Two Inodilators Postsurgery in Neonates

April 11, 2012 updated by: Adelina Pellicer, Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz

Phase I Study of Two Inodilators in Neonates Undergoing Cardiovascular Surgery

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
      • Madrid, Spain, 28046
        • Hospital Universitario La Paz

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 1 month (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

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

Exclusion Criteria:

  • Parental consent refused
  • Inodilators contraindicated

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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 Names:
  • Simdax
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 Names:
  • cronotrope

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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.
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.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
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.
Blood pressure
Time Frame: preoperative (baseline) to post-operative day 6.
preoperative (baseline) to post-operative day 6.
temperature
Time Frame: preoperative (baseline) to post-operative day 6.
central (axilla) and peripheral (foot) temperature
preoperative (baseline) to post-operative day 6.
arterial oxygen saturation
Time Frame: preoperative (baseline) to post-operative day 6.
preoperative (baseline) to post-operative day 6.
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.
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.
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.
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.
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.
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.
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.
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.
Biochemical markers
Time Frame: baseline, at 24h after surgery and on day 6 post-surgery
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
baseline, at 24h after surgery and on day 6 post-surgery
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.
Milrinone and Levosimendan plasma concentration
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.
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.
calculated according to Wernovsky
preoperative (baseline) and then one evaluation every 6 hours until 24 h post-surgery. At 48h post-surgery. At 96 h post-surgery.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz

Collaborators

Fondo de Investigacion Sanitaria
Hospital Universitario La Paz

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2009

Primary Completion (Actual)

November 1, 2010

Study Completion (Actual)

November 1, 2010

Study Registration Dates

First Submitted

March 31, 2012

First Submitted That Met QC Criteria

April 11, 2012

First Posted (Estimate)

April 12, 2012

Study Record Updates

Last Update Posted (Estimate)

April 12, 2012

Last Update Submitted That Met QC Criteria

April 11, 2012

Last Verified

April 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MilevoNeo

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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