Congenital Heart Defects
Conditions
Brief summary
The aim of the study is to assess the ability of Levosimendan to reduce the postoperative acute kidney injury in pediatric patients undergoing surgery for congenital heart disease (CHDs).
Detailed description
Young children, between the age of 1 to 12 months, with congenital heart disease in need of elective heart surgery will be included in this study. The trial will contain two study groups, 35 patients in each. One group will receive Levosimendan and the second group will receive Milrinone as a heart muscle-strengthening agent during and after the operation. Milrinone is currently used as the drug of choice in many pediatric cardiac surgery centers. It remains to see if Levosimendan can exert a kidney protecting function in addition to its heart muscle-strengthening properties. The primary objective of this study is to investigate the preventive effect of Levosimendan on postoperative acute kidney injury in pediatric patients undergoing surgery for their CHDs. Creatinine levels postoperatively will be the primary endpoint. Creatinine, the common marker of kidney injury, will be measured daily. The treatment with Levosimendan or Milrinone will be started during the operation (after initiation of cardiopulmonary bypass) and will last 24 hours. Blood samples will be obtained at six occasions perioperatively. Patients will be followed 4 days after termination of treatment (totally 5 days). The duration of study will be 30 days (24 hours treatment + 4 days follow up + 30-days-mortality registration). Creatinine is the primary outcome in this study. Inflammatory biomarkers and other relevant biomarkers will comprise the secondary outcome variables.
Interventions
DRUGLevosimendan
The drug infusion will be started after initiation of cardiopulmonary bypass and will continue for 24 hours.
DRUGMilrinone
The drug infusion will be started after initiation of cardiopulmonary bypass and will continue for 24 hours.
Sponsors
Helsinki University Central Hospital
Göteborg University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
1 Months to 12 Months
Healthy volunteers
No
Inclusion criteria
1. Provision of informed consent prior to any study specific procedures 2. Female and male children between 1 and 12 months of age 3. Non-restrictive VSD (corrective surgery) 4. Complete AVSD (biventricular repair) 5. Tetralogy of Fallot
Exclusion criteria
1. Unbalanced AtrioVentricular Septal Defect or AVSD with cyanosis 2. Age less than one month and more than one year 3. Acute operation that is unscheduled operation during the first 24 hours after presentation to the department for thoracic surgery 4. Mild, moderate, or severe kidney dysfunction and known anatomical anomalies of kidneys 5. Liver impairment or disease 6. Ongoing infection 7. Use of nephrotoxic drugs (like ibuprofen, angiotensin-converting-enzyme inhibitors, gentamicin, vancomycin) preoperative or postoperative until first post operative day. Contrast agents whithin 24 hours before operation. 8. Use of inhibitors of membrane transport proteins (cimetidine, cetirizine, trimethoprim, probenecid, rifampin and gemfibrosil). 9. Allergy to Levosimendan or substance included in the preparation or previous use of Levosimendan. 10. Severe arrhythmias needing pace-maker treatment prior to the operation 11. Severe cardiac dysfunction needing for treatment with extracorporeal membrane oxygenation (ECMO) prior to the operation. 12. Preoperative need for mechanical ventilation and/or inotropic agents. 13. Re-operation (open heart surgery). Earlier surgical closure of the arterial duct does not count as an
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| S-creatinine | One day after cardiac surgery | The primary outcome variable was the absolute value of serum creatinine data on postoperative day 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Acute Kidney Injury (AKI) | Two days (second postoperative day) | Secondary outcomes included the occurrence rate of AKI, defined as a 50% rise in serum creatinine, or more, within 48 hours after surgery. All stages of AKI (stage 1 and stage 2 and stage 3) |
| 30 Days Mortality | 30 days | Mortality at 30th day |
Countries
Finland, Sweden
Participant flow
Recruitment details
Assessed for eligibility (n= 123) Excluded (n=51) * Lack of informed consent (n=15) * Other exclusion criteria (n=21) * Study personnel not available (n=14) * Patient moved to another center (n=1) Randomized (n= 72)
Participants by arm
| Arm | Count |
|---|---|
| Milrinone In this arm the patients will receive Milrinone as an inotrope agent. Concentration: 0.2 mg/mL Infusion rate: 0.12 mL / kg / hr = Dose delivered 0.4 μg / kg / min --- Bolus dose: 1.44 ml / kg / hr in ten minutes (a maximum volume 0.24 ml / kg) = 48 μg / kg
Milrinone: The drug infusion will be started after initiation of cardiopulmonary bypass and will continue for 24 hours. | 38 |
| Levosimendan In this arm the patients will receive Levosimendan as an inotrope agent. Concentration: 0.05 mg/mL Infusion rate: 0.12 mL / kg / hr = Dose delivered 0.1 μg / kg / min --- Bolus dose: 1.44 ml / kg / hr in ten minutes (a maximum volume 0.24 ml / kg) = 12 μg/kg
Levosimendan: The drug infusion will be started after initiation of cardiopulmonary bypass and will continue for 24 hours. | 32 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Milrinone | Levosimendan | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 38 Participants | 32 Participants | 70 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 | 5.6 Months STANDARD_DEVIATION 2.7 | 5.9 Months STANDARD_DEVIATION 2.9 | 5.6 Months STANDARD_DEVIATION 2.8 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Finland | 24 participants | 14 participants | 38 participants |
| Region of Enrollment Sweden | 14 participants | 18 participants | 32 participants |
| S-Creatinine | 23.9 μmole/L STANDARD_DEVIATION 6.1 | 25.9 μmole/L STANDARD_DEVIATION 5.9 | 24.5 μmole/L STANDARD_DEVIATION 6 |
| Sex: Female, Male Female | 20 Participants | 16 Participants | 36 Participants |
| Sex: Female, Male Male | 18 Participants | 16 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 38 | 0 / 32 |
| other Total, other adverse events | 11 / 38 | 8 / 32 |
| serious Total, serious adverse events | 6 / 38 | 9 / 32 |
Outcome results
Primary
S-creatinine
The primary outcome variable was the absolute value of serum creatinine data on postoperative day 1.
Time frame: One day after cardiac surgery
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Milrinone | S-creatinine | Preoperative | 23.9 μmol/L | Standard Deviation 6.1 |
| Milrinone | S-creatinine | Postop day 1 | 33.7 μmol/L | Standard Deviation 12.9 |
| Levosimendan | S-creatinine | Preoperative | 25.9 μmol/L | Standard Deviation 5.9 |
| Levosimendan | S-creatinine | Postop day 1 | 34.2 μmol/L | Standard Deviation 2 |
Comparison: To test whether there were any significant differences between the two treatment groups over time (group vs time interaction), a repeated measurement mixed-model approach was used. This assumed an unstructured covariance pattern.p-value: 0.45Mixed Models Analysis
Secondary
30 Days Mortality
Mortality at 30th day
Time frame: 30 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Milrinone | 30 Days Mortality | 0 participants |
| Levosimendan | 30 Days Mortality | 0 participants |
Secondary
Acute Kidney Injury (AKI)
Secondary outcomes included the occurrence rate of AKI, defined as a 50% rise in serum creatinine, or more, within 48 hours after surgery. All stages of AKI (stage 1 and stage 2 and stage 3)
Time frame: Two days (second postoperative day)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Milrinone | Acute Kidney Injury (AKI) | 15 Participants |
| Levosimendan | Acute Kidney Injury (AKI) | 15 Participants |
p-value: 0.7Regression, Logistic