Clinical trial NCT02882074
Conditions: Endothelial Dysfunction
Sponsor: The Cleveland Clinic
Start date: 2016-06-01; Completion date: 2020-02-20
Enrollment: 85 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: Human albumin 5% during surgery. arm 2: Hydroxyethyl starch 6% (130/0.4) solution during surgery
Interventions: intervention 1: Human albumin intervention 2: Hydroxyethyl starch
Intervention descriptions: intervention 1: human albumin 5% during surgery intervention 2: 6% Hydroxyethyl starch 130/0.4 during surgery

Protocol documents:
Prot_SAP_000.pdf: 
 
1
 
 
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 
 
 
June, 2016 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: 
Marta Kelava, M.D. 
Email: kelavam@ccf.org 
 
Staff mentor: 
Andra E. Duncan, M.D. 
Email: duncana@ccf.org 
 
Department of Cardiothoracic Anesthesia and Outcomes Research 
Cleveland Clinic, Cleveland, OH 
Mailing address: 9500 Euclid Avenue / J4 
Department of Cardiothoracic Anesthesia, 
Cleveland, OH  44195 
USA 
 


 
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SPECIFIC AIMS 
Systemic inflammation caused by exposure to cardiopulmonary bypass or other conditions such 
as sepsis, ischemia-reperfusion, trauma, major surgery and prolonged hyperglycemia leads to endothelial 
activation by circulating citokines and subsequent injury to glycocalix and endothelium.[1, 2] Intravascular 
solutions used for plasma volume replacement, such as human albumin 5%, demonstrate endothelial 
protective effects which may mitigate the postoperative inflammatory response and consequent 
endothelial injury.[3, 4] Administration of hydroxyethyl starch (HES) solutions, which have known adverse 
effects on endothelial function, increases mortality and kidney injury in patients with sepsis [5, 6] perhaps 
due to aggravation of endothelial and glycocalyceal injury.[7-9] Whether endothelial function is improved 
in cardiac surgical patients receiving plasma volume resuscitation with 5% human albumin compared with 
HES solutions, however, is unknown. Our proposed investigation will test the primary hypothesis that 
postoperative endothelial function, measured with peripheral arterial tonometry as reactive hyperemia 
index (RHI) within 2 hours following surgery, is improved in cardiac surgical patients who are 
randomized to receive human albumin for plasma volume replacement, compared with 6% HES 
solutions. Secondarily, we hypothesize that patients who receive 5% human albumin will have 
reduced plasma concentrations of molecular biomarkers of glycocalyceal injury (syndecan 1 and 
endocan) compared with those who receive 6% HES solutions. If plasma volume resuscitation with 5% 
human albumin preserves perioperative endothelial function, kidney dysfunction and other organ injury 
following cardiac surgery may be reduced. 
Specific aim 1.  To determine whether human albumin 5% improves postoperative endothelial 
function compared with 6% HES (130/0.4). Endothelial function will be assessed 2 hours following 
surgery by measuring RHI using peripheral arterial tonometry (EndoPAT, Itamar Medical Inc., Caesarea, 
Israel), a well validated tool used in endothelial dysfunction diagnostics and cardiovascular risk 
stratification.[10-12] We hypothesize that patients who receive human albumin 5% for intravascular 
volume replacement during surgery will have improved endothelial function at 2 hours following surgery 
compared with those who receive 6% HES (130/0.4).  
Sub-aim 1. Our preliminary data suggest that post-operative endothelial function is poorly correlated 
with baseline (preoperative) endothelial function. In a subset of patients, we will describe the 
expected changes that occur in endothelial function during the perioperative period (baseline, early 
postoperative, 24 hours postoperative. We will assess this for 40 patients (20 per group), at baseline, 
within 2 hours after surgery, and 24 hours after surgery. We hypothesise that there will be a decline in 
endothelial function from baseline to 2 hours after surgery and no significant difference in function 
between baseline and at 24 hours after surgery. 
Specific aim 2.  To determine whether human albumin 5% reduces plasma biomarkers of 
endothelial and glycocalyceal damage. We will measure plasma concentrations of syndecan 1 and 
endocan at baseline (before surgery), and 1 and 24 hours following surgery. Syndecan 1 and endocan 
are components of glycocalyx, and increased blood concentrations of these molecules indicate 
glycocalyceal shedding and endothelial dysfunction.[13, 14] We hypothesize that patients who receive 
human albumin 5% for intravascular volume replacement during surgery will have reduced concentrations 
of syndecan 1 and endocan at 1 and 24 hours following surgery compared with those who receive 6% 
HES (130/0.4). 
BACKGROUND AND SIGNIFICANCE 
Inflammation causes endothelial injury and degradation of the glycocalyx 
The vascular endothelium and its proteinaceous coating, the glycocalyx, is omnipresent 
throughout the circulatory system and plays a key role in preserving vascular integrity and function. The 
endothelium regulates vascular tone, inhibits intravascular thrombosis and modulates the inflammatory 
response by modifying the adhesion/migration of leukocytes and other mediators.[8, 14-17]  During 
inflammation induced by cardiopulmonary bypass or sepsis, leukocytes and other inflammatory mediators 
target the endothelium and glycocalyx causing disruption of vascular endothelial function. Vascular 
permeability, leukocyte trafficking, and oxidative stress are increased, while vascular tone is reduced. 
Oxygen and nutrient delivery to cells is impaired and a procoagulant state is promoted.[1, 2, 16, 18] 


 
3
Leukocyte activation and endothelial adherence contribute to microvascular flow impairment. Vascular 
hyperpermeability and albuminuria occur, and microthrombi form in the kidney and other organs.[19-22] 
 
Human albumin 5% has beneficial effects on endothelial and glycocalyceal function compared 
with HES solutions 
Human albumin has demonstrated beneficial effects on vascular endothelial and glycocalyceal 
function in ex vivo models. It prevents fluid extravasation more effectively compared with crystalloid or 
synthetic HES solutions in an ex vivo heart model, and has been shown to inhibit binding of activated 
polymorphonuclear leukocytes to bovine aortic endothelial cells. [3] [4] Shear stress-mediated nitric oxide 
release and coronary vasodilatation is potentiated with administration of human albumin compared with 
HES solutions.[9] Further, binding of neutrophil-derived myeloperoxidase to bovine aortic endothelial 
cells, a mediator of multiple oxidative and nitric oxide-consuming reactions, is inhibited by human serum 
albumin, while it is amplified by HES solutions.[4]Thus the protective characteristics of plasma volume 
administration with human albumin may reduce endothelial injury in the kidney and other organs, and, 
ultimately, reduce postoperative organ dysfunction in cardiac surgical patients, especially compared with 
use of HES solutions.  
 
Endothelial function can be assessed by validated noninvasive techniques 
Endothelial function is measured by the magnitude of arterial dilation that occurs following the 
release of nitric oxide or other endothelium-derived vasoactive substance.[23] Brachial flow-mediated 
dilation (FMD), a standard measure of endothelial function,[24] is a noninvasive ultrasound-based method 
that measures the increase in arterial diameter caused by shear stress-mediated endothelial release of 
nitric oxide. FMD is closely correlated with invasive measures of endothelial function;[25] however, it is 
technically demanding, affected by the cardiac cycle, and dependent upon the quality of ultrasound 
images.[24] Peripheral arterial tonometry (PAT) is a sensitive, accurate, and reproducible noninvasive 
measure of endothelial function. PAT measures endothelium-mediated changes in vascular tone using 
beat-to-beat plethysmographic recordings of the finger pulse wave amplitude with pneumatic probes at 
baseline and following release of a 5-min occlusion of the brachial artery (using a standard blood 
pressure cuff). The endothelium-dependent flow mediated dilation response is manifested as reactive 
hyperemia which is quantified by the post-occlusion to pre-occlusion ratio.  PAT correlates closely with 
FMD assessed with brachial arterial ultrasound.[12] Use of PAT in patients after cardiac surgery provides 
a noninvasive reliable and reproducible measure of systemic endothelial function. 
 
Endothelial function can be measured by biomarkers in the blood  
Plasma concentration of syndecan 1 serves as a biomarker of endothelial injury and glycocalyx 
degradation and correlates with serum levels of inflammatory cytokines and mortality in trauma 
patients.[13] Endocan is another component of the glycocalyx which is released during inflammation in 
response to tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), and correlates with severity of 
sepsis.[14] Assessment of plasma concentrations of syndecan 1 and endocan provide quantifiable 
measures of perioperative endothelial injury and glycocalyceal disruption. 
 
SIGNIFICANCE 
Perioperative inflammation and endothelial dysfunction lead to multi-organ system dysfunction 
following cardiac surgery, including postoperative kidney injury, pulmonary insufficiency, coagulopathy, 
vasoplegia, hemodynamic instability, and postoperative delirium. Determining whether plasma volume 
resuscitation with 5% human albumin reduces perioperative endothelial/glycocalyceal dysfunction 
compared with 6% HES solutions will 1) improve our understanding of the clinical effects of volume 
replacement solutions, 2) provide evidence to support a mechanism of perioperative and sepsis-
associated kidney injury associated with HES solutions, 3) identify potential targets for therapeutic 
intervention and aid in the development of novel strategies to reduce perioperative and sepsis-induced 
kidney and other organ injury, 4) contribute to our ultimate goal of reducing postoperative morbidity and 
mortality in patients who require cardiac surgery.  
Preliminary data 


 
4
 
We examined the changes in endothelial function in 3 patients having cardiac surgery using 
peripheral arterial tonometry.  All three patients had normal endothelial function (normal lnRHI>0.51) 
before surgery which worsened significantly after surgery (1 – 4 hours postoperatively).    
 
 
 
 
 
 
 
 
 
 
 
 
 
EXPERIMENTAL METHODS AND DATA ANALYSIS 
 
Research Design and Methods 
 
This investigation will represent a substudy of a current ongoing clinical trial (SHARP: Voluven vs. 
Albumin comparing effect of 5% human albumin vs. 6% HES (130/0.4) on  postoperative kidney function 
and coagulation. Patients who consent for SHARP study will be invited for participation in this substudy of 
endothelial/glycocalyceal function. 
Inclusion criteria: Patients aged 40 – 85 years old who signed a written, informed consent for 
participation in this investigation, scheduled for elective aortic valve replacement with or without coronary 
artery bypass grafting involving nonpulsitile cardiopulmonary bypass, with or without additional minor 
surgical procedure. 
Exclusion criteria: Patients with Raynaud's disease or other disease associated with upper 
extremity vascular insufficiency, and inability to perform EndoPAT exam (inability to lie still for 15 min, or 
significant finger deformity), patients meeting SHARP exclusion criteria (renal failure with oliguria or 
anuria not related to hypovolemia, dialysis, preoperative creatinine > 1.6 mg/dL, anticipated deep 
hypothermic circulatory arrest, known hypersensitivity or allergy to HES, clinical conditions with volume 
overload e.g., patients in pulmonary edema or congestive heart failure, severe hypernatremia or severe 
hyperchloremia, intracranial bleeding, pregnant or breast feeding women, critically ill adult patients e.g. 
patients who are hospitalized in the intensive care unit prior to surgery, severe liver disease, pre-existing 
coagulopathy). 
Randomization 
Patients will be randomized to receive either HES 130/0.4 (Voluven) or albumin 5% for treatment 
of intraoperative acute hypovolemia. (Treatment assignments will be generated using a reproducible 
algorithm in the PLAN procedure in SAS statistical software. Randomization will be conducted using an 
existing password-protected web randomization site used for all clinical trials coordinated by the 
Department of Outcomes Research and maintained by the Anesthesia Institute statistical team.) 
 
Outcomes  
 
Primary outcome is postoperative endothelial function measured by Reactive Hyperemia Index 
(RHI) using a peripheral arterial tonometer (EndoPAT, Itamar Medical Inc., Caesarea, Israel) within 2 
hours following completion of surgery. A subset of patients will also have RHI measured at baseline and 
24 hours after surgery. 
Secondary outcomes will include blood biomarkers indicative of endothelial/glycocalyceal injury 
including plasma concentrations of syndecan 1 and endocan measured at baseline (after arterial line 
Figure 1. Baseline (preoperative) and postoperative endothelial reactive hyperemia 
index, a measure of endothelial function. This patient had a lnRHI of 0.82 at 
baseline (normal >0.51), which significantly worsened immediately after surgery. 


 
5
placement), within one hour (± 1 hour) of ICU arrival, and 24 hours (± 2 hours) following completion of 
surgery (or within 2 hours prior to ICU discharge if patient is discharged in less than 24 hours). 
Experimental Protocol 
 
Cardiac surgical patients enrolled in the SHARP study will be randomized to either 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. 
At 1 and 24 hours following surgery completion, blood will be collected for measurement of syndecan 1 
and endocan. Within two hours of ICU arrival, PAT will be performed in ICU. In a subset of patients, PAT 
will be performed preoperatively and at 24 hours after surgery. 
Because vasoactive substances may influence EndoPAT measurement, we will collect data on 
use of all preoperative antihypertensive medications that have direct or indirect effect on smooth muscle 
relaxation. Cardiac surgery patients often need intraoperative and postoperative inotropic support. Data 
on use of perioperative vasoactive medications that may influence EndoPAT results including 
epinephrine, norepinephrine, vasopressin, milrinone, nitroglycerine, nitroprusside, and sedatives such as 
propofol, dexmedetomidine and others will be recorded and subsequently adjusted for in the analysis. 
Data on transfusion of packed red blood cells and blood components will be collected from Anesthesia 
Record Keeping System. Minimum hematocrit (HCT) will be approximately 23% following 
cardiopulmonary bypass and 21% on cardiopulmonary bypass. Packed blood cell, platelets, fresh frozen 
plasma and/or cryoprecipitate transfusions may be administered as determined necessary by attending 
anesthesiologist or surgeon. Any imbalance in blood product transfusion between the two study groups 
will be adjusted for in analysis. 
 
Data Management 
 
Study Personnel will record data on Case Report Forms. Case report forms will be kept in a 
locked storage room with access limited to study personnel. Data from Case report forms will be inputted 
into the study database in REDCap for Data collection and storage. REDCap is a mature, secure web 
application for building and managing online surveys and databases.The REDCap application allows 
users to build and manage online surveys and databases quickly and securely, and is currently in 
production use or development build-status for more than 244,000 projects with over 335,000 users 
spanning numerous research focus areas across the consortium.  
 
Statistical analysis 
 
Balance of randomized HES and albumin groups on potentially confounding baseline and 
procedural characteristics will be assessed using absolute standardized difference (ASD), defined as the 
absolute difference in means, mean ranks, or proportions divided by the pooled standard deviation. We 
define any variable with ASD > 0.25 as imbalanced and will adjust for such variables in the following 
analyses. This substudy will be modified intent-to-treat, including all patients who enrolled in SHARP. 
 
Primary analysis 
 
We will estimate the albumin effect on RHI using multivariable linear regression adjusting for 
imbalanced patient and procedure characteristics. Though we expect RHI to be normally distributed, 
appropriate transformations will be made if this is not the case (e.g., log transformation). If 
transformations are not successful, we will use nonparametric methods (i.e., Wilcoxon rank-sum test).  
 
Sub aim analysis 
 
We will estimate the difference in endothelial function from baseline to 2 hours after surgery and 
baseline to 24 hours after surgery using separate paired t-tests on the subset of 40 patients with these 
measurements. We will also summarize RHI over time graphically.  
 


 
6
Secondary analyses 
The albumin effect on each biomarker (i.e., syndecan 1 and endocan) at 1 hour and 24 hours 
after surgery will be assessed using separate repeated measures linear regression models adjusting for 
within-subject correlation, baseline biomarkers and imbalanced baseline variables. We will assess the 
heterogeneity of the treatment effect over time by testing the group-by-time interaction for each model 
using a criterion of P < 0.15. If heterogeneity is detected, we will analyze outcomes separately at each 
time, using additional Bonferroni correction as necessary. We expect that biomarkers will be lognormally 
distributed, so we will perform a log transformation and compare groups on ratio of geometric means. An 
alpha of 0.05 will be used for each set of the primary and sub/secondary analyses, with a significance 
criterion of 0.05 for the primary analysis and 0.0125 for each sub or secondary analysis (i.e., 0.05/4, 
Bonferroni). We will complete analyses using SAS version 9.4 or newer (SAS Institute, Cary, NC, USA) 
and R version 3.2.3 or newer (R Project for Statistical Computing, Vienna, Austria). 
 
Descriptive analyses 
 
 
Additional morbidity related outcomes will also be reported descriptively for the entire study 
population. Continuous variables will be reported as mean ± standard deviation or median [interquartile 
range] as appropriate, while binary outcomes will be reported as N (%). 
 
Sample size analysis 
 
This will be limited to the 85 patients expected to enroll in the SHARP study. Moerland et al found 
the a mean ± SD of 1.8 ± 0.5 in a healthy study population and 2.9 ± 1.4 in a population with renal injury 
[M. Moerland, A. J. Kales, L. Schrier, M. G. J. van Dongen, D. Bradnock, and J. Burggraaf, “Evaluation of 
the EndoPAT as a Tool to Assess Endothelial Function,” International Journal of Vascular Medicine, vol. 
2012, Article ID 904141, 8 pages, 2012. doi:10.1155/2012/904141]. We expect similar variability in our 
cardiac surgery population. Assuming a conservative standard deviation of 1.4, we will have 90% power 
at the 0.05 significance level to detect an differance of 1.0 or greater in our study population. We will have 
65% power to detect a clinically important difference of 0.73 (i.e., 25% of 2.9). 
 
Project Timeline 
 
This project would take 2 years to complete. Institutional Review Board approval would require  2-
3 weeks, followed by 1-2 weeks for training and certification of a Research Fellow in proper use of 
EndoPAT equipment by Itamar Medical representative. Patient enrollment is expected to be complete by 
January 2018, followed by additional 2-3 months for data interpretation and manuscript preparation.  
 
 
OTHER SUPPORT 
 
Budget  
 
Total estimated expenses for this proposed research are $25,000. These funds will be used to 
cover personell costs including 1.2 calendar months effort and 10% salary support for a trained Clinical 
Research Fellow and 0.6 calendar months effort and 5% salary support for an assigned Outcomes 
Research Department statistitian. These funds will also cover cost of equipment including EndoPAT 
probes and labarotory blood testing for endocan and syndecan 1 levels. This project will not involve use 
of Clinical Research Unit, Lerner Cores, or Biostats. 
 
Future investigation 
 
Perioperative endothelial dysfunction contributes to multi-organ system dysfunction after cardiac 
surgery. However, investigations examining perioperative endothelial dysfunction have been limited 
because of the inability to measure and quantify endothelial function.  Use of peripheral arterial tonometry 
provides a unique and effective research tool to measure perioperative endothelial function which can be 
applied to numerous interventions. The measurement of perioperative biomarkers of endothelial injury 


 
7
also characterize the consequence of perioperative inflammation in cardiac surgical patients and can be 
applied to future investigations. Our initial results will faciliate further analysis to determine the 
contribution of perioperative endothelial function to postoperative morbidity and mortality. Preliminary data 
gained from this investigation will be used to support future grant applications for investigation of new 
interventions on postoperative glycocalyceal and endothelial damage measured by peripheral arterial 
tonometry and other molecular biomarkers. This proposed investigation and future investigations will 
contribute to our ultimate goal of improving early and long-term patient outcomes following cardiac 
surgery. 
 
REFERENCES 
 
1. 
Henrich, M., M. Gruss, and M.A. Weigand, Sepsis-induced degradation of endothelial glycocalix. 
ScientificWorldJournal, 2010. 10: p. 917-23. 
2. 
Kolarova, H., et al., Modulation of endothelial glycocalyx structure under inflammatory conditions. Mediators 
Inflamm, 2014. 2014: p. 694312. 
3. 
Jacob, M., et al., Contrasting effects of colloid and crystalloid resuscitation fluids on cardiac vascular 
permeability. Anesthesiology, 2006. 104(6): p. 1223-31. 
4. 
Lang, J.D., Jr., et al., Albumin and hydroxyethyl starch modulate oxidative inflammatory injury to vascular 
endothelium. Anesthesiology, 2004. 100(1): p. 51-8. 
5. 
Perner, A., et al., Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med, 
2012. 367(2): p. 124-34. 
6. 
Myburgh, J.A., et al., Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med, 
2012. 367(20): p. 1901-11. 
7. 
Zafrani, L., et al., The microcirculation of the septic kidney. Semin Nephrol, 2015. 35(1): p. 75-84. 
8. 
Chelazzi, C., et al., Glycocalyx and sepsis-induced alterations in vascular permeability. Crit Care, 2015. 19: 
p. 26. 
9. 
Jacob, M., et al., The endothelial glycocalyx prefers albumin for evoking shear stress-induced, nitric oxide-
mediated coronary dilatation. J Vasc Res, 2007. 44(6): p. 435-43. 
10. 
McIlroy, D.R., et al., Automated preoperative assessment of endothelial dysfunction and risk stratification for 
perioperative myocardial injury in patients undergoing non-cardiac surgery. Br J Anaesth, 2014. 112(1): p. 
47-56. 
11. 
Bonetti, P.O., et al., Noninvasive identification of patients with early coronary atherosclerosis by assessment 
of digital reactive hyperemia. J Am Coll Cardiol, 2004. 44(11): p. 2137-41. 
12. 
Kuvin, J.T., et al., Assessment of peripheral vascular endothelial function with finger arterial pulse wave 
amplitude. Am Heart J, 2003. 146(1): p. 168-74. 
13. 
Steppan, J., et al., Sepsis and major abdominal surgery lead to flaking of the endothelial glycocalix. J Surg 
Res, 2011. 165(1): p. 136-41. 
14. 
Paulus, P., C. Jennewein, and K. Zacharowski, Biomarkers of endothelial dysfunction: can they help us 
deciphering systemic inflammation and sepsis? Biomarkers, 2011. 16 Suppl 1: p. S11-21. 
15. 
Li, L., M. Ly, and R.J. Linhardt, Proteoglycan sequence. Mol Biosyst, 2012. 8(6): p. 1613-25. 
16. 
Salmon, A.H. and S.C. Satchell, Endothelial glycocalyx dysfunction in disease: albuminuria and increased 
microvascular permeability. J Pathol, 2012. 226(4): p. 562-74. 
17. 
Woodcock, T.E. and T.M. Woodcock, Revised Starling equation and the glycocalyx model of transvascular 
fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth, 2012. 108(3): 
p. 384-94. 
18. 
Myburgh, J.A. and M.G. Mythen, Resuscitation fluids. N Engl J Med, 2013. 369(13): p. 1243-51. 
19. 
Adembri, C., et al., Sepsis induces albuminuria and alterations in the glomerular filtration barrier: a 
morphofunctional study in the rat. Crit Care, 2011. 15(6): p. R277. 
20. 
Creasey, A.A. and K. Reinhart, Tissue factor pathway inhibitor activity in severe sepsis. Crit Care Med, 
2001. 29(7 Suppl): p. S126-9. 
21. 
Lerolle, N., et al., Histopathology of septic shock induced acute kidney injury: apoptosis and leukocytic 
infiltration. Intensive Care Med, 2010. 36(3): p. 471-8. 
22. 
Levi, M., T. van der Poll, and H.R. Buller, Bidirectional relation between inflammation and coagulation. 
Circulation, 2004. 109(22): p. 2698-704. 
23. 
Flammer, A.J., et al., The assessment of endothelial function: from research into clinical practice. 
Circulation, 2012. 126(6): p. 753-67. 
24. 
Corretti, M.C., et al., Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated 
vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am 
Coll Cardiol, 2002. 39(2): p. 257-65. 
25. 
Patel, S. and D.S. Celermajer, Assessment of vascular disease using arterial flow mediated dilatation. 
Pharmacol Rep, 2006. 58 Suppl: p. 3-7 

ICF_001.pdf: 
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1 
  
The Cleveland Clinic Foundation 
Consent to Participate in a Research Study 
 
Study title: 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  
PI:  Marta Kelava, M.D.   216-213-3218   
After hours phone contact #:  216-444-2200 
 
You are being invited to participate in a research study.  A research study is designed to answer 
specific questions about new ways to prevent, detect, and treat disease.  Being in a research study 
is different from being a patient.  The purpose of this document is to provide a written summary 
of the discussion and exchange of research information you had with the research team.  It is also 
for use as a reference during the study.   
 
Please note: 
• You are being asked to participate in a research study. 
• Ask as many questions as needed so you can make an informed decision. 
• Carefully consider the risks, benefits, and alternatives of the research. 
• Your decision to participate is completely voluntary and will have no effect on the 
quality of your medical care if you choose not to participate. You can also withdraw 
from the study at anytime. 
 
This research study has been approved by the Institutional Review Board (IRB).  The IRB is a       
committee that reviews human research studies to ensure the safety and welfare of research 
volunteers are protected in accordance with federal human subject regulations and ethical 
principles. 
 
Why is the research study being done? 
 
You are being invited to take part in this research study because you are participating in a study 
(Main Study) to evaluate the safety of a standard fluid replacement called 6% 
Hydroxyethylstarch 130/0.4 during surgery on kidney function. During the study you may 
receive one of two possible fluid replacements during surgery, if your fluid volume decreases 
enough to need replacement with one of the colloid fluids.  These two possible fluid 
replacements are 6% Hydroxyethylstarch 130/0.4, a starch-containing fluid or 5% human 
albumin. 
 
Endothelial dysfunction, which is the inability of arteries and arterioles to dilate fully are 
common following cardiac surgery.  This study is being done to compare the reduction of 
endothelial dysfunction between 5% human albumin and 6% Hydroxyethylstarch 130/0.04. 
 
How Many People Will Take Part In The Study? 
 
About 85 patients will take part in this study at the Cleveland Clinic. 


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2 
What is involved if you decide to take part in this research study? 
 
If you decide to take part in this study, the blood samples that have been taken for the Main 
Study will also be used to measure the plasma concentrations of two biomarkers that measure 
endothelial injury.   
 
However, within two hours of your arrival to the ICU peripheral arterial tonometry will be 
performed.  A finger probe will be placed on each hand to record your arterial pulse.  This pulse 
will be recorded for 5 minutes.  Then a blood pressure cuff will be inflated on one arm.  The 
pulse will be recorded for another 5 minutes, followed by cuff deflation and measurement for 
another 5 minutes (total of 15 minutes) 
 
What are the alternatives to participation in the research study?   
 
You do not have to take part in this research study to receive treatment at this hospital.  This is a 
research study and you do not have to volunteer. 
 
What are the risks of participating in the research study? 
 
The EndoPat may cause some discomfort during the blood pressure inflation, which may feel 
similar to a limb “falling asleep”.  You may also notice a “tingly” feeling when the blood 
pressure cuff is released.  These sensations will resolve completely within a few minutes after the 
completion of the test. 
 
What are possible benefits of participating in the research? 
 
There is no direct benefit to you from participation in this study.  Knowledge gained from this 
research may help us determine if 5% human albumin or 6% Hydroxyethylstarch 130/0.04 
reduces endothelial dysfunction more after cardiac surgery. 
 
Are there any costs to you if you participate in this study? 
 
There are no additional costs to you for participation in this research study.  The cost for routine 
tests and services that would normally be performed even if you do not participate in the study 
will be billed to you or your insurance provider. 
 
Are there any payments to you if you participate in this study? 
 
You will not be compensated for your participation in this study. 
       
What will happen if you are injured as a result of taking part in the research? 
 
In the event you are injured as a result of participation in this research, medical care is available 
to you.  The cost of such medical care will be billed to you or your insurance company.  There 
are no plans to provide compensation for lost wages, direct or indirect losses.  The Cleveland 


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Clinic will not voluntarily provide compensation for research related injury.  You are not 
waiving any legal rights by signing this form. 
 
Further information about research related injury is available by contacting the institutional 
review board at 216-444-2924. 
 
 
What will happen to your information that is collected for this research? 
 
If you volunteer to participate in this research, your protected health information (PHI) that 
identifies you will be used or disclosed to Marta Kelava, M.D. and the research staff at 
Cleveland Clinic for the purposes of this research.  Any information obtained in connection with 
this research study that can identify you will remain confidential.  Your information will only be 
used for the purpose of this research project and it will only be disclosed with your permission, 
except required by law. 
 
All participants will be given a study code number.  All information about you that is collected 
for the study will be labeled with this number, not your name or hospital number.  The key to the 
code will be stored separately to your information. 
 
The PHI that we may use or disclose (release) for this research may include your name, address, 
phone number, date of birth and information from your medical records. 
 
In addition to the investigators and research staff listed above, your PHI may be looked at by 
other groups involved with the study such as the Cleveland Clinic Institutional Review Board 
and governmental agencies.    
 
Records are collected and stored either in folders (for paper records) or put onto a secure 
computer, which can only be accessed by the researchers.  All written data will be stored in a 
locked filing cabinet in a locked room.  Only the researchers will have access to stored written or 
electronic data.  Information collected from participants will be kept for 15 years after which it 
will be destroyed.   
 
Once your personal health information is released it may be re-disclosed and no longer protected 
by privacy laws. 
 
You may stop the uses and disclosures of your information at any time by writing to Marta 
Kelava, M.D. Cleveland Clinic 9500 Euclid Ave., E-30R Cleveland, Ohio 44195 (216-213-
3218).  Your participation in the research will stop, but any information previously recorded 
about you cannot be removed from the records and will continue to be used as part of this 
research.  Also, any information already disclosed outside the Cleveland Clinic cannot be 
retrieved.  This will not affect your rights to treatment or benefits outside the research study. 
 
The Cleveland Clinic will not use your information collected in this study for another research 
purpose without your written permission unless the Cleveland Clinic Institutional Review Board 


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(IRB) assures your privacy and confidentiality is protected.  The IRB is a committee whose job it 
is to protect the safety and welfare of research subjects. 
 
It is anticipated that the results of this research project will be published and/or presented in a 
variety of forums.  In any publication and/or presentation, information will be provided in such a 
way that you cannot be identified, except with your permission. 
 
Information about your participation in this research study will be recorded in your health 
records. 
 
You have the right to request access to your information collected and stored by the research 
team.  You also have the right to request that any information with which you disagree be 
corrected.  Contact the study team member named at the end of this document if you would like 
to access your information. 
 
By signing this informed consent form, you are authorizing such access to your research and 
medical record information.  If you choose not to sign this consent form, you will not be able to 
participate in this research study.  This Authorization does not have an expiration date.   
 
Who do you call if you have any questions or problems?  
 
If you have any questions, you can ask the Principal Investigator and/or research staff. 
Marta Kelava, M.D. at 216-213-3218. 
 
If you are a Cleveland Clinic patient, you should contact the page operator at 216-444-2200 and 
ask to page 80756. 
 
If you have any questions about your rights as a research subject, you may contact the 
Institutional Review Board (IRB) at Cleveland Clinic IRB 216-444-2924. 
 
 
What are your rights as a research participant? 
 
Participation in this research project is voluntary.  If you do not wish to take part, you do not 
have to.  If you decide to take part and later change your mind, you are free to withdraw from the 
study at any time. 
 
If you do decide to take part, you will be given this Participant Information and Consent Form to 
sign and you will be given a copy to keep. 
 
Your decision whether to take part or not to take part, or to take part and then withdraw, will not 
affect your routine treatment, your relationship with those treating you or your relationship with 
the Cleveland Clinic. 
 


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In the event new information becomes available, that may affect the risks or benefits associated 
with this study or your willingness to participate in it, you will be notified so that you can decide 
whether or not to continue participating. 
 
 
□   Please check this box if you agree to two additional EndoPAT exams. First one would be 
performed prior to your surgery after your preoperative assessment with an anesthesiologist. The 
second additional EndoPAT exam would be performed 24 (± 2) hours after your surgery.  
 
Participation in additional measurements is optional. While you will likely be sedated for 
EndoPAT exam within 2 hours after your arrival to ICU, you will likely be awake for both 
additional measurements. Please refer to the information on the top of page 2 of this document 
for detailed description of the EndoPAT exam. 
 
 
 
 
Statement of Participant 
 
I have read and have had verbally explained to me the above information and have had all my 
questions answered to my satisfaction.  I understand that my participation is voluntary and that I 
may stop my participation in the study at any time.  Signing this form does not waive any of my 
legal rights.   I understand that a copy of this consent will be provided to me.  By signing below, 
I agree to take part in this research study.   
 
_____________________________ 
Printed name of Participant 
 
_____________________________  
___________  
 
Participant Signature  
 
 
Date 
 
 
 
 
Statement of Person Conducting Informed Consent Discussion 
 
I have discussed the information contained in this document with the participant and it is my 
opinion that the participant understands the risks, benefits, alternatives and procedures involved 
with this research study. 
 
 
_____________________________ 
Printed name of person obtaining consent 
 
_____________________________  
___________  
 
Signature of person obtaining consent 
Date