AOrtic Surgery: Systemic Inflammatory Response Versus Sepsis

Infections Clinical Trial

— AOSIS  

Official title:

Differential Diagnosis of Sterile Systemic Inflammation and Sepsis in Patients Undergoing Thoracic Aortic Surgery

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06028789
• Other study ID #: 202202 P02
• Status: Recruiting
• Start date: April 1, 2022
• Est. completion date: June 30, 2024

Study information

• Verified date: May 2024
• Source: University Hospital Hradec Kralove
• Contact: Jan Gofus, MD, PhD
• Phone: +420 722 301 527
• Email: jan.gofus[@]gmail.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The goal of the prospective observational study is to evaluate the immunological background of inflammatory response often seen after open thoracic aortic surgery. Patients scheduled for this type of procedure will undergo a series of blood testing (preoperatively, and several times postoperatively). The blood samples will be used for a wide scale of immunological tests to better evaluate potential differential markers against infection. A control group will include patients with active infective endocarditis (preoperatively).

The main question is if there is a biomarker able to determine a difference between sterile systemic inflammation and infection after thoracic aortic surgery. The second question is if there is a difference in dynamics of evaluated biomarkers between sterile postoperative inflammation and active endocarditis.

Description:

It has been observed in daily clinical practice that patients after thoracic aortic replacement (of any extent, of any reason) often develop a set of specific symptoms. Those include fever, weakness and prolonged rise of standard laboratory parameters of inflammation (CRP and leucocyte level) in absence of infection. Those symptoms may, but do not have to, coincide with typical signs of postcardiotomy syndrome, rather characteristic by pericardial / pleural effusion and indifferent chest pain. They rather resemble a so called "postimplantation" syndrome, described after endovascular aortic repair. As a reaction to foreign vascular graft material, pro-inflammatory cytokines are being released, thus leading to flu-like symptoms in absence of true infection. Those occur in the short-term postoperatively, usually in the first 2 weeks after the surgery.

Patients after thoracic aortic surgery represent a high-risk patient cohort vulnerable to infections of any kind, mostly respiratory, urinary, wound infections, and, last but not least, early valve endocarditis / endoaortitis being the most feared of them. While clinicians (and patients) are often afraid of the abovementioned complications, the patients are forced to undergo complex diagnostic process including repeated echocardiography, collection of microbiology cultures and blood samples, chest computer tomography imaging with extensive radiation burden. The prolonged broad-spectrum empiric antibiotic treatment is often in place together with prolonged hospital stay and limited patient satisfaction. The question of starting the immunosuppressive treatment is often weighed against the potential aggravation of infection with eventual fatal consequences.

In absence of a specific biomarker to distinguish between the sterile systemic inflammation and infection, the clinicians must rely on complex evaluation of patient symptoms, clinical examination, imaging modalities, standard laboratory measures of inflammation and microbiology cultures (with some delay). However, in the era of molecular biology and extensive progress in immunology research, there has been a long row of potential biomarkers able to specify the etiology of inflammatory process significantly sooner.

The potential biomarkers of inflammation suitable for this issue are mentioned in detail further. Conventional biomarkers include CRP, leukocyte count, differential blood count, recently also procalcitonin (PCT), tumor necrosis factor-α (TNF- α) and interleukin-6 (IL-6). Hematology tests have reported novel early markers of sepsis, e.g. mean neutrophil volume or neutrophil-to-lymphocyte ratio. Novel serology markers (mostly assessed by ELISA) include soluble triggering receptor expressed on myeloid cell-1 (sTREM-1), presepsin, serum amyloid-A, pentraxin 3, hemoxygenase-1 (HO-1), soluble CD64 (sCD64), soluble CD163 (sCD163), high mobility group box-1 (HMGB-1), lipopolysaccharide-binding protein (LBP) and others. Newly, the molecules expressed on the surface of circulating blood cells may be examined using flow cytometry: CD64 on polymorphonuclears (PMN CD64 index) or monocytes, CD163, CD167, HLA-DR etc. Cell function assays which test ability of blood cells to respond to microbial stimuli (represented by LPS, flagellin, etc.) may reveal changes in soluble biomarkers, such as IL-18 or IFN-γ that reflect nature of inflammation in patients.

Recently, several scoring systems have emerged combining panels of various biomarkers. There is a promising evidence for a composite of serum and cell-expressed parameters, called "Bioscore", including procalcitonin, sTREM-1 and PMN CD64 index. A composite of 5 hematological parameters has proven to be a reliable marker of early sepsis, being called intensive care infection score (ICIS). Another scoring systems have been developed by group of Kofoed et al. Nevertheless, most of these scoring systems have been tested in the settings of unstable patients in the intensive care unit. The issue of inflammatory response described above is mostly a matter of stable patients in the standard ward who develop signs of undetermined inflammation. Eventual diagnostic modalities in these settings have been only scarcely evaluated before. The topic of inflammatory response after aortic surgery (IRAS) has not been studied in the literature yet.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: June 30, 2024
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria (for study group):

• patient scheduled for elective replacement of thoracic aorta of any extent by artificial vascular graft, including Bentall procedure, Yacoub procedure, supracoronary aortic replacement, also Ross procedure with supracoronary aortic replacement, hemiarch and total aortic arch replacement

• signature of informed patient consent

Exclusion Criteria (for study group):

• active endocarditis or other infection

• unstable preoperative condition

Inclusion Criteria (for control group):

• patient with active infectious endocarditis

• signature of informed patient consent

Exclusion Criteria (for control group):

• more than 5 days since diagnosis

Related Conditions & MeSH terms

• Aneurysm
• Aortic Aneurysm
• Aortic Aneurysm, Thoracic
• Aortic Diseases
• Immunological Abnormality
• Infections
• Systemic Inflammatory Response Syndrome
• Thoracic Aortic Aneurysm

Intervention

Diagnostic Test:
• Blood sample test
The following groups of biomarkers will be examined: standard panel of inflammation markers: CRP, PCT, IL-6, Leukocyte count, differential blood count microbiology cultures according to the clinical status serum biomarkers: sCD64, sTREM-1, calprotectin, pentraxin 3 flow cytometry: HLA-DR, CD14, CD16, CD40, CD45, CD64, CD163 expression on granulocytes and monocytes cell function assay: IL-18 and IFN-? hematology: ICIS, Neutrophil-to-lymphocyte ratio - examined together with conventional hematological parameters. The schedule of blood sample taking will be as follows: A. the study group: preoperatively (T-1), 1st postoperative day (T1), 3rd postoperative day (T2), 7th postoperative day (T3), 10th postoperative day (T4) B. the control group: at admission or the next day (T1), 3rd day of hospital stay (T2), 7th day of hospital stay (T3), 10th day of hospital stay (T4)

Procedure:
• Thoracic Aortic Surgery
Scheduled surgical intervention, i.e. replacement of pre-specified part of thoracic aorta by a vascular prosthesis.

Locations

Country	Name	City	State
Czechia	University Hospital Hradec Králové	Hradec Králové	Královehradecký Kraj

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Hradec Kralove	American Association for Thoracic Surgery

Country where clinical trial is conducted

Czechia, 

References & Publications (8)

Daye D, Walker TG. Complications of endovascular aneurysm repair of the thoracic and abdominal aorta: evaluation and management. Cardiovasc Diagn Ther. 2018 Apr;8(Suppl 1):S138-S156. doi: 10.21037/cdt.2017.09.17. — View Citation

Djebara S, Biston P, Fosse E, Daper A, Joris M, Boudjeltia KZ, Lelubre C, Cauchie P, Piagnerelli M. Time Course of CD64, a Leukocyte Activation Marker, During Cardiopulmonary Bypass Surgery. Shock. 2017 Feb;47(2):158-164. doi: 10.1097/SHK.0000000000000751. — View Citation

Gabaldo K, Sutlic Z, Miskovic D, Knezevic Pravecek M, Prvulovic D, Vujeva B, Cvitkusic Lukenda K, Hadzibegovic I. Postpericardiotomy syndrome incidence, diagnostic and treatment strategies: experience AT two collaborative centers. Acta Clin Croat. 2019 Mar;58(1):57-62. doi: 10.20471/acc.2019.58.01.08. — View Citation

Gibot S, Bene MC, Noel R, Massin F, Guy J, Cravoisy A, Barraud D, De Carvalho Bittencourt M, Quenot JP, Bollaert PE, Faure G, Charles PE. Combination biomarkers to diagnose sepsis in the critically ill patient. Am J Respir Crit Care Med. 2012 Jul 1;186(1):65-71. doi: 10.1164/rccm.201201-0037OC. Epub 2012 Apr 26. — View Citation

Kofoed K, Andersen O, Kronborg G, Tvede M, Petersen J, Eugen-Olsen J, Larsen K. Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage migration inhibitory factor, soluble urokinase-type plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diagnose infections: a prospective study. Crit Care. 2007;11(2):R38. doi: 10.1186/cc5723. — View Citation

Kolackova M, Kudlova M, Kunes P, Lonsky V, Mandak J, Andrys C, Jankovicova K, Krejsek J. Early expression of FcgammaRI (CD64) on monocytes of cardiac surgical patients and higher density of monocyte anti-inflammatory scavenger CD163 receptor in "on-pump" patients. Mediators Inflamm. 2008;2008:235461. doi: 10.1155/2008/235461. — View Citation

Nierhaus A, Linssen J, Wichmann D, Braune S, Kluge S. Use of a weighted, automated analysis of the differential blood count to differentiate sepsis from non-infectious systemic inflammation: the intensive care infection score (ICIS). Inflamm Allergy Drug Targets. 2012 Apr;11(2):109-15. doi: 10.2174/187152812800392841. — View Citation

Raveendran AV, Kumar A, Gangadharan S. Biomarkers and newer laboratory investigations in the diagnosis of sepsis. J R Coll Physicians Edinb. 2019 Sep;49(3):207-216. doi: 10.4997/JRCPE.2019.308. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Serum concentration of C-Reactive protein	A significant difference in the absolute values or dynamics of C-Reactive protein serum concentrations value between the study groups.	After completion of the study - until the end of 2023
Other	Serum concentration of procalcitonin	A significant difference in the absolute values or dynamics of procalcitonin serum concentrations value between the study groups.	After completion of the study - until the end of 2023
Other	Serum concentration of IL-6	A significant difference in the absolute values or dynamics of IL-6 serum concentrations value between the study groups.	After completion of the study - until the end of 2023
Other	Leukocyte blood count	A significant difference in the absolute values or dynamics of leukocyte blood count values between the study groups. Differential blood count will also be included in analysis.	After completion of the study - until the end of 2023
Other	Neutrophil-to-lymphocyte ratio	A significant difference in the absolute values or dynamics of neutrophil-to-lymphocyte values between the study groups.	After completion of the study - until the end of 2023
Primary	Serum concentration of sCD64	A statistically significant difference in absolute value or dynamics of serum concentrations of sCD64 between the study groups to help distinguish between the specified clinical syndromes.	After completion of the study - until the end of 2023
Primary	Expression of CD64 on granulocytes	A statistically significant difference in absolute values or dynamics of the expression of CD64 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.	After completion of the study - until the end of 2023
Primary	Cell function assay of INF-?	A significant difference in the outcomes of cell function assay of INF-? between the study groups to distinguish between the specified clinical syndromes.	After completion of the study - until the end of 2023
Secondary	Serum concentration of sTREM-1	A statistically significant difference in absolute value or dynamics of serum concentrations of sTREM-1 between the study groups to help distinguish between the specified clinical syndromes.	After completion of the study - until the end of 2023
Secondary	Serum concentration of calprotectin	A statistically significant difference in absolute value or dynamics of serum concentrations of calprotectin between the study groups to help distinguish between the specified clinical syndromes.	After completion of the study - until the end of 2023
Secondary	Serum concentration of pentraxin 3	A statistically significant difference in absolute value or dynamics of serum concentrations of pentraxin 3 between the study groups to help distinguish between the specified clinical syndromes.	After completion of the study - until the end of 2023
Secondary	Expression of HLA-DR on granulocytes	A statistically significant difference in absolute values or dynamics of the expression of HLA-DR on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.	After completion of the study - until the end of 2023
Secondary	Expression of CD-14 on granulocytes	A statistically significant difference in absolute values or dynamics of the expression of CD-14 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.	After completion of the study - until the end of 2023
Secondary	Expression of CD-16 on granulocytes	A statistically significant difference in absolute values or dynamics of the expression of CD-16 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.	After completion of the study - until the end of 2023
Secondary	Expression of CD-40 on granulocytes	A statistically significant difference in absolute values or dynamics of the expression of CD-40 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.	After completion of the study - until the end of 2023
Secondary	Expression of CD-45 on granulocytes	A statistically significant difference in absolute values or dynamics of the expression of CD-45 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.	After completion of the study - until the end of 2023
Secondary	Expression of CD-163 on granulocytes	A statistically significant difference in absolute values or dynamics of the expression of CD-163 on granulocytes between the study groups to distinguish between the specified clinical syndromes. Expression on monocytes will be also assessed.	After completion of the study - until the end of 2023
Secondary	Cell function assay of IL-18	A significant difference in the outcomes of cell function assay of IL-18 between the study groups to distinguish between the specified clinical syndromes.	After completion of the study - until the end of 2023
Secondary	ICIS score	A significant difference in the absolute values or dynamics of ICIS (intensive care infection score) score value between the study groups.	After completion of the study - until the end of 2023