Clinical trial NCT06781294: SIRAKI 02 Posthoc Analysis.
Official title: SIRAKI02 POST-HOC ANALYSIS.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Cardiac Surgery Requiring Cardiopulmonary Bypass
Acute Kidney Injury
Chronic Kidney Disease(CKD)
Kidney Failure, Acute
Keywords: cytokines
heparin
protamine
propofol
vasopressors
insulin
Acute kidney disease
chronic kidney disease
renal recovery
extracorporeal blood purification
hemadsorption
oXiris
cardiopulmonary bypass
cardiac surgery
acute kidney injury
Lead sponsor: Hospital Universitari de Bellvitge
Sponsor class: OTHER
Collaborators: name: University of Barcelona
name: FundaciÃ³ Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
name: Hospital Germans TrÃ-es i Pujol de Badalona
First posted: 2025-01-17
Enrollment: 343
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Our randomized controlled trial with 343 patients requiring non emergent cardiac surgery with a prolonged expected cardiopulmonary bypass (CPB) time (\>90 minutes) demonstrated that the use of an extracorporeal blood purification (EBP) device (oXiris) connected to the CPB circuit during all surgery was associated with a decrease in the incidence of CSA-AKI within the first 7 days from surgery (nearly 12% reduction). The study was conducted in two university centres of the Barcelona metropolitan area between 2016 and 2022, randomising 343 patients (1:1) to receive either an EBP device connected to the CPB circuit or a standard strategy with CPB alone.

First of all the rate of acute kidney disease (AKD) and chronic kidney disease (CKD) in the sutdy population has not been reported and we will analyse if there were differences between groups as other studies have suggested with different interventions.

Concerning the intervention safety, no differences were observed in terms of intraoperative blood products (red blood cells, plasma and platelets) requirements between both groups. In order to improve knowledge about the safety of the technique it is very important to ensure that antibiotics levels in plasma during the time the adsorption device is connected to CPB, are not being modified by the intervention. Antibiotic prophylaxis during cardiac surgery is one of the cornerstones and has proved to effectively reduce perioperative infection especially concerning valve replacement procedures. In this sense, our two centres use the same strategy with cephalosporins (Cefazolin in Germans Trias Hospital and Cefuroxime in Bellvitge Hospital) with an early administration at the operating room (OR) before connecting patient to CPB and a late dose after removing CPB (3 hours after the first dose). We know from previous reports that the use of antibiotics during CRRT with oXiris is safe and normally does not require dose adjustments although no reports have been made of its use connected to CPB and antibiotics dosing.

Completing the safety issues, heparin and protamine doses during surgery have been registered in the patient's electronic history and should be checked and transferred to a database that allows to adequately analyse potential differences between groups. Other studies performed in cardiac surgery with adsorption devices have reported safety issues with platelets consumption and heparin requirements during surgery. In our protocol, heparin was administered prior to CPB initiation either based on the patient's weight or using hemostasis management system (HMS) plus technology in order to minimise overdosing. Heparin was administered during all CPB time in order to maintain activated clotting time (ACT) over 500 seconds and based on HMS plus technology. Protamine for heparin reversal at CPB withdrawal was administered using both methods too. Protamine administration can be associated with hypotensive episodes.

In our study, the decrease in CSA-AKI within the first 7 days from surgery achieved with the use of EBP connected to the CPB was more significant in CKD, DM, Low LVEF, Hypertension and non-obese patients. Whether this effect can be partially explained by the mild cytokines concentration differences observed in IL-8 and TNF-a at T1 (after removing clamp from surgery) and T2 (at ICU admission) has still not been evaluated. This reduction of inflammatory response syndrome (SIRS) during CPB time that could be related with the use of adsorption devices, should be also translated into a decrease of catecholamines and probably insulin requirements during surgery.

A noteworthy point to consider is that although the use of propofol has been extended in cardiac surgery, little is known about the potential antiinflammatory effect it may have in patients. It is important to identify those patients who received propofol to control this potential bias in terms of antiinflammatory effect. Besides this objective it is also very important to ensure that no adsorption of propofol took place with the use of EBP, as previous studies have reported higher requirements of sedation drugs with the use of CRRT or other devices with adsorption properties.

Finally, nearly 25% of the patients in the EBP group received ultrafiltration with doses that vary from 200 mL up to 3000 mL. We know from previous trials that ultrafiltration is clearly related with the removal of middle weight molecules which is presumably beneficial for patients with SIRS but that in specific scenarios this effect could be even detrimental for some patients. Whether the ultrafiltration performed in our study may have an effect in antibiotics, heparin, protamine, catecholamines, insulin or even propofol should be elucidated in order to settle the idoneous modality in which EBP should be performed when connected to CPB during cardiac surgery.

All these outcomes will be assessed controled by gender and age.

Detailed description: The study was conducted in two university centres of the Barcelona metropolitan area between 2016 and 2022 randomising 343 patients (1:1) to receive either an intervention strategy with EBP connected to the CPB circuit (169 patients) or a standard strategy with CPB alone (174 patients).

Cefuroxime was employed as antibiotic prophylaxis in 223 patients and Cefazolin was employed as antibiotic prophylaxis in the other 120 patients. These variations were due to the different hospital protocols for cardiac surgery antibiotic prophylaxis.

In 205 patients (111 in the control group and 94 in the EBP group), we recollected blood samples that were centrifuged, aliquoted and stored at -70º Celsius. 119 patients received Cefazolin protocol prophylaxis and 86 patients received Cefuroxime protocol prophylaxis. The samples from these patients were obtained at the beginning of the surgical intervention (T0), at the clamp withdrawal (T1), at the ICU admission (T2) and 24 hours after (T3). To evaluate the primary endpoint, antibiotic mass concentrations in plasma samples from T1 checkpoint will be measured using a previously validated ultra-high-performance liquid chromatography-tandem mass spectrometry method (Rigo-Bonnin R, Ribera A, Arbiol-Roca A, et al. Development and validation of a measurement procedure based on ultra-high performance liquid chromatography-tandem mass spectrometry for simultaneous measurement of β-lactam antibiotic concentration in human plasma. Clin Chim Acta. 2017;468:215-24).

In all patients (343 patients, 174 in the control group and 169 in the EBP group), we have planned to complete collecting all the hemodynamic and respiratory data in the operating room (OR) besides all the drugs administered in the OR (antibiotics, heparin, protamine, norepinephrine, insulin, and propofol). Laboratory parameters during surgery will be obtained from the medical records. Specific CPB parameters and ultrafiltration data when performed will also be collected. Kidney function parameters (creatinine and other biomarkers) will be registered up to 90 days after cardiac surgery and CKD incidence will be monitored up to 1 year after cardiac surgery.

Eligibility criteria: Inclusion Criteria:

* Non emergent cardiac surgery requiring cardiopulmonary bypass with expected CPB time over 90 minutes (double valve replacement or valve replacement plus CABG).
* Written informed consent from patient or legal surrogates.

Exclusion Criteria:

* Transplant receptor.
* Advanced Chronic Kidney Disease (CKD 4 or 5).
* Renal replacement therapy in the last 90 days.
* Documented intolerance to study device.
* Inclusion in other ongoing study within the last 30 days.
* Pregnancy.
* Immunosuppressive treatment or steroids (prednisone \> 0.5 mg/kg/day or equivalent).
* Autoimmune disorder.
* Coexisting illness with a high probability of death (inferior to 6 months).

Primary outcomes:
measure: Cytokines differences in subgroups
timeFrame: 24 hours
Secondary outcomes:
measure: Intraoperatory antibiotic concentrations.
timeFrame: During surgery
measure: Heparin administration
timeFrame: During surgery
measure: Protamine administration.
timeFrame: During surgery
measure: Insulin subcutaneous administration.
timeFrame: During surgery
measure: Vasopressor administration (Norepinephrine).
timeFrame: During surgery
measure: Propofol administration.
timeFrame: During surgery
measure: Acute Kidney Disease rate
timeFrame: 90 days
measure: Chronic Kidney Disease (CKD) rate.
timeFrame: One year
measure: PenKid and BioADM determinations.
timeFrame: 24 hours
measure: Urinary CCL-14 evaluation.
timeFrame: During surgery
measure: Adsorption circuit blood flow
timeFrame: During surgery.
measure: Ultrafiltration rates
timeFrame: During surgery.
measure: EBP time and Clamp time.
timeFrame: During surgery.
measure: Delirium during ICU stay
timeFrame: 7 days
Other outcomes:
Locations:
city: L'Hospitalet de Llobregat
country: Spain
facility: Universitat de Barcelona
state: Barcelona
Study officials:
References:
citation: Perez-Fernandez X, Ulsamer A, Camara-Rosell M, Sbraga F, Boza-Hernandez E, Moret-Ruiz E, Plata-Menchaca E, Santiago-Bautista D, Boronat-Garcia P, Gumucio-Sanguino V, Penafiel-Munoz J, Camacho-Perez M, Betbese-Roig A, Forni L, Campos-Gomez A, Sabater-Riera J; SIRAKI02 Study Group. Extracorporeal Blood Purification and Acute Kidney Injury in Cardiac Surgery: The SIRAKI02 Randomized Clinical Trial. JAMA. 2024 Nov 5;332(17):1446-1454. doi: 10.1001/jama.2024.20630.