Cardiac Surgical Procedures, Coronary Artery Bypass
Conditions
Keywords
Thiamine, Vitamin B1, Coronary artery bypass grafting, Cardiac surgery, Lactate, Pyruvate dehydrogenase
Brief summary
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.
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.
Interventions
DRUGThiamine
200 mg thiamine in 50 mL normal saline once immediately before surgery and once immediately after (at arrival in the intensive care unit)
DRUGNormal saline solution
50 mL normal saline once immediately before surgery and once immediately after (at arrival in the intensive care unit)
Sponsors
American Heart Association
University of Aarhus
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Lactate Levels | Post-surgery within 1 hour of arrival to the ICU |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Pyruvate Dehydrogenase (PDH) Enzyme Activity | Post-surgery within 1 hour of arrival to the ICU | 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. |
| Patients With Post-operative Complications | Until hospital discharge, limit 60 days | Atrial fibrillation, delirium, renal failure, stroke, myocardial infarction, acute respiratory distress syndrome, infection |
| Length of Stay | Until hospital discharge, limit 60 days | Duration of intensive care unit stay |
| Mortality | Until hospital discharge, limit 60 days | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Lactate Levels | Six hours after end of surgery surgery | — |
| Cellular Oxygen Consumption | Post-surgery within 1 hour of arrival to the ICU | Cellular (peripheral blood mononuclear cells) oxygen consumption measured with the XFe24 Extracellular Flux Analyzers |
| Pyruvate Dehydrogenase (PDH) Enzyme Activity | Six hours after end of surgery surgery | PDH activity will be measured in isolated peripheral blood mononuclear cells using a novel immunocapture and microplate-based method |
| Time on Mechanical Ventilation | Limit 60 days | — |
| Time on Vasopressors | Limit 60 days | — |
| Global Oxygen Consumption (VO2) | From arrival to ICU to extubation, limit 6 hours | VO2 will be measured with a Compact Anesthesia monitor |
Countries
United States
Participant flow
Recruitment details
275 coronary artery bypass grafting patients screened between January and July 2015
Pre-assignment details
206 patients not included for various reasons. 5 patients were randomized, but never received the assigned treatment and was therefore not included in the pre-specified modified intend-to-treat analysis.
Participants by arm
| Arm | Count |
|---|---|
| Control Arm 50 mL normal saline solution
Normal saline solution: 50 mL normal saline once immediately before surgery and once immediately after (at arrival in the intensive care unit) | 33 |
| Thiamine 200 mg thiamine in 50 mL normal saline solution
Thiamine: 200 mg thiamine in 50 mL normal saline once immediately before surgery and once immediately after (at arrival in the intensive care unit) | 31 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Met exclusion criteria | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Surgery cancelled | 1 | 2 |
Baseline characteristics
| Characteristic | Control Arm | Total | Thiamine |
|---|---|---|---|
| Age, Continuous | 73 years | 72 years | 71 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 63 Participants | 31 Participants |
| Region of Enrollment United States | 33 participants | 64 participants | 31 participants |
| Sex: Female, Male Female | 10 Participants | 16 Participants | 6 Participants |
| Sex: Female, Male Male | 23 Participants | 48 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 33 | 0 / 31 |
| serious Total, serious adverse events | 0 / 33 | 0 / 31 |
Outcome results
Primary
Lactate Levels
Time frame: Post-surgery within 1 hour of arrival to the ICU
Population: Modified intention to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Arm | Lactate Levels | 2 mmol/L |
| Thiamine | Lactate Levels | 2.0 mmol/L |
Secondary
Length of Stay
Duration of intensive care unit stay
Time frame: Until hospital discharge, limit 60 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Arm | Length of Stay | 2.3 days |
| Thiamine | Length of Stay | 2.4 days |
Secondary
Mortality
Time frame: Until hospital discharge, limit 60 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control Arm | Mortality | 1 participants |
| Thiamine | Mortality | 0 participants |
Secondary
Patients With Post-operative Complications
Atrial fibrillation, delirium, renal failure, stroke, myocardial infarction, acute respiratory distress syndrome, infection
Time frame: Until hospital discharge, limit 60 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Control Arm | Patients With Post-operative Complications | 16 participants |
| Thiamine | Patients With Post-operative Complications | 16 participants |
Secondary
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.
Time frame: Post-surgery within 1 hour of arrival to the ICU
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Control Arm | Percentage Change From Baseline in Pyruvate Dehydrogenase (PDH) Enzyme Activity | 28 Percent change from baseline |
| Thiamine | Percentage Change From Baseline in Pyruvate Dehydrogenase (PDH) Enzyme Activity | 15 Percent change from baseline |
Other Pre-specified
Cellular Oxygen Consumption
Cellular (peripheral blood mononuclear cells) oxygen consumption measured with the XFe24 Extracellular Flux Analyzers
Time frame: Post-surgery within 1 hour of arrival to the ICU
Other Pre-specified
Global Oxygen Consumption (VO2)
VO2 will be measured with a Compact Anesthesia monitor
Time frame: From arrival to ICU to extubation, limit 6 hours
Other Pre-specified
Lactate Levels
Time frame: Six hours after end of surgery surgery
Other Pre-specified
Pyruvate Dehydrogenase (PDH) Enzyme Activity
PDH activity will be measured in isolated peripheral blood mononuclear cells using a novel immunocapture and microplate-based method
Time frame: Six hours after end of surgery surgery
Other Pre-specified
Time on Mechanical Ventilation
Time frame: Limit 60 days
Other Pre-specified
Time on Vasopressors
Time frame: Limit 60 days