Is Levosimendan Superior to Milrinone Regarding Acute Kidney Injury After Cardiac Surgery for Congenital Heart Disease? (MiLe-1)

The Prophylactic Effect of Levosimendan in Reducting Acute Kidney Injury Postoperatively in Pediatric Patients Undergoing Corrective Heart Surgery

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).

Study Overview

• Status: Completed
• Conditions: Congenital Heart Defects
• Intervention / Treatment: Drug: Milrinone; Drug: Levosimendan

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.

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, FIN-00029 HYKS
    • Children´s Hospital, Helsinki University Central Hospital
• Sweden
  • Västra Götaland
    • Göteborg, Västra Götaland, Sweden, 416 85
      • Queen Silvia Children´s Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 1 year (Child)
• Accepts Healthy Volunteers: No

Description

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 exclusion criteria.
14. Prematurity: Gestational age < 30 weeks, irrespective of postpartum age. Gestational age 30-34 weeks if patient is included at postpartum age under 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Drug: Milrinone; The drug infusion will be started after initiation of cardiopulmonary bypass and will continue for 24 hours.; Other Names: Corotrop
Experimental: 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	Drug: Levosimendan; The drug infusion will be started after initiation of cardiopulmonary bypass and will continue for 24 hours.; Other Names: Simdax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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	Mortality at 30th day	30 days

Collaborators and Investigators

• Sponsor: Göteborg University
• Collaborators: Helsinki University Central Hospital
• Investigators: Principal Investigator: Albert Castellheim, MD, PhD, Queen Silvia Children´s Hospital, Department of anesthesia and intensive care; Study Chair: 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

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2014
• Primary Completion (Actual): April 25, 2017
• Study Completion (Actual): April 25, 2017

Study Registration Dates

• First Submitted: September 2, 2014
• First Submitted That Met QC Criteria: September 4, 2014
• First Posted (Estimated): September 5, 2014

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 23, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Kidney Diseases; Urologic Diseases; Congenital Abnormalities; Renal Insufficiency; Cardiovascular Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Acute Kidney Injury; Heart Defects, Congenital; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Simendan; Milrinone
• Other Study ID Numbers: MiLe-1; 2013-003105-25 (EudraCT Number)