Two Inodilators Postsurgery in Neonates

This study has been completed.
Sponsor:
Collaborators:
Hospital Universitario La Paz
Fondo de Investigacion Sanitaria
Information provided by (Responsible Party):
Adelina Pellicer, Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
ClinicalTrials.gov Identifier:
NCT01576094
First received: March 31, 2012
Last updated: April 11, 2012
Last verified: April 2012
  Purpose

Congenital heart defects are the most prevalent group of congenital malformations in newborns. Surgery-related low cardiac output syndrome (LCOS) could be one of the reason for the unfavourable outcome of this population. The early use of inodilators (INDs), specifically milrinone (MR), is proposed to reduce afterload and increase inotropism. Studies in the paediatric population appear to support a clinical usefulness of MR similar to that observed in adults. Levosimendan (LEVO) is a novel class IND developed for the treatment of heart failure. Experience with LEVO in paediatric patients is scarce. The purpose of this study was to systematically test the efficacy and safety of milrinone (MR) and levosimendan (LEVO) in newborns undergoing cardiovascular surgery with cardiopulmonary bypass (CPB). Given the uncertainty about LEVO pharmacokinetics in neonates, the study was designed as a pilot, phase I feasibility study.


Condition Intervention Phase
Low Cardiac Output Syndrome
Drug: Milrinone
Drug: Levosimendan
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Phase I Study of Two Inodilators in Neonates Undergoing Cardiovascular Surgery

Resource links provided by NLM:


Further study details as provided by Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz:

Primary Outcome Measures:
  • Perfusion-oxygenation [ Time Frame: NIRS evaluation started immediately after surgery and was maintained during 24 h. At 48 h after surgery, a new NIRS evaluation during 4 hours. At 96 h post-surgery, during 4h. ] [ Designated as safety issue: No ]
    Changes in cerebral and thigh oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb), total haemoglobin (THb) and tissue oxygenation index (TOI). The cerebral and peripheral intravascular oxygenation as c∆HbD was also assessed.


Secondary Outcome Measures:
  • Blood gases [ Time Frame: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery. ] [ Designated as safety issue: No ]
  • Blood pressure [ Time Frame: preoperative (baseline) to post-operative day 6. ] [ Designated as safety issue: No ]
  • temperature [ Time Frame: preoperative (baseline) to post-operative day 6. ] [ Designated as safety issue: No ]
    central (axilla) and peripheral (foot) temperature

  • arterial oxygen saturation [ Time Frame: preoperative (baseline) to post-operative day 6. ] [ Designated as safety issue: No ]
  • cooximetry [ Time Frame: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery. ] [ Designated as safety issue: No ]
  • lactate [ Time Frame: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery. ] [ Designated as safety issue: No ]
  • glucose [ Time Frame: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery. ] [ Designated as safety issue: No ]
  • haemoglobin concentration [ Time Frame: preoperative (baseline) and then one determination every 6 hours until 24 h post-surgery. One determination at 48h post-surgery. One determination at 96 h post-surgery. ] [ Designated as safety issue: No ]
  • Biochemical markers [ Time Frame: baseline, at 24h after surgery and on day 6 post-surgery ] [ Designated as safety issue: No ]
    Serum creatinine, N-terminal pro-brain natriuretic peptide (NT-proBNP), troponine I (TnI) and proinflammatory and antinflammatory factors [interleukin (IL) beta 1, IL 6, IL 7, IL 8, IL 10, and tumor necrotic factor alpha

  • Inodilators concentration [ Time Frame: Basal, two hours after dose 2; and at 24 and 48h from the start of the IND infusion in infants receiving IND dose 3. Beyond that period (open study), daily samples were obtained for LEVO up to day 7 postsurgery, and at 10 and 14 days. ] [ Designated as safety issue: No ]
    Milrinone and Levosimendan plasma concentration

  • inotrope score [ Time Frame: preoperative (baseline) and then one evaluation every 6 hours until 24 h post-surgery. At 48h post-surgery. At 96 h post-surgery. ] [ Designated as safety issue: No ]
    calculated according to Wernovsky


Enrollment: 20
Study Start Date: November 2009
Study Completion Date: November 2010
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Milrinone
Milrinone (MR) lactate 1 mg/ml: dose 1, starting immediately after central lines were placed and maintained for the duration of the surgical procedure; dose 2, on NICU admission; dose 3, after 2 hours of stability with dose 2, and maintained up to 48 hours. Accordingly, patients randomised to MR received 0.5 , 0.75 and 1 microg/kg per min
Drug: Milrinone
Before surgery, patients received milrinone (MR) (milrinone lactate 1 mg/ml). Intravenous continuous infusion of the study drug through a separate central line started intraoperatively and was increased step-wise at predefined time points: dose 1, starting immediately after central lines were placed and maintained for the duration of the surgical procedure; dose 2, on NICU admission providing the patient was in stable haemodynamic condition; dose 3, starting after 2 hours of stability with dose 2, and maintained up to 48 hours IND infusion started. Accordingly, patients randomised to MR received 0.5 , 0.75 and 1 microg/kg per min
Other Name: cronotrope
Active Comparator: Levosimendan Drug: Levosimendan
Before surgery patients received levosimendan (levosimendan 2.5 mg/ml). Intravenous continuous infusion of the study drug through a separate central line started intraoperatively and was increased step-wise at predefined time points: dose 1, starting immediately after central lines were placed and maintained for the duration of the surgical procedure; dose 2, on NICU admission providing the patient was in stable haemodynamic condition; dose 3, starting after 2 hours of stability with dose 2, and maintained up to 48 hours IND infusion started. Accordingly, patients randomised to LEVO received 0.1 , 0.15 and 0.2 microg/kg per min, for doses 1, 2 and 3, respectively.
Other Name: Simdax

Detailed Description:

Surgical repair is the primary therapy for congenital heart defects in the newborn. The neonatal cardiovascular system is at particular risk to develop the surgery-related low cardiac output syndrome (LCOS), thus vasoactive agents are routinely used in the postoperative management. Systematic research on the efficacy of these drugs is scarce in the newborn. As LCOS pathophysiology joints impaired myocardial contractility and the peripheral effects of ischemia/reperfusion injury on the endothelium, early use of inodilators (IND) are strongly recommended to reduce afterload and improve contractility. This study aims to test the equivalence in dose-dependent hemodynamic effects of 2 IND, Milrinone and Levosimendan, used early without loading dose in the preoperative period to prevent LCOS. By means of non-invasive technology the investigators will assess cardiac function (serial structural and functional echocardiography), the cerebral and peripheral perfusion and oxygenation (continuous near-infrared monitoring), cerebral function (continuous amplitude integrated EEG monitoring), will rule out CNS acquired lesions (serial transfontanelar echo-Doppler studies), and will follow up different biochemical markers of myocardial stress and apoptosis. Pharmacokinetic studies will be also performed.

  Eligibility

Ages Eligible for Study:   up to 40 Days
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Newborns undergoing cardiovascular surgery who were in stable pre-operative haemodynamic condition
  • Parental consent given

Exclusion Criteria:

  • Parental consent refused
  • Inodilators contraindicated
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01576094

Locations
Spain
Hospital Universitario La Paz
Madrid, Spain, 28046
Sponsors and Collaborators
Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
Hospital Universitario La Paz
Fondo de Investigacion Sanitaria
Investigators
Principal Investigator: Adelina Pellicer, PhD Dept. of Neonatology, La Paz University Hospital, Madrid
Study Chair: Joan Riera, MBE Bio-Engineer and Nanotechnology Dept., Polytechnic University of Madrid
Study Chair: Paloma López, MD Dept. of Neonatology, La Paz University Hospital, Madrid
Study Chair: María Carmen Bravo, PhD Dept. of Neonatology, La Paz University Hospital, Madrid
Study Chair: Rosario Madero, MD Division of Biostatistics, La Paz University Hospital, Madrid
Study Chair: Jesús Pérez-Rodríguez, PhD Dept. of Neonatology, La Paz University Hospital, Madrid
Study Chair: Carlos Labrandero, MD Dept. Paediatric Cardiology, La Paz University Hospital, Madrid
Study Chair: José Quero, PhD Dept. of Neonatology, La Paz University Hospital, Madrid
Study Chair: Antonio Buño, PhD Clinical Pathology Service, La Paz University Hospital, Madrid
Study Chair: Luis Castro, MD Dept. Paediatric Anaesthesiology, La Paz University Hospital, Madrid
Study Chair: Fernando Cabañas, PhD Dept. of Neonatology, La Paz University Hospital, Madrid
  More Information

Publications:
Responsible Party: Adelina Pellicer, Principal Investigator, Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
ClinicalTrials.gov Identifier: NCT01576094     History of Changes
Other Study ID Numbers: MilevoNeo
Study First Received: March 31, 2012
Last Updated: April 11, 2012
Health Authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz:
congenital heart disease

Additional relevant MeSH terms:
Cardiac Output, Low
Heart Diseases
Cardiovascular Diseases
Signs and Symptoms
Simendan
Milrinone
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Cardiotonic Agents
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Protective Agents
Physiological Effects of Drugs
Platelet Aggregation Inhibitors
Hematologic Agents
Phosphodiesterase 3 Inhibitors

ClinicalTrials.gov processed this record on September 16, 2014