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Randomized Control Trial of Fluid Therapy for Pediatric Diabetic Ketoacidosis

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ClinicalTrials.gov Identifier: NCT01365793
Recruitment Status : Completed
First Posted : June 3, 2011
Results First Posted : June 25, 2018
Last Update Posted : June 25, 2018
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
University of California, Davis

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.


Condition or disease Intervention/treatment Phase
Cerebral Edema Diabetic Ketoacidosis Drug: 0.45% saline replacement fluid Drug: 0.9% saline replacement fluid Drug: 0.45% saline intravenous fluid Drug: 0.9% saline Intravenous fluid Phase 3

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1389 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Fluid Therapy and Cerebral Injury in Pediatric Diabetic Ketoacidosis
Study Start Date : November 2010
Actual Primary Completion Date : September 2016
Actual Study Completion Date : January 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Edema

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




Primary Outcome Measures :
  1. the Number of Participants With Glasgow Coma Score (GCS) < 14 Within the First 24 Hours of Treatment for Diabetic Ketoacidosis (DKA) [ Time Frame: 24 hours ]
    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.


Secondary Outcome Measures :
  1. Frequency of Clinically Apparent Brain Injury [ Time Frame: 24 hours ]
    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.

  2. Hourly Improvement in Forward and Backward Digit Span Scores During DKA Treatment (Mean Difference Per Hour) [ Time Frame: 24 hours ]
    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.

  3. Mean Scores on Tests of Memory Capacity 3 Months After Recovery From DKA. [ Time Frame: 3 months ]
    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.

  4. Intelligence Quotient (IQ) Testing [ Time Frame: 3 months ]
    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.



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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01365793


Locations
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United States, California
University of California, Davis
Sacramento, California, United States, 95817
United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
United States, Delaware
Alfred I. duPont Hospital for Children
Wilmington, Delaware, United States, 19803
United States, District of Columbia
Children's National Medical Center
Washington, District of Columbia, United States, 20010
United States, Illinois
Ann & Robert Lurie Children's Hospital of Chicago
Chicago, Illinois, United States, 60614
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University & St. Louis Children's Hospital
Saint Louis, Missouri, United States, 63110
United States, New York
Columbia University
New York, New York, United States, 10032
United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Rhode Island
Hasbro Children's Hospital/Rhode Island Hospital
Providence, Rhode Island, United States, 02903
United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84158
Sponsors and Collaborators
University of California, Davis
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Nathan Kuppermann, MD, MPH University of California, Davis
Principal Investigator: Nicole S Glaser, MD University of California, Davis

Additional Information:
Publications:
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Responsible Party: University of California, Davis
ClinicalTrials.gov Identifier: NCT01365793     History of Changes
Other Study ID Numbers: 230233
U01HD062417 ( U.S. NIH Grant/Contract )
First Posted: June 3, 2011    Key Record Dates
Results First Posted: June 25, 2018
Last Update Posted: June 25, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of California, Davis:
cerebral edema
diabetic ketoacidosis
pediatric diabetes
fluid therapy
Additional relevant MeSH terms:
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Brain Edema
Ketosis
Acidosis
Diabetic Ketoacidosis
Acid-Base Imbalance
Metabolic Diseases
Diabetes Mellitus
Glucose Metabolism Disorders
Diabetes Complications
Endocrine System Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases