Dexamethasone, Olanzapine, Hemodynamics, and Ventilation in Cardiac Surgery

NCT05635227 | Recruiting DMC

• 1 other identifier: 2021-HJEPharma-002
• Study Type: interventional
• Target: 1,200
• Locations: 1 country
• Sites: 1

Brief Summary

Open heart surgery, including coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) is associated with a significant risk of mortality. This study is a randomized clinical trial with the purpose of investigating four different interventions on the primary endpoint 'days alive and outside of hospital within 90 days'. The interventions are:

• Dexamethasone vs. placebo administered after induction of anesthesia.
• Olanzapine vs. placebo administered prior to anesthesia.
• A blood-flow targeted vs. a blod-pressure targeted hemodynamic strategy while the patient is on cardio-pulmonary bypass (CPB)
• Low-tidal volume ventilation vs. no ventilation of the lungs while the patient is on CPB

Conditions

Coronary Artery Disease; Aortic Valve Disease

Outcome Measures

Primary Outcomes (1)

• Days alive and outside hospital

  90 days from surgery

Secondary Outcomes (12)

• Time to composite outcome of death and major organ damage

  90 days

• Number (fraction) of patients with severe post-operative complications during index admission, defined as a Clavien-Dindo class of 3 to 5.

  During index admission up to 30 days after surgery. Outcome will be assessed upon hospital discharge.

• Number (fraction) of patients with delirium, defined as a positive Confusion Assessment Method for the ICU (CAM-ICU) or wards (CAM).

  During index admission up to 30 days after surgery.

• Quality of Recovery-15 (QoR-15) score

  3 days or as soon as possible after surgery

• Survival

  Within 90 days

Other Outcomes (7)

• Surgical wound infection

  Within 90 days

• Sepsis

  Within 90 days

• Acute kidney injury

  Within 90 days

Study Arms (8)

Dexamethasone

EXPERIMENTAL

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.

Drug: Dexamethasone phosphate

Placebo (for Dexamethasone)

PLACEBO COMPARATOR

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.

Drug: Isotonic sodium chloride (0.9%)

Olanzapine

EXPERIMENTAL

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.

Drug: Olanzapine 10 MG

Placebo (for Olanzapine)

PLACEBO COMPARATOR

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.

Drug: Placebo capsule

Flow-targeted hemodynamic management

EXPERIMENTAL

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.

Procedure: Flow-targeted hemodynamic management

Pressure-targeted hemodynamic management

ACTIVE COMPARATOR

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.

Procedure: Pressure-targeted hemodynamic management

Low tidal-volume ventilation

EXPERIMENTAL

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.

Procedure: Low tidal-volume ventilation

No ventilation

ACTIVE COMPARATOR

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.

Procedure: No ventilation

Interventions

Dexamethasone phosphate DRUG

See description of arms

Dexamethasone

Isotonic sodium chloride (0.9%) DRUG

See description of arms

Placebo (for Dexamethasone)

Olanzapine 10 MG DRUG

Olanzapine tablet pre-hidden in capsule identical to the placebo tablet

Olanzapine

Placebo capsule DRUG

capsule identical to capsule containing olanzapine

Placebo (for Olanzapine)

Flow-targeted hemodynamic management PROCEDURE

See description of arms

Flow-targeted hemodynamic management

Pressure-targeted hemodynamic management PROCEDURE

See description of arms

Pressure-targeted hemodynamic management

Low tidal-volume ventilation PROCEDURE

See description of arms

Low tidal-volume ventilation

No ventilation PROCEDURE

See description of arms

No ventilation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult, i.e., above 18 years of age
• Scheduled for CABG and/or AVR, irrespective of other concomitant valve surgery.

You may not qualify if:

• 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

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead

Study Sites (1)

The Heart Centre, Rigshospitalet

Copenhagen, 2200, Denmark

RECRUITING

MeSH Terms

Conditions

Coronary Artery Disease; Aortic Valve Disease

Interventions

dexamethasone 21-phosphate; Sodium Chloride; Olanzapine

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Heart Valve Diseases

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Christian Hassager, MD, DMSc

  Sponsor GmbH

  STUDY CHAIR

Central Study Contacts

Sebastian Wiberg, MD, PhD

CONTACT

+45 35 45 17 10; sebastian.christoph.wiberg@regionh.dk

Christian Hassager, MD, DMSc

CONTACT

christian.hassager@regionh.dk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The dexamethasone intervention will be carried out by the nurse anesthetist and the perfusionist, and accordingly will be un-blinded. The perfusionists and the nurse anaesthetist will not be involved in any postoperative clinical care, outcome evaluation, or data analyses. The participant, trial staff, and all clinical personnel with the exception of the nurse anaesthetist and perfusionist will be blinded. The olanzapine intervention will be blinded for all; including the participant, trial staff, and all clinical personnel. The hemodynamic and ventilatory strategy interventions will be unblinded for the staff in the operating theatre (OR). The interventions will be blinded for the participants, trial staff and clinical personnel outside the OR.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, MD, PhD

Model Details: The trial assumes a priori that any effect of each of the four interventions are independent from any effect of another intervention.

Study Record Dates

• First Submitted: November 13, 2022
• First Posted: December 2, 2022
• Study Start: November 10, 2022
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): February 1, 2028
• Last Updated: April 4, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)