Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass

• ClinicalTrials.gov Identifier: NCT01579513
• Recruitment Status: Completed
• First Posted: April 18, 2012
• Results First Posted: June 18, 2019
• Last Update Posted: December 9, 2019
• Sponsor: Medical University of South Carolina
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH)
• Information provided by (Responsible Party): Medical University of South Carolina

Tracking Information

• First Submitted Date: April 13, 2012
• First Posted Date: April 18, 2012
• Results First Submitted Date: May 7, 2019
• Results First Posted Date: June 18, 2019
• Last Update Posted Date: December 9, 2019
• Study Start Date: June 2012
• Actual Primary Completion Date: May 25, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 29, 2019)

Number of Participants With a Clinically Derived Composite Morbidity-mortality Outcome [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 5 weeks ]

The composite morbidity-mortality outcome will be met if any of the following occur after surgery but before hospital discharge: death, cardiac arrest, extracorporeal membrane oxygenation, renal insufficiency (creatinine more than two times normal), hepatic insufficiency (aspartate aminotransferase or alanine aminotransferase more than two times normal), or rising lactic acidosis (>5mmol/L). This outcome was choosen because death rarely occurs in this population. We have found this endpoint to be highly associated with other important clinical outcomes in this population.

Original Primary Outcome Measures (submitted: April 16, 2012)

Incidence of a clinically derived composite morbidity-mortality outcome [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 5 weeks ]

The composite morbidity-mortality outcome will be met if any of the following occur after surgery but before hospital discharge: death, cardiac arrest, extracorporeal membrane oxygenation, renal insufficiency (creatinine more than two times normal), hepatic insufficiency (aspartate aminotransferase or alanine aminotransferase more than two times normal), or lactic acidosis (>5mmol/L). This outcome was choosen because death rarely occurs in this population. We have found this endpoint to be highly associated with other important clinical outcomes in this population.

Current Secondary Outcome Measures (submitted: November 25, 2019)

• Duration of Mechanical Ventilation Post Cardiac Surgery. [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 5 weeks ]
  Amount of time on mechanical ventilation following cardiac surgery
• Intensive Care Unit Stay [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 5 weeks ]
  Amount of time in the intensive care unit following cardiac surgery
• Hospital Stay [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 5 weeks ]
  Total duration of hospital stay following cardiac surgery
• Neurodevelopmental Outcome [ Time Frame: 1 year ]
  Bayley Scales of Infant and Toddler Development version 3 at 1 year. Cognitive, language, and motor composite scores will be used. The general population has a mean of 100 with a standard deviation of 15 for each composite score. Higher scores are better. The minimum composite score is 46 and maximum 154.

Original Secondary Outcome Measures (submitted: April 16, 2012)

• Duration of Mechanical Ventilation Post Cardiac Surgery. [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 5 weeks ]
  Amount of time on mechanical ventilation following cardiac surgery
• Intensive Care Unit Stay [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 5 weeks ]
  Amount of time in the intensive care unit following cardiac surgery
• Hospital Stay [ Time Frame: Participants will be followed for the duration of hospital stay, an expected average of 5 weeks ]
  Total duration of hospital stay following cardiac surgery
• Neurodevelopmental Outcome [ Time Frame: 1 year ]
  Bayley Scale of Infant Development at 1 year

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass
• Official Title: Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass
• Brief Summary: Although cardiopulmonary bypass (heart-lung machine) is a necessary component of heart surgery, it is not without consequences. Cardiopulmonary bypass initiates a potent inflammatory response secondary to the body's recognition of the abnormal environment of the heart-lung machine. This inflammatory response may lead to poor heart, lung and kidney function after the heart surgery. This is turn can lead to longer times on the ventilator (breathing machine), the need for higher doses of heart medications, a longer stay in the intensive care unit and even death. This is particularly true in infants less than one month of age due to their size and the immaturity of their organs. The appreciation of the post-cardiopulmonary bypass inflammatory response has resulted in a number of interventions directed at its reduction. No therapy has been recognized as the standard of care; however steroid therapy has been applied most often despite unclear evidence of a benefit. This study aims to determine if steroids improve the outcomes of babies undergoing heart surgery.
• Detailed Description: This study is a multi-institutional randomized double-blind placebo controlled trial of the use of glucocorticoids to improve the clinical course of neonates following cardiac surgery. Cardiopulmonary bypass (CPB) is critical to cardiac surgery, but the pathophysiologic processes engendered by CPB play an important role in post-operative recovery. The use, doses and schedule of glucocortiocoid administration to ameliorate these CPB induced processes is highly variable and without clear data to provide direction. The Primary Aim of this study is to compare the effects of intraoperative methylprednisolone to placebo on a composite morbidity-mortality outcome following neonatal CPB. Secondary Endpoints include: inotropic requirements, incidence of low cardiac output syndrome, fluid balance, ICU stay parameters, levels of inflammatory molecules, neuro-developmental outcomes, and safety parameters. The study will focus on neonates because their post-CPB clinical course is typically more severe, and that high level of severity itself provides a substrate for identifying the positive effects of a particular therapy. Finally, a therapy identified as beneficial has the greatest potential for benefit in this vulnerable population
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Congenital Heart Disease
• Disorder of Fetus or Newborn

Intervention

• Drug: Methylprednisolone
  Methylprednisolone at a dose of 30 mg/kg body weight and a concentration of 62.5 mg/cc. The study drug will be delivered in a blinded fashion to the anesthesiologist and will be administered intravenously with the induction of anesthesia.
  Other Names:

  • Solulmedrol
  • Medrol
  • Corticosteroid
  • Steroid
  • Glucocorticoid
• Drug: Placebo
  Normal saline will be drawn up in an identical volume to that needed for active study drug. The study drug will be delivered in a blinded fashion to the anesthesiologist and will be administered intravenously with the induction of anesthesia.
  Other Name: Normal Saline

Study Arms

• Active Comparator: Intraoperative Methylprednisone
  Neonates with congenital heart disease requiring surgery utilizing cardiopulmonary bypass(CPB) in the first month of life that receive one dose of intravenous methylprednisolone (30 mg/kg) during anesthetic induction.
  Intervention: Drug: Methylprednisolone
• Placebo Comparator: Placebo
  Neonates with congenital heart disease requiring surgery utilizing cardiopulmonary bypass (CPB) in the first month of life that receive one dose of placebo (normal saline) during anesthetic induction.
  Intervention: Drug: Placebo

Publications *

• 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.
• Seghaye MC. The clinical implications of the systemic inflammatory reaction related to cardiac operations in children. Cardiol Young. 2003 Jun;13(3):228-39. Review.
• Seghaye MC, Heyl W, Grabitz RG, Schumacher K, von Bernuth G, Rath W, Duchateau J. The production of pro- and anti-inflammatory cytokines in neonates assessed by stimulated whole cord blood culture and by plasma levels at birth. Biol Neonate. 1998;73(4):220-7.
• Checchia PA, Bronicki RA, Costello JM, Nelson DP. Steroid use before pediatric cardiac operations using cardiopulmonary bypass: an international survey of 36 centers. Pediatr Crit Care Med. 2005 Jul;6(4):441-4.
• Robertson-Malt S, Afrane B, El Barbary M. Prophylactic steroids for pediatric open heart surgery. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD005550. Review. Update in: Cochrane Database Syst Rev. 2015;10:CD005550.
• Pasquali SK, Hall M, Li JS, Peterson ED, Jaggers J, Lodge AJ, Marino BS, Goodman DM, Shah SS. Corticosteroids and outcome in children undergoing congenital heart surgery: analysis of the Pediatric Health Information Systems database. Circulation. 2010 Nov 23;122(21):2123-30. doi: 10.1161/CIRCULATIONAHA.110.948737. Epub 2010 Nov 8.
• 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.
• 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.
• Everett AD, Buckley JP, Ellis G, Yang J, Graham D, Griffiths M, Bembea M, Graham EM. Association of Neurodevelopmental Outcomes With Environmental Exposure to Cyclohexanone During Neonatal Congenital Cardiac Operations: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2020 May 1;3(5):e204070. doi: 10.1001/jamanetworkopen.2020.4070.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 16, 2012): 190
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: December 19, 2018
• Actual Primary Completion Date: May 25, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age < 1 month
• Male and female patients who are scheduled to undergo cardiac surgery involving CPB

Exclusion Criteria:

• Prematurity: < 37 weeks post gestational age at time of surgery
• Treatment with intravenous steroids within the two days prior to scheduled surgery.
• Participation in research studies involving the evaluation of investigational drugs within 30 days of randomization.
• Suspected infection that would contraindicate steroid use (eg - Herpes)
• Known hypersensitivity to IVMP or one of its components or other contraindication to steroid therapy (eg - gastrointestinal bleeding).
• Preoperative use of mechanical circulatory support or active resuscitation at the time of proposed randomization.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 30 Days (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01579513
• Other Study ID Numbers: Pro16545; R01HL112968 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Medical University of South Carolina
• Study Sponsor: Medical University of South Carolina

Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)
• National Institutes of Health (NIH)

Investigators

• Principal Investigator: Eric M Graham, MD; Medical University of South Carolina

• PRS Account: Medical University of South Carolina
• Verification Date: November 2019