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| ID | Type | Description | Link |
|---|---|---|---|
| 2013-003105-25 | EudraCT Number |
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| Name | Class |
|---|---|
| Helsinki University Central Hospital | OTHER |
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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Milrinone | Active Comparator | 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 |
|
| Levosimendan | Experimental | 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 |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Levosimendan | Drug | The drug infusion will be started after initiation of cardiopulmonary bypass and will continue for 24 hours. |
|
| Measure | Description | Time Frame |
|---|---|---|
| S-creatinine | The primary outcome variable was the absolute value of serum creatinine data on postoperative day 1. | One day after cardiac surgery |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | Two days (second postoperative day) |
| 30 Days Mortality |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Albert Castellheim, MD, PhD | Queen Silvia Children´s Hospital, Department of anesthesia and intensive care | Principal Investigator |
| Håkan Wåhlander, MD, PhD | Queen Silvia Children´s Hospital, Department of pediatric cardiology | Study Chair |
| Birgitta Romlin, MD, PhD | Queen Silvia Children´s Hospital, Department of anesthesiology and intensive care | Study Chair |
| Elin Thorlacius, MD | Queen Silvia Children´s Hospital, Department of anesthesiology and intensive care | Study Chair |
| Sven-Erik Ricksten, MD, PhD | Sahlgrenska University Hospital, Department of anesthesiology and intensive care | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children´s Hospital, Helsinki University Central Hospital | Helsinki | FIN-00029 HYKS | Finland | |||
| Queen Silvia Children´s Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33739957 | Derived | Thorlacius EM, Vistnes M, Ojala T, Keski-Nisula J, Molin M, Romlin BS, Synnergren M, Ricksten SE, Wahlander H, Castellheim A. Levosimendan Versus Milrinone and Release of Myocardial Biomarkers After Pediatric Cardiac Surgery: Post Hoc Analysis of Clinical Trial Data. Pediatr Crit Care Med. 2021 Jul 1;22(7):e402-e409. doi: 10.1097/PCC.0000000000002712. |
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Assessed for eligibility (n= 123)
Excluded (n=51)
Randomized (n= 72)
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| ID | Title | Description |
|---|---|---|
| FG000 | Milrinone | Allocated to milrinone (n=39) • Received allocated intervention (n=39) Did not receive allocated intervention (n=0) |
| FG001 | Levosimendan | Allocated to levosimendan (n=33)
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| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | S-creatinine | The primary outcome variable was the absolute value of serum creatinine data on postoperative day 1. | Posted | Mean | Standard Deviation | μmol/L | One day after cardiac surgery |
|
|
Up to 30 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Milrinone | Patients who received milrinone | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Arrhythmia | Cardiac disorders | Systematic Assessment | Nodal tachycardia and low cardiac output syndrome postoperatively. Re-operation on the first operative night; Study drug was stopped on the first postoperative night and the patient was excluded from the study |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Inotropic score > 20 | Nervous system disorders | Systematic Assessment |
The trial included merely three types of heart defects with relatively short CPB-times.
Patient with higher risk for postoperative AKI were excluded (patients with univentricular circulation, renal disease, history of open-heart surgery or receiving nephrotoxic agents
Unequal number of patients in the study groups (due to use of the stratification program which was set to stratify the patients according to age and diagnosis).
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Albert Gyllencreutz Castellheim | University of Gothenburg | +46708979820 | albert.castellheim@gu.se |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Feb 22, 2017 | May 2, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Nov 6, 2017 | May 2, 2022 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D006330 | Heart Defects, Congenital |
| ID | Term |
|---|---|
| D018376 | Cardiovascular Abnormalities |
| D002318 | Cardiovascular Diseases |
| D006331 | Heart Diseases |
| D000013 | Congenital Abnormalities |
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| ID | Term |
|---|---|
| D000077464 | Simendan |
| D020105 | Milrinone |
| ID | Term |
|---|---|
| D006835 | Hydrazones |
| D006834 | Hydrazines |
| D009930 | Organic Chemicals |
| D011724 | Pyridazines |
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| Milrinone | Drug | The drug infusion will be started after initiation of cardiopulmonary bypass and will continue for 24 hours. |
|
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Mortality at 30th day |
| 30 days |
| Gothenburg |
| Västra Götaland County |
| 416 85 |
| Sweden |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Standard Deviation | Months |
|
| Sex: Female, Male | Count of Participants | Participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| S-Creatinine | Mean | Standard Deviation | μmole/L |
|
|
|
|
| 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) | Posted | Count of Participants | Participants | Two days (second postoperative day) |
|
|
|
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| Secondary | 30 Days Mortality | Mortality at 30th day | Posted | Number | participants | 30 days |
|
|
|
| 38 |
| 6 |
| 38 |
| 11 |
| 38 |
| EG001 | Levosimendan | Patients who received levosimendan | 0 | 32 | 9 | 32 | 8 | 32 |
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| Pericardial fluid and sepsis | Cardiac disorders | Systematic Assessment | Prolonged hospital stay due to: 1) Operation for pericardial fluid drainage 2) treatment for sepsis with antibiotics |
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| Pericard effusion | Cardiac disorders | Systematic Assessment | Prolonged hospital stay due to: Pericardiac drainage on postop day 11, due to pericardial effusion |
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| Verified bacterial sepsis | Infections and infestations | Systematic Assessment | Prolongation of existing hospitalization due to verified bacterial sepsis (Staphylococcus aureus) |
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| Closure of another small VSD + tricuspid valve plasty + permanent pacemaker due to total AV-block | Cardiac disorders | Systematic Assessment | Prolonged hospital stay due to two re-operations; first for closure of another small VSD and tricuspid valve plastic, and second for inserting permanent pacemaker due to total AV-block. |
|
| Readmission for pericardal fluid drainage | Cardiac disorders | Systematic Assessment | Readmission due to pericardial fluid and re-operation for drainage of the fluid. |
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| Readmission | Cardiac disorders | Systematic Assessment | Readmission on postop day 20 due to common cold and vomiting. |
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| Re-operation and dialysis post re-operation | Cardiac disorders | Systematic Assessment | Prolonged hospitalisation due to re-operation on postop day 6 and prolonged PICU stay after re-operation. Peritoneal dialysis for total 11 days. |
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| Enalapril caused prolonged hospitalisation | Cardiac disorders | Systematic Assessment | Increased creatinine and increased need for diuretics. Patient recovered when enalapril was removed. |
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| Fever and diarrea | Infections and infestations | Systematic Assessment | Fever and diarrhoea in ward on postoperative day 8. High CRP but negative blood cultures. Was treated as sepsis. |
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| Upper respiratory tract infection | Infections and infestations | Systematic Assessment | Prolonged hospital stay due to Upper respiratory infection postoperatively in PICU |
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| AV block III | Cardiac disorders | Systematic Assessment | AV block III, received permanent pacemaker |
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| Blood culture verified S. aureus sepsis | Infections and infestations | Systematic Assessment | Prolonged hospitalisation due to blood culture verified S. aureus sepsis. |
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| Postoperative AV-block | Cardiac disorders | Systematic Assessment | AV-block Episodes postoperatively, received permanent pace-maker 4 months after the operation |
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| hydrocephalus and seizure | Nervous system disorders | Systematic Assessment | hydrocephalus and bleeding from an old cerebral infarction. Ventriculostomy |
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| Junctional ectopic tachycardia | Cardiac disorders | Systematic Assessment |
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| Third-degree atrioventricular block | Cardiac disorders | Systematic Assessment |
|
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| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D006573 |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D000676 | Amrinone |
| D000631 | Aminopyridines |
| D000588 | Amines |
| D011725 | Pyridines |