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

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Congenital Heart Disease; Disorder of Fetus or Newborn
• Interventions: Drug: Methylprednisolone; Drug: Placebo
• Enrollment: 190

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Intraoperative Methylprednisone	Placebo
Arm/Group Description	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. 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.	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. 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.
Period Title: Primary Hospitalization
Started	91	99
Completed	81	95
Not Completed	10	4
Period Title: 1 Year Neurodevelopmental Follow up
Started	81	95
Completed	61	68
Not Completed	20	27

Baseline Characteristics

Arm/Group Title		Intraoperative Methylprednisone	Placebo	Total
Arm/Group Description		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. 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.	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. 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.	Total of all reporting groups
Overall Number of Baseline Participants		81	95	176
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Days
	Number Analyzed	81 participants	95 participants	176 participants
		9.1 (5.4)	8.2 (5.6)	8.6 (5.5)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	81 participants	95 participants	176 participants
	Female	35 43.2%	35 36.8%	70 39.8%
	Male	46 56.8%	60 63.2%	106 60.2%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	81 participants	95 participants	176 participants
	Hispanic or Latino	4 4.9%	8 8.4%	12 6.8%
	Not Hispanic or Latino	77 95.1%	87 91.6%	164 93.2%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	81 participants	95 participants	176 participants
	American Indian or Alaska Native	0 0.0%	1 1.1%	1 0.6%
	Asian	0 0.0%	2 2.1%	2 1.1%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	22 27.2%	27 28.4%	49 27.8%
	White	55 67.9%	60 63.2%	115 65.3%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	4 4.9%	5 5.3%	9 5.1%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	81 participants	95 participants	176 participants
		81	95	176
Weight at surgery [1]; Mean (Standard Deviation); Unit of measure: Kg
	Number Analyzed	81 participants	95 participants	176 participants
		3.2 (0.5)	3.4 (0.5)	3.3 (0.5)
		[1] Measure Description: Weight in Kg at the time of surgery

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intraoperative Methylprednisone	Placebo
Arm/Group Description:	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. 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.	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. 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.
Overall Number of Participants Analyzed	81	95
Measure Type: Count of Participants; Unit of Measure: Participants
	27 33.3%	40 42.1%

2. Secondary Outcome

Title	Duration of Mechanical Ventilation Post Cardiac Surgery.
Description	Amount of time on mechanical ventilation following cardiac surgery
Time Frame	Participants will be followed for the duration of hospital stay, an expected average of 5 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intraoperative Methylprednisone	Placebo
Arm/Group Description:	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. 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.	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. 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.
Overall Number of Participants Analyzed	81	95
Median (Inter-Quartile Range); Unit of Measure: Days
	4; (3 to 7)	5; (3 to 8)

3. Secondary Outcome

Title	Intensive Care Unit Stay
Description	Amount of time in the intensive care unit following cardiac surgery
Time Frame	Participants will be followed for the duration of hospital stay, an expected average of 5 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intraoperative Methylprednisone	Placebo
Arm/Group Description:	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. 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.	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. 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.
Overall Number of Participants Analyzed	81	95
Mean (Inter-Quartile Range); Unit of Measure: Days
	11; (7 to 18)	11; (7 to 20)

4. Secondary Outcome

Title	Hospital Stay
Description	Total duration of hospital stay following cardiac surgery
Time Frame	Participants will be followed for the duration of hospital stay, an expected average of 5 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intraoperative Methylprednisone	Placebo
Arm/Group Description:	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. 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.	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. 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.
Overall Number of Participants Analyzed	81	95
Mean (Inter-Quartile Range); Unit of Measure: Days
	20; (13 to 35)	22; (12 to 35)

5. Secondary Outcome

Title	Neurodevelopmental Outcome
Description	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.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intraoperative Methylprednisone	Placebo
Arm/Group Description:	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. 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.	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. 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.
Overall Number of Participants Analyzed	61	68
Mean (Standard Deviation); Unit of Measure: score on a scale
Cognitive Domain	105 (15)	104 (14)
Language Domain	101 (15)	100 (13)
Motor Domain	90 (16)	91 (19)

Adverse Events

Time Frame	For the entirety of the initial neonatal hospitalization, an expected average of up to 5 weeks
Adverse Event Reporting Description	Death or the use of extracorporeal membrane oxygenation
Arm/Group Title	Intraoperative Methylprednisone	Placebo
Arm/Group Description	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. 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.	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. 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.
All-Cause Mortality
	Intraoperative Methylprednisone	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	5/81 (6.17%)	6/95 (6.32%)
Serious Adverse Events
	Intraoperative Methylprednisone	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	4/81 (4.94%)	11/95 (11.58%)
Cardiac disorders
Extracorporeal membrane oxygenation †	4/81 (4.94%)	11/95 (11.58%)
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Intraoperative Methylprednisone	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/81 (2.47%)	2/95 (2.11%)
Endocrine disorders
Insulin therapy †	2/81 (2.47%)	2/95 (2.11%)
† Indicates events were collected by systematic assessment

Limitations and Caveats

Nearly one third of the subjects received additional steroids in the early postoperative period, potentially diminishing the ability to detect both beneficial and adverse effects.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Eric Graham, MD
• Organization: Medical University of South Carolina
• Phone: 843-792-9570
• EMail: grahamem@musc.edu

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Medical University of South Carolina
• ClinicalTrials.gov Identifier: NCT01579513
• Other Study ID Numbers: Pro16545; R01HL112968 ( U.S. NIH Grant/Contract )
• First Submitted: April 13, 2012
• First Posted: April 18, 2012
• Results First Submitted: May 7, 2019
• Results First Posted: June 18, 2019
• Last Update Posted: December 9, 2019