Effects of different modes of cardiopulmonary bypass in patients undergoing cardiac surgery

ISRCTN	ISRCTN11243508
DOI	https://doi.org/10.1186/ISRCTN11243508
Secondary identifying numbers	ARIS-HRZZ: J3-50120

Submission date: 20/05/2024
Registration date: 21/05/2024
Last edited: 21/05/2024

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Surgery

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
Cardiac (heart) surgery is a high-risk procedure commonly performed with cardiopulmonary bypass (CPB), a machine that temporarily takes over the function of the heart and lungs, which is associated with disturbances in microcirculation (circulation of the blood in the smallest blood vessels). This can lead to complications such as decreased tissue perfusion (blood flow) and hypoxia (low blood oxygen) with organ dysfunction which can complicate the course of the patient’s recovery. Cardiac surgery causes inflammation, ischemia-reperfusion injury (damage caused when blood supply returns to tissue) and acute trauma that contribute to endothelial dysfunction (impaired functioning of the lining of blood vessels).
The surface of the vascular (blood vessel) endothelium is covered with glycocalyx, a gel-like layer lining. It has an important role in maintaining vascular tone and permeability. The endothelial glycocalyx is a dynamic structure with a tenuous balance between degradation and synthesis. Under pathological conditions or trauma, such as cardiac surgery, the inflammatory response can adversely affect this balance. Increased levels of degradation markers are associated with organ dysfunction and poor outcomes in critically ill patients. Degraded endothelial glycocalyx components can be measured to estimate the degree of endothelial degradation and possible organ dysfunction.
Although CPB is a non-physiological procedure, it is widely accepted as a safe and effective method for open heart surgery. One of the most non-physiological features of CPB is the non-pulsatile flow generated by the pump. Recent evidence suggests that pulsatile CPB might be more physiological but the role of pulsatile versus non-pulsatile CPB is still far from being completely understood.
This study aims to investigate the difference between non-pulsatile and pulsatile CPB on endothelial dysfunction, oxidative stress, inflammatory response, and clinical outcomes in patients undergoing cardiac surgery.

Who can participate?
Adult patients aged 18 years and over undergoing cardiac surgery with CPB (see detailed inclusion and exclusion criteria)

What does the study involve?
Participants are randomly allocated to be treated with pulsatile or non-pulsatile CPB. Otherwise, the patients' perioperative care is the same for all three participating centres and both groups. At seven predefined times blood samples will be taken and stored for tests.

What are the possible benefits and risks of participating?
Both methods of CPB are used in practice, but the non-pulsatile CPB is most commonly used. Thus, the risks of surgery and CPB as such are not supposed to differ between the groups. The potential expected benefits of pulsatile CPB would include less endothelial glycocalyx degradation, less pronounced pro-inflammatory response, less oxidative stress and possibly improved organ function.

Where is the study run from?
The study is run in three university hospitals: Ljubljana (Slovenia), Rijeka (Slovenia), and Maribor (Croatia)

When is the study starting and how long is it expected to run for?
January 2023 to January 2027

Who is funding the study?
1. Slovenian Research and Innovation Agency
2. Croatian Science Foundation

Who is the main contact?
1. Assist Prof Marko Zdravkovic, marko.zdravkovic@ukc-mb.si
2. Prof. Vlatka Sotosek, vlatkast@medri.uniri.hr

Contact information

Prof Marko Zdravkovic
Public, Scientific, Principal Investigator

Ljubljanska ulica 5
Maribor
2000
Slovenia

ORCID ID	0000-0002-0033-7071
Phone	+386 (0)23211569
Email	marko.zdravkovic@ukc-mb.si

Study information

Study design	Multi-centric randomized controlled trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use contact details to request a participant information sheet
Scientific title	Endothelial Dysfunction, Inflammation and Oxidative Stress (EDIOS) in patients undergoing cardiac surgery with pulsatile or non-pulsatile cardiopulmonary bypass: a multi-centric randomised controlled trial
Study acronym	EDIOS
Study objectives	H1: Pulsatile cardiopulmonary bypass reduces endothelial dysfunction in patients undergoing cardiac surgery when compared with non-pulsatile cardiopulmonary bypass. H2: Pulsatile cardiopulmonary bypass reduces inflammatory response in patients undergoing cardiac surgery when compared with non-pulsatile cardiopulmonary bypass. H3: Pulsatile cardiopulmonary bypass reduces oxidative stress in patients undergoing cardiac surgery when compared with non-pulsatile cardiopulmonary bypass. H4: Pulsatile cardiopulmonary bypass improves microcirculatory function in patients undergoing cardiac surgery when compared with non-pulsatile cardiopulmonary bypass. H5: Pulsatile cardiopulmonary bypass improves clinical outcomes in patients undergoing cardiac surgery when compared with non-pulsatile cardiopulmonary bypass.
Ethics approval(s)	1. Approved 01/03/2024, Komisiji Republike Slovenije za medicinsko etiko (KME RS) (Štefanova ulica 5, Ljubljana, 1000, Slovenia; +386 (0)1478 69 06; kme.mz@gov.si), ref: 0120-33/2024-2711-3 2. Approved 28/02/2023, Klinicki bolnicki centar Rijeka, Eticko povjerenstvo (Kresimirova 42, Rijeka, 51000, Croatia; +385 (0)51658808; pravna-ivanaa@kbc-rijeka.hr), ref: 2170-29-02/1-23-2
Health condition(s) or problem(s) studied	Effects of pulsatile cardiopulmonary bypass (CPB) in patients undergoing cardiac surgery with median sternotomy
Intervention	Group allocation - institution-stratified permuted block randomization: Patients will be randomly allocated in a 1:1 ratio in blocks of 6 patients within each institution (i.e., stratified by institution) to receive either pulsatile or non-pulsatile CPB. A random number generator software will be used. Each centre is expected to recruit 48 patients, making a total of 144 patients (see power calculations). Interim analysis for clinical outcomes is planned at the 50% of the target number of patients is reached within each institution. Pulsatile CPB: For pulsatile CPB the roller pump must be used in all centres. CPB tubing systems should be used according to institutional standards, a hollow fiber oxygenator membrane (LivaNova F8 with a surface area of 1.8 m2), 1/2 or 3/8 inch pump boot, CPB tubing from the pump of 3/8 inch size and a straight 24 Fr aortic cannula (EOPA, Medtronic®). The pulsatile CPB starts at the time of aortic cross-clamp and finishes upon the cross-clamp release (i.e., continuously during the aortic cross-clamp time). Pulsatile CPB parameters should be set as: 1. Frequency (min-1) 75 2. Width (% of time at high speed) 60 3. Basic flow (%) 30 The target minimum pulse pressure on the arterial line (most commonly radial artery) should be 15 mmHg. Further adjustments will be performed according to the patient's pressure curve and pulse amplitude, for example, if the target pulse pressure is not achieved then the width should be reduced to 50% or 40% if needed. The mean arterial pressure during CPB should be maintained between 55 and 80 mmHg; for that purpose the cardiac index of 2.0-2.4 L/min/m2 will be maintained for all patients in a balanced manner with the vasoactive agents (first-line noradrenaline, first-line vasodilator glyceryl trinitrate - as in the hemodynamics protocol). Normothermic CPB should be used with the range of 35.0 - 37.0 C core body temperature. Non-pulsatile CPB (control group): For non-pulsatile CPB the roller pump must be used in all centres. CPB tubing systems should be used according to institutional standards, CPB tubing systems should be used according to institutional standards, a hollow fiber oxygenator membrane a hollow fiber oxygenator membrane (LivaNova F8 with a surface area of 1.8 m2), 1/2 or 3/8 inch pump boot, CPB tubing from the pump of 3/8 inch size and a straight 24 Fr aortic cannula (EOPA, Medtronic®). The mean arterial pressure during CPB should be maintained between 55 and 80 mmHg; for that purpose the cardiac index of 2.0-2.4 L/min/m2 will be maintained for all patients in a balanced manner with the vasoactive agents (first-line noradrenaline, first-line vasodilator: glyceryl trinitrate - as in the hemodynamics protocol). Normothermic CPB should be used with the range of 35.0 - 37.0 C core body temperature. All parameters will be monitored until 66 hours after CPB; additionally, complications will be followed up to 7 days following surgery.
Intervention type	Device
Pharmaceutical study type(s)	Not Applicable
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Cardiopulmonary bypass device settings: pulsatile or non-pulsatile flow
Primary outcome measure	1. Endothelial dysfunction: peak plasma syndecan-1 level measured with ELISA at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB. 2. Inflammation: peak plasma IL-6/IL-10 ratio measured with ELISA at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB. 3. Oxidative stress: peak plasma malondialdehyde (MDA) measured with ELISA at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB. 4. Microcirculation: perfused vessel density (variable of diffusive capacity) measured with GlycoCheck at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB. 5. Clinical outcomes: peak lactate levels measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB.
Secondary outcome measures	1. Other markers of endothelial dysfunction, all measured with ELISA at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB: 1.1. Heparan sulphate 1.2. Angiopoetin Ang-1 and angiopoetin Ang-2 and Ang-2/Ang-1 ratio 1.3. Endokan 1.4. Syndecan-4 1.5. Glypican-1 1.6. Hyaluronic acid 1.7. Orosomucoid 1.8. Fractalkine 1.9. Von Willebrand factor 1.10. Vascular endothelial growth factor (VEGF) 2. Other markers of inflammation, all measured with ELISA at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB: 2.1. IL-6/IL-10 patterns 2.2. IL-10 2.3. IL-6 2.4. IL-5 2.5. IL-16 2.6. IL-8 2.7. MMP-9 2.8. MMP-13 2.9. IL-1β 2.10. IL-7 2.11. IL-17 2.12. IL-18 2.13. IL-18BP 3. Other markers of oxidative stress, all measured with ELISA at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB: 3.1. Reactive oxygen species 3.2. Reactive nitrogen species 4. Other microcirculatory parameters, all measured with GlycoCheck at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB: 4.1. Convective blood flow: proportion of perfused vessels (proportion of perfused vessels = perfused vessel density/total vessel density) 4.2. Variables of diffusive capacity: Total vessel density and De Backer score 4.3. Variable of heterogeneity: Heterogeneity index 4.4. Variable of glycocalyx: Perfused boundary region 5. Clinical outcomes: Vascular (extracted from patients’ medical records for all): 1. Total dose of NA administered intraoperatively and in ICU until the first discharge or up to 66 h after the end of CPB (mcg/kg) 2. Total dose of V administered intraoperatively and in ICU (IE) until the first discharge or up to 66 h after the end of CPB 3. NA and V maximum rate intraoperatively and in ICU (mcg/kg/min // IE/h) until the first discharge or up to 66 h after the end of CPB 4. NA and V duration of treatment since the end of CPB until the first discharge from ICU or up to 66 h after the end of CPB 5. Frequency of vasoplegic syndrome: defined as MAP lower than 65 mmHg despite preload optimization requiring norepinephrine infusion for more than 4 hours after CPB 6. Fluid administration and fluid balance, defined as for ICU and HDU ([total fluid intake/24h] to blood loss + urine output/ 24h) (mL) and in OR ([total fluid intake anaesthesia + perfusionist/end of surgery] to blood loss + urine output/end of surgery) up to 66 h after the end of CPB 7. Incidence and extent of fluid overload defined as fluid balance > 5% = [fluid intake (L) - fluid output (L)]/body weight (kg) × 100% 8. Patients requiring vasodilator infusion intraoperatively and in ICU up to 66 h after the end of CPB (n, %) 9. NA equivavelents intraoperatively and in ICU (mcg/kg/min) until the first discharge or up to 66 h after the end of CPB Heart: 1. Patients requiring any inotropic support intraoperatively and in ICU until the first discharge or up to 66 hours after CPB (n, %) [extracted from patients’ medical records] 2. Total dose of inotropes administered intraoperatively and in ICU (IE) until the first discharge or up to 66 h after the end of CPB [extracted from patients’ medical records] 3. Peak hsTnI (ng/L), measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB 4. Peak heart-type fatty-acid binding protein, ELISA, measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB 5. Peak NT-proBNP (ng/L), measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB 6. New-onset atrial fibrillation (n, %) in ICU and in HDU up to 7 days after the end of CPB [extracted from patients’ medical records] 7. Type 5 myocardial infarction : biomarker values above five times the 99th percentile of the normal reference range during the initial 72 hrs following CABG + new pathological Q-waves or new LBBB, or angiographically documented new graft or native coronary artery occlusion, or imaging evidence of new loss of viable myocardium [extracted from patients’ medical records] Kidney: 1. Urine output intraoperatively (mL/kg/h), in ICU (mL/kg/h) and in HDU (mL/kg/h) [extracted from patients’ medical records] 2. Peak creatinine and maximum change in creatinine from pre-operative (μmol/L), measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB 3. Peak urea (mmol/L), measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB 4. Creatinine clearance (mL/min), measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB 5. Furosemide dose (mg) in ICU and in HDU up to 66 h after the end of CPB [extracted from patients’ medical records] 6. Renal replacement therapy up to 66 h after the end of CPB (n, %) [extracted from patients’ medical records] 7. AKI presence and stage by Kidney Disease Improving Global Outcomes (KDIGO) criteria: stage 1 is defined as an increase in serum creatinine (SCr) by ≥26.5 μmol/L or an increase in SCr to ≥1.5 times baseline, or urine output < 0.5 mL/kg/h for 6−12 h. AKI stage 2 is defined as an increase in SCr to ≥2.0–2.9 times the baseline, or urine output < 0.5 mL/kg/h for ≥12 h. AKI stage 3 is defined as an SCr of up to 3.0 times the baseline or SCr increased to ≥354 μmol/L or the initiation of renal replacement therapy or urine output <0.3 mL/kg/h for ≥24 h or anuria for ≥12 h. Lungs: 1. Time of mechanical ventilation (intubation to extubation) until the first discharge from ICU or up to 66 h after the end of CPB (extracted from patients’ medical records) 2. Time to extubation from the end of surgery until the first discharge from ICU or up to 66 h after the end of CPB (extracted from patients’ medical records) 3. (Lowest) PaO2/FiO2 level measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB Liver (all measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB [i.e., the next morning following surgery], 42 hours after CPB and 66 hours after CPB): 1. Concentration of ALT (μkat/L) 2. Concentration of AST (μkat/L) 3. INR 4. Bilirubin μmol/L 5. Concentration of GGT (μkat/L) Other: 1. Peak CRP (mg/L) measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB 2. Peak PCT (μg/L) measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB 3. Peak leucocytes count (109 cells per L) measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB 4. Lowest BE measured at baseline, 45 minutes after aortic cross-clamp, 2 hours after CPB, 6 hours after CPB, 18 hours after CPB (i.e., the next morning following surgery), 42 hours after CPB and 66 hours after CPB 5. Total heparin given during CPB (IE/kg) 6. Substitution of blood products intraoperatively and up to 66 hours after CPB (total number of packs and volume) 7. Chest tube drainage up to 66 hours after CPB 8. Hemostatic reoperation frequency within 7 days (n, %) 9. Duration of ICU stay 10. Duration of hospital stay Major complications: 1. Occurrence of major adverse cardiovascular events (MACCE) within the 7 days following cardiac surgery. The criteria for MACCE required the occurrence of at least one outcome among the following: in-hospital mortality, successful resuscitated cardiac arrest, stroke, acute kidney injury, and mesenteric ischemia. 2. Stroke was defined as an embolic, thrombotic, or hemorrhagic cerebral event with persistent residual motor, sensory, or cognitive dysfunction (e.g., hemiplegia, hemiparesis, aphasia, sensory deficit, impaired memory) diagnosed by brain computed tomography scan 3. Additional complications: homeostatic revision surgery, deep sternal wound infection, superficial wound infection Subgroup analyses: 1. The researchers will split the patients into two groups based on the duration of ACC: the shorter duration group will be compared to the longer duration (50:50 in each group) 2. They will split the patients into two groups based on the elevated AKI risk preoperatively: elevated AKI risk is defined by a score of ≥1.5 points using the following risk score: pre-operative haemoglobin <130 g.l-1 (2 points); pre-operative creatinine >100 μmol.l- 1 (2 points); age >70 years (1.5 points), BMI >30 kg.m-2 (1.5 points) and New York Heart Association (NYHA) status 4 (1.5 points) CORRELATIONS and ASSOCIATIONS (univariate and multivariable logistic regression analyses) between the collected variables.
Overall study start date	01/01/2023
Completion date	01/01/2027

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	144
Key inclusion criteria	1. Adult patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) 2. Expected aortic cross-clamp (ACC) time of >45 minutes 3. Full or partial median sternotomy with central cannulation (mini-CPB should not be used) 4. surgery starting in the morning: 4.1. Cardiac valve surgery 4.2. Isolated coronary artery bypass grafting (CABG) 4.3. Combination of valvular and CABG surgery 4.4. Any of the above combined with ascending aorta surgery (NO concomitant radio-frequency ablations, NO concomitant carotid artery surgery)
Key exclusion criteria	Exclusion criteria: 1. Refusal to participate in the study 2. Pregnant women 3. Patients with previous cardiac surgery (i.e., redo surgery) 4. Patients with left ventricular ejection fraction <30% 5. Patients on chemo/immunosuppressive therapy (including inhaled corticosteroids, antileukocyte drugs or TNF-α blockers) 6. Patients with body mass index, >35 kg·m-2 or <18 kg·m-2 7. Patients with a body surface area (BSA - duBois formula) >2.20 m2 (as it would be impossible to achieve pulsatile pump flow equivalent to a cardiac index of 2.0-2.4, without exceeding maximum safe line pressure in the extracorporeal circuit) 8. Patients with any autoimmune diseases, immunocompromised patients (e.g., with AIDS) or with leucopoenia (<3.5·109 cells·L−1) 9. Clinical and/or laboratory signs of infection 10. Patients with advanced chronic lung disease with pO2 on air: <9.8 kPa 11. Patients with known liver disease (albumin <30 g/L; bilirubin >34.2μmol·L−1) 12. Patients with renal failure (serum creatinine >176 μmol·L−1) 13. Patients with malignant diseases within the last 5 years (i.e., remission or cure 5 years or longer) 14. Patients with ischemic stroke or myocardial infarction (STEMI) within the last 3 months 15. Patients with known epilepsy 16. Patients with known allergy to any drugs used in the study protocol Exclusion criteria - after enrolment: Two analyses will be performed, one based on the treatment received and the second one with the additional exclusion criteria which could have an additional effect on the measured outcomes of endothelial dysfunction, inflammation, and/or oxidative stress; for example, patients who received systemic glucocorticoid medication before the last blood sampling.
Date of first enrolment	28/05/2024
Date of final enrolment	31/12/2025

Locations

Countries of recruitment

Croatia
Slovenia

Study participating centres

University Medical Centre Maribor

Ljubljanska ulica 5
Maribor
2000
Slovenia

University Medical Centre Ljubljana

Zaloska 2
Ljubljana
1000
Slovenia

Klinicki bolnicki centar Rijeka

Kresimirova 42
Rijeka
51000
Croatia

Sponsor information

Slovenian Research and Innovation Agency
Government

Bleiweisova cesta 30
Ljubljana
1000
Slovenia

Phone	+386 (0)1400 5910
Email	info@aris-rs.si
Website	https://www.arrs.si/en/

Croatian Science Foundation
Government

Ilica 24
Zagreb
10000
Croatia

Phone	+385 (0)1 2356 600
Email	ured@hrzz.hr
Website	https://hrzz.hr/en/
"ROR"	https://ror.org/03n51vw80

Funders

Funder type

Government

Slovenian Research and Innovation Agency

No information available

Hrvatska Zaklada za Znanost
Government organisation / Local government

Alternative name(s): Croatian Science Foundation, HRZZ
Location: Croatia

Results and Publications

Intention to publish date	30/06/2026
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Planned publication in a peer-reviewed journal
IPD sharing plan	The datasets generated and/or analysed during the current study will be available upon request from Marko Zdravkovic (marko.zdravkovic@ukc-mb.si).

Editorial Notes

20/05/2024: Study's existence confirmed by the Komisiji Republike Slovenije za medicinsko etiko (KME RS).