STeroids to REduce Systemic Inflammation After Infant Heart Surgery

Summary

This study's objective is to determine the pharmacokinetics (PK)/pharmacodynamics (PD), safety and efficacy of methylprednisolone in infants undergoing heart surgery with cardiopulmonary bypass. This is a prospective, double blind, multi-center, placebo-controlled safety and efficacy study. Blood samples will be collected from a subset of enrolled study participants to evaluate multiple dose methylprednisolone PK/PD. Participants will be randomized in a 1:1 fashion to intravenous methylprednisolone versus placebo. Study drug/placebo will be administered 8 to 12 hours before the anticipated start time of surgery and in the operating room at the time of initiation of cardiopulmonary bypass. Patients will be followed for primary and secondary outcomes for the duration of their hospitalization. Serious study drug-related adverse events will be collected for 7 days after the last dose of study drug.

Timeline

Start

2017-10-18

Primary completion

2022-03-31

Completion

2022-03-31

Publications

• Background Petrini J, Damus K, Johnston RB Jr. An overview of infant mortality and birth defects in the United States. Teratology. 1997 Jul-Aug;56(1-2):8-10. doi: 10.1002/(SICI)1096-9926(199707/08)56:1/23.0.CO;2-U. No abstract available.
• Background Petrini J, Damus K, Russell R, Poschman K, Davidoff MJ, Mattison D. Contribution of birth defects to infant mortality in the United States. Teratology. 2002;66 Suppl 1:S3-6. doi: 10.1002/tera.90002.
• Background Yang Q, Chen H, Correa A, Devine O, Mathews TJ, Honein MA. Racial differences in infant mortality attributable to birth defects in the United States, 1989-2002. Birth Defects Res A Clin Mol Teratol. 2006 Oct;76(10):706-13. doi: 10.1002/bdra.20308.
• Background Yang Q, Khoury MJ, Mannino D. Trends and patterns of mortality associated with birth defects and genetic diseases in the United States, 1979-1992: an analysis of multiple-cause mortality data. Genet Epidemiol. 1997;14(5):493-505. doi: 10.1002/(SICI)1098-2272(1997)14:53.0.CO;2-2.
• Background Hoffman TM, Wernovsky G, Atz AM, Kulik TJ, Nelson DP, Chang AC, Bailey JM, Akbary A, Kocsis JF, Kaczmarek R, Spray TL, Wessel DL. Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation. 2003 Feb 25;107(7):996-1002. doi: 10.1161/01.cir.0000051365.81920.28.
• Background Parr GV, Blackstone EH, Kirklin JW. Cardiac performance and mortality early after intracardiac surgery in infants and young children. Circulation. 1975 May;51(5):867-74. doi: 10.1161/01.cir.51.5.867.
• Background Wernovsky G, Wypij D, Jonas RA, Mayer JE Jr, Hanley FL, Hickey PR, Walsh AZ, Chang AC, Castaneda AR, Newburger JW, Wessel DL. Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation. 1995 Oct 15;92(8):2226-35. doi: 10.1161/01.cir.92.8.2226.
• Background Wan S, LeClerc JL, Vincent JL. Inflammatory response to cardiopulmonary bypass: mechanisms involved and possible therapeutic strategies. Chest. 1997 Sep;112(3):676-92. doi: 10.1378/chest.112.3.676.
• Background Ando M, Park IS, Wada N, Takahashi Y. Steroid supplementation: a legitimate pharmacotherapy after neonatal open heart surgery. Ann Thorac Surg. 2005 Nov;80(5):1672-8; discusison 1678. doi: 10.1016/j.athoracsur.2005.04.035.
• Background Bronicki RA, Backer CL, Baden HP, Mavroudis C, Crawford SE, Green TP. Dexamethasone reduces the inflammatory response to cardiopulmonary bypass in children. Ann Thorac Surg. 2000 May;69(5):1490-5. doi: 10.1016/s0003-4975(00)01082-1.
• Background Checchia PA, Backer CL, Bronicki RA, Baden HP, Crawford SE, Green TP, Mavroudis C. Dexamethasone reduces postoperative troponin levels in children undergoing cardiopulmonary bypass. Crit Care Med. 2003 Jun;31(6):1742-5. doi: 10.1097/01.CCM.0000063443.32874.60.
• Background Clarizia NA, Manlhiot C, Schwartz SM, Sivarajan VB, Maratta R, Holtby HM, Gruenwald CE, Caldarone CA, Van Arsdell GS, McCrindle BW. Improved outcomes associated with intraoperative steroid use in high-risk pediatric cardiac surgery. Ann Thorac Surg. 2011 Apr;91(4):1222-7. doi: 10.1016/j.athoracsur.2010.11.005.
• Background Graham EM, Atz AM, Butts RJ, Baker NL, Zyblewski SC, Deardorff RL, DeSantis SM, Reeves ST, Bradley SM, Spinale FG. Standardized preoperative corticosteroid treatment in neonates undergoing cardiac surgery: results from a randomized trial. J Thorac Cardiovasc Surg. 2011 Dec;142(6):1523-9. doi: 10.1016/j.jtcvs.2011.04.019. Epub 2011 May 20.
• Background Graham EM, Atz AM, McHugh KE, Butts RJ, Baker NL, Stroud RE, Reeves ST, Bradley SM, McGowan FX Jr, Spinale FG. Preoperative steroid treatment does not improve markers of inflammation after cardiac surgery in neonates: results from a randomized trial. J Thorac Cardiovasc Surg. 2014 Mar;147(3):902-8. doi: 10.1016/j.jtcvs.2013.06.010. Epub 2013 Jul 16.
• Background Toledo-Pereyra LH, Lin CY, Kundler H, Replogle RL. Steroids in heart surgery: a clinical double-blind and randomized study. Am Surg. 1980 Mar;46(3):155-60.
• Background Graham EM. The utility of steroids in pediatric cardiac operations*. Pediatr Crit Care Med. 2014 Jun;15(5):492-3. doi: 10.1097/PCC.0000000000000139. No abstract available.
• Background Pasquali SK, Li JS, He X, Jacobs ML, O'Brien SM, Hall M, Jaquiss RD, Welke KF, Peterson ED, Shah SS, Gaynor JW, Jacobs JP. Perioperative methylprednisolone and outcome in neonates undergoing heart surgery. Pediatrics. 2012 Feb;129(2):e385-91. doi: 10.1542/peds.2011-2034. Epub 2012 Jan 23.
• Background Garg AX, Vincent J, Cuerden M, Parikh C, Devereaux PJ, Teoh K, Yusuf S, Hildebrand A, Lamy A, Zuo Y, Sessler DI, Shah P, Abbasi SH, Quantz M, Yared JP, Noiseux N, Tagarakis G, Rochon A, Pogue J, Walsh M, Chan MT, Lamontagne F, Salehiomran A, Whitlock R; SIRS Investigators. Steroids In caRdiac Surgery (SIRS) trial: acute kidney injury substudy protocol of an international randomised controlled trial. BMJ Open. 2014 Mar 5;4(3):e004842. doi: 10.1136/bmjopen-2014-004842.
• Background Scrascia G, Rotunno C, Guida P, Amorese L, Polieri D, Codazzi D, Paparella D. Perioperative steroids administration in pediatric cardiac surgery: a meta-analysis of randomized controlled trials*. Pediatr Crit Care Med. 2014 Jun;15(5):435-42. doi: 10.1097/PCC.0000000000000128.
• Background Jacobs ML, O'Brien SM, Jacobs JP, Mavroudis C, Lacour-Gayet F, Pasquali SK, Welke K, Pizarro C, Tsai F, Clarke DR. An empirically based tool for analyzing morbidity associated with operations for congenital heart disease. J Thorac Cardiovasc Surg. 2013 Apr;145(4):1046-1057.e1. doi: 10.1016/j.jtcvs.2012.06.029. Epub 2012 Jul 24.
• Background Ungerleider RM. Practice patterns in neonatal cardiopulmonary bypass. ASAIO J. 2005 Nov-Dec;51(6):813-5. doi: 10.1097/01.mat.0000183473.93237.10. No abstract available.
• Hill KD, Koerner J, Hong H, Li JS, Hornik C, Kannankeril PJ, Jacobs JP, Baldwin HS, Jacobs ML, Graham EM, Blasiole B, Vener DF, Husain AS, Kumar SR, Benscoter A, Wald E, Karamlou T, Van Bergen AH, Overman D, Eghtesady P, Butts R, Kim JS, Scott JP, Anderson BR, Swartz MF, O'Brien SM. A Bayesian re-analysis of the STRESS trial. Am Heart J. 2026 Feb;292:107282. doi: 10.1016/j.ahj.2025.09.014. Epub 2025 Sep 25.
• Hill KD, Kannankeril PJ, Jacobs JP, Baldwin HS, Jacobs ML, O'Brien SM, Bichel DP, Graham EM, Blasiole B, Resheidat A, Husain AS, Kumar SR, Kirchner JL, Gallup DS, Turek JW, Bleiweis M, Mettler B, Benscoter A, Wald E, Karamlou T, Van Bergen AH, Overman D, Eghtesady P, Butts R, Kim JS, Scott JP, Anderson BR, Swartz MF, McConnell PI, Vener DF, Li JS; STRESS Network Investigators. Methylprednisolone for Heart Surgery in Infants - A Randomized, Controlled Trial. N Engl J Med. 2022 Dec 8;387(23):2138-2149. doi: 10.1056/NEJMoa2212667. Epub 2022 Nov 6.
• Gibbison B, Villalobos Lizardi JC, Aviles Martinez KI, Fudulu DP, Medina Andrade MA, Perez-Gaxiola G, Schadenberg AW, Stoica SC, Lightman SL, Angelini GD, Reeves BC. Prophylactic corticosteroids for paediatric heart surgery with cardiopulmonary bypass. Cochrane Database Syst Rev. 2020 Oct 12;10(10):CD013101. doi: 10.1002/14651858.CD013101.pub2.
• Hill KD, Baldwin HS, Bichel DP, Butts RJ, Chamberlain RC, Ellis AM, Graham EM, Hickerson J, Hornik CP, Jacobs JP, Jacobs ML, Jaquiss RD, Kannankeril PJ, O'Brien SM, Torok R, Turek JW, Li JS; STRESS Network Investigators. Rationale and design of the STeroids to REduce Systemic inflammation after infant heart Surgery (STRESS) trial. Am Heart J. 2020 Feb;220:192-202. doi: 10.1016/j.ahj.2019.11.016. Epub 2019 Dec 9.

Drugs

Indications