Steroids In caRdiac Surgery Trial (SIRS Trial)

Study Overview
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Brief Summary
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SIRS trial is a large simple study in which high-risk patients undergoing cardiac surgery requiring the use of cardiopulmonary bypass (CPB) are randomly allocated to receive a pulse dose of Methylprednisolone or a matching placebo. Cardiopulmonary bypass initiates a systemic inflammatory response that facilitates development of post-operative complications. SIRS will confirm or deny the potential clinical benefits of suppressing this response through the use of systemic steroids. Specifically, does 250 mg of intravenous Methylprednisolone given twice, once on anesthetic induction and again on CPB initiation, result in improved early survival and less myocardial infarction in high-risk cardiac surgery patients requiring CPB?

Detailed Description
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Cardiopulmonary bypass (CPB) is a commonly performed surgical procedure with over 500,000 per year in North America. CPB initiates a systemic inflammatory response characterized by both cell and protein activation. Platelets, neutrophils, monocytes, macrophages, coagulation, fibrinolytic, and kallikrein cascades all take part in what results in increased endothelial permeability, vascular, and parenchymal damage. These inflammatory pathways facilitate development of post-operative complications including thrombosis, myocardial injury and infarction, respiratory failure, renal and neurological dysfunction, bleeding disorders, altered liver function and ultimately, multiple organ failure. In an attempt to minimize the deleterious effects of CPB, investigators have tested a variety of strategies in cardiac surgery ranging from the complete avoidance of CPB, to the use of biocompatible circuits and pharmacologic agents to abrogate the systemic response. Investigators have consistently demonstrated the efficacy of steroids as the most potent anti-inflammatory agent for use during CPB. In fact, from the available evidence, the 2004 AHA guidelines for coronary artery bypass grafting (CABG) support liberal prophylactic use in patients undergoing extracorporeal circulation. However, the trials that do exist within this literature are focused on biochemical endpoints and are insufficiently powered to make conclusions on hard clinical endpoints. Our pilot RCT, SIRS I, demonstrated the efficacy of a low dose steroid protocol in the suppression of this inflammatory cascade. We hypothesize that this low dose protocol will yield clinical benefit while avoiding the potential adverse effects of steroids which are known to be dose dependent. The primary aim of the SIRS trial is to determine if perioperative pulse dose Methylprednisolone results in improved early survival and less myocardial infarction in cardiac surgery requiring CPB. Additional secondary aims of the SIRS trial are to determine the effect of steroids on other clinical outcomes including length of stay, new onset atrial fibrillation, transfusion requirements, infectious, wound, and gastrointestinal complications. The design of the SIRS trial is a prospective multicentre international double-blind placebo controlled randomized clinical trial. The sample size of 7500 patients will have 80% to 90% power to detect a 20-30% RRR for the primary outcome with an α=0.05 (two-sided), anticipating a 6% rate of death in the control arm. Our aim is to have 85 international centers participate which, recruiting at 5 patients per month, would complete recruitment in 36 months. This will be a large trial with a simple design and objective outcomes. A sub-group of patients will be enrolled in a renal sub-study. This sub-study will determine if the risk of acute kidney injury is lower in patients treated with intravenous steroid versus placebo, if steroids lead to better preservation of kidney function six months after cardiac surgery, and whether the impact of steroid exposure differs in patients with and without pre-operative chronic kidney disease.

Official Title
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Phase IV Study of Perioperative Steroid's Effects on Death or MI in High-Risk Patients Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass

Conditions
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Cardiac Surgical Procedures, Cardiopulmonary Bypass, Systemic Inflammatory Response Syndrome

Intervention / Treatment
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* Drug: Methylprednisolone
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than 18 years Require CPB for any cardiac surgical procedure (such as CABG, Valve, Aorta, or combined procedures) Must have a EuroSCORE ≥ 6 Provide written informed consent NOTE: For participating sites in India, China and Hong Kong, the following eligibility criteria will be applied: Age greater than 18 years Require CPB for any cardiac surgical procedure (such as CABG, Valve, Aorta, or combined procedures) Must have at least one of the following: EuroSCORE greater than or equal to 4 and undergoing valvular surgery EuroSCORE greater than or equal to 6 and undergoing any other cardiac surgery procedure (i.e. CABG, Aorta) Provide written informed consent Exclusion Criteria: Use of systemic corticosteroids History of bacterial or fungal infection in last 30 days Allergy/intolerance to corticosteroids Will receive Aprotinin Previous participation in study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>500 mg of methylprednisolone divided into two intravenous doses of 250 mg each, one during anesthetic induction and the other on CPB initiation | Drug: Methylprednisolone<br>* Given by IV in 2 doses (250 mg each dose for a total of 500 mg)<br>|
| Placebo Comparator: Placebo<br>500 mg of matching placebo (normal saline solution) divided into two intravenous doses of 250 mg each, one during anesthetic induction and the other on CPB initiation | Other: Placebo<br>* Given in 2 IV doses (approximately 4 ml of 0.9% normal saline solution in each dose)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality at 30 days |  | 30 days post-randomization | 
| Composite | Incidence of the composite outcome of death, myocardial infarction, stroke, renal failure (KDIGO Stage III acute kidney injury, 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines), or respiratory failure within 30 days | 30 days post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MI or Mortality at 30 days | Composite of death or significant myocardial infarction within 30 days post-randomization | 30 days post-randomization | 
| Mortality at 6 months | All-cause mortality at 6 months post-randomization | 6 months post-randomization | 
| Atrial Fibrillation | New onset atrial fibrillation within 30 days post-randomization | 30 days post-randomization | 
| Transfusion Requirements | Transfusion requirements within first 24 hours post-operative | 24 hours post-surgery | 
| Chest Tube Output | Chest tube output within first 24 hours post-operative | 24 hours post-surgery | 
| ICU and Hospital Length of Stay | Length of ICU stay and hospital stay | Hospital Discharge | 
| Infection | Infection within 30 days post-randomization | 30 days post-randomization | 
| Delirium | Delirium at day 3 post-operative | 3 days post-surgery | 
| Wound Complication | Wound complication within 30 days post-randomization | 30 days post-randomization | 
| GI Hemorrhage | GI hemorrhage or GI perforation within 30 days post-randomization | 30 days post-randomization | 
| Insulin Use | Post-operative insulin use within the first 24 hours after surgery | 24 hours post-surgery | 
| Peak Blood Glucose | Peak blood glucose within the first 24 hours after surgery | 24 hours post-surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiac Surgical Procedures, Cardiopulmonary Bypass, Systemic inflammatory Response Syndrome, Steroid, Myocardial Infarction, Randomized Clinical Trial