Elsevier

The Lancet

Volume 386, Issue 10000, 26 September–2 October 2015, Pages 1243-1253
The Lancet

Articles
Methylprednisolone in patients undergoing cardiopulmonary bypass (SIRS): a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(15)00273-1Get rights and content

Summary

Background

Cardiopulmonary bypass initiates a systemic inflammatory response syndrome that is associated with postoperative morbidity and mortality. Steroids suppress inflammatory responses and might improve outcomes in patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass. We aimed to assess the effects of steroids in patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass.

Methods

The Steroids In caRdiac Surgery (SIRS) study is a double-blind, randomised, controlled trial. We used a central computerised phone or interactive web system to randomly assign (1:1) patients at high risk of morbidity and mortality from 80 hospital or cardiac surgery centres in 18 countries undergoing cardiac surgery with the use of cardiopulmonary bypass to receive either methylprednisolone (250 mg at anaesthetic induction and 250 mg at initiation of cardiopulmonary bypass) or placebo. Patients were assigned with block randomisation with random block sizes of 2, 4, or 6 and stratified by centre. Patients aged 18 years or older were eligible if they had a European System for Cardiac Operative Risk Evaluation of at least 6. Patients were excluded if they were taking or expected to receive systemic steroids in the immediate postoperative period or had a history of bacterial or fungal infection in the preceding 30 days. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcomes were 30-day mortality and a composite of death and major morbidity (ie, myocardial injury, stroke, renal failure, or respiratory failure) within 30 days, both analysed by intention to treat. Safety outcomes were also analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00427388.

Findings

Patients were recruited between June 21, 2007, and Dec 19, 2013. Complete 30-day data was available for all 7507 patients randomly assigned to methylprednisolone (n=3755) and to placebo (n=3752). Methylprednisolone, compared with placebo, did not reduce the risk of death at 30 days (154 [4%] vs 177 [5%] patients; relative risk [RR] 0·87, 95% CI 0·70–1·07, p=0·19) or the risk of death or major morbidity (909 [24%] vs 885 [24%]; RR 1·03, 95% CI 0·95–1·11, p=0·52). The most common safety outcomes in the methylprednisolone and placebo group were infection (465 [12%] vs 493 [13%]), surgical site infection (151 [4%] vs 151 [4%]), and delirium (295 [8%] vs 289 [8%]).

Interpretation

Methylprednisolone did not have a significant effect on mortality or major morbidity after cardiac surgery with cardiopulmonary bypass. The SIRS trial does not support the routine use of methylprednisolone for patients undergoing cardiopulmonary bypass.

Funding

Canadian Institutes of Health Research.

Introduction

Cardiac surgery is a common surgical procedure and cardiopulmonary bypass is used in most procedures.1 Cardiopulmonary bypass initiates a systemic inflammatory response syndrome, which is associated with adverse clinical outcomes.2 Inflammatory responses include activation of platelets, neutrophils, monocytes, macrophages, cascades (coagulation, fibrinolytic, and kallikrein),3, 4, 5 which results in increased endothelial permeability and vascular and parenchymal damage.6, 7, 8, 9 These inflammatory responses are associated with the development of postoperative complications including myocardial injury and infarction, respiratory failure, renal and neurological dysfunction, excessive bleeding, altered liver function, multiple organ failure, and death.10, 11, 12, 13, 14, 15

Steroids attenuate the inflammatory response to cardiopulmonary bypass,16 but their effect on clinical outcomes is uncertain. Meta-analyses17 of small trials suggest that steroids decrease perioperative atrial fibrillation and possibly mortality, but definitive evidence is not available. After this meta-analysis was published,17 the Dexamethasone for Cardiac Surgery (DECS) trial18 did not show a benefit of dexamethasone for patients undergoing cardiopulmonary bypass, but suggested that steroids might benefit patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass.

Research in context

Evidence before this study

In 2008, we published a systematic review and meta-analysis of 44 randomised trials assessing the effect of a steroid in patients undergoing cardiopulmonary bypass. These trials were identified through a search of Embase, MEDLINE, Cochrane, CINAHL, and OVID between 1977 and October, 2007, using the search terms “cardiac surgery”, “cardiac surgical procedure”, “open heart surgery”, “coronary artery bypass”, “mitral valve”, “aortic valve”, “heart valve”, “cardiopulmonary bypass”, “extracorporeal circulation”, and “preoperative” and “prophylactic” in combination with generic and trade names of steroid preparations. We hand searched the reference lists from eligible trials. Trials were eligible irrespective of their primary objective or language of publication. This meta-analysis showed a non-significant reduction in mortality with the use of steroids (relative risk [RR] 0·73, 95% CI 0·45–1·18) that, if real, would be clinically important. This meta-analysis result was based on few events (n=65 deaths) and the results were inconclusive. Subsequently, the Dexamethasone for Cardiac Surgery (DECS) trial of 4494 patients did not show a reduction in mortality (RR 0·92, 0·57–1·49) or a significant reduction in the primary outcome of death, myocardial infarction, stroke, renal failure, or respiratory failure within 30 days (RR 0·83, 0·67–1·01). A subgroup analysis suggested the possibility that the steroid was beneficial in patients at higher risk of morbidity and mortality (EuroSCORE ≥5; RR 0·77, 0·61–0·98).

Added value of this study

The SIRS trial included 7500 patients with a EuroSCORE of at least 6. In the SIRS trial, methylprednisolone compared with placebo had no effect on mortality (154 deaths vs 177; RR 0·87, 0·70–1·07). An updated meta-analysis that included 14 027 patients showed no effect of steroids on mortality (RR 0·85, 0·71–1·02). SIRS identified a significant increase in myocardial injury based on raised cardiac enzymes.

Implications of all the available evidence

The collective data from all trials suggests no benefit to perioperative steroids but an increased risk of myocardial injury with routine use of steroids in patients undergoing cardiac surgery; therefore, the routine use of steroids for cardiopulmonary bypass is cautioned. Future studies should elucidate the mechanism of myocardial injury associated with the administration of steroids at the time of cardiac surgery with cardiopulmonary bypass.

We aimed to assess whether prophylactic steroids benefit patients at high risk of morbidity and mortality undergoing cardiac surgery with cardiopulmonary bypass.

Section snippets

Study design and participants

The Steroids In caRdiac Surgery (SIRS) trial was an international, multicentre, parallel-group, double-blind, randomised, placebo-controlled trial of adult patients at high risk of morbidity and mortality undergoing cardiopulmonary bypass. Patients were recruited from 80 hospital-based cardiac surgery practices in 18 countries by dedicated local research teams. Patients aged 18 years or older were eligible if they had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) of at

Results

Between June 21, 2007, and Dec 19, 2013, we recruited 7507 patients to this study (figure 1). The 30-day follow-up was complete in 7507 patients (100%) and the 6-month follow-up was complete in 7499 patients (99·9%). All 7507 patients were included in the 30-day and 6-month intention-to-treat analyses.

The baseline characteristics were similar in the methylprednisolone and placebo groups (table 1). Of 7507 patients, the mean age was 67·4 years (SD 13·7), 1587 (21%) underwent isolated coronary

Discussion

In patients at high risk of morbidity and mortality undergoing cardiac surgery with the use of cardiopulmonary bypass, administration of perioperative methylprednisolone did not decrease the risk of death, or the composite risk of death, myocardial injury, stroke, renal failure, and respiratory failure at 30 days. Perioperative methylprednisolone did, however, significantly increase the risk of myocardial injury (as defined by the SIRS protocol; RR 1·22, 95% CI 1·07–1·38).

Our previously

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