Clinical trial NCT01576094: Two Inodilators Postsurgery in Neonates
Official title: Phase I Study of Two Inodilators in Neonates Undergoing Cardiovascular Surgery
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Low Cardiac Output Syndrome
Keywords: congenital heart disease
Lead sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
Sponsor class: OTHER
Collaborators: name: Hospital Universitario La Paz
name: Fondo de Investigacion Sanitaria
First posted: 2012-04-12
Enrollment: 20
Sex: ALL
Maximum age (years): 40
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Perfusion-oxygenation
timeFrame: 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 outcomes:
measure: Blood gases
timeFrame: 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.
measure: Blood pressure
timeFrame: preoperative (baseline) to post-operative day 6.
measure: temperature
timeFrame: preoperative (baseline) to post-operative day 6.
measure: arterial oxygen saturation
timeFrame: preoperative (baseline) to post-operative day 6.
measure: cooximetry
timeFrame: 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.
measure: lactate
timeFrame: 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.
measure: glucose
timeFrame: 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.
measure: haemoglobin concentration
timeFrame: 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.
measure: Biochemical markers
timeFrame: baseline, at 24h after surgery and on day 6 post-surgery
measure: Inodilators concentration
timeFrame: 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.
measure: inotrope score
timeFrame: preoperative (baseline) and then one evaluation every 6 hours until 24 h post-surgery. At 48h post-surgery. At 96 h post-surgery.
Other outcomes:
Locations:
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
Study officials:
affiliation: Dept. of Neonatology, La Paz University Hospital, Madrid
name: Adelina Pellicer, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Bio-Engineer and Nanotechnology Dept., Polytechnic University of Madrid
name: Joan Riera, MBE
role: STUDY_CHAIR
affiliation: Dept. of Neonatology, La Paz University Hospital, Madrid
name: Paloma López, MD
role: STUDY_CHAIR
affiliation: Dept. of Neonatology, La Paz University Hospital, Madrid
name: María Carmen Bravo, PhD
role: STUDY_CHAIR
affiliation: Division of Biostatistics, La Paz University Hospital, Madrid
name: Rosario Madero, MD
role: STUDY_CHAIR
affiliation: Dept. of Neonatology, La Paz University Hospital, Madrid
name: Jesús Pérez-Rodríguez, PhD
role: STUDY_CHAIR
affiliation: Dept. Paediatric Cardiology, La Paz University Hospital, Madrid
name: Carlos Labrandero, MD
role: STUDY_CHAIR
affiliation: Dept. of Neonatology, La Paz University Hospital, Madrid
name: José Quero, PhD
role: STUDY_CHAIR
affiliation: Clinical Pathology Service, La Paz University Hospital, Madrid
name: Antonio Buño, PhD
role: STUDY_CHAIR
affiliation: Dept. Paediatric Anaesthesiology, La Paz University Hospital, Madrid
name: Luis Castro, MD
role: STUDY_CHAIR
affiliation: Dept. of Neonatology, La Paz University Hospital, Madrid
name: Fernando Cabañas, PhD
role: STUDY_CHAIR
References:
citation: Bravo MC, Lopez P, Cabanas F, Perez-Rodriguez J, Perez-Fernandez E, Quero J, Pellicer A. Acute effects of levosimendan on cerebral and systemic perfusion and oxygenation in newborns: an observational study. Neonatology. 2011;99(3):217-23. doi: 10.1159/000314955. Epub 2010 Sep 25.