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