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NCT Number: NCT01576094

Two Inodilators Postsurgery in Neonates

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.

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Key information

Conditions

Low Cardiac Output Syndrome Cardiac Output, Low Cardiovascular Abnormalities Cardiovascular Diseases Congenital Abnormalities Congenital, Hereditary, and Neonatal Diseases and Abnormalities Heart Defects, Congenital Heart Diseases Pathological Conditions, Signs and Symptoms Signs and Symptoms

Age range

Up to 40 day

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Hospital Universitario La Paz

Madrid, 28046, Spain

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

Exclusion criteria

  • Parental consent refused
  • Inodilators contraindicated

Treatment and study plan

Milrinone

Drug

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

Levosimendan

Drug

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

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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.

  2. Blood pressure

    Time frame: preoperative (baseline) to post-operative day 6.

  3. temperature

    Time frame: preoperative (baseline) to post-operative day 6.

    central (axilla) and peripheral (foot) temperature

  4. arterial oxygen saturation

    Time frame: preoperative (baseline) to post-operative day 6.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. 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

Sponsors and collaborators

Lead sponsor

Fundacion para la Investigacion Biomedica del Hospital Universitario la Paz

Other

Collaborators

  • Fondo de Investigacion Sanitaria
  • Hospital Universitario La Paz

Registry information

Official study title

Phase I Study of Two Inodilators in Neonates Undergoing Cardiovascular Surgery

Important dates

Study start
2009
Primary completion
2010
Study completion
2010
First posted
Apr 12, 2012
Registry last updated
Apr 12, 2012

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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