Tocilizumab, Dexamethasone, Olanzapine, Hemodynamics, and Ventilation in Cardiac Surgery (GLORIOUS-II)
Coronary Artery Disease, Aortic Valve Disease
About this trial
This is an interventional treatment trial for Coronary Artery Disease
Eligibility Criteria
Inclusion Criteria: Adult, i.e., above 18 years of age Scheduled for CABG and/or AVR, irrespective of other concomitant valve surgery. Exclusion Criteria: Acute surgery (i.e. off hours surgery) Pregnancy or currently breastfeeding. Pregnancy in all fertile women will be ruled out by pregnancy testing prior to randomization. Known endocarditis at time of screening Previous participation in the trial Active infection, including bacterial, viral, and/or fungal infection Known hepatic cirrhosis Known severe thrombocytopenia with thrombocyte levels < 50 x 109/L Known severe neutropenia with neutrocyte levels < 2 x 109/L On the waiting list for a heart transplant Recipient of any major organ transplant Obstructive hypertrophic cardiomyopathy, active myocarditis, constrictive pericarditis, untreated hypothyroidism or hyperthyroidism Having received cytotoxic/cytostatic chemotherapy or radiation therapy for treatment of malignancy within the last 6 months. Clinical evidence of current malignancy except for basal or localized squamous cell carcinoma, cervical intraepithelial neoplasia or stable prostate cancer. Known narrow-angle glaucoma Known phenylketonuria Type I diabetes Known long QT syndrome Known allergy for any of the included study drugs Having received tocilizumab within the past 6 months Any condition, where participation in the study, in the investigator's opinion could put the subject at risk, confound the study results or interfere significantly with participation in the study Patients with extracardiac arteriopathy (assessed as part of the pre-operative EuroSCORE) will be excluded from the intervention 'flow-targeted vs. pressure-targeted hemodynamic management during CPB'.
Sites / Locations
- The Heart Centre, RigshospitaletRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm 9
Arm 10
Experimental
Placebo Comparator
Experimental
Placebo Comparator
Experimental
Placebo Comparator
Experimental
Active Comparator
Experimental
Active Comparator
Tocilizumab
Placebo (for Tocilizumab)
Dexamethasone
Placebo (for Dexamethasone)
Olanzapine
Placebo (for Olanzapine)
Flow-targeted hemodynamic management
Pressure-targeted hemodynamic management
Low tidal-volume ventilation
No ventilation
The tocilizumab kit will contain 280 mg tocilizumab (RoActemra®, Roche), 20mg/mL, i.e. 14 mL. Tocilizumab will be administered as an intravenous bolus infusion over 15 minutes after induction of anaesthesia.
The placebo kit will contain 14 mL of isotonic (0.9%) normal saline. Placebo will be administered as an intravenous bolus infusion over 15 minutes after induction of anaesthesia.
The dexamethasone kit will contain 20 mg of dexamethasonphosfat (Dexavit®,Vital Pharma Nordic), 4mg/mL, i.e. 5 mL, which corresponds to 16.67 mg of dexamethasone. Dexamethasone will be administered as an intravenous bolus infusion over 2 minutes after induction of anaesthesia.
The placebo kit will contain 5 mL of isotonic (0.9%) normal saline. Placebo will be administered as an intravenous bolus infusion over 2 minutes after induction of anaesthesia.
The olanzapine kit will consist of two capsules each containing two 2.5 mg tablets of olanzapine (Olanzapine Stada®, STADA Nordic); i.e. total dose 10mg. The capsules will be delivered to the patient with instruction to take the capsule orally along with other standardized pre-procedure medicine. Patient intake will be recorded.
The placebo kit will consist of two placebo capsules identical to the capsules containing the olanzapine tablet. The capsules will be delivered to the patient with instruction to take the capsule orally along with other standardized pre-procedure medicine. Patient intake will be recorded.
In the 'flow group', an arterial oxygen delivery (DO2) above 274 mL/min/m2 BSA AND a central venous oxygen saturation (ScvO2) above 70% will be targeted. CPB pump flow will be initiated at a flow rate of 2.4 L/min/m2. If DO2 or ScvO2 are below target, CPB pump flow will be gradually increased until targets are reached up to a maximum CPB pump flow of 3.2 L/min/m2. If DO2 or ScvO2 are below targets despite a maximum CPB pump flow, PaO2 will be gradually increased from an initial target of 15-20 kPa to a maximum of 40 kPa. A haematocrit level equal to or above 21% will be targeted, however, if DO2 or ScvO2 are below target despite a CPB pump flow of 3.2 L/min/m2, the haematocrit target level will be increased to equal to or above 25%. A MAP down to 35 mmHg will be tolerated throughout. The MAP target will be achieved by administration of boluses of phenylephrine up to a total of 2.0 mg, which can be followed by a continuous infusion of norepinephrine up to 0.6 μg per kg per min.
In the 'pressure group' a MAP between 70 to 80 mmHg will be targeted. The assigned MAP target will be achieved by administration of boluses of phenylephrine up to a total of 2.0 mg, which can be followed by a continuous infusion of norepinephrine up to 0.6 μg per kg per min. CPB pump flow will be fixed at a flow rate of 2.4 L per minute per square meter body surface area. A haematocrit level equal to or above 21% will be targeted throughout. A PaO2 of 15-20 kPa will be targeted throughout.
During initiation of CPB, the 'ventilation' group will receive a tidal volume at 3ml/kg and a set PEEP of 3 cm H2O. The respiratory frequency (RF) will be set at 10, and the inspiratory: expiratory (I:E) ratio will be set to 5:1. Peak pressures (Pmax) will be limited to < 25 cm H2O. FiO2 will be set at 50%. The ventilation strategy will be maintained during CPB. Any recruitment manoeuvres will be initiated solely at the discretion of the attending anaesthesiologist, and only if the patient's oxygen saturation drops below 88%. All recruitment manoeuvres will be completed by increasing the inspiratory pressure to 20 cmH2O for 10 seconds. The manoeuvre will be repeated three times.
The 'no-ventilation' group will receive no ventilation or PEEP. The ventilation strategy will be maintained during CPB. Any recruitment manoeuvres will be initiated solely at the discretion of the attending anaesthesiologist, and only if the patient's oxygen saturation drops below 88%. All recruitment manoeuvres will be completed by increasing the inspiratory pressure to 20 cmH2O for 10 seconds. The manoeuvre will be repeated three times.