Randomized Control Trial of Fluid Therapy for Pediatric Diabetic Ketoacidosis

NCT01365793 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 230233U01HD062417
• Study Type: interventional
• Target: 1,389
• Locations: 1 country
• Sites: 13

Brief Summary

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.

Conditions

Cerebral Edema; Diabetic Ketoacidosis

Keywords

cerebral edema; diabetic ketoacidosis; pediatric diabetes; fluid therapy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Frequency of Clinically Apparent Brain Injury

  24 hours

• Hourly Improvement in Forward and Backward Digit Span Scores During DKA Treatment (Mean Difference Per Hour)

  24 hours

• Mean Scores on Tests of Memory Capacity 3 Months After Recovery From DKA.

  3 months

• Intelligence Quotient (IQ) Testing

  3 months

Study Arms (4)

Rapid rehydration using 0.45% saline replacement fluid

EXPERIMENTAL

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

Rapid rehydration using 0.9% saline replacement fluid

EXPERIMENTAL

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

Slower rehydration using 0.45% saline intravenous fluid

EXPERIMENTAL

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

Slower rehydration using 0.9% saline intravenous fluid

EXPERIMENTAL

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

Interventions

0.45% saline replacement fluid DRUG

10cc/Kg bolus of 0.9% saline followed by 0.45% saline used as the replacement fluid

Rapid rehydration using 0.45% saline replacement fluid

0.9% saline replacement fluid DRUG

10cc/Kg bolus of 0.9% saline followed by 0.9% saline used as the replacement fluid.

Rapid rehydration using 0.9% saline replacement fluid

0.45% saline intravenous fluid DRUG

0.45% saline fluid

Slower rehydration using 0.45% saline intravenous fluid

0.9% saline Intravenous fluid DRUG

0.9% saline fluid

Slower rehydration using 0.9% saline intravenous fluid

Eligibility Criteria

• Age: Up to 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of California, Davis: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (13)

University of California, Davis

Sacramento, California, 95817, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Alfred I. duPont Hospital for Children

Wilmington, Delaware, 19803, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Ann & Robert Lurie Children's Hospital of Chicago

Chicago, Illinois, 60614, United States

Location

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

Washington University & St. Louis Children's Hospital

St Louis, Missouri, 63110, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Hasbro Children's Hospital/Rhode Island Hospital

Providence, Rhode Island, 02903, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

University of Utah

Salt Lake City, Utah, 84158, United States

Location

Related Publications (1)

• 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.

  PMID: 23490311 BACKGROUND

Related Links

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

MeSH Terms

Conditions

Brain Edema; Diabetic Ketoacidosis

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Ketosis; Acidosis; Acid-Base Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases

Limitations and Caveats

Fluid infusion rates for this study represent the upper and lower ends of DKA protocols in use. Rates above or below this range were not evaluated. There were fewer patients with GCS decline to \<14 than anticipated.

Results Point of Contact

• Title: Nathan Kuppermann
• Organization: University of California, Davis (UC Davis Health)

nkuppermann@ucdavis.edu

916-734-1535

Study Officials

• Nathan Kuppermann, MD, MPH

  University of California, Davis

  PRINCIPAL INVESTIGATOR

• Nicole S Glaser, MD

  University of California, Davis

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 1, 2011
• First Posted: June 3, 2011
• Study Start: November 1, 2010
• Primary Completion: September 1, 2016
• Study Completion: January 1, 2017
• Last Updated: June 25, 2018
• Results First Posted: June 25, 2018

Record last verified: 2018-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (13)