A Prospective Observational Study on Assessment of the Soluble Urokinase Plasminogen Activator Receptor in Adult Patients Undergoing Major Non-cardiac Surgery
Conditions: Surgery--Complications
Sponsor: University of Thessaly

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University of Thessaly, School of Health Sciences 
Faculty of Medicine 
Department of Anesthesiology 
 
STUDY PROTOCOL 
A Prospective Observational Study on Assessment of the Soluble 
Urokinase Plasminogen Activator Receptor in Adult Patients 
Undergoing Major Non-cardiac Surgery (SPARSE): Study protocol 
(SPARSE: if our hypothesis is correct, the SuPAR will help to investigate whether the 
preoperative suPAR level can aid in identifying patients at high risk for  postoperative 
complications, morbidity and mortality.) 
 
BACKGROUND  
Soluble urokinase plasminogen activator receptor  
The biomarker soluble urokinase plasminogen activator receptor (suPAR) is 
the soluble form of the cell membrane-bound protein urokinase plasminogen activator 
receptor (uPAR), which is expressed mainly on immune cells, endothelial cells, and 
smooth muscle cells. uPAR is released during inflammation or immune activation, 
and therefore the suPAR level reflects the extent of immune activation in the 
individual.1 All human beings have a baseline level of suPAR that is individually 
determined and increases with age. Studies have shown that the suPAR level is 

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associated with morbidity and mortality in a number of acute and chronic diseases and 
in the general population.2-15 The suPAR level is elevated across diseases, and not 
solely associated with one specific disease. Therefore, suPAR is applicable as a 
prognostic marker and not as a diagnostic marker. This characteristic may be utilized 
for risk stratification in unselected patients.  
Originally, uPAR was proven a receptor for urokinase (uPA) which splits 
plasminogen into active plasmin. Moreover, uPAR interacts with other proteins and 
plays a role in several important cell processes like migration, adhesion, angiogenesis, 
proliferation, and chemotaxis.1 The suPAR protein was discovered in 1991, when it 
was found to be a marker of cancer progression.1 In recent years, several studies have 
shown that suPAR is associated with a number of chronic diseases (including 
cardiovascular, hepatic, renal, and pulmonary diseases), and that the level is a 
predictor of a negative outcome of various infectious diseases (tuberculosis, HIV, 
malaria, sepsis, meningitis, pneumonia) and in critically ill patients.2-12, 15,17-21 
Across diseases, the suPAR level discriminates non-survivors from survivors. 
suPAR reflects the level of chronic inflammation, and therefore it has been studied as 
a potential marker of development of diseases, and studies have shown that an 
elevated level predicts development of chronic diseases and cancer in the general 
population.2-15 The suPAR blood level is stable with no diurnal variation and no 
changes following fasting, while suPAR can be measured in blood, plasma, urine, 
cerebrospinal fluid, ascites fluid and pleural fluid.1 The level increases and decreases 
with progression and improvement of a disease, respectively, but more slowly 
compared to e.g. C-reactive protein (CRP). The normal suPAR plasma level is 2-3 
ng/mL in healthy individuals, about 3-4 ng/mL in unselected patients in emergency 
departments, and about 9-10 ng/mL in critically ill patients. 

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suPAR in intensive care  
In critically ill patients, the suPAR level is significantly increased. suPAR is 
an independent prognostic marker, and the change over time correlates with organ 
dysfunction. suPAR is elevated and has a prognostic value in patients with: SIRS 
(systemic inflammatory response syndrome),22,23 sepsis/septic shock,24-30 burn 
injuries,31 and  traumatic brain injuries.32 The suPAR level reflects the body’s immune 
response to infections, and the level increases with the severity of the infection. In 
patients with organ dysfunction, the suPAR value is often a two-digit value. In 
particular hepatic and renal dysfunction affects the suPAR level.24-26 suPAR has been 
studied in patients with SIRS who were acutely admitted to the emergency department 
(n=902). The studies showed that suPAR is a stronger marker of 2-day, 30-day, and 
90-day mortality than age, CRP, IL-6, creatinine, and procalcitonin. However, for 
diagnostic purposes, IL-6 and CRP are superior to suPAR in predicting a positive 
blood culture.22,23 A Greek multicenter study including 1914 patients with sepsis 
showed that suPAR is a strong predictor of mortality, and that a suPAR level above 
12 ng/mL is linked to a >80% sensitivity for mortality and a negative predictive value 
of 94.5%.27 In addition, the prognostic value of suPAR in patients with sepsis is 
independent of relevant covariates like APACHE score, CRP, etc.27-30 
In patients with burn injuries and inhalation trauma requiring mechanical 
ventilation, the plasma suPAR level and bronchoalveolar lavage fluid level correlate 
to IL-6 and coagulation factors. An elevated plasma suPAR level is associated with 
prolonged Intensive Care Unit (ICU) stay and the duration of mechanical 
ventilation.31 The suPAR level is elevated in patients with traumatic brain injury. In 
trauma patients who suffered a brain injury within 12 hours prior to blood sampling, 
the mean suPAR level is 14.9 ng/mL ± 6.9 vs. 2.8 ng/mL ± 0.7 in control subjects. In 

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these patients suPAR is associated with severity of the brain injury and with 
mortality.32 
 
suPAR in surgery  
The suPAR level is elevated in patients with infections, chronic diseases, and 
cancer compared to healthy individuals. A high suPAR level is associated with 
increased mortality risk,33 poor prognosis,34-38 postoperative pneumonia,39 and 
prosthetic joint infection.40 suPAR is a well-studied biomarker predicting prognosis, 
disease severity, and organ dysfunction and is being considered as a marker of the 
individual’s inflammatory status. It has been demonstrated that biomarkers are able to 
improve triage and are effective in identifying high and low risk patients among 
acutely admitted patients.41 Improving the preoperative risk stratification using 
biomarkers may optimize the patient's clinical outcome.42  
Available data on use of biomarkers in addition to risk stratification are 
observational data, and suPAR has mainly been studied in medical and oncological 
patients. Gastric surgery patients and orthopedic surgery patients were included in a 
study conducted in the emergency department at Hillerød Hospital, Denmark. The 
TRIAGE study included 5992 unselected patients and confirmed the prognostic value 
of suPAR regarding mortality, and found it similar in both medical and surgical 
patients.41 In the same study, it was shown that triage based on suPAR level was 
superior to the current triage system in predicting 30-day mortality: AUC 0.84 (0.82-
0.87) vs. 0.62 (0.58-0.66), respectively. In multivariate analyses of 30-day mortality 
in relation to suPAR quartiles, adjusted for sex, age, CRP, leucocytes, and triage 
category, HR was 1.0, 2.2, 8.3, and 26.9 in the upper quartile. A high suPAR level has 

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been demonstrated in both tumor tissue and in blood, and in several cancers, the 
suPAR level is shown to correlate with a poor prognosis.43 In a few studies, suPAR 
has been studied as a potential biomarker in gastric surgery.  
In a cohort of 518 elective colorectal cancer patients, preoperative 
measurement of the suPAR level was performed. In multivariate analyses adjusted for 
age, sex, tumor classification, and localization, suPAR was significantly associated 
with mortality, HR 1.74 (1.33-2.26; p<0.0001). In addition, the suPAR level was 
associated with tumor stage and localization; and in colon cancer patients the suPAR 
level was significantly higher compared to rectal cancer patients.34 The same cohort 
was also followed in another study, in which the suPAR plasma level was found to be 
an independent prognostic marker.35 To identify risk patients among elective colon 
cancer patients the suPAR level was studied. In patients receiving blood transfusion 
during surgery, the suPAR level was higher, and a significant association between the 
suPAR level and postoperative infections was shown. Occurrence of pneumonia was 
significantly associated with the suPAR level, but any significant association with 
other infectious complications could not be found.39 In patients with gastric cancer, 
the suPAR level was significantly higher compared to healthy controls (2.3 ng/mL ± 
0.77), and the suPAR level was significantly higher in cancer patients with metastatic 
disease (7.0 ng/mL ± 6.1) than in patients with no metastases (4.8 ng/mL ± 4.4). In 
the group of patients with a suPAR value above 5.2 ng/mL, the mortality was 
significantly increased.36 In patients with rectal cancer and colon cancer, a similar 
prognostic value is found, indicating an increased mortality risk.37,38  
The diagnostic value of suPAR in prosthetic knee/hip joint infection has been 
examined in a study.40 The study included 80 patients of which 45 experienced 
prosthetic joint infection defined by presence of clinical signs (swelling, redness, 

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tenderness, and pus inside the joint) and a positive culture. In these patients, a 
significantly higher median suPAR level (6.8 ng/mL) was found compared to patients 
without infection, who had revision surgery done. Furthermore, suPAR was positively 
correlated with CRP, and the study showed that suPAR was more precise in 
diagnosing prosthetic knee/hip joint infection than CRP. 
 
AIM 
SPARSE is a single-center observational study aiming to investigate if suPAR 
measured preoperatively and immediately after surgery can predict the risk of future 
complications and post-operative mortality in adults following major non-cardiac 
surgery. 
 
METHODS 
Design 
This is a prospective observational study designed in accordance with the 
declaration of Helsinki. The study will be register at Clinical Trials.gov and has been 
approved by the Institutional Review Board of the University Hospital of Larisa, 
under the reference number 60580/11-12-2018. 
 
Patient eligibility 
Consecutive patients who are scheduled to undergo elective major non-cardiac 
surgery with expected duration ≥2 hours under general anesthesia will be screened for 

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inclusion. All operative approaches will be eligible for inclusion, including open, 
laparoscopic and robotic procedures. Patients fulfilling the following inclusion criteria 
will be included: age ≥ 18 years, and American Society of Anesthesiologists’ (ASA) 
physical status I to IV.  
Exclusion criteria will be age <18 years, any infection within the previous 4 
weeks, severe liver disease, patients on renal replacement therapy pre-operatively, 
patients who had previously received a transplant, patients with allergies, 
inflammatory or immune system disorders, and/or connective tissue disease including 
rheumatoid arthritis, ankylosing spondylitis, and systemic lupus erythematosus, 
administration of steroid, antipsychotic, or anti-inflammatory/immunomodulatory 
medication during the 3 months prior to surgery, administration of opioids during the 
past week, asthma, obesity (BMI ≥ 30 kg m-2), mental disability or severe psychiatric 
disease, alcohol or other abuse, legal incapacity or limited legal capacity, and subjects 
within the exclusion period of another study. 
 
Management of Anesthesia and Surgical Procedures 
Endotracheal intubation and anesthetic care will be performed according to 
our institutional routine. Intravenous induction of general anaesthesia will include 
midazolam 0.15-0.35 mg/kg iv over 20-30 seconds, fentanyl 1μg/kg, propofol 1.5-
2 mg/kg, ketamine 0.2 mg/kg (intravenous bolus), and rocuronium 0.6 mg/kg. All 
drugs will be prepared in labelled syringes and induction will be achieved by 
administration of a predetermined iv bolus dose on the basis of the patient’s weight 
and/or age. Laryngoscopy and intubation will proceed in a standard fashion, while the 
position of the endotracheal tube will be confirmed by auscultation and 

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capnography/capnometry. The patients will then connected to an automated ventilator 
(Draeger Primus®; Drägerwerk AG & Co., Lübeck, Germany). 
All patients will be ventilated using a lung-protective strategy with tidal 
volume of 7 mL/kg, positive end-expiratory pressure of 6-8 cmH2O, plateau pressures 
<30 cmH2O, and recruitment maneuvers repeated every 30 min after tracheal 
intubation.44 Maintenance of general anesthesia will include desflurane 1.0 MAC with 
40% oxygen and 60% air, while intraoperative dose changes will be left to the 
anesthesiologist in charge of the patient. Depth of anesthesia (bispectral index-BIS, 
Covidien, France) will be monitored, with the target ranging between 40 and 60.45,46 
Normocapnia will be maintained by adjusting the respiratory rate as needed, while 
normothermia (37ºC) will be maintained throughout the intraoperative period. 
All patients will be operated by at least two consultant surgeons who will be 
supervised by a Professor of Surgery. 
 
Sampling and laboratory measurements 
Participants will undergo sampling of peripheral venous blood, immediately 
after arrival to the OR, and at the Post-Anesthesia Care Unit (PACU). Blood samples 
drawn from all patients and EDTA plasma will be stored at -80° C until later 
measurement. Plasma suPAR levels will be determined using the suPARnostic® 
quick triage lateral flow assay (ViroGates, Denmark), according to the manufactures 
instructions. 
 
 

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Microcirculation flow analysis  
In addition to routine hemodynamic data, sublingual microvascular flow will 
be measured using noninvasive technology. We will obtain measurements 
preoperatively (PRE), intraoperatively (INT), and postoperatively after arrival in the 
PACU (POST). At each time point, we will image the microcirculatory network of the 
sublingual mucosa with sidestream darkfield (SDF+) videomicroscopy which has an 
increased optical resolution resulting in one pixel recording an area of 0.56 μm2. This 
device uses the new SDF+ technology that allows the red blood cells to be visualised 
with greater accuracy and detail, which is essential for enhancing the capabilities of 
the analysis application.  
We will use the sublingual space as the site of imaging because it shares the 
same embryologic origin as the splanchnic mucosa and can reflect derangements in 
splanchnic blood flow; impaired sublingual microcirculatory blood flow is associated 
with increased mortality and worsening organ failure in patients with sepsis.47-51  
 
Outcomes 
The primary endpoint will be the presence of complications and/or admission 
to ICU and/or mortality within the first 60 postoperative days.  
Secondary endpoints will be intraoperative complications (including 
desaturation [SpO2 <92% for 3 minutes or more], need for unplanned recruitment 
maneuvers, hypotension [defined as systolic blood pressure <90 mmHg or mean 
arterial pressure <65 mmHg for 3 minutes or more or need of vasoactive drugs for 
correction], need for unplanned vasoactive drugs [need for vasoactive drugs not 

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planned before and/or continuous infusion], and/or acute new arrhythmia [atrial 
fibrillation, sustained ventricular tachycardia, supraventricular tachycardia, and/or 
cardiac arrest]), reintubation, hospital length of stay, and length of stay in ICU. 
Secondary endpoints will also include postoperative complications within 90 days 
after surgery defined as in the SURPAS studies,52-54 with the inclusion of atelectasis 
and ileus, resulting in 22 possible postoperative complications, as well as survival at 
hospital discharge, at 90 days, and at 1 year. 
 
Data Collection and Monitoring 
Data analysis will be based on predefined data points on a prospective data 
collection form. The staff will be blinded to measurements until the end of the study 
and all data are analyzed. Clinical monitoring throughout the study will be performed 
to maximize protocol adherence, while an independent Data and Safety Monitoring 
research staff will monitor safety, ethical, and scientific aspects of the study. Data 
collection will include demographics, anesthesia parameters, C-reactive protein, P-
POSSUM score, ACS-NSQIP score, APACHE II, SOFA, and the Charlson Age-
Comorbidity Index (Charlson score).55 We will use a SAS macro based on ICD-10 
diagnoses to calculate the Charlson score,56,57 Two other simpler models adding 
predictive value to the ASA classification will be also used; the Surgical Mortality 
Probability Model and a similar model proposed by Glance and Donati.58,59 
 
 
 

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Data management 
The goal of the clinical data management plan is to provide high-quality data 
by adopting standardized procedures to minimize the number of errors and missing 
data, and consequently, to generate an accurate database for analysis. Remote 
monitoring is performed to signal early aberrant patterns, issues with consistency, 
credibility and other anomalies. Any missing and outlier data values are individually 
revised and completed or corrected whenever possible. 
 
Sample size and predefined statistical analysis plan 
Patients will be consecutively included during the study period, in a 
convenience sample and will be stratified into low-risk or high-risk groups, according 
to suPAR level (suPARhigh above and suPARlow below 5.5 ng/ml), respectively.60 An a 
priori power analysis was done set to detect a difference of 0.50 on the suPAR 
(between suPARhigh and suPARlow group, based on the researchers’ preference. The 
number of patients planned for recruitment was rounded up to 100 to allow for 
flexibility in the study. This sample size was estimated to achieve 80 percent power to 
detect the suggested difference. The sample size calculation was made using G*Power 
3.1.61 The association between ASA classification, suPAR level, CRP and the rate of 
postoperative complications will be analyzed with logistic regression and Cox 
regression analyses, estimating odds ratios (ORs) and hazard ratios (HRs). 
 
 
 

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Ethics and dissemination 
The study will be performed according to national and international 
guidelines. The study will not begin until approval has been obtained from the 
Hospital’s Institutional Review Board, according to local regulation. Prospective 
written informed consent will be or will be not requested before inclusion of all 
eligible patients based on the Review Board’s decision; if a waiver of consent is 
decided by the Review Board, it will follow local guidelines. 
 
Competing interests 
None declared. 
 
 
 
 
 
 
 
 
 
 

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SPARSE Study                                                                                 December 11, 2018                               
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