Cerebral Edema, Diabetic Ketoacidosis
Conditions
Keywords
cerebral edema, diabetic ketoacidosis, pediatric diabetes, fluid therapy
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.
Detailed description
These data will be compared to observational data from children with type 1 diabetes without DKA.
Interventions
DRUG0.45% saline replacement fluid
10cc/Kg bolus of 0.9% saline followed by 0.45% saline used as the replacement fluid
DRUG0.9% saline replacement fluid
10cc/Kg bolus of 0.9% saline followed by 0.9% saline used as the replacement fluid.
DRUG0.45% saline intravenous fluid
0.45% saline fluid
DRUG0.9% saline Intravenous fluid
0.9% saline fluid
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of California, Davis
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| the Number of Participants With Glasgow Coma Score (GCS) < 14 Within the First 24 Hours of Treatment for Diabetic Ketoacidosis (DKA) | 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
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Clinically Apparent Brain Injury | 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. |
| Hourly Improvement in Forward and Backward Digit Span Scores During DKA Treatment (Mean Difference Per Hour) | 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. |
| Mean Scores on Tests of Memory Capacity 3 Months After Recovery From DKA. | 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. |
| Intelligence Quotient (IQ) Testing | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rapid Rehydration Using 0.45% Saline Replacement Fluid This arm involved more rapid intravenous fluid treatment which included a second 10cc/Kg bolus of 0.9% saline and assumed a 10% fluid deficit. Intravenous fluids were infused to replace half of the estimated fluid deficit over 12 hours and the remaining half over the following 24 hours, in addition to maintenance fluids. 0.45% saline was used as the replacement fluid for this arm. | 344 |
| Rapid Rehydration Using 0.9% Saline Replacement Fluid This arm involved more rapid intravenous fluid treatment which included a second 10cc/Kg bolus of 0.9% saline and assumed a 10% fluid deficit. Intravenous fluids were infused to replace half of the estimated fluid deficit over 12 hours and the remaining half over the following 24 hours, in addition to maintenance fluids. 0.9% saline was used as the replacement fluid for this arm. | 351 |
| Slower Rehydration Using 0.45% Saline Replacement Fluid This arm involved slower rehydration (assumed 5% fluid deficit and no additional fluid bolus). Intravenous fluids were infused to replace the estimated deficit over 48 hours, in addition to maintenance fluids. 0.45% saline was used as the replacement fluid for this arm. | 345 |
| Slower Rehydration Using 0.9% Saline Replacement Fluid This arm involved slower rehydration (assumed 5% fluid deficit and no additional fluid bolus). Intravenous fluids were infused to replace the estimated deficit over 48 hours, in addition to maintenance fluids. 0.9% saline was used as the replacement fluid for this arm. | 349 |
| Total | 1,389 |
Baseline characteristics
| Characteristic | Rapid Rehydration Using 0.45% Saline Replacement Fluid | Rapid Rehydration Using 0.9% Saline Replacement Fluid | Slower Rehydration Using 0.45% Saline Replacement Fluid | Slower Rehydration Using 0.9% Saline Replacement Fluid | Total |
|---|---|---|---|---|---|
| Age, Customized 0 to less than 6 years old | 43 Participants | 42 Participants | 42 Participants | 35 Participants | 162 Participants |
| Age, Customized 6 to less than 18 years old | 301 Participants | 309 Participants | 303 Participants | 314 Participants | 1227 Participants |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 48 Participants | 62 Participants | 49 Participants | 69 Participants | 228 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino, Other, or Unknown | 296 Participants | 289 Participants | 296 Participants | 280 Participants | 1161 Participants |
| Race/Ethnicity, Customized Race Black or African American | 73 Participants | 82 Participants | 68 Participants | 63 Participants | 286 Participants |
| Race/Ethnicity, Customized Race Other | 19 Participants | 14 Participants | 16 Participants | 23 Participants | 72 Participants |
| Race/Ethnicity, Customized Race Unknown | 17 Participants | 23 Participants | 14 Participants | 20 Participants | 74 Participants |
| Race/Ethnicity, Customized Race White | 235 Participants | 232 Participants | 247 Participants | 243 Participants | 957 Participants |
| Sex: Female, Male Female | 179 Participants | 187 Participants | 187 Participants | 186 Participants | 739 Participants |
| Sex: Female, Male Male | 165 Participants | 164 Participants | 158 Participants | 163 Participants | 650 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 342 | 0 / 344 | 0 / 338 | 0 / 347 |
| other Total, other adverse events | 112 / 342 | 124 / 344 | 117 / 338 | 129 / 347 |
| serious Total, serious adverse events | 5 / 342 | 4 / 344 | 11 / 338 | 10 / 347 |
Outcome results
Primary
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.
Time frame: 24 hours
Population: Patients with a GCS of 14 or 15 at randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rapid Rehydration Using 0.45% Saline Replacement Fluid | the Number of Participants With Glasgow Coma Score (GCS) < 14 Within the First 24 Hours of Treatment for Diabetic Ketoacidosis (DKA) | 10 Participants |
| Rapid Rehydration Using 0.9% Saline Replacement Fluid | the Number of Participants With Glasgow Coma Score (GCS) < 14 Within the First 24 Hours of Treatment for Diabetic Ketoacidosis (DKA) | 11 Participants |
| Slower Rehydration Using 0.45% Saline Replacement Fluid | the Number of Participants With Glasgow Coma Score (GCS) < 14 Within the First 24 Hours of Treatment for Diabetic Ketoacidosis (DKA) | 11 Participants |
| Slower Rehydration Using 0.9% Saline Replacement Fluid | the Number of Participants With Glasgow Coma Score (GCS) < 14 Within the First 24 Hours of Treatment for Diabetic Ketoacidosis (DKA) | 16 Participants |
Comparison: The study uses a factorial experimental design, and tests two null hypotheses. The first of these hypotheses - the frequency of GCS score declines to \<14 is equal between the Rapid Rehydration and Slower Rehydration groups - is reported here. The analysis of the second hypothesis is reported below.p-value: 0.34Cochran-Mantel-Haenszel
Comparison: The study uses a factorial experimental design, and tests the two null hypotheses. The second of these hypotheses - the frequency of GCS score declines to \<14 is equal between the 0.45% Saline group and the 0.90% Saline group - is reported here. The analysis of the first hypothesis is reported above.p-value: 0.43Cochran-Mantel-Haenszel
Secondary
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.
Time frame: 24 hours
Population: All randomized patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rapid Rehydration Using 0.45% Saline Replacement Fluid | Frequency of Clinically Apparent Brain Injury | 2 Participants |
| Rapid Rehydration Using 0.9% Saline Replacement Fluid | Frequency of Clinically Apparent Brain Injury | 2 Participants |
| Slower Rehydration Using 0.45% Saline Replacement Fluid | Frequency of Clinically Apparent Brain Injury | 5 Participants |
| Slower Rehydration Using 0.9% Saline Replacement Fluid | Frequency of Clinically Apparent Brain Injury | 3 Participants |
Secondary
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.
Time frame: 24 hours
Population: All randomized patients with digit span measured during DKA
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rapid Rehydration Using 0.45% Saline Replacement Fluid | Hourly Improvement in Forward and Backward Digit Span Scores During DKA Treatment (Mean Difference Per Hour) | Digit span recall test Forward slope | 0.065 Digit Span Change per Hour | Standard Error 0.01 |
| Rapid Rehydration Using 0.45% Saline Replacement Fluid | Hourly Improvement in Forward and Backward Digit Span Scores During DKA Treatment (Mean Difference Per Hour) | Digit span recall test Backward slope | 0.052 Digit Span Change per Hour | Standard Error 0.009 |
| Rapid Rehydration Using 0.9% Saline Replacement Fluid | Hourly Improvement in Forward and Backward Digit Span Scores During DKA Treatment (Mean Difference Per Hour) | Digit span recall test Backward slope | 0.053 Digit Span Change per Hour | Standard Error 0.009 |
| Rapid Rehydration Using 0.9% Saline Replacement Fluid | Hourly Improvement in Forward and Backward Digit Span Scores During DKA Treatment (Mean Difference Per Hour) | Digit span recall test Forward slope | 0.058 Digit Span Change per Hour | Standard Error 0.01 |
| Slower Rehydration Using 0.45% Saline Replacement Fluid | Hourly Improvement in Forward and Backward Digit Span Scores During DKA Treatment (Mean Difference Per Hour) | Digit span recall test Forward slope | 0.046 Digit Span Change per Hour | Standard Error 0.01 |
| Slower Rehydration Using 0.45% Saline Replacement Fluid | Hourly Improvement in Forward and Backward Digit Span Scores During DKA Treatment (Mean Difference Per Hour) | Digit span recall test Backward slope | 0.042 Digit Span Change per Hour | Standard Error 0.009 |
| Slower Rehydration Using 0.9% Saline Replacement Fluid | Hourly Improvement in Forward and Backward Digit Span Scores During DKA Treatment (Mean Difference Per Hour) | Digit span recall test Forward slope | 0.039 Digit Span Change per Hour | Standard Error 0.01 |
| Slower Rehydration Using 0.9% Saline Replacement Fluid | Hourly Improvement in Forward and Backward Digit Span Scores During DKA Treatment (Mean Difference Per Hour) | Digit span recall test Backward slope | 0.043 Digit Span Change per Hour | Standard Error 0.009 |
Secondary
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.
Time frame: 3 months
Population: All randomized subjects aged 3 years and older with 3-month follow-up and successful completion of IQ testing.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rapid Rehydration Using 0.45% Saline Replacement Fluid | Intelligence Quotient (IQ) Testing | 102 IQ points | Standard Deviation 12 |
| Rapid Rehydration Using 0.9% Saline Replacement Fluid | Intelligence Quotient (IQ) Testing | 102 IQ points | Standard Deviation 13 |
| Slower Rehydration Using 0.45% Saline Replacement Fluid | Intelligence Quotient (IQ) Testing | 102 IQ points | Standard Deviation 13 |
| Slower Rehydration Using 0.9% Saline Replacement Fluid | Intelligence Quotient (IQ) Testing | 103 IQ points | Standard Deviation 13 |
Secondary
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.
Time frame: 3 months
Population: All randomized subjects aged 6 years old and older with 3-month follow-up and successful completion of memory score tests, and d-prime (a measure of chance agreement) \>0.50
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rapid Rehydration Using 0.45% Saline Replacement Fluid | Mean Scores on Tests of Memory Capacity 3 Months After Recovery From DKA. | 0.60 Item-context association rate | Standard Deviation 0.14 |
| Rapid Rehydration Using 0.9% Saline Replacement Fluid | Mean Scores on Tests of Memory Capacity 3 Months After Recovery From DKA. | 0.60 Item-context association rate | Standard Deviation 0.14 |
| Slower Rehydration Using 0.45% Saline Replacement Fluid | Mean Scores on Tests of Memory Capacity 3 Months After Recovery From DKA. | 0.61 Item-context association rate | Standard Deviation 0.14 |
| Slower Rehydration Using 0.9% Saline Replacement Fluid | Mean Scores on Tests of Memory Capacity 3 Months After Recovery From DKA. | 0.60 Item-context association rate | Standard Deviation 0.14 |