Steroids In caRdiac Surgery Trial (SIRS Trial)

Phase 4

• Conditions: Systemic Inflammatory Response Syndrome; Cardiac Surgical Procedures; Cardiopulmonary Bypass
• Interventions: Drug: Methylprednisolone; Other: Placebo

• Registration Number: NCT00427388
• Lead Sponsor: Population Health Research Institute

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2007-01-26
• Study First Submitted QC: 2007-01-26
• Study First Posted: 2007-01-29
• Study Start: 2007-06
• Primary Completion: 2014-02
• Status Verified: 2014-07
• Last Update Submitted: 2014-07-31
• Study Completion: 2014-08
• Last Update Posted: 2014-08-04

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 7507

Inclusion Criteria

1. Age greater than 18 years
2. Require CPB for any cardiac surgical procedure (such as CABG, Valve, Aorta, or combined procedures)
3. Must have a EuroSCORE ≥ 6
4. Provide written informed consent

NOTE: For participating sites in India, China and Hong Kong, the following eligibility criteria will be applied:

1. Age greater than 18 years

2. Require CPB for any cardiac surgical procedure (such as CABG, Valve, Aorta, or combined procedures)

3. Must have at least one of the following:

   1. EuroSCORE greater than or equal to 4 and undergoing valvular surgery
   2. EuroSCORE greater than or equal to 6 and undergoing any other cardiac surgery procedure (i.e. CABG, Aorta)

4. Provide written informed consent

Exclusion Criteria

1. Use of systemic corticosteroids
2. History of bacterial or fungal infection in last 30 days
3. Allergy/intolerance to corticosteroids
4. Will receive Aprotinin
5. Previous participation in study

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment	Methylprednisolone	500 mg of methylprednisolone divided into two intravenous doses of 250 mg each, one during anesthetic induction and the other on CPB initiation
Placebo	Placebo	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

Primary Outcome Measures

Name	Time	Method
Composite	30 days post-randomization	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
Mortality at 30 days	30 days post-randomization

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Hamilton General Hospital; 🇨🇦 Hamilton, Ontario, Canada