Two Inodilators Postsurgery in Neonates

Low Cardiac Output Syndrome Clinical Trial

Official title:

Phase I Study of Two Inodilators in Neonates Undergoing Cardiovascular Surgery

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01576094
• Other study ID #: MilevoNeo
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: March 31, 2012
• Last updated: April 11, 2012
• Start date: November 2009
• Est. completion date: November 2010

Study information

• Verified date: April 2012
• Source: Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Agencia Española de Medicamentos y Productos Sanitarios
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: November 2010
• Est. primary completion date: November 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 40 Days

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cardiac Output, Low
• Low Cardiac Output Syndrome

Intervention

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
• 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.

Locations

Country	Name	City	State
Spain	Hospital Universitario La Paz	Madrid

Sponsors (3)

Lead Sponsor	Collaborator
Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz	Fondo de Investigacion Sanitaria, Hospital Universitario La Paz

Country where clinical trial is conducted

Spain, 

References & Publications (1)

Bravo MC, López P, Cabañas F, Pérez-Rodríguez J, Pérez-Fernández 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. Erratum in: Neonatology. 2011;99(4):301. Bravo, María del Carmen [corrected to Bravo, María Carmen]; Quero, José [added]. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Perfusion-oxygenation	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.	No
Secondary	Blood gases		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.	No
Secondary	Blood pressure		preoperative (baseline) to post-operative day 6.	No
Secondary	temperature	central (axilla) and peripheral (foot) temperature	preoperative (baseline) to post-operative day 6.	No
Secondary	arterial oxygen saturation		preoperative (baseline) to post-operative day 6.	No
Secondary	cooximetry		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.	No
Secondary	lactate		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.	No
Secondary	glucose		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.	No
Secondary	haemoglobin concentration		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.	No
Secondary	Biochemical markers	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	No
Secondary	Inodilators concentration	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.	No
Secondary	inotrope score	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.	No