Congenital Heart Disease, Disorder of Fetus or Newborn
Conditions
Keywords
Cardiopulmonary Bypass (CPB), System Inflammatory Response, Low Cardiac Output Syndrome (LCOS) in Neonates, Methylprednisolone, Cardiopulmonary Bypass (CPB) in Neonates, Glucocorticoid Use in Neonatal Cardiac Surgery, Steroid
Brief summary
Randomized controlled trial of the use of glucocorticoids to improve the clinical course of neonates post-cardiopulmonary bypass (CPB).
Detailed description
This study proposes a randomized controlled trial of the use of glucocorticoids to improve the clinical course of neonates post-cardiopulmonary bypass (CPB). The study will focus on neonates for a few reasons. Although their post-CPB clinical course is typically more severe and intensive care unit (ICU) care more prolonged than older children, their modes of morbidity are also well characterized. Further, the 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. The well characterized scenario of low cardiac output syndrome (LCOS) will be used as the primary endpoint, while a variety of secondary endpoints will be related to the biochemical anti-inflammatory effects of therapy, ICU care and late neurological outcome.
Interventions
Neonates with congenital heart disease requiring surgery utilizing a cardiopulmonary bypass (CPB)machine in the first month of life that receive ONE doses intravenous methylprednisolone (IVMP) prior to heart surgery.Compare the effects and preoperative and intraoperative IVMP (2 dose steroid)to intraoperative IVMP alone (single dose steroid) on the inflammatory response to CPB cardiopulmonary bypass.
DRUGmethylprednisolone (two doses IVMP)
Neonates with congenital heart disease requiring surgery utilizing a cardiopulmonary bypass (CPB)machine in the first month of life that receive TWO doses intravenous methylprednisolone (IVMP) prior to heart surgery.Compare the effects and preoperative and intraoperative IVMP to intraoperative IVMP alone on the inflammatory response to CPB cardiopulmonary bypass. The hypothesis is that neonates treated with preoperative IVMP as well as the standard intraoperative IVMP will have decreased production of pro-inflammatory cytokines.
Sponsors
Medical University of South Carolina
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 30 Days
Healthy volunteers
No
Inclusion criteria
* Neonates Age \</= 1 month * Scheduled to undergo cardiac surgery involving Cardiopulmonary Bypass (CPB) (reparative or palliative procedures) * Inpatient Status at MUSC a minimum of 8 hours prior to planned surgery
Exclusion criteria
* Prematurity: \</= 36 weeks post gestational age at time of surgery * Treatment with steroids, other than inhaled forms, in the two weeks 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 (e.g., gastrointestinal bleeding) * Preoperative use of mechanical circulatory support or active resuscitation at the time of proposed randomization * Inability to begin the pre-operative study drug at least 8 hours prior to surgery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Endpoint: Number of Participants With Low Cardiac Output Syndrome (LCOS) or Death at 36 Hours From Admission to the Intensive Care Unit (ICU) After Surgery. | 36 hours | The presence of low cardiac output syndrome (LCOS) was defined by the same definition used in the PRIMACORP study (Hoffman TM.et.al. Circulation 2003 107:996-1002). Specifically, if there were clinical signs and symptoms of low cardiac output (e.g., tachycardia, oliguria, cold extremities, cardiac arrest, etc.) which required one or more of the following interventions: mechanical circulatory support, the escalation of existing pharmacological circulatory support to \>100% over baseline, or the initiation of new pharmacological circulatory support. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Inotropic Score | over the first 36 hours after surgery | The inotropic score was calculated by the equation using drug dosages in micrograms/kg/min, (dopamine+dobutamine) + (milrinonex10) + (epinephrinex100) and recorded hourly upon arrival to the ICUthrough 36 hours postoperatively. The highest score during this timeframe was recorded. This score converts dosages of commonly used inotropic medications into a score. The higher the score the more inotropic medications required. The minimum score would be zero indicating no inotropic medications were used. There is no maximum score. |
| Number of Participants Who Died Between 36 Hours and 30 Days Following Cardiac Surgery | at 36 hours and 30 days | Number of participants who died of any cause between 36 hours and 30 days following cardiac surgery |
| Urine Output | over 36 hours | Total urine output in mL over the first 36 hours after cardiac surgery |
| Total Intake/Output of Fluid | over 36 hours | Total amount of all fluids in and out during the first 36 hours postoperatively in mL. |
Countries
United States
Participant flow
Recruitment details
All inpatient neonates (≤ 30 days of age), scheduled to undergo cardiac surgery involving cardiopulmonary bypass from the time period of July 2007 through July 2009 were eligible for this study.
Participants by arm
| Arm | Count |
|---|---|
| MP Single Dose Neonates with congenital heart disease requiring surgery utilizing a cardiopulmonary bypass (CPB) machine in the first month of life that receive ONE dose (operatively)intravenous methylprednisolone (IVMP, 30 mg/kg) prior to heart surgery. | 37 |
| MP Two Dose Neonates with congenital heart disease requiring surgery utilizing a cardiopulmonary bypass (CPB) machine in the first month of life that receive TWO (8 hours preoperatively and operatively) doses intravenous methylprednisolone (IVMP, 30 mg/kg/dose) prior to heart surgery. | 40 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | MP Two Dose | MP Single Dose | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 40 Participants | 37 Participants | 77 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age Continuous | 9.4 days STANDARD_DEVIATION 6.3 | 8.2 days STANDARD_DEVIATION 5 | 8.8 days STANDARD_DEVIATION 5.7 |
| Region of Enrollment United States | 40 participants | 37 participants | 77 participants |
| Sex: Female, Male Female | 19 Participants | 18 Participants | 37 Participants |
| Sex: Female, Male Male | 21 Participants | 19 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 37 | 10 / 39 |
| serious Total, serious adverse events | 1 / 37 | 0 / 39 |
Outcome results
Primary
Primary Endpoint: Number of Participants With Low Cardiac Output Syndrome (LCOS) or Death at 36 Hours From Admission to the Intensive Care Unit (ICU) After Surgery.
The presence of low cardiac output syndrome (LCOS) was defined by the same definition used in the PRIMACORP study (Hoffman TM.et.al. Circulation 2003 107:996-1002). Specifically, if there were clinical signs and symptoms of low cardiac output (e.g., tachycardia, oliguria, cold extremities, cardiac arrest, etc.) which required one or more of the following interventions: mechanical circulatory support, the escalation of existing pharmacological circulatory support to \>100% over baseline, or the initiation of new pharmacological circulatory support.
Time frame: 36 hours
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MP Single Dose | Primary Endpoint: Number of Participants With Low Cardiac Output Syndrome (LCOS) or Death at 36 Hours From Admission to the Intensive Care Unit (ICU) After Surgery. | 17 participants |
| MP Two Dose | Primary Endpoint: Number of Participants With Low Cardiac Output Syndrome (LCOS) or Death at 36 Hours From Admission to the Intensive Care Unit (ICU) After Surgery. | 15 participants |
Comparison: The current study was designed with an anticipated enrollment of 87 patients per treatment arm to achieve a statistical power of 80% (1- β) while controlling type I error at 0.05 (α) using a more conservative estimate of LCOS rate in the Single Dose MP group of 33%, and an incidence of LCOS in the Two Dose MP group of 15%.p-value: 0.3595% CI: [0.45, 1.33]Multivariate risk computation
Secondary
Inotropic Score
The inotropic score was calculated by the equation using drug dosages in micrograms/kg/min, (dopamine+dobutamine) + (milrinonex10) + (epinephrinex100) and recorded hourly upon arrival to the ICUthrough 36 hours postoperatively. The highest score during this timeframe was recorded. This score converts dosages of commonly used inotropic medications into a score. The higher the score the more inotropic medications required. The minimum score would be zero indicating no inotropic medications were used. There is no maximum score.
Time frame: over the first 36 hours after surgery
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MP Single Dose | Inotropic Score | 14.4 Scores on a scale | Standard Deviation 3.6 |
| MP Two Dose | Inotropic Score | 15.0 Scores on a scale | Standard Deviation 3.9 |
p-value: 0.43ANCOVA
Secondary
Number of Participants Who Died Between 36 Hours and 30 Days Following Cardiac Surgery
Number of participants who died of any cause between 36 hours and 30 days following cardiac surgery
Time frame: at 36 hours and 30 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MP Single Dose | Number of Participants Who Died Between 36 Hours and 30 Days Following Cardiac Surgery | 1 participants |
| MP Two Dose | Number of Participants Who Died Between 36 Hours and 30 Days Following Cardiac Surgery | 0 participants |
Secondary
Total Intake/Output of Fluid
Total amount of all fluids in and out during the first 36 hours postoperatively in mL.
Time frame: over 36 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MP Single Dose | Total Intake/Output of Fluid | Total Fluid in at 36 hr | 575 mL | Standard Deviation 145 |
| MP Single Dose | Total Intake/Output of Fluid | Total Fluid out at 36 hr | 600 mL | Standard Deviation 250 |
| MP Two Dose | Total Intake/Output of Fluid | Total Fluid in at 36 hr | 586 mL | Standard Deviation 156 |
| MP Two Dose | Total Intake/Output of Fluid | Total Fluid out at 36 hr | 558 mL | Standard Deviation 203 |
p-value: 0.047ANCOVA
Secondary
Urine Output
Total urine output in mL over the first 36 hours after cardiac surgery
Time frame: over 36 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MP Single Dose | Urine Output | 498 mL | Standard Deviation 227 |
| MP Two Dose | Urine Output | 453 mL | Standard Deviation 213 |
p-value: 0.052ANCOVA