% saline used as the replacement fluid.	Drug: 0.9% saline Intravenous fluid; 0.9% saline fluid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the Number of Participants With Glasgow Coma Score (GCS) < 14 Within the First 24 Hours of Treatment for Diabetic Ketoacidosis (DKA)	The primary outcome is the binary indicator that a patient's GCS score drops below 14 (i.e. abnormal score) within the first 24 hours of treatment of DKA. There will be two treatment factors: sodium concentration of re-hydration fluids and rate of rehydration. These effects will be tested separately, using the Mantel-Haenszel chi-square test, stratified by hospital, and by the other main factor.	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Clinically Apparent Brain Injury	Deterioration in neurological status requiring interventions such as hyperosmolar therapy or endotracheal intubation, or resulting in death. This outcome was determined by an adjudication committee.	24 hours
Hourly Improvement in Forward and Backward Digit Span Scores During DKA Treatment (Mean Difference Per Hour)	The Digit Span subtest is adapted from the Wechsler Intelligence Scale for Children, 4th version (WISC-IV) and it assesses working memory. It consists of a Digit Span Forward task in which individuals are asked to repeat numbers in the same sequence as they were presented verbally and a Digit Span Backward task in which participants repeat the numbers in the reversed order to which they were heard. Each task yields a score ranging from 0 to 16. Higher scores represent better outcomes for this test. The trajectory of digit span scores during the course of the hospitalization was used to assess improvements in mental status and whether these varied systematically as a function of treatment protocol. Digit span measurements were collected every four hours during waking hours (7AM to 10PM). The measure analyzed is the average linear change in scores between enrollment and either 24-hours or DKA resolution, whichever occurred first.	24 hours
Mean Scores on Tests of Memory Capacity 3 Months After Recovery From DKA.	Contextual memory was assessed via color and spatial-position tasks. Color-Task: black-ink items on a white square background were shown on a computer screen with a colored border. Subjects were asked to remember the item and the item's border color. Items were shown for 1 second, followed by a 1-second interval in which a fixation point was shown. Then, subjects were given a self-paced recognition test including studied drawings and new drawings shown in random order with no color border. Subjects determined if they had seen the drawing before. For recognized drawings, subjects reported the previously shown border color. Spatial-Position task: identical to the color task except that the items instead varied in their spatial position on the computer screen. The item-context association rate is the rate of correct item-color and item-spatial position recalled over the total of previously viewed items correctly recognized. Score range: 0-1 with higher scores indicating a better outcome.	3 months
Intelligence Quotient (IQ) Testing	IQ was assessed with the WASI (6-18 year olds) or WPPSI-III (3-5 year olds) at the 3 month follow-up visit. The Wechsler Abbreviated Scale of Intelligence (WASI) is a measure of IQ designed for individuals aged 6 to 89. The WASI includes four subtests; the Block Design and Matrix Reasoning tests measure Performance IQ, and the Vocabulary and Similarities tests measure Verbal IQ. Full scale IQ was computed from these scores and used for analyses. Scores typically vary from 75 to 135 with higher scores representing a better outcome.	3 months

Collaborators and Investigators

• Sponsor: University of California, Davis
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Nathan Kuppermann, MD, MPH, University of California, Davis; Principal Investigator: Nicole S Glaser, MD, University of California, Davis

Publications and helpful links

General Publications

• Glaser NS, Ghetti S, Casper TC, Dean JM, Kuppermann N; Pediatric Emergency Care Applied Research Network (PECARN) DKA FLUID Study Group. Pediatric diabetic ketoacidosis, fluid therapy, and cerebral injury: the design of a factorial randomized controlled trial. Pediatr Diabetes. 2013 Sep;14(6):435-46. doi: 10.1111/pedi.12027. Epub 2013 Mar 13.

Helpful Links

• Official website of the Pediatric Emergency Care Applied Research Network (PECARN), funded by HRSA/MCHB

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: June 1, 2011
• First Submitted That Met QC Criteria: June 2, 2011
• First Posted (Estimate): June 3, 2011

Study Record Updates

• Last Update Posted (Actual): June 25, 2018
• Last Update Submitted That Met QC Criteria: June 19, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: diabetic ketoacidosis; fluid therapy; cerebral edema; pediatric diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Acid-Base Imbalance; Acidosis; Ketosis; Diabetic Ketoacidosis; Brain Edema
• Other Study ID Numbers: 230233; U01HD062417 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No