Elsevier

American Heart Journal

Volume 220, February 2020, Pages 192-202
American Heart Journal

Trial Design
Rationale and design of the STeroids to REduce Systemic inflammation after infant heart Surgery (STRESS) trial

https://doi.org/10.1016/j.ahj.2019.11.016Get rights and content

For decades, physicians have administered corticosteroids in the perioperative period to infants undergoing heart surgery with cardiopulmonary bypass (CPB) to reduce the postoperative systemic inflammatory response to CPB. Some question this practice because steroid efficacy has not been conclusively demonstrated and because some studies indicate that steroids could have harmful effects. STRESS is a randomized, placebo-controlled, double-blind, multicenter trial designed to evaluate safety and efficacy of perioperative steroids in infants (age < 1 year) undergoing heart surgery with CPB. Participants (planned enrollment = 1,200) are randomized 1:1 to methylprednisolone (30 mg/kg) administered into the CPB pump prime versus placebo. The trial is nested within the existing infrastructure of the Society of Thoracic Surgeons Congenital Heart Surgery Database. The primary outcome is a global rank score of mortality, major morbidities, and hospital length of stay with components ranked commensurate with their clinical severity. Secondary outcomes include several measures of major postoperative morbidity, postoperative hospital length of stay, and steroid-related safety outcomes including prevalence of hyperglycemia and postoperative infectious complications. STRESS will be one of the largest trials ever conducted in children with heart disease and will answer a decades-old question related to safety and efficacy of perioperative steroids in infants undergoing heart surgery with CPB. The pragmatic “trial within a registry” design may provide a mechanism for conducting low-cost, high-efficiency trials in a heretofore-understudied patient population.

Section snippets

Inflammatory response to CPB and use of perioperative corticosteroids

Cardiac surgery with CPB elicits a systemic inflammatory cascade stimulated by the body's immune response to surgical injury, the effects of hypothermia, hemodilution, shear stress within the CPB circuit, and cell activation from exposure to both CPB circuit surfaces and transfused blood products.8., 23. The systemic inflammatory response is broad, with both hyperactivation and inhibition of immunocompetent cells, stimulation of the complement and coagulation systems, as well as increased

Pragmatic trial within a registry approach

Although RCTs have been the mainstay of clinical research, traditional RCTs are often slow and expensive, and these challenges are amplified when studying rare diseases in children.35 The pragmatic “trial within a registry” approach used in STRESS aims to leverage existing registry resources to reduce trial costs and improve trial efficiency.36 Previous adult trials have demonstrated the potential cost-savings and efficiency benefits of this approach.37., 38. These benefits occur at multiple

Sample size

The sample size of 1,200 (600 per group) was formulated to provide high power (>90%) for detecting a clinically important treatment benefit in patients randomized to steroids versus placebo as measured by the trial's primary global ranking end point categories with testing based on the Wilcoxon rank sum test or, equivalently, the proportional odds logistic regression model score test, assuming that the distribution of global ranking categories in STRESS is similar to the STS registry and that

Discussion

For decades, perioperative steroids have been administered to patients undergoing CPB in hopes that they might reduce the postbypass inflammatory response and thereby improve outcomes. Two recent large adult trials (DECS and SIRS) have failed to demonstrate a beneficial effect of perioperative steroid administration.13., 30. However, the DECS trial demonstrated benefit in a prespecified high-risk subgroup. Graham et al recently completed an RCT evaluating intraoperative methylprednisolone

Sources of funding

The STRESS trial is supported by grants from the National Centers for Advancing Translational Sciences (U01TR-001803-01, U24TR-001608-03) and from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U18FD-006298-02).

Disclosures

Drs Hill, Baldwin, Bichel, Ellis, Jeffrey Jacobs, Marshall Jacobs, Kannankeril, O'Brien, and Li and Mr Hickerson receive support from the National Centers for Advancing Translational Sciences for their work in pediatric drug development (U01TR-001803-01). Dr Hornik receives salary support for research from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant 1K23HD090239) and the US government and industry for his work in pediatric and neonatal clinical

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    Trial Registration Number: NCT03229538

    Anne Marie Valente, MD, served as guest editor for this article.

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