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Endothelial Function After Cardiac Surgery

Does Plasma Volume Replacement With 5% Human Albumin Reduce Endothelial Injury and Glycocalyceal Disruption Compared With 6% Hydroxyethylstarch (130/0.4) in Patients Having Cardiac Surgery? A Substudy of the SHARP Clinical Trial

Status
Completed
Phases
NA
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT02882074
Enrollment
85
Registered
2016-08-29
Start date
2016-06-30
Completion date
2020-02-20
Last updated
2024-02-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Endothelial Dysfunction

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

DRUGHuman albumin

human albumin 5% during surgery

6% Hydroxyethyl starch 130/0.4 during surgery

Sponsors

The Cleveland Clinic
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)

Eligibility

Sex/Gender
ALL
Age
40 Years to 85 Years
Healthy volunteers
No

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

MeasureTime frameDescription
Reactive Hyperemia Index (RHI)2 hours after surgeryRHI 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

MeasureTime frameDescription
Plasma Concentrations of Syndecan1 hour after surgery, 24 hours after surgeryBlood samples will be obtained at specified times
Plasma Concentrations of Endocan1 hour after surgery, 24 hours after surgeryBlood samples will be obtained at specified times

Other

MeasureTime frameDescription
Reactive Hyperemia Index (RHI)24 hours after surgeryRHI 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

ArmCount
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
Total85

Baseline characteristics

CharacteristicHuman AlbuminHydroxyethyl StarchTotal
Age, Continuous69 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 Participants4 Participants6 Participants
Race/Ethnicity, Customized
White
41 Participants38 Participants79 Participants
Sex: Female, Male
Female
18 Participants16 Participants34 Participants
Sex: Female, Male
Male
25 Participants26 Participants51 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
0 / 430 / 42
other
Total, other adverse events
0 / 430 / 42
serious
Total, serious adverse events
0 / 430 / 42

Outcome results

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.

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).

ArmMeasureValue (MEAN)Dispersion
Human AlbuminReactive Hyperemia Index (RHI)1.88 ratioStandard Deviation 0.8
Hydroxyethyl StarchReactive Hyperemia Index (RHI)1.61 ratioStandard Deviation 0.71
p-value: 0.15895% CI: [-0.11, 0.64]Regression, Linear
Secondary

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.

ArmMeasureGroupValue (MEDIAN)
Human AlbuminPlasma Concentrations of Endocanendocan 1 hour after surgery280 pg/mL
Human AlbuminPlasma Concentrations of Endocanendocan 24 hours after surgery154 pg/mL
Hydroxyethyl StarchPlasma Concentrations of Endocanendocan 1 hour after surgery233 pg/mL
Hydroxyethyl StarchPlasma Concentrations of Endocanendocan 24 hours after surgery132 pg/mL
p-value: 0.25797.5% CI: [0.84, 1.68]Mixed Models Analysis
Secondary

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.

ArmMeasureGroupValue (MEDIAN)
Human AlbuminPlasma Concentrations of SyndecanSyndecan 1 hour after surgery684 ng/mL
Human AlbuminPlasma Concentrations of SyndecanSyndecan 24 hours after surgery282 ng/mL
Hydroxyethyl StarchPlasma Concentrations of SyndecanSyndecan 1 hour after surgery746 ng/mL
Hydroxyethyl StarchPlasma Concentrations of SyndecanSyndecan 24 hours after surgery344 ng/mL
p-value: 0.38897.5% CI: [0.57, 1.28]Mixed Models Analysis
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.

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.

ArmMeasureValue (MEAN)Dispersion
Human AlbuminReactive Hyperemia Index (RHI)2.22 ratioStandard Deviation 0.68
Hydroxyethyl StarchReactive Hyperemia Index (RHI)1.60 ratioStandard Deviation 0.62
p-value: 0.00395% CI: [0.23, 1.01]Regression, Linear

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026