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The purpose of this study is to evaluate whether patients receiving human albumin for plasma volume replacement during cardiac surgery have improved postoperative endothelial function compared to patients receiving 6% hydroxyethyl starch solutions. The postoperative endothelial function, measured with peripheral arterial tonometry as reactive hyperemia index (RHI) within 2 hours following surgery, will be compared in cardiac surgical patients randomized to receive human albumin or 6% HES solutions for intraoperative volume replacement. Within two hours of arrival to the ICU peripheral arterial tonometry using EndoPAT will be performed. In a subset of 40 consecutive patients the investigators will perform additional EndoPAT measurements to describe the expected changes that occur in endothelial function during the perioperative period (baseline, early postoperative and 24 hours postoperative) using RHI.
This study will also determine whether human albumin 5% reduces plasma biomarkers of endothelial and glycocalyceal damage by measuring plasma concentrations of syndecan 1 and endocan at baseline (before surgery), and 1 and 24 hours following surgery. Blood samples will be taken on the morning of the surgery, within one hour of arrival to the intensive care unit (ICU), and 24 hours after surgery or within 2 hours before discharge from the ICU (three times altogether). These samples will be used to measure the plasma concentrations of two biomarkers that measure endothelial injury.
Cardiac surgical patients enrolled in the SHARP study will be randomized to 5% human albumin or 6% HES on entrance to the operating room. Anesthetic and Surgical management will follow protocol established by SHARP study including administration of a blinded study solution which contains 5% human albumin or 6% HES following separation from cardiopulmonary bypass. Blood will collected for measurement of baseline syndecan 1 and endocan following arterial line and urinary catheter placement before surgical incision. At 1 and 24 hrs following surgery completion, blood will be collected for measurement of syndecan 1 and endocan. Within two hours of ICU arrival, assessment of endothelial function will be performed.
In a subset of patients (patients who consent for multiple measurements), assessment of endothelial function will be performed preoperatively (baseline) and 24 hours after surgery.
Vasoactive substances may influence EndoPAT measurement. Thus the investigators will collect data on use of preoperative antihypertensive medications that have direct or indirect effect on arterial smooth muscle relaxation. Use of epinephrine, norepinephrine, vasopressin, milrinone, nitroglycerine, nitroprusside, and sedatives such as propofol, dexmedetomidine and others will be recorded and adjusted for in the analysis. Data on packed red blood cells (PRBC) and blood component transfusion will be collected from Anesthesia Record Keeping System. Indications for PRBC transfusion include hematocrit (HCT) <22% on cardiopulmonary bypass and <24% off cardiopulmonary bypass, and hypovolemia with anemia (HCT<25% with mean arterial blood pressure <60 mmHg or heart rate >100 bpm). Blood component transfusion (platelets, fresh frozen plasma, cryoprecipitate) may be administered as necessary following institutional standard of care. Imbalances in blood product transfusion between study groups will be adjusted for in the analysis.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Human albumin | Other | Human albumin 5% during surgery. |
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| Hydroxyethyl starch | Other | Hydroxyethyl starch 6% (130/0.4) solution during surgery |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Human albumin | Drug | human albumin 5% during surgery |
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| Measure | Description | Time Frame |
|---|---|---|
| Reactive Hyperemia Index (RHI) | RHI measures endothelial dysfunction using noninvasive peripheral arterial tonometry (PAT) with the EndoPAT device. It is a ratio of the post-to-pre occlusion PAT amplitude of the tested arm, divided by the post-to-pre occlusion ratio of the control arm. RHI less than 1.67 is considered a sign of endothelial dysfunction and RHI equal to or greater than 1.67 is considered normal function. Increasing score indicates the improvement of coronary endothelial function. | 2 hours after surgery |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma Concentrations of Syndecan | Blood samples will be obtained at specified times | 1 hour after surgery, 24 hours after surgery |
| Plasma Concentrations of Endocan | Blood samples will be obtained at specified times |
| Measure | Description | Time Frame |
|---|---|---|
| Reactive Hyperemia Index (RHI) | RHI measures endothelial dysfunction using noninvasive peripheral arterial tonometry (PAT) with the EndoPAT device. It is a ratio of the post-to-pre occlusion PAT amplitude of the tested arm, divided by the post-to-pre occlusion ratio of the control arm. RHI less than 1.67 is considered a sign of endothelial dysfunction and RHI equal to or greater than 1.67 is considered normal function. Increasing score indicates the improvement of coronary endothelial function. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Daniel Sessler, M.D. | Department Chair | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cleveland Clinic | Cleveland | Ohio | 44195 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Human Albumin | Human albumin 5% during surgery. Human albumin: human albumin 5% during surgery |
| FG001 | Hydroxyethyl Starch | Hydroxyethyl starch 6% (130/0.4) solution during surgery Hydroxyethyl starch: 6% Hydroxyethyl starch 130/0.4 during surgery |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Human Albumin | Human albumin 5% during surgery. Human albumin: human albumin 5% during surgery |
| BG001 | Hydroxyethyl Starch | Hydroxyethyl starch 6% (130/0.4) solution during surgery Hydroxyethyl starch: 6% Hydroxyethyl starch 130/0.4 during surgery |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Reactive Hyperemia Index (RHI) | RHI measures endothelial dysfunction using noninvasive peripheral arterial tonometry (PAT) with the EndoPAT device. It is a ratio of the post-to-pre occlusion PAT amplitude of the tested arm, divided by the post-to-pre occlusion ratio of the control arm. RHI less than 1.67 is considered a sign of endothelial dysfunction and RHI equal to or greater than 1.67 is considered normal function. Increasing score indicates the improvement of coronary endothelial function. | The primary endpoint, the Reactive Hyperaemia Index measured within 2 hours of ICU arrival, was missing in 12 patients from the albumin group and 8 patients from the HES group, related to the inability to obtain good quality Reactive Hyperaemia Index measurement most commonly due to movement or other artifacts. The missing primary endpoint was independent of randomization (p=0.34). | Posted | Mean | Standard Deviation | ratio | 2 hours after surgery |
|
24 hours after surgery
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Human Albumin | Human albumin 5% during surgery. Human albumin: human albumin 5% during surgery |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Marta Kelava | Cleveland Clinic | 2162133218 | kelavam@ccf.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 1, 2016 | Oct 26, 2023 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Mar 4, 2016 | Oct 26, 2023 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D000075462 | Serum Albumin, Human |
| D000418 | Albumins |
| D006895 | Hydroxyethyl Starch Derivatives |
| ID | Term |
|---|---|
| D012709 | Serum Albumin |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D001798 | Blood Proteins |
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| Hydroxyethyl starch | Drug | 6% Hydroxyethyl starch 130/0.4 during surgery |
|
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| 1 hour after surgery, 24 hours after surgery |
| 24 hours after surgery |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Body Mass Index (BMI) | Mean | Standard Deviation | kg/m2 |
|
Human albumin 5% during surgery. Human albumin: human albumin 5% during surgery |
| OG001 | Hydroxyethyl Starch | Hydroxyethyl starch 6% (130/0.4) solution during surgery Hydroxyethyl starch: 6% Hydroxyethyl starch 130/0.4 during surgery |
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| Secondary | Plasma Concentrations of Syndecan | Blood samples will be obtained at specified times | Of 141 patients in the primary clinical trial (NCT02192502), 85 patients consented to the measurement of the Reactive Hyperaemia Index. For secondary outcomes, laboratory markers were measured in the initial 141 patients (N=72 albumin, 69 hydroxyethyl starch). Syndecan 1 hour after surgery was missing in 3 patients from the albumin group and 3 patients from the HES group. Syndecan 24 hours after surgery was missing in 4 patients from the albumin group and 4 patients from the HES group. | Posted | Median | Inter-Quartile Range | ng/mL | 1 hour after surgery, 24 hours after surgery |
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| Secondary | Plasma Concentrations of Endocan | Blood samples will be obtained at specified times | Of 141 patients in the primary clinical trial (NCT02192502), 85 patients consented to the measurement of the Reactive Hyperaemia Index. For secondary outcomes, laboratory markers were measured in the initial 141 patients (N=72 albumin, 69 hydroxyethyl starch). Endocan 1 hour after surgery was missing in 1 patient from the albumin group and 2 patients from the HES group. Endocan 24 hours after surgery was missing in 3 patients from the albumin group and 4 patients from the HES group. | Posted | Median | Inter-Quartile Range | pg/mL | 1 hour after surgery, 24 hours after surgery |
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| Other Pre-specified | Reactive Hyperemia Index (RHI) | RHI measures endothelial dysfunction using noninvasive peripheral arterial tonometry (PAT) with the EndoPAT device. It is a ratio of the post-to-pre occlusion PAT amplitude of the tested arm, divided by the post-to-pre occlusion ratio of the control arm. RHI less than 1.67 is considered a sign of endothelial dysfunction and RHI equal to or greater than 1.67 is considered normal function. Increasing score indicates the improvement of coronary endothelial function. | The secondary endpoint, the Reactive Hyperaemia Index measured within 24 hours of ICU arrival, was missing in 19 patients from the albumin group and 21 patients from the HES group, related to the inability to obtain good quality Reactive Hyperaemia Index measurement most commonly due to movement or other artifacts. | Posted | Mean | Standard Deviation | ratio | 24 hours after surgery |
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| 0 |
| 43 |
| 0 |
| 43 |
| 0 |
| 43 |
| EG001 | Hydroxyethyl Starch | Hydroxyethyl starch 6% (130/0.4) solution during surgery Hydroxyethyl starch: 6% Hydroxyethyl starch 130/0.4 during surgery | 0 | 42 | 0 | 42 | 0 | 42 |
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| D013213 |
| Starch |
| D004040 | Dietary Carbohydrates |
| D002241 | Carbohydrates |
| D005936 | Glucans |
| D011134 | Polysaccharides |
| Syndecan 24 hours after surgery |
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| endocan 24 hours after surgery |
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