Inflammatory Reaction After Neonatal Cardiac Surgery, Ischemia/Reperfusion Injury After Neonatal Cardiac Surgery
Conditions
Keywords
Ischemia/reperfusion injury
Brief summary
Around 7500 neonates born yearly in the United States have complex congenital heart disease that require surgical repair in the first few days of life. The complexity of the surgical repair requires long periods of cardiopulmonary bypass (CPB) and the use of intermittent periods of low flow or complete circulatory arrest. The immature neonatal vital organs are more prone to the complications of the cardiopulmonary bypass circulation, namely ischemia/reperfusion (I/R) injury and systemic inflammatory response. Inhaled nitric oxide (NO) is used frequently in neonates for the treatment of pulmonary hypertension, Additionally, many studies have shown that NO has an anti-inflammatory effect by reducing I/R injury and endothelial dysfunction. The purpose of this pilot study is to assess the efficacy of NO administration via the CPB circuit in attenuating the CPB induced I/R injury and systemic inflammatory reaction in neonates undergoing repair of complex congenital heart defects. Specific goals will be to demonstrate that NO use via CPB will: * Decrease markers of I/R injury and systemic inflammatory response. * Decrease platelet activation leading to reduced postoperative bleeding and transfusion requirements. * Decrease postoperative organ dysfunction, and hence decrease operative mortality and postoperative morbidity. Twelve neonates undergoing repair of complex congenital heart defects will receive NO via the CPB circuit, for the duration of surgery. They will be compared to a control group of 12 similar patients. Serum levels of different ischemic reperfusion injury and inflammatory markers will be measured at different time points after surgery and will be correlated with different end organ function tests and clinical course in the postoperative period. The results will be compared between the two groups to try to determine the clinical benefit of NO administration through CPB circuit.
Interventions
DRUGInhaled Nitric Oxide
delivering inhaled Nitric Oxide into the cardiopulmonary bypass circuit during neonatal cardiac surgery
DRUGplacebo
inhaled Nitric Oxide not delivered to the cardiopulmonary bypass circuit during neonatal cardiac surgery
Sponsors
Mallinckrodt
Wake Forest University Health Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
1 Days to 30 Days
Healthy volunteers
No
Inclusion criteria
* Neonates, age 0-30 days * Full term, \> 37 weeks gestation * Birth weight ≥ 2.6 kg
Exclusion criteria
* Preoperative sepsis * Preoperative renal dysfunction * Preoperative intracranial hemorrhage * Chromosomal abnormalities and/or genetic syndromes * Prior intervention (catheter based or surgical)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | Pre-op baseline and up to 12 hours after surgery | The primary study endpoints are to evaluate whether NO delivered through the neonatal cardiopulmonary bypass (CPB) circuit can decrease various biochemical markers of ischemia/reperfusion injury and oxidative damage. Markers to be analyzed will include cardiac troponin I, interleukins (IL), tumor necrosis factor, N-terminal prohormone for brain natriuretic peptide (NT-proBNP),lactate dehydrogenase (LDH), plasma anti-oxidant levels, plasma malondialdehyde (MDA) levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total Fluid Balance at 48 Hours | 48 hours post surgery | The secondary study endpoints are to evaluate whether NO delivered through the neonatal CPB circuit can decrease the clinical signs of ischemia/reperfusion injury and/or cardiac dysfunction. Clinical parameters (post surgery) include inotropic support, fluid balances, diuretic support, ventilator times, and length of ICU stay will be evaluated. |
| Time Until Start of Diuretic Therapy | Pre-op to 72 hours post surgery | hours until start of diuretic therapy |
| Inotropic Score Day 1 | 24 hours post surgery | The Inotropic Score is an objective clinical tool used to quantify the need for cardiovascular support in children and adolescents after surgery and to predict prognosis of pediatric septic shock (higher score predicts higher risk or worse prognosis).The Inotropic Score is low if \<= 20, intermediate if 21-30, and high if \> 30. Formula used in the study: Daily inotropic score (mcg/kg/min) = Dopamine drip dose+ dobutamine drip dose+ (milrinone drip dose times 10) + (epinephrine drip dose times 100 ) |
| Length of Intubation and PSHU Stay | Surgery to discharge | Days to extubation and Pediatric Surgical Heart Unit (PSHU) length of stay (LOS) as measuring patient surgical outcomes. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Surgical Morbidity | 1 month after cardiac surgery | include all complications that may happen after cardiac surgery for the whole period of hospital stay, that is expected to be around 1 month. This include renal failure, prolonged intubation and ventilatory support, infections.. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nitric Oxide on CPB neonates receiving inhaled NO into the cardiopulmonary bypass circuit during cardiac surgery
Inhaled Nitric Oxide: delivered inhaled Nitric Oxide into the cardiopulmonary bypass circuit during neonatal cardiac surgery
12 patients were enrolled prospectively over 4 years period | 12 |
| Control neonates not receiving inhaled NO into the cardiopulmonary bypass
placebo: inhaled Nitric Oxide not delivered to the cardiopulmonary bypass circuit during neonatal cardiac surgery
12 patients were enrolled prospectively over 4 years period | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Nitric Oxide on CPB | Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 12 Participants | 12 Participants | 24 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 | 5.67 days STANDARD_DEVIATION 1.87 | 5.92 days STANDARD_DEVIATION 1.78 | 5.79 days STANDARD_DEVIATION 1.82 |
| anatomical diagnosis, hypoplastic left heart syndrome | 10 Participants | 11 Participants | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 9 Participants | 19 Participants |
| Region of Enrollment United States | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 2 / 12 | 1 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op)
The primary study endpoints are to evaluate whether NO delivered through the neonatal cardiopulmonary bypass (CPB) circuit can decrease various biochemical markers of ischemia/reperfusion injury and oxidative damage. Markers to be analyzed will include cardiac troponin I, interleukins (IL), tumor necrosis factor, N-terminal prohormone for brain natriuretic peptide (NT-proBNP),lactate dehydrogenase (LDH), plasma anti-oxidant levels, plasma malondialdehyde (MDA) levels.
Time frame: Pre-op baseline and up to 12 hours after surgery
Population: Intent to treat (ITT)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nitric Oxide on CPB | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | NT pro-BNP change | 7.03 ng/ml | Standard Deviation 22.84 |
| Nitric Oxide on CPB | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | IL-8 change | 49.36 ng/ml | Standard Deviation 42.86 |
| Nitric Oxide on CPB | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | LDH change | 48.85 ng/ml | Standard Deviation 117.39 |
| Nitric Oxide on CPB | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | cardiac troponin I change | 0.46 ng/ml | Standard Deviation 0.55 |
| Nitric Oxide on CPB | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | Superoxide Dismutase change | -0.04 ng/ml | Standard Deviation 0.04 |
| Nitric Oxide on CPB | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | TNF alpha change | 0.03 ng/ml | Standard Deviation 0.2 |
| Nitric Oxide on CPB | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | Plasma MDA change | 7.61 ng/ml | Standard Deviation 12.9 |
| Nitric Oxide on CPB | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | IL-6 change | 11.52 ng/ml | Standard Deviation 12.98 |
| Control | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | Plasma MDA change | 10.65 ng/ml | Standard Deviation 14.99 |
| Control | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | cardiac troponin I change | 0.64 ng/ml | Standard Deviation 0.64 |
| Control | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | IL-8 change | 68.46 ng/ml | Standard Deviation 81.09 |
| Control | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | TNF alpha change | -0.12 ng/ml | Standard Deviation 0.21 |
| Control | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | NT pro-BNP change | 1.51 ng/ml | Standard Deviation 2.29 |
| Control | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | LDH change | 53.44 ng/ml | Standard Deviation 73.58 |
| Control | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | Superoxide Dismutase change | -0.05 ng/ml | Standard Deviation 0.06 |
| Control | Change in Biochemical Markers of Ischemia/Reperfusion Injury and Oxidative Damage (Positive ~ Increase From Pre-op) | IL-6 change | 26.98 ng/ml | Standard Deviation 27.67 |
Comparison: Null: mean cardiac troponin I changes in the NO group = mean cardiac troponin I changes in the controlp-value: >0.05t-test, 2 sided
Secondary
Inotropic Score Day 1
The Inotropic Score is an objective clinical tool used to quantify the need for cardiovascular support in children and adolescents after surgery and to predict prognosis of pediatric septic shock (higher score predicts higher risk or worse prognosis).The Inotropic Score is low if \<= 20, intermediate if 21-30, and high if \> 30. Formula used in the study: Daily inotropic score (mcg/kg/min) = Dopamine drip dose+ dobutamine drip dose+ (milrinone drip dose times 10) + (epinephrine drip dose times 100 )
Time frame: 24 hours post surgery
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitric Oxide on CPB | Inotropic Score Day 1 | 16.5 mcg/kg/min |
| Control | Inotropic Score Day 1 | 15 mcg/kg/min |
Secondary
Length of Intubation and PSHU Stay
Days to extubation and Pediatric Surgical Heart Unit (PSHU) length of stay (LOS) as measuring patient surgical outcomes.
Time frame: Surgery to discharge
Population: ITT
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nitric Oxide on CPB | Length of Intubation and PSHU Stay | Days to extubation | 7.5 days |
| Nitric Oxide on CPB | Length of Intubation and PSHU Stay | PSHU Length of Stay (LOS) | 15 days |
| Control | Length of Intubation and PSHU Stay | Days to extubation | 6.5 days |
| Control | Length of Intubation and PSHU Stay | PSHU Length of Stay (LOS) | 12 days |
Secondary
Time Until Start of Diuretic Therapy
hours until start of diuretic therapy
Time frame: Pre-op to 72 hours post surgery
Population: Intent to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitric Oxide on CPB | Time Until Start of Diuretic Therapy | 25 hour |
| Control | Time Until Start of Diuretic Therapy | 21.5 hour |
Secondary
Total Fluid Balance at 48 Hours
The secondary study endpoints are to evaluate whether NO delivered through the neonatal CPB circuit can decrease the clinical signs of ischemia/reperfusion injury and/or cardiac dysfunction. Clinical parameters (post surgery) include inotropic support, fluid balances, diuretic support, ventilator times, and length of ICU stay will be evaluated.
Time frame: 48 hours post surgery
Population: Intent to treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nitric Oxide on CPB | Total Fluid Balance at 48 Hours | 32.24 ml/kg |
| Control | Total Fluid Balance at 48 Hours | 15.93 ml/kg |
Comparison: Null: NO group fluid balances are the same as the controlp-value: >0.05Wilcoxon (Mann-Whitney)
Other Pre-specified
Surgical Morbidity
include all complications that may happen after cardiac surgery for the whole period of hospital stay, that is expected to be around 1 month. This include renal failure, prolonged intubation and ventilatory support, infections..
Time frame: 1 month after cardiac surgery
Population: Intent to treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nitric Oxide on CPB | Surgical Morbidity | 0 Participants |
| Control | Surgical Morbidity | 0 Participants |