An interventional study of Hydrocortisone and Normal Saline in Heart Disease Congenital Complex, sponsored by University of Alabama at Birmingham. Completed at 1 site in United States. Open to participants aged 1 Day to 28 Days. Per ClinicalTrials.gov, last updated 2015-11-10.
Sponsored by University of Alabama at Birmingham · Not applicable, Interventional, and Treatment
This protocol is designed to offer insight into critical illness related corticosteroid insufficiency and steroid supplementation in neonates undergoing cardiac surgery with cardiopulmonary bypass by administering exogenous steroids in the immediate post-operative period.
Open-heart surgery with cardiopulmonary bypass (CPB) induces an acute systemic inflammatory response (SIRS) via synthesis and release of inflammatory mediators. These inflammatory cascades may result in the development of capillary leak and generalized tissue edema, which are associated with multiorgan dysfunction involving the myocardium, lungs, kidneys, pancreas, and central nervous system. Neonates are especially susceptible to the injurious effects of SIRS. In attempt to blunt post-bypass SIRS, most neonatal heart programs have protocols in which patients receive preoperative and/or intraoperative steroids. Despite this widespread use, studies have not demonstrated consistent benefit in this therapy, and neonates often continue to suffer the deleterious effects of SIRS postoperatively. Only one study was designed to evaluate the impact of prophylactic postoperative steroid administration on outcomes after neonatal CPB. The early postoperative periods is a crucial time during which attenuation of CPB-induced SIRS by exogenous steroids may lead to improved clinical outcomes.
Adrenal insufficiency in neonates post-CPB may accentuate the harmful effects of SIRS by diminishing the anti-inflammatory and hemodynamic stabilization benefits of endogenous cortisol. Evidence suggests that neonates may suffer from inadequate cortisol activity relative to the severity of illness post-CPB, in part related to immaturity of their hypothalamic-pituitary-adrenal (HPA) axis. This so-called critical illness-related corticosteroids insufficiency (CIRCI) may contribute to low cardiac output syndrome (LCOS), respiratory dysfunction, and capillary leak in the postoperative period.
Much of the support for CIRCI as a contributor to LCOS after CPB originates from small clinical studies that demonstrate benefit of exogenous steroid supplementation on various short term clinical outcomes in patients with shock. Yet it is not clear if benefit from exogenous steroids suggests by dysregulation of the HPA axis or whether these are merely alternative effects of steroids. Investigators have recently begun to describe the cortisol response in neonates post-CPB, but there is no consensus regarding the incidence of clinically important adrenal insufficiency, its identification, or who should receive exogenous steroids.
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Exclusion Criteria:
The subjects will receive a bolus after successful completion of bypass and the post-pump adrenal corticotrophin hormone (ACTH) stim test equal to a 50mg/m2 dose of Hydrocortisone. This will be followed by a continuous infusion comparable to the rates a Hydrocortisone drip would run at. This infusion will be tapered down over the next 120 hours.
Drug: Normal Saline
Subjects enrolled in this arm of the study will receive a 50mg/m2 bolus of Hydrocortisone after successful completion of CPB and the post-pump ACTH stim test has been performed. This will be followed by a continuous infusion of Hydrocortisone that will be tapered over the next 120 hours.
Drug: Hydrocortisone
The drug will be bolused at 50mg/m2 followed by a continuous infusion that will start at 50mg/m2 for the first 48 hours and then be tapered as follows: 40mg/m2/day over 24 hours, 30mg/m2/day over 12 hours, 20 mg/m2/day over 12 hours, 10mg/m2/day over 24 hours, then off.
Also known as: Solu Cortef
This will be bolused and infused in the same manner as the hydrocortisone arm to ensure blinding of study arm.
Also known as: 0.9% Sodium Chloride
Incidence of Low Cardiac Output Syndrome (LCOS)
Low Cardiac Output Syndrome (LCOS) within the first 48 hours after post-operative admission to the Pediatric Cardiac Intensive Care Unit was used as the primary outcome. This was defined as a double in inotropic support from post-operative admit, requiring Extracorporeal Membrane Oxygenation (ECMO) support, receiving Cardiopulmonary Resuscitation, or death.
Time frame: first 48 hours after cardiac intensive care unit (CICU) admission post-op
Mean Number of Days Subjects Alive and Ventilator Free
Respiratory variables include such as alive, ventilator free days at 28 days post-op will be used as secondary outcome. The mean number of days subjects were live and ventilator free up to the 28 days after surgery.
Time frame: up to 28 days post op
Hospital Length of Stay
The average length of hospital stay from the time the subject is admitted to the CICU post-op until they are discharged will be used as a secondary outcome.
Time frame: Admit to CICU till hospital discharge, approximately 3 weeks
Changes in Baseline Inflammatory Mediators
Changes in pre-op inflammatory mediators will be assessed at 0, 4, 12, 24 and 48 hours post bypass and used as a secondary outcome.
Time frame: 0, 4,12, 24, and 48 hours post bypass
Average Inotrope Score
Average inotrope score over first 48 hours after Cardiac Intensive Care Unit admission was used as a secondary outcome. Inotrope Score is calculated based on the dose of inotropes currently infusing at a given time points. The formula for calculation is as follows: Epinephrine/Norepinephrine (mcg/kg/min) dose x100, plus Dopamine/Dobutamine (mcg/kg/min) dose x 1, plus Neosynephrine (mcg/kg/min) dose x10, plus Vasopressin (units/kg/hr) \[(dose x60)/10,000\] = Inotrope Score. Our institution does not include Milrinone in our inotrope score calculation because every patient receives a continuous infusion in the immediate post-operative period. The higher the inotrope score the more cardiac support the patient is requiring or the worse their cardiac function is becoming.
Time frame: first 48 hours post-op
Fluid Balance
Hemodynamic variable such as total fluid balance within the first 48 hours post-op will be used as a secondary outcome. Fluid balance is a calculation of the overall fluid status for a given time period. The total input (fluid, medications, etc) that are given to a patient during a given time frame (24 hours) minus the total output (urine, stool, drainage, etc. ) that comes out of a patient during a given time frame.
Time frame: 1st 48 hours post-op
Changes in Baseline Arterial-venous Oxygen Saturation Difference
Respiratory values such as changes in baseline arterial-venous oxygen saturation difference at admission to the pediatric cardiac intensive care unit will be used as a secondary outcome.
Time frame: admit to the CICU
Time Until First Extubation
Respiratory values such as duration of intubation will be used as a secondary outcome.
Time frame: Until discharge from hospital, approximately 2 weeks
CICU Length of Stay
CICU length of stay will be calculated from the time the subject is admitted to the CICU post-op until they are discharged from the unit. This will be used as a secondary outcome.
Time frame: approximately 1 week
Mortality
Subject mortality will in the CICU will be used as a secondary outcome.
Time frame: Duration of CICU stay, approximately 1 week
ACTH Stimulation Test
AdrenoCorticoTropic Hormone stimulation test will be performed at least 24 hours pre-bypass and immediately after successful discontinuation of bypass and compared. These outcomes will be used as a secondary outcome.
Time frame: 24 hours prebypass and 0 hours post-bypass
| Milestone | Normal Saline | Hydrocortisone |
|---|---|---|
| Started | 21 | 19 |
| Completed | 21 | 19 |
| Not completed | 0 | 0 |
Low Cardiac Output Syndrome (LCOS) within the first 48 hours after post-operative admission to the Pediatric Cardiac Intensive Care Unit was used as the primary outcome. This was defined as a double in inotropic support from post-operative admit, requiring Extracorporeal Membrane Oxygenation (ECMO) support, receiving Cardiopulmonary Resuscitation, or death.
| percentage of patients | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| Incidence of Low Cardiac Output Syndrome (LCOS) | 57 | 26 |
Respiratory variables include such as alive, ventilator free days at 28 days post-op will be used as secondary outcome. The mean number of days subjects were live and ventilator free up to the 28 days after surgery.
| days | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| Mean Number of Days Subjects Alive and Ventilator Free | 24 (17 to 26.5) | 25 (23 to 26) |
The average length of hospital stay from the time the subject is admitted to the CICU post-op until they are discharged will be used as a secondary outcome.
| days | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| Hospital Length of Stay | 13.5 (9 to 24) | 19 (9 to 24) |
Changes in pre-op inflammatory mediators will be assessed at 0, 4, 12, 24 and 48 hours post bypass and used as a secondary outcome.
| pg/mL | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| Pre-op Il-10 | 4 (2.9 to 5.4) | 4.3 (3 to 6.7) |
| 0 hr post bypass Il-10 | 225 (119 to 298) | 164 (105.3 to 312) |
| 4 hr post bypss Il-10 | 53.5 (31.4 to 84.9) | 92.2 (54.5 to 141) |
| 12 hr post bypass Il-10 | 17.5 (8.9 to 28) | 20.1 (17.3 to 34.8) |
| 24 hr post bypass Il-10 | 11.4 (7.9 to 21.7) | 10.7 (7 to 16.4) |
| 48 hr post bypass Il-10 | 7.9 (4.8 to 10.2) | 9.4 (7 to 15.4) |
| Pre-op Il-1 beta | 0.49 (0.28 to 0.87) | 0.53 (0.29 to 0.78) |
| 0 hr post bypass Il-1 beta | 0.44 (0.28 to 1.15) | 0.5 (0.28 to 0.63) |
| 4 hr post bypass Il-1 beta | 0.83 (0.55 to 1.24) | 1.2 (0.58 to 1.57) |
| 12 hr post bypss Il-1 beta | 0.49 (0.37 to 1.37) | 0.33 (0.21 to 0.8) |
| 24 hr post bypass Il-1 beta | 1.71 (0.89 to 4.01) | 0.77 (0.38 to 1.13) |
| 48 hr post bypass Il-1 beta | 0.76 (0.45 to 1.08) | 0.29 (0.13 to 0.54) |
| Pre-op Il-6 | 3.6 (1.2 to 18.8) | 5.8 (2.8 to 15.1) |
| 0 hr post bypass IL-6 | 13.6 (9.2 to 20.6) | 12.4 (9.7 to 19.8) |
| 4 hr post bypsas Il-6 | 58 (44.8 to 83.4) | 65.2 (40.3 to 89) |
| 12 hr post bypass Il-6 | 93.7 (61.5 to 164) | 50.4 (39.8 to 84.7) |
| 24 hr post bypass Il-6 | 110 (59.2 to 199) | 45.5 (33.4 to 91.6) |
| 48 hr post bypass Il-6 | 40.1 (23.2 to 78.9) | 15.3 (10.9 to 24.6) |
| Pre-op Il-8 | 27.1 (21.7 to 37.7) | 23.5 (19.2 to 32.3) |
| 0 hr post bypass Il-8 | 118 (88.7 to 255) | 99.8 (71.4 to 188.5) |
| 4 hr post bypss IL-8 | 212 (160 to 456) | 261.5 (183.3 to 331.5) |
| 12 hr post bypass IL-8 | 153 (105 to 223) | 97 (62.9 to 139) |
| 24 hr post bypass Il-8 | 129 (97.8 to 277) | 103 (63.3 to 134.5) |
| 48 hr post bypass Il-8 | 67.3 (43.3 to 127) | 50.3 (37.4 to 59.1) |
| Pre-op tumor necrosis factor (TNF)-alpha | 4.7 (3.4 to 5.4) | 4.3 (2.9 to 5) |
| 0 hr post bypass TNF-alpha | 3.6 (2.5 to 5.4) | 2.9 (2.2 to 4.1) |
| 4 hr post bypass TNF-alpha | 6.4 (4.5 to 8.7) | 5.5 (4.9 to 6.9) |
| 12 hr post bypss TNF-alpha | 6.6 (4.5 to 8.7) | 4.2 (3.2 to 4.8) |
| 24 hr post bypass TNF-alpha | 5.8 (4.5 to 8.7) | 4.1 (3.2 to 5) |
| 48 hr post bypass TNF-alpha | 5.1 (4.5 to 8.7) | 3 (2.3 to 4.4) |
Average inotrope score over first 48 hours after Cardiac Intensive Care Unit admission was used as a secondary outcome. Inotrope Score is calculated based on the dose of inotropes currently infusing at a given time points. The formula for calculation is as follows: Epinephrine/Norepinephrine (mcg/kg/min) dose x100, plus Dopamine/Dobutamine (mcg/kg/min) dose x 1, plus Neosynephrine (mcg/kg/min) dose x10, plus Vasopressin (units/kg/hr) \[(dose x60)/10,000\] = Inotrope Score. Our institution does not include Milrinone in our inotrope score calculation because every patient receives a continuous infusion in the immediate post-operative period. The higher the inotrope score the more cardiac support the patient is requiring or the worse their cardiac function is becoming.
| Inotrope Score | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| Inotrope Score at 12 hours post bypass | 5.3 (1.5 to 12.7) | 4.7 (1.7 to 10.7) |
| Inotrope Score 24 hours post bypass | 0 (0 to 7.7) | 4 (0 to 7.3) |
| Inotrope Score 48 hours post bypass | 0 (0 to 7.1) | 0 (0 to 0) |
Hemodynamic variable such as total fluid balance within the first 48 hours post-op will be used as a secondary outcome. Fluid balance is a calculation of the overall fluid status for a given time period. The total input (fluid, medications, etc) that are given to a patient during a given time frame (24 hours) minus the total output (urine, stool, drainage, etc. ) that comes out of a patient during a given time frame.
| mL/kg | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| Fluid Balance | -64 (-107 to 12) | -114 (-148 to -60) |
Respiratory values such as changes in baseline arterial-venous oxygen saturation difference at admission to the pediatric cardiac intensive care unit will be used as a secondary outcome.
| percentage of arterial-venous saturation | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| Changes in Baseline Arterial-venous Oxygen Saturation Difference | 14 (10 to 24.2) | 9.5 (7.7 to 13.5) |
Respiratory values such as duration of intubation will be used as a secondary outcome.
| hours | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| Time Until First Extubation | 55 (21 to 195) | 51 (34 to 83) |
CICU length of stay will be calculated from the time the subject is admitted to the CICU post-op until they are discharged from the unit. This will be used as a secondary outcome.
| hours | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| CICU Length of Stay | 162 (137 to 389) | 213 (118 to 501) |
Subject mortality will in the CICU will be used as a secondary outcome.
| percentage of patients | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| Mortality | 14 | 0 |
AdrenoCorticoTropic Hormone stimulation test will be performed at least 24 hours pre-bypass and immediately after successful discontinuation of bypass and compared. These outcomes will be used as a secondary outcome.
| microg/dL | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| Pre-op ACTH | 24.5 (10 to 33) | 31 (16.5 to 54) |
| Pre-op Pre-stimulation cortisol | 18.2 (7.5 to 26) | 23.3 (11.4 to 30.4) |
| Pre-op Post-stimulation cortisol | 43.6 (34.6 to 51) | 47.1 (35 to 53.3) |
| Post-op ACTH | 10.5 (6.5 to 14) | 7.5 (6.4 to 9.6) |
| Post-op Pre-Stimulation cortisol | 89.4 (40.5 to 130.8) | 87.2 (58.1 to 131) |
| Post-op Post-stimulation cortisol | 112.3 (66.6 to 145.9) | 118.8 (72.9 to 143.4) |
Collected over Adverse events were collected from admit to the cardiac intensive care unit post-op until discharge from the cardiac intensive care unit.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Normal Saline-Placebo | — | 3/21 (14.3%) | 19/21 (90.5%) |
| Hydrocortisone | — | 1/19 (5.3%) | 17/19 (89.5%) |
| Event | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| DeathSurgical and medical procedures | 3/21 | 0/19 |
| Extracorporeal Membrane OxygenationCardiac disorders | 2/21 | 1/19 |
| Event | Normal Saline-Placebo | Hydrocortisone |
|---|---|---|
| HyperglycemiaEndocrine disorders | 15/21 | 10/19 |
| Antibiotics for suspected infectionInfections and infestations | 8/21 | 7/19 |
| Acute Kidney injuryRenal and urinary disorders | 7/21 | 7/19 |
| Age, Continuous(Days) | Normal Saline-Placebo | Hydrocortisone | Total |
|---|---|---|---|
| Median | 6 (5 to 11) | 5 (4 to 7) | 6 (5 to 8) |
| Sex: Female, Male(Participants) | Normal Saline-Placebo | Hydrocortisone | Total |
|---|---|---|---|
| Female | 8 | 5 | 13 |
| Male | 13 | 14 | 27 |
| Race (NIH/OMB)(Participants) | Normal Saline-Placebo | Hydrocortisone | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 5 | 3 | 8 |
| White | 16 | 16 | 32 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Normal Saline-Placebo | Hydrocortisone | Total |
|---|---|---|---|
| United States | 21 | 19 | 40 |
| Surgical Procedure(number of patients) | Normal Saline-Placebo | Hydrocortisone | Total |
|---|---|---|---|
| Norwood | 7 | 6 | 13 |
| Arterial switch operation | 6 | 6 | 12 |
| Interrupted aortic arch repair | 3 | 4 | 7 |
| Aortic arch augmentation | 1 | 1 | 2 |
| Truncus arteriosus repair | 3 | 0 | 3 |
| other | 1 | 2 | 3 |
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University of Alabama at Birmingham