Thiamine as an Adjunctive Therapy in Cardiac Surgery

• Sponsor: Beth Israel Deaconess Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02322892
• Collaborator: American Heart Association (Other), University of Aarhus (Other)
• Enrollment: 64
• Location: 1
• Arms: 2
• Duration (Months): 7
• Patients Per Site Per Month: 9.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Bypass; Cardiac Surgical Procedures	Drug: Thiamine; Drug: Normal saline solution	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Thiamine as an Adjunctive Therapy in Cardiac Surgery
• Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Lactate Levels [Post-surgery within 1 hour of arrival to the ICU]

Secondary Outcome Measures

1. 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.

2. Patients With Post-operative Complications [Until hospital discharge, limit 60 days]

   Atrial fibrillation, delirium, renal failure, stroke, myocardial infarction, acute respiratory distress syndrome, infection

3. Length of Stay [Until hospital discharge, limit 60 days]

   Duration of intensive care unit stay

4. Mortality [Until hospital discharge, limit 60 days]

Other Outcome Measures

1. Lactate Levels [Six hours after end of surgery surgery]

2. 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

3. Time on Mechanical Ventilation [Limit 60 days]

4. Time on Vasopressors [Limit 60 days]

5. Global Oxygen Consumption (VO2) [From arrival to ICU to extubation, limit 6 hours]

   VO2 will be measured with a Compact Anesthesia monitor

6. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Beth Israel Deaconess Medical Center
• American Heart Association
• University of Aarhus

Investigators

• Principal Investigator: Michael W Donnino, M.D., Beth Israel Deaconess Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Michael Donnino, M.D., Beth Israel Deaconess Medical Center
• ClinicalTrials.gov Identifier: NCT02322892
• Other Study ID Numbers: 2014P000257
• First Posted: Dec 23, 2014
• Last Update Posted: Mar 30, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Michael Donnino, M.D., Beth Israel Deaconess Medical Center: Thiamine; Vitamin B1; Coronary artery bypass grafting; Cardiac surgery; Lactate; Pyruvate dehydrogenase
• Additional relevant MeSH terms: Thiamine

Study Results

Participant Flow

Recruitment Details	275 coronary artery bypass grafting patients screened between January and July 2015
Pre-assignment Detail	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.

Arm/Group Title	Control Arm	Thiamine
Arm/Group Description	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)	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)
Period Title: Overall Study
STARTED	35	34
COMPLETED	33	31
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Control Arm	Thiamine	Total
Arm/Group Description	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)	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)	Total of all reporting groups
Overall Participants	33	31	64
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	73	71	72
Sex: Female, Male (Count of Participants)
Female	10 30.3%	6 19.4%	16 25%
Male	23 69.7%	25 80.6%	48 75%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 3%	0 0%	1 1.6%
White	32 97%	31 100%	63 98.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	33 100%	31 100%	64 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Modified intention to treat

Arm/Group Title	Control Arm	Thiamine
Arm/Group Description	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)	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)
Measure Participants	33	31
Median (Inter-Quartile Range) [mmol/L]	2	2.0

2. Secondary Outcome

Title	Percentage Change From Baseline in Pyruvate Dehydrogenase (PDH) Enzyme Activity
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control Arm	Thiamine
Arm/Group Description	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)	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)
Measure Participants	33	31
Median (Inter-Quartile Range) [Percent change from baseline]	28	15

3. Secondary Outcome

Title	Patients With Post-operative Complications
Description	Atrial fibrillation, delirium, renal failure, stroke, myocardial infarction, acute respiratory distress syndrome, infection
Time Frame	Until hospital discharge, limit 60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control Arm	Thiamine
Arm/Group Description	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)	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)
Measure Participants	33	31
Number [participants]	16 48.5%	16 51.6%

4. Secondary Outcome

Title	Length of Stay
Description	Duration of intensive care unit stay
Time Frame	Until hospital discharge, limit 60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control Arm	Thiamine
Arm/Group Description	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)	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)
Measure Participants	33	31
Median (Inter-Quartile Range) [days]	2.3	2.4

5. Secondary Outcome

Title	Mortality
Time Frame	Until hospital discharge, limit 60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control Arm	Thiamine
Arm/Group Description	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)	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)
Measure Participants	33	31
Number [participants]	1 3%	0 0%

6. Other Pre-specified Outcome

Title	Lactate Levels
Time Frame	Six hours after end of surgery surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Pyruvate Dehydrogenase (PDH) Enzyme Activity
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Time on Mechanical Ventilation
Time Frame	Limit 60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Time on Vasopressors
Time Frame	Limit 60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Global Oxygen Consumption (VO2)
Description	VO2 will be measured with a Compact Anesthesia monitor
Time Frame	From arrival to ICU to extubation, limit 6 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Cellular Oxygen Consumption
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Control Arm		Thiamine
Arm/Group Description	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)		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)
All Cause Mortality
	Control Arm		Thiamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Control Arm		Thiamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/31 (0%)
Other (Not Including Serious) Adverse Events
	Control Arm		Thiamine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/31 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.