The Effect of the Hyperinsulinemic Normoglycemic Clamp on Myocardial Function and Utilization of Glucose

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01187329
• Collaborator: National Institutes of Health (NIH) (NIH)
• Enrollment: 100
• Location: 1
• Arms: 2
• Duration (Months): 38
• Patients Per Site Per Month: 2.6

Study Details

Study Description

Brief Summary

The overall research plan is to test the hypothesis that intraoperative treatment of hyperinsulinemic normoglycemic clamp (HNC) in cardiac surgical patients improves myocardial function and short-term outcomes compared with standard glucose management.

Condition or Disease	Intervention/Treatment	Phase
Hyperglycemia; Aortic Valve Replacement; Aortic Stenosis; Cardiac Surgery	Other: hyperinsulinemic normoglycemic clamp (HNC); Other: control group	N/A

Detailed Description

Specific Aim #1:To determine whether intraoperative use of HNC affords cardioprotective benefits measured by improved echocardiographic measures of myocardial function, serum markers of cardiomyocyte injury, and hemodynamic indices measured immediately (at end of surgery) and during the short-term (initial hospitalization).

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effect of the Hyperinsulinemic Normoglycemic Clamp on Myocardial Function and Utilization of Glucose
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: hyperinsulinemic normoglycemic clamp (HNC) Patients will be randomized to receive treatment with HNC during cardiac surgery.	Other: hyperinsulinemic normoglycemic clamp (HNC); Prior to anesthetic induction, a baseline blood glucose value will be obtained, followed by an insulin infusion of 5 mU.Kg-1.min-1. When blood glucose is <110 mg/dL, a variable continuous infusion of glucose (dextrose 20%) supplemented with potassium (40 mEq/L) and phosphate (30 mmol/L) is administered to preserve normoglycemia (80-110 mg/dL). The glucose infusion is titrated to target glucose levels by checking blood glucose every 5 - 15 min with Accu-Check (Roche Diagnostics, Switzerland) glucose monitor. At sternal closure, insulin infusion is decreased to 1 mU/Kg/min. On admission to the ICU, insulin treatment follows the ICU protocol. The dextrose infusion is slowly weaned off over 2 - 4 hrs maintaining blood glucose > 80 mg/dL. Arterial blood glucose is measured every 30 - 60 min for 2 hrs, then, as stated in ICU protocol.
Placebo Comparator: standard glucose management Patients will be randomized to receive treatment with standard glucose management during cardiac surgery.	Other: control group; Baseline arterial blood glucose will be obtained before anesthetic induction. Repeat measurements are performed every 30-90 min. Glucose >150 on CPB will receive insulin according to intraoperative protocol. After surgery, insulin is given according to ICU protocol. Target glucose < 180 mg/dL.; Other Names: glucose standard of care

Outcome Measures

Primary Outcome Measures

1. Myocardial Function: Left Ventricular Global Longitudinal Strain (%) [end of surgery (closure), an average of 5 minutes]

   Left ventricular global longitudinal strain measured by intraoperative transesophageal echocardiography at end of surgery and assessed using off-line speckle-tracking echocardiography. higher values (%) mean a worse outcome.

2. Intraoperative Left Ventricular (LV) Global Longitudinal Strain Rate [end of surgery (closure) an average of 5 minutes]

   Left ventricular global longitudinal strain rate measured by intraoperative transesophageal echocardiography at end of surgery and assessed using off-line speckle-tracking echocardiography. higher values mean a worse outcome

Secondary Outcome Measures

1. Intraoperative Right Ventricular (RV) Systolic Longitudinal Strain [end of surgery (closure) an average of 5 minutes]

   Right ventricular global longitudinal strain measured by intraoperative transesophageal echocardiography at end of surgery and assessed using off-line speckle-tracking echocardiography. higher values mean a worse outcome.

2. Intraoperative Right Ventricular (RV) Systolic Longitudinal Strain Rate [end of surgery (closure) an average of 5 minutes]

   Right ventricular global longitudinal strain rate measured by intraoperative transesophageal echocardiography at end of surgery and assessed using off-line speckle-tracking echocardiography. higher values mean a worse outcome

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 84 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 40 - 84 years old, Aortic stenosis, Scheduled for Aortic valve replacement.

Exclusion Criteria:

• Poor quality echocardiographic images unsuitable for analysis

• Off -pump surgical procedure

• Anticipated deep hypothermic circulatory arrest

• Any contraindications to transesophageal echocardiogram (TEE) or other proposed intervention

• Unable to give written informed consent (non-English speaking, vulnerable patients, etc.)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• The Cleveland Clinic
• National Institutes of Health (NIH)

Investigators

• Principal Investigator: Andra Duncan, MD, The Cleveland Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT01187329
• Other Study ID Numbers: 10-526
• First Posted: Aug 24, 2010
• Last Update Posted: Nov 20, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by The Cleveland Clinic: Hyperglycemia; open heart surgery; bypass
• Additional relevant MeSH terms: Aortic Valve Stenosis; Hyperglycemia

Study Results

Participant Flow

Arm/Group Title	Hyperinsulinemic Normoglycemic Clamp (HNC)	Standard Glucose Management
Arm/Group Description	Patients will be randomized to receive treatment with HNC during cardiac surgery. hyperinsulinemic normoglycemic clamp (HNC): Prior to anesthetic induction, a baseline blood glucose value will be obtained, followed by an insulin infusion of 5 mU.Kg-1.min-1. When blood glucose is <110 mg/dL, a variable continuous infusion of glucose (dextrose 20%) supplemented with potassium (40 mEq/L) and phosphate (30 mmol/L) is administered to preserve normoglycemia (80-110 mg/dL). The glucose infusion is titrated to target glucose levels by checking blood glucose every 5 - 15 min with Accu-Check (Roche Diagnostics, Switzerland) glucose monitor. At sternal closure, insulin infusion is decreased to 1 mU/Kg/min. On admission to the ICU, insulin treatment follows the ICU protocol. The dextrose infusion is slowly weaned off over 2 - 4 hrs maintaining blood glucose > 80 mg/dL. Arterial blood glucose is measured every 30 - 60 min for 2 hrs, then, as stated in ICU protocol.	Patients will be randomized to receive treatment with standard glucose management during cardiac surgery. control group: Baseline arterial blood glucose will be obtained before anesthetic induction. Repeat measurements are performed every 30-90 min. Glucose >150 on CPB will receive insulin according to intraoperative protocol. After surgery, insulin is given according to ICU protocol. Target glucose < 180 mg/dL.
Period Title: Overall Study
STARTED	50	50
COMPLETED	49	48
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Hyperinsulinemic Normoglycemic Clamp (HNC)	Standard Glucose Management	Total
Arm/Group Description	Patients will be randomized to receive treatment with HNC during cardiac surgery. hyperinsulinemic normoglycemic clamp (HNC): Prior to anesthetic induction, a baseline blood glucose value will be obtained, followed by an insulin infusion of 5 mU.Kg-1.min-1. When blood glucose is <110 mg/dL, a variable continuous infusion of glucose (dextrose 20%) supplemented with potassium (40 mEq/L) and phosphate (30 mmol/L) is administered to preserve normoglycemia (80-110 mg/dL). The glucose infusion is titrated to target glucose levels by checking blood glucose every 5 - 15 min with Accu-Check (Roche Diagnostics, Switzerland) glucose monitor. At sternal closure, insulin infusion is decreased to 1 mU/Kg/min. On admission to the ICU, insulin treatment follows the ICU protocol. The dextrose infusion is slowly weaned off over 2 - 4 hrs maintaining blood glucose > 80 mg/dL. Arterial blood glucose is measured every 30 - 60 min for 2 hrs, then, as stated in ICU protocol.	Patients will be randomized to receive treatment with standard glucose management during cardiac surgery. control group: Baseline arterial blood glucose will be obtained before anesthetic induction. Repeat measurements are performed every 30-90 min. Glucose >150 on CPB will receive insulin according to intraoperative protocol. After surgery, insulin is given according to ICU protocol. Target glucose < 180 mg/dL.	Total of all reporting groups
Overall Participants	49	48	97
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70 (9)	70 (11)	70 (10)
Sex: Female, Male (Count of Participants)
Female	13 26.5%	17 35.4%	30 30.9%
Male	36 73.5%	31 64.6%	67 69.1%

Outcome Measures

1. Primary Outcome

Title	Myocardial Function: Left Ventricular Global Longitudinal Strain (%)
Description	Left ventricular global longitudinal strain measured by intraoperative transesophageal echocardiography at end of surgery and assessed using off-line speckle-tracking echocardiography. higher values (%) mean a worse outcome.
Time Frame	end of surgery (closure), an average of 5 minutes

Outcome Measure Data

Analysis Population Description

some patient's echocardiography were low quality and can not be used

Arm/Group Title	Hyperinsulinemic Normoglycemic Clamp (HNC)	Standard Glucose Management
Arm/Group Description	Patients will be randomized to receive treatment with HNC during cardiac surgery. hyperinsulinemic normoglycemic clamp (HNC): Prior to anesthetic induction, a baseline blood glucose value will be obtained, followed by an insulin infusion of 5 mU.Kg-1.min-1. When blood glucose is <110 mg/dL, a variable continuous infusion of glucose (dextrose 20%) supplemented with potassium (40 mEq/L) and phosphate (30 mmol/L) is administered to preserve normoglycemia (80-110 mg/dL). The glucose infusion is titrated to target glucose levels by checking blood glucose every 5 - 15 min with Accu-Check (Roche Diagnostics, Switzerland) glucose monitor. At sternal closure, insulin infusion is decreased to 1 mU/Kg/min. On admission to the ICU, insulin treatment follows the ICU protocol. The dextrose infusion is slowly weaned off over 2 - 4 hrs maintaining blood glucose > 80 mg/dL. Arterial blood glucose is measured every 30 - 60 min for 2 hrs, then, as stated in ICU protocol.	Patients will be randomized to receive treatment with standard glucose management during cardiac surgery. control group: Baseline arterial blood glucose will be obtained before anesthetic induction. Repeat measurements are performed every 30-90 min. Glucose >150 on CPB will receive insulin according to intraoperative protocol. After surgery, insulin is given according to ICU protocol. Target glucose < 180 mg/dL.
Measure Participants	36	36
Mean (Standard Deviation) [percentage of myocardial shortening]	-16.8 (4.6)	-15.9 (4.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hyperinsulinemic Normoglycemic Clamp (HNC), Standard Glucose Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 97.5%; -2.87 to 0.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Intraoperative Left Ventricular (LV) Global Longitudinal Strain Rate
Description	Left ventricular global longitudinal strain rate measured by intraoperative transesophageal echocardiography at end of surgery and assessed using off-line speckle-tracking echocardiography. higher values mean a worse outcome
Time Frame	end of surgery (closure) an average of 5 minutes

Outcome Measure Data

Analysis Population Description

some patient's echocardiography were low quality and can not be used

Arm/Group Title	Hyperinsulinemic Normoglycemic Clamp (HNC)	Standard Glucose Management
Arm/Group Description	Patients will be randomized to receive treatment with HNC during cardiac surgery. hyperinsulinemic normoglycemic clamp (HNC): Prior to anesthetic induction, a baseline blood glucose value will be obtained, followed by an insulin infusion of 5 mU.Kg-1.min-1. When blood glucose is <110 mg/dL, a variable continuous infusion of glucose (dextrose 20%) supplemented with potassium (40 mEq/L) and phosphate (30 mmol/L) is administered to preserve normoglycemia (80-110 mg/dL). The glucose infusion is titrated to target glucose levels by checking blood glucose every 5 - 15 min with Accu-Check (Roche Diagnostics, Switzerland) glucose monitor. At sternal closure, insulin infusion is decreased to 1 mU/Kg/min. On admission to the ICU, insulin treatment follows the ICU protocol. The dextrose infusion is slowly weaned off over 2 - 4 hrs maintaining blood glucose > 80 mg/dL. Arterial blood glucose is measured every 30 - 60 min for 2 hrs, then, as stated in ICU protocol.	Patients will be randomized to receive treatment with standard glucose management during cardiac surgery. control group: Baseline arterial blood glucose will be obtained before anesthetic induction. Repeat measurements are performed every 30-90 min. Glucose >150 on CPB will receive insulin according to intraoperative protocol. After surgery, insulin is given according to ICU protocol. Target glucose < 180 mg/dL.
Measure Participants	33	34
Mean (Standard Deviation) [Percent / sec]	-1.1 (0.3)	-1.0 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hyperinsulinemic Normoglycemic Clamp (HNC), Standard Glucose Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	t-test, 2 sided
	Comments	paired t-test
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 97.5%; -0.3 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Intraoperative Right Ventricular (RV) Systolic Longitudinal Strain
Description	Right ventricular global longitudinal strain measured by intraoperative transesophageal echocardiography at end of surgery and assessed using off-line speckle-tracking echocardiography. higher values mean a worse outcome.
Time Frame	end of surgery (closure) an average of 5 minutes

Outcome Measure Data

Analysis Population Description

some patient's echocardiography were low quality and can not be used

Arm/Group Title	Hyperinsulinemic Normoglycemic Clamp (HNC)	Standard Glucose Management
Arm/Group Description	Patients will be randomized to receive treatment with HNC during cardiac surgery. hyperinsulinemic normoglycemic clamp (HNC): Prior to anesthetic induction, a baseline blood glucose value will be obtained, followed by an insulin infusion of 5 mU.Kg-1.min-1. When blood glucose is <110 mg/dL, a variable continuous infusion of glucose (dextrose 20%) supplemented with potassium (40 mEq/L) and phosphate (30 mmol/L) is administered to preserve normoglycemia (80-110 mg/dL). The glucose infusion is titrated to target glucose levels by checking blood glucose every 5 - 15 min with Accu-Check (Roche Diagnostics, Switzerland) glucose monitor. At sternal closure, insulin infusion is decreased to 1 mU/Kg/min. On admission to the ICU, insulin treatment follows the ICU protocol. The dextrose infusion is slowly weaned off over 2 - 4 hrs maintaining blood glucose > 80 mg/dL. Arterial blood glucose is measured every 30 - 60 min for 2 hrs, then, as stated in ICU protocol.	Patients will be randomized to receive treatment with standard glucose management during cardiac surgery. control group: Baseline arterial blood glucose will be obtained before anesthetic induction. Repeat measurements are performed every 30-90 min. Glucose >150 on CPB will receive insulin according to intraoperative protocol. After surgery, insulin is given according to ICU protocol. Target glucose < 180 mg/dL.
Measure Participants	26	28
Mean (Standard Deviation) [percentage of myocardial shortening]	-17.2 (4.3)	-17.3 (3.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hyperinsulinemic Normoglycemic Clamp (HNC), Standard Glucose Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -2.6 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Intraoperative Right Ventricular (RV) Systolic Longitudinal Strain Rate
Description	Right ventricular global longitudinal strain rate measured by intraoperative transesophageal echocardiography at end of surgery and assessed using off-line speckle-tracking echocardiography. higher values mean a worse outcome
Time Frame	end of surgery (closure) an average of 5 minutes

Outcome Measure Data

Analysis Population Description

some patient's echocardiography were low quality and can not be used

Arm/Group Title	Hyperinsulinemic Normoglycemic Clamp (HNC)	Standard Glucose Management
Arm/Group Description	Patients will be randomized to receive treatment with HNC during cardiac surgery. hyperinsulinemic normoglycemic clamp (HNC): Prior to anesthetic induction, a baseline blood glucose value will be obtained, followed by an insulin infusion of 5 mU.Kg-1.min-1. When blood glucose is <110 mg/dL, a variable continuous infusion of glucose (dextrose 20%) supplemented with potassium (40 mEq/L) and phosphate (30 mmol/L) is administered to preserve normoglycemia (80-110 mg/dL). The glucose infusion is titrated to target glucose levels by checking blood glucose every 5 - 15 min with Accu-Check (Roche Diagnostics, Switzerland) glucose monitor. At sternal closure, insulin infusion is decreased to 1 mU/Kg/min. On admission to the ICU, insulin treatment follows the ICU protocol. The dextrose infusion is slowly weaned off over 2 - 4 hrs maintaining blood glucose > 80 mg/dL. Arterial blood glucose is measured every 30 - 60 min for 2 hrs, then, as stated in ICU protocol.	Patients will be randomized to receive treatment with standard glucose management during cardiac surgery. control group: Baseline arterial blood glucose will be obtained before anesthetic induction. Repeat measurements are performed every 30-90 min. Glucose >150 on CPB will receive insulin according to intraoperative protocol. After surgery, insulin is given according to ICU protocol. Target glucose < 180 mg/dL.
Measure Participants	26	28
Mean (Standard Deviation) [Percent / sec]	-1.1 (0.3)	-1.1 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hyperinsulinemic Normoglycemic Clamp (HNC), Standard Glucose Management
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.45
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	Hyperinsulinemic Normoglycemic Clamp (HNC)		Standard Glucose Management
Arm/Group Description	Patients will be randomized to receive treatment with HNC during cardiac surgery. hyperinsulinemic normoglycemic clamp (HNC): Prior to anesthetic induction, a baseline blood glucose value will be obtained, followed by an insulin infusion of 5 mU.Kg-1.min-1. When blood glucose is <110 mg/dL, a variable continuous infusion of glucose (dextrose 20%) supplemented with potassium (40 mEq/L) and phosphate (30 mmol/L) is administered to preserve normoglycemia (80-110 mg/dL). The glucose infusion is titrated to target glucose levels by checking blood glucose every 5 - 15 min with Accu-Check (Roche Diagnostics, Switzerland) glucose monitor. At sternal closure, insulin infusion is decreased to 1 mU/Kg/min. On admission to the ICU, insulin treatment follows the ICU protocol. The dextrose infusion is slowly weaned off over 2 - 4 hrs maintaining blood glucose > 80 mg/dL. Arterial blood glucose is measured every 30 - 60 min for 2 hrs, then, as stated in ICU protocol.		Patients will be randomized to receive treatment with standard glucose management during cardiac surgery. control group: Baseline arterial blood glucose will be obtained before anesthetic induction. Repeat measurements are performed every 30-90 min. Glucose >150 on CPB will receive insulin according to intraoperative protocol. After surgery, insulin is given according to ICU protocol. Target glucose < 180 mg/dL.
All Cause Mortality
	Hyperinsulinemic Normoglycemic Clamp (HNC)		Standard Glucose Management
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/49 (0%)		0/48 (0%)
Serious Adverse Events
	Hyperinsulinemic Normoglycemic Clamp (HNC)		Standard Glucose Management
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/49 (0%)		0/48 (0%)
Other (Not Including Serious) Adverse Events
	Hyperinsulinemic Normoglycemic Clamp (HNC)		Standard Glucose Management
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/49 (0%)		0/48 (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.