Dexamethasone, Olanzapine, Flow-targeted Versus Pressure-targeted Hemodynamic Management, and Low Tidal Volume Ventilation in Patients Undergoing On-pump Cardiac Surgery - a Multifactorial Design Randomized Trial
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 1,200
- 试验地点
- 1
- 主要终点
- Days alive and outside hospital
研究概览
简要总结
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
详细描述
- BACKGROUND
1.1 Coronary artery bypass grafting and valve replacement Open heart surgery, including coronary artery bypass grafting (CABG) and/or aortic valve replacement (AVR) is associated with a significant risk of mortality. Elective CABG remains associated with a mortality of approximately 1.5 % after 30 days and increases to approximately 9 % after 5 years, with higher percentages in the subacute setting. Aortic valve replacement (AVR) is associated with a mortality of approximately 6% after 30 days, while mitral valve replacement (MVR) is associated with a mortality of approximately 4%. Additionally, open heart surgery is associated with a significant risk of morbidity caused by organ injury, including multi-organ failure, cerebral injury, pulmonary injury, cardiac injury, renal injury and/or endothelial injury.
1.2 Organ injury associated with cardiac surgery and cardiopulmonary bypass The primary indication for CABG with/without AVR is atherosclerotic disease with associated coronary artery disease and/or valvular disease. Atherosclerotic disease may affect the perfusion and function of other organs, such as the brain, heart, lungs and kidneys, and make them vulnerable to the homeostatic changes that occur during open heart surgery. As such, pre-existing organ disease increases the risk of organ injury, and the clinically applied risk scores 'European System for Cardiac Operative Risk Evaluation' (EuroSCORE II) and 'Society of Thoracic Surgeons' (STS) score both include extracardiac vascular disease, heart failure, kidney function and lung disease, as independent predictors of in-hospital or 30-day mortality after open heart surgery. During CABG/AVR, extracorporeal circulation is applied in the form of cardiopulmonary bypass (CPB). Changes in blood flow occur during initiation and weening of CPB and also as a consequence of the fixed, non-pulsatile flow of the CPB circuit. These flow changes may affect end-organ perfusion, cause reperfusion injury, trigger inflammatory cascades and play a part in ensuing morbidity or mortality. Furthermore, open heart surgery induces severe systemic inflammation caused by the surgical procedure itself (sternotomy and ensuing lung collapse) as well as the result of mechanical stress and exposure to the artificial surfaces of the CPB circuit for the blood.
1.3 Dexamethasone The use of glucocorticoids for mitigation of the inflammatory response during cardiac surgery has been investigated previously. In earlier studies, the use of prophylactic glucocorticoids have been suggested to lower the risk of post-operative atrial fibrillation, reduce post-operative bleeding, shorten the duration of mechanical ventilation and the length of stay in the intensive care unit (ICU) as well as shorten length of hospital stay. However, these earlier clinical trials have been assessed mostly as being of low quality and underpowered to draw conclusions regarding patient-centred outcomes. In non-cardiac surgery, the use of low to intermediate dose glucocorticoids have been suggested to have opioid-sparing effects and to decrease post-operative pain as well as nausea and vomiting.
Two large, well-conducted randomized clinical trials (RCTs) have investigated high-dose glucocorticoid prophylaxis in patients undergoing CPB. In the Dexamethasone for Cardiac Surgery (DECS) trial, a total of 4,494 patients undergoing heart surgery with CPB were randomized to a single intraoperative dose of 1mg/kg of dexamethasone versus placebo. The study found no significant difference in a composite endpoint consisting of death, myocardial infarction (MI), stroke, renal failure or respiratory failure within 30 days of randomization (relative risk (RR) 0.83 (95%CI 0.67 - 1.01, p=0.07). Dexamethasone was associated with a reduction in postoperative infection, the need for mechanical ventilation and reduced length of ICU and hospital stay and with higher postoperative glucose levels. In the Steroids In cardiac Surgery (SIRS) trial, a total of 7,507 patients undergoing cardiac surgery with CPB were randomized to a total of 500mg of methylprednisolone versus placebo, initiated in the operating room. The study found no significant difference in 30-day mortality between the groups (RR 0.87 (95%CI 0.70 - 1.07, p=0.19). Furthermore, the study found no significant differences in the pre-specified safety outcomes with the exception of higher blood glucose levels in the patients who received methylprednisolone. A patient-level meta-analysis of the DECS SIRS trials show a reduction in the rates of respiratory failure and infections in favour of glucocorticoids while glucocorticoids were associated with an increase in myocardial injury but not MI as defined by the 3rd universal definition. Both the DECS and the SIRS trial used high dose glucocorticoids. A previous dose-response meta-analyses have suggested that low dose glucocorticoids maybe beneficial compared to high dose glucocorticoids. Accordingly, for non-cardiac surgery, lower doses of glucocorticoids of between 0.1 mg/kg to 0.2 mg/kg are frequently applied, which may balance positive effects with adverse effects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult, i.e., above 18 years of age
- •Scheduled for CABG and/or AVR, irrespective of other concomitant valve surgery.
排除标准
- •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
- •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'.
研究组 & 干预措施
Dexamethasone
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.
干预措施: Dexamethasone phosphate (Drug)
Placebo (for Dexamethasone)
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.
干预措施: Isotonic sodium chloride (0.9%) (Drug)
Olanzapine
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.
干预措施: Olanzapine 10 MG (Drug)
Placebo (for Olanzapine)
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.
干预措施: Placebo capsule (Drug)
Flow-targeted hemodynamic management
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.
干预措施: Flow-targeted hemodynamic management (Procedure)
Pressure-targeted hemodynamic management
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.
干预措施: Pressure-targeted hemodynamic management (Procedure)
Low tidal-volume ventilation
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.
干预措施: Low tidal-volume ventilation (Procedure)
No ventilation
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.
干预措施: No ventilation (Procedure)
结局指标
主要结局
Days alive and outside hospital
时间窗: 90 days from surgery
次要结局
- 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(180 days)
- Graft patency, assessed by cardiac computed tomography (CT) scan(After 90 days)
- Myocardial resting perfusion, assessed by cardiac CT scan(After 90 days)
- Change in modified Rankin Scale (mRS) from baseline(After 90 days)
- Health-related quality of life (EQ-5D-5L)(After 90 days)
- Change in self-perceived function "two simple questions"(After 90 days)
- Days alive outside ICU within 90 days(90 days)
研究者
Sebastian Wiberg
Principal Investigator, MD, PhD
Rigshospitalet, Denmark