Thiamine as an Adjunctive Therapy in Cardiac Surgery

The main purpose of this pilot study is to test the effects of thiamine (vitamin B1) administration before and after major cardiac surgery. Half of patients will receive thiamine and the other half will receive placebo.

The investigators' main hypothesis is that thiamine will improve cellular oxygen consumption and lead to decreased levels of post-operative lactate levels and ultimately improved patient outcomes.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Bypass; Cardiac Surgical Procedures
• Intervention / Treatment: Drug: Normal saline solution; Drug: Thiamine

Detailed Description

Over 230,000 patients in the United States undergo Coronary Artery Bypass Grafting (CABG) each year. While mortality is relatively low, morbidity remains substantial with a significant risk of prolonged time on mechanical ventilation, prolonged length of hospital and intensive care unit stay and many other complications. CABG causes a profound stress response and significant metabolic alterations occur, including a shift from aerobic to anaerobic metabolism, causing increased levels of pyruvate and lactate. Elevated lactate, a marker of anaerobic metabolism, is a common and significant finding in patients after CABG and is correlated with increased mortality and morbidity.

Aerobic metabolism occurs when pyruvate enters the mitochondria through pyruvate decarboxylation to acetyl-Coenzyme A, facilitated by the enzyme pyruvate dehydrogenase (PDH). Decreased PDH activity may cause a shift toward anaerobic metabolism and play a role in the changes seen in patients undergoing CABG. Thiamine (vitamin B1) is a key co-factor for PDH function and will increase activity even in non-deficient states. The investigators hypothesize that thiamine administration will increase PDH activity in patients undergoing CABG, leading to increased cellular oxygen consumption, as represented by decreased lactate levels after surgery, and ultimately improved clinical outcomes.

In order to test the investigators' hypothesis and to obtain data for a large-scale clinical trial evaluating relevant clinical endpoints, the investigators are conducting a randomized, double-blind, pilot trial of thiamine in high-risk patients undergoing CABG.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adult (≥ 21 years)
• Coronary artery bypass grafting (CABG) with or without concomitant valve procedures
• EuroSCORE II > 1.5%

Exclusion Criteria:

• Current thiamine supplementation
• 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)
• Emergent or salvage CABG (as defined by the Society of Thoracic Surgeons)
• Off-pump surgery (i.e. surgery without cardiopulmonary bypass)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control Arm; 50 mL normal saline solution	Drug: Normal saline solution; 50 mL normal saline once immediately before surgery and once immediately after (at arrival in the intensive care unit)
Experimental: Thiamine; 200 mg thiamine in 50 mL normal saline solution	Drug: Thiamine; 200 mg thiamine in 50 mL normal saline once immediately before surgery and once immediately after (at arrival in the intensive care unit); Other Names: vitamin B1; Thiamin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Lactate Levels	Post-surgery within 1 hour of arrival to the ICU

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Baseline in Pyruvate Dehydrogenase (PDH) Enzyme Activity	PDH activity will be measured in isolated peripheral blood mononuclear cells using a novel immunocapture and microplate-based method. Reported as relative change from before the surgery.	Post-surgery within 1 hour of arrival to the ICU
Patients With Post-operative Complications	Atrial fibrillation, delirium, renal failure, stroke, myocardial infarction, acute respiratory distress syndrome, infection	Until hospital discharge, limit 60 days
Length of Stay	Duration of intensive care unit stay	Until hospital discharge, limit 60 days
Mortality		Until hospital discharge, limit 60 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lactate Levels		Six hours after end of surgery surgery
Pyruvate Dehydrogenase (PDH) Enzyme Activity	PDH activity will be measured in isolated peripheral blood mononuclear cells using a novel immunocapture and microplate-based method	Six hours after end of surgery surgery
Time on Mechanical Ventilation		Limit 60 days
Time on Vasopressors		Limit 60 days
Global Oxygen Consumption (VO2)	VO2 will be measured with a Compact Anesthesia monitor	From arrival to ICU to extubation, limit 6 hours
Cellular Oxygen Consumption	Cellular (peripheral blood mononuclear cells) oxygen consumption measured with the XFe24 Extracellular Flux Analyzers	Post-surgery within 1 hour of arrival to the ICU

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: University of Aarhus; American Heart Association
• Investigators: Principal Investigator: Michael W Donnino, M.D., Beth Israel Deaconess Medical Center

Publications and helpful links

General Publications

• Andersen LW, Holmberg MJ, Berg KM, Chase M, Cocchi MN, Sulmonte C, Balkema J, MacDonald M, Montissol S, Senthilnathan V, Liu D, Khabbaz K, Lerner A, Novack V, Liu X, Donnino MW. Thiamine as an adjunctive therapy in cardiac surgery: a randomized, double-blind, placebo-controlled, phase II trial. Crit Care. 2016 Mar 14;20:92. doi: 10.1186/s13054-016-1245-1.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): August 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: December 14, 2014
• First Submitted That Met QC Criteria: December 22, 2014
• First Posted (Estimate): December 23, 2014

Study Record Updates

• Last Update Posted (Actual): March 30, 2017
• Last Update Submitted That Met QC Criteria: March 3, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Vitamin B1; Cardiac surgery; Lactate; Coronary artery bypass grafting; Thiamine; Pyruvate dehydrogenase
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Thiamine
• Other Study ID Numbers: 2014P000257