Diabetic Ketoacidosis
Conditions
Keywords
diabetic ketoacidosis, DKA, thiamine, acidosis, oxygen consumption, lactate
Brief summary
This is a randomized, double-blind, placebo-controlled trial to determine if administration of intravenous thiamine will lead to quicker resolution of acidosis in patients admitted to the hospital with diabetic ketoacidosis. The investigators will secondarily investigate whether thiamine improves cellular oxygen consumption, shortens intensive care unit (ICU) and hospital stay or decreases hospital resource utilization.
Detailed description
Thiamine (vitamin B1) is a water-soluble vitamin that plays a key role in aerobic glucose metabolism. Thiamine is a cofactor of pyruvate dehydrogenase (PDH), an enzyme that must be activated for entry into the Krebs Cycle for aerobic metabolism. PDH activity is reduced in thiamine deficient states, resulting in a shift in pyruvate metabolism to the anaerobic pathway. This leads to increased lactate production and acidosis. Thiamine loss in the urine, with consequent thiamine deficiency, is not uncommon in diabetes. The investigators' preliminary studies have found that thiamine deficiency in occurs in as many as 39% of patients with DKA, and that thiamine levels are inversely associated with lactate and acidosis. The investigator hypothesizes that treating DKA patients with intravenous thiamine will lead to faster resolution of acidosis and improved aerobic metabolism. The investigator's secondary hypothesis is that thiamine treatment will shorten stays in the ICU and hospital and lead to utilization of fewer hospital resources. In this randomized, double-blind, placebo-controlled trial, patients admitted to the hospital with DKA who are enrolled in the study will be randomized to either intravenous thiamine (200mg in 0.9% saline) twice daily for two days or an identical volume of 0.9% saline on the same schedule. The investigator's primary outcome is change in bicarbonate over the 24 hours following enrollment, with measurements at 0, 6, 12, 18, 24 hours, using a linear mixed-effects model. Secondarily, patients will be stratified by Type I and Type II DM. Additionally, a pre-planned sub-analysis of thiamine deficient subjects will be performed.
Interventions
DRUG200mg IV thiamine in 50mL 0.9% saline
Thiamine 200mg IV every 12 hours for 2 days
DRUGPlacebo
50mL 0.9% saline
Sponsors
Beth Israel Deaconess Medical Center
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Bicarbonate ≤15 mEq/L * Anion gap \> 12 mEq/L * Blood pH≤ 7.24 (if already obtained by clinical team) * Urine ketones (qualitative) or serum ketones (β-hydroxybutyric acid) \> 3 mmol/L * Enrollment within 6 hours of presentation
Exclusion criteria
* Current thiamine supplementation ≥ 6 milligrams per day (i.e., more than a multivitamin) * Competing causes of severe acidosis including seizure, carbon monoxide poisoning, cyanide toxicity, cardiac arrest, liver dysfunction (specifically defined as known cirrhosis) * Known allergy to thiamine * Competing indication for thiamine administration as judged by the clinical team (e.g., significant alcohol use) * Research-protected populations (pregnant women and prisoners) * Patient enrolled previously in same study * Code status of Do Not Resuscitate/Do Not Intubate (DNR/DNI) or Comfort Measures Only (CMO)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Bicarbonate Levels | 6, 12, 18, and 24 hours after enrollment | Primary outcome of plasma bicarbonate levels over 24 hours (6, 12, 18, 24 hours) following enrollment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lactate | 6, 12, 18, and 24 hours after enrollment | Secondary outcome of lactate over 24 hours (6, 12, 18, 24 hours) following enrollment |
| Anion Gap | 6, 12, 18, and 24 hours after enrollment | Secondary outcome of anion gap over 24 hours (6, 12, 18, 24 hours) following enrollment |
| ICU Length of Stay | 45 days | ICU length of stay reflects the number of ICU admission days. |
| Hospital Length of Stay | 45 days | Hospital length of stay reflects how long it takes a diabetic ketoacidosis patient to recover to the point where he/she can be released from the hospital. |
| Duration of Insulin Therapy | First 7 days after enrollment | The duration of insulin therapy is calculated by examining the hospital clinical information systems for all records of IV insulin infusion beginning at the time of enrollment. The start and the stop time-stamps of medication infusion are used to calculate a duration of infusion. |
| SOFA Score (Sequential Organ Failure Assessement Score) | 24 hours | The SOFA score is a validated measure of organ dysfunction commonly used in critically ill patients, particularly those with sepsis. It evaluates the function of six organ systems-respiratory, cardiovascular, neurologic, hepatic, renal, and coagulation-based on routinely collected clinical and laboratory data. Each organ system is assigned a score from 0 (normal function) to 4 (most severe dysfunction), resulting in a total score ranging from 0 to 24. Higher SOFA scores indicate greater severity of organ failure and a higher risk of adverse outcomes. SOFA score in this study uses a modification in which the arterial oxygen saturation/fraction of inspired oxygen (SaO2 /FiO2) ratio is substituted for the partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2 /FiO2 ratio). |
| Oxygen Consumption by Circulating Mononuclear Cells | 24 hours | Oxygen consumption rate of circulating peripheral blood mononuclear cells measured using Seahorse. Basal respiration represents oxygen consumption under baseline conditions. ATP-linked respiration represents oxygen consumption coupled to ATP production, while proton leak represents oxygen consumption not linked to ATP synthesis. Maximal respiration represents the maximal capacity of the electron transport chain after uncoupling. Spare respiratory capacity represents the difference between maximal and basal respiration and indicates the ability to respond to increased energy demand. Non-mitochondrial respiration represents oxygen consumption independent of mitochondrial activity. |
| Pyruvate Dehydrogenase Activity | 24 hours and 72 hours (or at discharge if hostpial length of stay was less than 72 hours) | Secondary outcome of change in PDH specific activity over 72 hours or at discharge if patient's hospital length of stay was less than 72 hours. PDH activity and total PDH protein quantity were measured in isolated peripheral blood mononuclear cells (PBMCs) following selective disruption of the mitochondrial membrane, using a previously validated immunocapture and microplate-based enzymatic assay protocol. PDH-specific activity was calculated as the ratio of measured PDH enzymatic activity to the natural logarithm of PDH protein quantity (PDH activity / ln\[PDH quantity\]), providing a normalized metric that reflects the functional efficiency of the enzyme independent of its expression level. Higher values suggest higher enzymatic efficiency. |
| Neurocognitive: Hopkins Verbal Learning Test - Total Recall | At hospital discharge, median of 4 days | The Hopkins Verbal Learning Test-Revised (HVLT-R) Total Recall score is a measure of verbal learning and immediate memory. Participants are read a list of 12 words (from three semantic categories) and asked to recall as many words as possible across three consecutive learning trials. The Total Recall score is calculated as the sum of correctly recalled words across the three trials, yielding a possible range of 0 to 36, with higher scores indicating better verbal learning and memory performance. This score reflects both initial acquisition and short-term retention of verbal information and is commonly used to assess cognitive function in clinical research. |
| Neurocognitive: Hopkins Verbal Learning Test - Delayed Recall | At hospital discharge, median of 4 days | The Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall score assesses retention of verbal information after a delay. Following completion of the three learning trials, participants are asked to recall the previously presented word list after a delay period (typically 20-25 minutes) without re-exposure to the words. The Delayed Recall score is calculated as the number of correctly recalled words, with a possible range of 0 to 12, where higher scores indicate better memory retention. This measure reflects the ability to consolidate and retrieve learned information over time and is commonly used to evaluate memory function in clinical and research settings. |
| Neurocognitive: Hopkins Verbal Learning Test - Retention | At hospital discharge, median of 4 days | The Hopkins Verbal Learning Test-Revised (HVLT-R) Retention (%) score reflects the proportion of learned information that is retained over a delay. It is calculated as the ratio of the Delayed Recall score to the highest number of words recalled on any of the three immediate recall trials, multiplied by 100, yielding a percentage value. Scores typically range from 0% to 100%, with higher values indicating better retention of previously learned material. This measure provides an index of memory retention independent of initial learning performance. |
| Neurocognitive: Hopkins Verbal Learning Test - Recognition Discrimination Index | At hospital discharge, median of 4 days | The Hopkins Verbal Learning Test-Revised (HVLT-R) Recognition Discrimination Index assesses recognition memory by evaluating the ability to distinguish previously learned words from novel distractors. During the recognition phase, participants are presented with a list of target words and distractor words and asked to identify those that were previously learned. The Recognition Discrimination Index is calculated as the number of true positives (correctly identified target words) minus the number of false positives (incorrectly identified distractor words), yielding a score typically ranging from -12 to 12. Higher scores indicate better recognition accuracy and discrimination ability, reflecting the integrity of memory retrieval processes. |
| Neurocognitive: Brief Visuospatial Memory Test | At hospital discharge, median of 4 days | The Brief Visuospatial Memory Test (BVMT) assesses visuospatial learning and memory. Participants are shown six geometric designs for a brief period and asked to reproduce them from memory across three learning trials. Performance is scored based on the accuracy and placement of each design, with a total recall score ranging from 0 to 36, where higher scores indicate better visuospatial memory. A delayed recall trial is administered after a delay to assess retention of visual information. This measure evaluates the ability to encode, store, and retrieve visuospatial material. |
| Neurocognitive: Trail Making Test - Test Part A | At hospital discharge, median of 4 days | The Trail Making Test Part A (TMT-A) assesses visual attention, processing speed, and psychomotor function. Participants are instructed to connect numbered circles in sequential order as quickly as possible. The primary outcome is the time to completion, measured in seconds, with lower times indicating better performance. There is no fixed maximum score, although testing is typically discontinued at a predefined time limit (commonly 300 seconds). |
| Neurocognitive: Trail Making Test - Test Part B | At hospital discharge, median of 4 days | The Trail Making Test Part B (TMT-B) assesses executive function, including cognitive flexibility and set-shifting, in addition to processing speed. Participants are required to alternate between numbers and letters in sequence (e.g., 1-A-2-B) as quickly as possible. The primary outcome is the time to completion, measured in seconds, with lower times indicating better performance. As with TMT-A, there is no fixed maximum score, and testing is typically discontinued at a predefined time limit (commonly 300 seconds). |
| Neurocognitive: WAIS-IV Digit Span | At hospital discharge, median of 4 days | The Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) Digit Span subtest assesses attention, working memory, and concentration. Participants are asked to repeat sequences of numbers in forward order (Digit Span Forward), reverse order (Digit Span Backward), and ascending order (Digit Span Sequencing). Scores are based on the total number of correctly recalled sequences, with higher scores indicating better attention and working memory capacity. The total score ranges from 0 to 48. |
| Neurocognitive: Test of Verbal Fluency and Animal Naming | At hospital discharge, median of 4 days | The Animal Naming test is a measure of semantic verbal fluency and executive function. Participants are asked to name as many animals as possible within a fixed time period. The score is the total number of unique, correct animal names generated, with higher scores indicating better semantic memory retrieval and executive functioning. Scores range from 0 with no fixed upper limit. |
| Neurocognitive: Test of Premorbid Functioning | At hospital discharge, median of 4 days | The Test of Premorbid Functioning (TOPF) estimates an individual's baseline cognitive ability prior to illness or injury. Participants are asked to read aloud a list of irregularly spelled words, and performance is scored based on correct pronunciation. Scores are used to estimate premorbid intellectual functioning. Scores range from 0 to 70, with higher scores indicating higher estimated premorbid functioning. This measure helps contextualize current cognitive performance relative to expected baseline levels. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMichael Donnino, MD
Beth Israel Deaconess Medical Center
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 43 years |
| Anion Gap | 25.0 mEq/L STANDARD_DEVIATION 6.4 |
| Baseline Sequential Organ Failure Assessment (SOFA) Score | 1 scores on a scale |
| Bicarbonate | 8 mEq/L |
| Diabetes Mellitus Type Type 1 diabetes mellitus | 37 Participants |
| Diabetes Mellitus Type Type 2 diabetes mellitus | 15 Participants |
| DKA History None | 23 Participants |
| DKA History Previous DKA | 44 Participants |
| DKA History Unknown | 1 Participants |
| Glucose | 315 mg/dL |
| Insulin Drip at Enrollment No | 1 Participants |
| Insulin Drip at Enrollment Yes | 51 Participants |
| Insulin Pump Use No | 43 Participants |
| Insulin Pump Use Yes | 9 Participants |
| Lactate | 2.2 mmol/L |
| pH | 7.19 pH |
| Prior Insulin Use No | 13 Participants |
| Prior Insulin Use Yes | 73 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants |
| Race (NIH/OMB) Black or African American | 31 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 54 Participants |
| Region of Enrollment United States | 100 Participants |
| Selected Past Medical History (PMH) Alcohol use disorder | 0 Participants |
| Selected Past Medical History (PMH) CAD | 3 Participants |
| Selected Past Medical History (PMH) CHF | 2 Participants |
| Selected Past Medical History (PMH) COPD | 0 Participants |
| Selected Past Medical History (PMH) Dementia | 0 Participants |
| Selected Past Medical History (PMH) Diabetes | 39 Participants |
| Selected Past Medical History (PMH) HIV/AIDS | 1 Participants |
| Selected Past Medical History (PMH) Liver Disease | 1 Participants |
| Selected Past Medical History (PMH) Malignancy | 7 Participants |
| Selected Past Medical History (PMH) No PMH | 7 Participants |
| Selected Past Medical History (PMH) Renal Disease | 8 Participants |
| Selected Past Medical History (PMH) Stroke/TIA | 1 Participants |
| Selected Past Medical History (PMH) Tobacco Use | 7 Participants |
| Selected Past Medical History (PMH) Transplant | 1 Participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 52 | 1 / 48 |
| other Total, other adverse events | 0 / 52 | 0 / 48 |
| serious Total, serious adverse events | 0 / 52 | 0 / 48 |
Outcome results
None listed