Endothelial Dysfunction
Conditions
Brief summary
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.
Detailed description
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.
Interventions
human albumin 5% during surgery
6% Hydroxyethyl starch 130/0.4 during surgery
Sponsors
Study design
Eligibility
Inclusion criteria
* Age 40 - 85 years old * Scheduled for elective aortic valve replacement with or without coronary artery bypass grafting with or without additional minor surgical procedure. * Written, informed consent for participation in this investigation.
Exclusion criteria
* Patients with Raynaud's disease or other disease associated with upper extremity vascular insufficiency, * Inability to perform EndoPAT exam (inability to lie still for 15 min, or significant finger deformity), * Patients with renal failure with oliguria or anuria not related to hypovolemia. * Patients receiving dialysis. * Patients with preoperative renal insufficiency (Creatinine \> 1.6 mg/dL) * Anticipated deep hypothermic circulatory arrest * Known hypersensitivity or allergy to hydroxyethyl starch or the excipients of hydroxyethyl starch * Clinical conditions with volume overload (e.g., patients in pulmonary edema or congestive heart failure) * Patients with severe hypernatremia or severe hyperchloremia * Patients with intracranial bleeding * Pregnant or breast feeding women * Critically ill adult patients, including patients with sepsis, due to increased risk of mortality and renal replacement therapy, (e.g. patients who are hospitalized in the intensive care unit prior to surgery) * Severe liver disease * Pre-existing coagulation or bleeding disorders * Any contraindications to proposed interventions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reactive Hyperemia Index (RHI) | 2 hours after surgery | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentrations of Syndecan | 1 hour after surgery, 24 hours after surgery | Blood samples will be obtained at specified times |
| Plasma Concentrations of Endocan | 1 hour after surgery, 24 hours after surgery | Blood samples will be obtained at specified times |
Other
| Measure | Time frame | Description |
|---|---|---|
| Reactive Hyperemia Index (RHI) | 24 hours after surgery | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Human Albumin Human albumin 5% during surgery.
Human albumin: human albumin 5% during surgery | 43 |
| Hydroxyethyl Starch Hydroxyethyl starch 6% (130/0.4) solution during surgery
Hydroxyethyl starch: 6% Hydroxyethyl starch 130/0.4 during surgery | 42 |
| Total | 85 |
Baseline characteristics
| Characteristic | Human Albumin | Hydroxyethyl Starch | Total |
|---|---|---|---|
| Age, Continuous | 69 years STANDARD_DEVIATION 7 | 68 years STANDARD_DEVIATION 10 | 69 years STANDARD_DEVIATION 6 |
| Body Mass Index (BMI) | 30 kg/m2 STANDARD_DEVIATION 5 | 30 kg/m2 STANDARD_DEVIATION 6 | 30 kg/m2 STANDARD_DEVIATION 4 |
| Race/Ethnicity, Customized Not White | 2 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 41 Participants | 38 Participants | 79 Participants |
| Sex: Female, Male Female | 18 Participants | 16 Participants | 34 Participants |
| Sex: Female, Male Male | 25 Participants | 26 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 0 / 42 |
| other Total, other adverse events | 0 / 43 | 0 / 42 |
| serious Total, serious adverse events | 0 / 43 | 0 / 42 |
Outcome results
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.
Time frame: 2 hours after surgery
Population: 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).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human Albumin | Reactive Hyperemia Index (RHI) | 1.88 ratio | Standard Deviation 0.8 |
| Hydroxyethyl Starch | Reactive Hyperemia Index (RHI) | 1.61 ratio | Standard Deviation 0.71 |
Plasma Concentrations of Endocan
Blood samples will be obtained at specified times
Time frame: 1 hour after surgery, 24 hours after surgery
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Human Albumin | Plasma Concentrations of Endocan | endocan 1 hour after surgery | 280 pg/mL |
| Human Albumin | Plasma Concentrations of Endocan | endocan 24 hours after surgery | 154 pg/mL |
| Hydroxyethyl Starch | Plasma Concentrations of Endocan | endocan 1 hour after surgery | 233 pg/mL |
| Hydroxyethyl Starch | Plasma Concentrations of Endocan | endocan 24 hours after surgery | 132 pg/mL |
Plasma Concentrations of Syndecan
Blood samples will be obtained at specified times
Time frame: 1 hour after surgery, 24 hours after surgery
Population: 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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Human Albumin | Plasma Concentrations of Syndecan | Syndecan 1 hour after surgery | 684 ng/mL |
| Human Albumin | Plasma Concentrations of Syndecan | Syndecan 24 hours after surgery | 282 ng/mL |
| Hydroxyethyl Starch | Plasma Concentrations of Syndecan | Syndecan 1 hour after surgery | 746 ng/mL |
| Hydroxyethyl Starch | Plasma Concentrations of Syndecan | Syndecan 24 hours after surgery | 344 ng/mL |
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.
Time frame: 24 hours after surgery
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Human Albumin | Reactive Hyperemia Index (RHI) | 2.22 ratio | Standard Deviation 0.68 |
| Hydroxyethyl Starch | Reactive Hyperemia Index (RHI) | 1.60 ratio | Standard Deviation 0.62 |