Outcomes Study of Hyperinsulinemic Glucose Control in Cardiac Surgery

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00524472
• Collaborator: (none)
• Enrollment: 1,439
• Locations: 2
• Arms: 2
• Actual Duration (Months): 93
• Patients Per Site: 719.5
• Patients Per Site Per Month: 7.7

Study Details

Study Description

Brief Summary

Patients undergoing cardiac surgery will be randomized into one of two groups. Group A will be administered insulin using the hyperinsulinemic-normoglycemic clamp to normalize blood glucose levels intra-operatively. Group B will be administered insulin at the standard of care levels established by the participating institution. Patients will be followed at 10 days, 15 days and one year post-operatively.

Condition or Disease	Intervention/Treatment	Phase
Cardiac Surgery	Other: Hyperinsulinemic-normoglycemic clamp; Other: insulin at the standard of care levels	N/A

Detailed Description

Using a randomized, controlled design, we propose to test the primary hypothesis that normalization of blood glucose using a hyperinsulinemic-normoglycemic clamp technique reduces the risk of a composite outcome (one or more) of 30-day postoperative mortality and serious postoperative cardiac, renal, neurologic, and infectious postoperative complications in patients undergoing cardiac surgery.

Our secondary hypothesis is that hyperinsulinemic normoglycemic therapy will reduce length of stay in intensive care unit, atrial dysrhythmias, creatinine elevation, hospital readmission, all-cause and cardiac one-year mortality.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1439 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Prevention
• Official Title: The Effect of Hyperinsulinemic Glucose Control on Outcomes Following Cardiac Surgery
• Actual Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Hyperinsulinemic-normoglycemic clamp Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL.	Other: Hyperinsulinemic-normoglycemic clamp; Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL.; Other Names: clamp Hyperinsulinemic
Other: Insulin at the standard of care levels Group B will be administered insulin at the standard of care levels established by the participating institution.	Other: insulin at the standard of care levels; Subjects will be administered insulin at the standard of care levels established by the participating institution.; Other Names: insulin

Outcome Measures

Primary Outcome Measures

1. Any Major Morbidity/30-day Mortality [within 30 days post surgery]

   a composite (any versus none) of the following major postoperative complications occurring: all-cause postoperative mortality failure to wean from cardiopulmonary bypass or postoperative low cardiac index requiring mechanical circulatory support with intraaortic balloon counterpulsation, ventricular assist device, and/or extracorporeal mechanical oxygenation serious postoperative infection acute postoperative kidney injury requiring renal replacement therapy; new postoperative focal or global neurologic deficit.

Secondary Outcome Measures

1. Post Operative Atrial Fibrillation [15 - 30 days post operative]

   Evidence suggests that maintaining intra-operative normoglycemia during cardiac surgery while providing exogenous glucose and high-dose insulin may decrease post-operative morbidity or mortality. Using a randomized, controlled design, we propose to test the primary hypothesis that normalization of blood glucose using a hyperinsulinemic-normoglycemic clamp technique reduces the risk of a composite of serious adverse outcomes in patients undergoing cardiac surgery

2. Duration of Hospitalization [starting post operative day one to discharge from hospital, on an average of 8 days]

   Days from date of surgery to hospital discharge

3. Duration of Intensive Care Stay [ICU stay hours during hospital stay after surgery, on average of 25 hours]

   Hours from date of surgery to discharge from intensive care unit

4. All-cause Mortality [one year post operative]

   All-cause mortality identified during one-year follow-up.

5. a Composite of Minor Postoperative Complications [within 30 days after surgery]

   a composite of minor postoperative complications, which includes: a) prolonged mechanical ventilation, b) low cardiac index, c) acute kidney injury, d) prolonged hospitalization, and 3) all-cause hospital readmission within 30 days.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 18-90 years old

• Scheduled for cardiac surgery requiring cardiopulmonary bypass

Exclusion Criteria:

• Off-pump surgical procedures

• Anticipated deep hypothermic circulatory arrest

• In available, baseline cardiac troponin I (>0.5 ng/L) or troponin T (> 0.1 ng/mL) levels (at RVH or CC, respectively)

• Any contraindications to the proposed interventions

• Active infection, including patients with endocarditis or infected pacemaker leads.

• Any infection requiring long- term antibiotics ( > 14 days)

• kidney disease requiring renal replacement therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic	Cleveland	Ohio	United States	44195
2	Royal Victoria Hospital	Montreal	Quebec	Canada	H3A 1A1

Sponsors and Collaborators

• The Cleveland Clinic

Investigators

• Principal Investigator: Andra I Duncan, M.D., The Cleveland Clinic
• Study Director: Daniel I Sessler, M.D., The Cleveland Clinic
• Principal Investigator: Thomas Schricker, MD, Royal Victoria Hospital, Montreal, Canada
• Principal Investigator: George Carvalho, MD, Royal Victoria Hospital, Montreal, Canada

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT00524472
• Other Study ID Numbers: 07-470
• First Posted: Sep 3, 2007
• Last Update Posted: Oct 26, 2018
• Last Verified: Feb 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by The Cleveland Clinic: Hyperinsulinemic glucose control; cardiac surgery; Outcome
• Additional relevant MeSH terms: Insulin; Insulin, Globin Zinc

Study Results

Participant Flow

Arm/Group Title	Hyperinsulinemic-normoglycemic Clamp	Insulin at the Standard of Care Levels
Arm/Group Description	Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL. Hyperinsulinemic-normoglycemic clamp: Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL.	Group B will be administered insulin at the standard of care levels established by the participating institution. insulin at the standard of care levels: Subjects will be administered insulin at the standard of care levels established by the participating institution.
Period Title: Overall Study
STARTED	709	730
COMPLETED	709	730
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Hyperinsulinemic-normoglycemic Clamp	Insulin at the Standard of Care Levels	Total
Arm/Group Description	Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL. Hyperinsulinemic-normoglycemic clamp: Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL.	Group B will be administered insulin at the standard of care levels established by the participating institution. insulin at the standard of care levels: Subjects will be administered insulin at the standard of care levels established by the participating institution.	Total of all reporting groups
Overall Participants	709	730	1439
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66 (11)	66 (11)	66 (11)
Sex: Female, Male (Count of Participants)
Female	189 26.7%	184 25.2%	373 25.9%
Male	520 73.3%	546 74.8%	1066 74.1%
Region of Enrollment (Count of Participants)
Canada	457 64.5%	464 63.6%	921 64%
United States	252 35.5%	266 36.4%	518 36%

Outcome Measures

1. Primary Outcome

Title	Any Major Morbidity/30-day Mortality
Description	a composite (any versus none) of the following major postoperative complications occurring: all-cause postoperative mortality failure to wean from cardiopulmonary bypass or postoperative low cardiac index requiring mechanical circulatory support with intraaortic balloon counterpulsation, ventricular assist device, and/or extracorporeal mechanical oxygenation serious postoperative infection acute postoperative kidney injury requiring renal replacement therapy; new postoperative focal or global neurologic deficit.
Time Frame	within 30 days post surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hyperinsulinemic-normoglycemic Clamp	Insulin at the Standard of Care Levels
Arm/Group Description	Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL. Hyperinsulinemic-normoglycemic clamp: Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL.	Group B will be administered insulin at the standard of care levels established by the participating institution. insulin at the standard of care levels: Subjects will be administered insulin at the standard of care levels established by the participating institution.
Measure Participants	709	730
Count of Participants [Participants]	46 6.5%	82 11.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hyperinsulinemic-normoglycemic Clamp, Insulin at the Standard of Care Levels
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0043
	Comments	P-values for combined sites: significant if P < 0.0085 for efficacy. Adjusted for interim analysis. Confidence intervals adjusted for interim analysis.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hyperinsulinemic-normoglycemic clamp

2. Secondary Outcome

Title	Post Operative Atrial Fibrillation
Description	Evidence suggests that maintaining intra-operative normoglycemia during cardiac surgery while providing exogenous glucose and high-dose insulin may decrease post-operative morbidity or mortality. Using a randomized, controlled design, we propose to test the primary hypothesis that normalization of blood glucose using a hyperinsulinemic-normoglycemic clamp technique reduces the risk of a composite of serious adverse outcomes in patients undergoing cardiac surgery
Time Frame	15 - 30 days post operative

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hyperinsulinemic-normoglycemic Clamp	Insulin at the Standard of Care Levels
Arm/Group Description	Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL. Hyperinsulinemic-normoglycemic clamp: Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL.	Group B will be administered insulin at the standard of care levels established by the participating institution. insulin at the standard of care levels: Subjects will be administered insulin at the standard of care levels established by the participating institution.
Measure Participants	709	730
Count of Participants [Participants]	209 29.5%	235 32.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hyperinsulinemic-normoglycemic Clamp, Insulin at the Standard of Care Levels
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.29
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.75 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	HN vs. standard

3. Secondary Outcome

Title	Duration of Hospitalization
Description	Days from date of surgery to hospital discharge
Time Frame	starting post operative day one to discharge from hospital, on an average of 8 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hyperinsulinemic-normoglycemic Clamp	Insulin at the Standard of Care Levels
Arm/Group Description	Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL. Hyperinsulinemic-normoglycemic clamp: Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL.	Group B will be administered insulin at the standard of care levels established by the participating institution. insulin at the standard of care levels: Subjects will be administered insulin at the standard of care levels established by the participating institution.
Measure Participants	686	713
Median (95% Confidence Interval) [days]	8	8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hyperinsulinemic-normoglycemic Clamp, Insulin at the Standard of Care Levels
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.99
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.91 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Duration of Intensive Care Stay
Description	Hours from date of surgery to discharge from intensive care unit
Time Frame	ICU stay hours during hospital stay after surgery, on average of 25 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hyperinsulinemic-normoglycemic Clamp	Insulin at the Standard of Care Levels
Arm/Group Description	Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL. Hyperinsulinemic-normoglycemic clamp: Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL.	Group B will be administered insulin at the standard of care levels established by the participating institution. insulin at the standard of care levels: Subjects will be administered insulin at the standard of care levels established by the participating institution.
Measure Participants	649	671
Median (95% Confidence Interval) [hours]	25	27

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hyperinsulinemic-normoglycemic Clamp, Insulin at the Standard of Care Levels
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	HN vs. Standard

5. Secondary Outcome

Title	All-cause Mortality
Description	All-cause mortality identified during one-year follow-up.
Time Frame	one year post operative

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hyperinsulinemic-normoglycemic Clamp	Insulin at the Standard of Care Levels
Arm/Group Description	Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL. Hyperinsulinemic-normoglycemic clamp: Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL.	Group B will be administered insulin at the standard of care levels established by the participating institution. insulin at the standard of care levels: Subjects will be administered insulin at the standard of care levels established by the participating institution.
Measure Participants	653	682
Count of Participants [Participants]	32 4.5%	22 3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hyperinsulinemic-normoglycemic Clamp, Insulin at the Standard of Care Levels
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.12
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.52
	Confidence Interval	(2-Sided) 95%; 0.74 to 3.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	HN vs. standard

6. Secondary Outcome

Title	a Composite of Minor Postoperative Complications
Description	a composite of minor postoperative complications, which includes: a) prolonged mechanical ventilation, b) low cardiac index, c) acute kidney injury, d) prolonged hospitalization, and 3) all-cause hospital readmission within 30 days.
Time Frame	within 30 days after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hyperinsulinemic-normoglycemic Clamp	Insulin at the Standard of Care Levels
Arm/Group Description	Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL. Hyperinsulinemic-normoglycemic clamp: Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL.	Group B will be administered insulin at the standard of care levels established by the participating institution. insulin at the standard of care levels: Subjects will be administered insulin at the standard of care levels established by the participating institution.
Measure Participants	709	730
Count of Participants [Participants]	200 28.2%	237 32.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hyperinsulinemic-normoglycemic Clamp, Insulin at the Standard of Care Levels
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.085
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	HN vs. Standard

Adverse Events

Time Frame	One Year Post-opeperative follow-up for All-Cause Mortality; 1 month Post-opeperative follow-up for Serious Adverse Events and Other (Not Including Serious) Adverse Events
Arm/Group Title	Hyperinsulinemic-normoglycemic Clamp		Insulin at the Standard of Care Levels
Arm/Group Description	Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL. Hyperinsulinemic-normoglycemic clamp: Patients will be randomized to receive the hyperinsulinemic-normoglycemic clamp titrating the blood glucose to 80-110 mg/dL.		Group B will be administered insulin at the standard of care levels established by the participating institution. insulin at the standard of care levels: Subjects will be administered insulin at the standard of care levels established by the participating institution.
All Cause Mortality
	Hyperinsulinemic-normoglycemic Clamp		Insulin at the Standard of Care Levels
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/709 (4.5%)		22/730 (3%)
Serious Adverse Events
	Hyperinsulinemic-normoglycemic Clamp		Insulin at the Standard of Care Levels
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/709 (2.5%)		27/730 (3.7%)
Surgical and medical procedures
sae	18/709 (2.5%)	18	27/730 (3.7%)	27
Other (Not Including Serious) Adverse Events
	Hyperinsulinemic-normoglycemic Clamp		Insulin at the Standard of Care Levels
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/709 (0%)		0/730 (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.