Thiamine as Adjunctive Therapy for Diabetic Ketoacidosis

Overview

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.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: April 21, 2023

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

  • Drug: 200mg IV thiamine in 50mL 0.9% saline
    • Thiamine 200mg IV every 12 hours for 2 days
  • Drug: Placebo
    • 50mL 0.9% saline

Arms, Groups and Cohorts

  • Experimental: Thiamine
    • 200mg IV thiamine in 50mL 0.9% saline twice daily for 2 days
  • Placebo Comparator: Placebo
    • 100mL 0.9% saline twice daily for two days

Clinical Trial Outcome Measures

Primary Measures

  • plasma bicarbonate levels
    • Time Frame: 24 hours
    • Our primary outcome is change in bicarbonate over the 24 hours following enrollment with measurements at 0, 6, 12, 18, 24 hours using a linear-effects model

Secondary Measures

  • anion gap
    • Time Frame: 24 hours
    • Our secondary outcomes include change in anion gap over the 24 hours following enrollment with measurements at 0, 6, 12, 18, 24 hours using a linear-effects model
  • lactate
    • Time Frame: 24 hours
    • Another secondary outcome is change in lactate over the 24 hours following enrollment with measurements at 0, 6, 12, 18, 24 hours using a linear-effects model
  • oxygen consumption by circulating mononuclear cells
    • Time Frame: 24 hours
    • Oxygen consumption by circulating mononuclear cells is an index of whole body oxidative glucose metabolism. It also reflects whole body thiamine status due to the critical cofactor role of thiamine in oxidative metabolism. Mononuclear cell oxygen consumption will be assessed by the investigators when the patient is admitted into the study and again after 24 hours to determine if there is a difference between the two groups.
  • ICU length of stay
    • Time Frame: 24 hours
    • ICU length of stay reflects how rapidly the patient recovers from the most severe consequences of diabetic ketoacidosis. The investigators will record this parameter from hospital records.to determine if there is a difference between the two groups.
  • hospital length of stay
    • Time Frame: 24 hours
    • 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. The investigators will record this parameter from hospital records to determine if there is a difference between the two groups.
  • hospital resource usage
    • Time Frame: 24 hours
    • The investigators will record this parameter from hospital records to determine if there is a difference between the two groups

Participating in This Clinical Trial

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., alcoholic) – Research-protected populations (pregnant women, prisoners, the intellectually disabled) – Patient enrolled previously in same study – Code status of Do Not Resuscitate/Do Not Intubate (DNR/DNI) or Comfort Measures Only (CMO)

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Beth Israel Deaconess Medical Center
  • Collaborator
    • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • Provider of Information About this Clinical Study
    • Principal Investigator: Michael Donnino, Associate Professor of Medicine and Emergency Medicine – Beth Israel Deaconess Medical Center
  • Overall Contact(s)
    • Michael W Donnino, MD, (617) 754-2341, mdonnino@bidmc.harvard.edu

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