Dobutamine Versus Placebo for Low Superior Vena Cava Flow in Newborns

Study Overview
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Brief Summary
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Low systemic flow as measured by Doppler-echocardiography has been associated with poor neurological outcome. Yet, it has not been systematically evaluated whether the treatment of this hemodynamic condition is beneficial or not. This study aims to evaluate if treating low systemic flow in preterm infants with dobutamine has any effect on the cerebral circulation and in newborn prognosis.

Detailed Description
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While rates of survival for very preterm infants are increasing, a significant number of these patients suffer from neurodevelopmental disabilities. The pathophysiology of brain injury in the preterm infant is unclear, although haemodynamic disturbances during the period of transitional circulation after birth leading to ischemia-reperfusion events seem to play an important role. Up to one third of infants born under 30 weeks of gestation develop low systemic flow as measured by Doppler-echocardiography (low superior vena cava flow, SVCF); this finding has been associated with poor neurological outcome. Yet, it has not been systematically evaluated whether the treatment of this hemodynamic condition is beneficial or not. This study aims to evaluate if treating low systemic flow in preterm infants with dobutamina, DB, (inotrope-sympathicomimetic drug) has any effect on the cerebral circulation; specific interest of our research would be to target DB dose for individual patient´s response. Secondly, by means of two non-invasive technologies (cerebral and cardiac ultrasonography-Doppler and near infrared spectroscopy, NIRS), the investigators search to characterise eventual differences in brain perfusion patterns during the adaptation to the transitional circulation that might be associated with the development of brain injury in the most vulnerable population.

Official Title
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Randomised Double Blind Clinical Trial of Dobutamine Versus Placebo for Low Superior Vena Cava Flow Treatment in Low Birth Weight Infants: Systematic Assessment of Cerebral and Systemic Hemodynamics Effects

Conditions
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Hemodynamic Instability

Intervention / Treatment
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* Drug: Dobutamine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Newborn infants born at ≤ 28 weeks of gestational age. Newborn infants born at > 28 weeks of gestational age and ≤ 30 weeks of gestational age with moderate-severe respiratory distress syndrome, defined as the necessity of respiratory support with a mean pressure ≥ 4 cm H2O or FiO2 ≥ 0.3 Admission at the NICU in the first 6 hours of life Inotrope treatment absent Inform consent signed Exclusion criteria Early systemic hypotension, defined as a mean arterial pressure (MAP) lower than the gestational age, during at least 60 minutes and maintained after volume infusion Major congenital malformation Informed consent declined

Ages Eligible for Study
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Maximum Age: 12 Hours

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dobutamine<br>Patients with low SVCF in the first 12 hours of life will be randomised to receive dobutamine or placebo. | Drug: Dobutamine<br>* Patients with low SVCF in the first 12 hours of life will be randomized to receive Dobutamine or Placebo. First dose: 5 microg/k/min; second dose: 10 microg/k/min; third dose: 15 microg/k/min; forth dose: 20 microg/k/min. Dobutamine concentration will be prepared in a 20 ml syringe and the dose will be adjusted so each 0.1 ml/kg per hour increase in flow rate would deliver the corresponding step-increase in the drug infusion dose. Dose increments will be 5, 10, 15, 20 microg/kg per minute The study drug was increased in a stepwise manner every 30 minutes until the optimal SVCF was attained and maintained for 60 minutes (SVCF-OP). Treatment duration: 24 hours of postnatal age, maintaining the infusion rate which achieves the SVCF-OP.<br>* Other names: DB;|
| Placebo Comparator: Placebo<br>Patients with low SVCF in the first 12 hours of life will be randomised to receive Dobutamine or Placebo. | Drug: Placebo<br>* Patients with low SVCF in the first 12 hours of life will be randomised to receive Dobutamine or Placebo (dextrose 5% in water, D5W, as Placebo)<br>* Other names: PL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Low SVCF prevalence | Low superior vena cava flow (SVCF) prevalence (<40cc/kg/min ) assessed with echocardiography | From birth to the 4th day of postnatal life | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Required dose for achieving SVCF-OP (≥40 cc/kg/min) | Required dose of dobutamine for achieving superior vena cava flow optimum (SVCF-OP) that is SVCF ≥40 cc/kg/min | From birth to the 4th day of postnatal life | 
| Required dose for achieving SVCF-OP-60 (≥40 cc/kg/min maintained during 60 minutes) | Required dose of dobutamine for achieving superior vena cava flow optimum for 60 min (SVCF-OP-60), that is SVCF ≥40 cc/kg/min maintained during 60 minutes | From birth to the 4th day of postnatal life | 
| NIRS variables | NIRS variables: TOI (tissue oxygenation index), ∆HbT (as a marker of changes in cerebral blood volume, ΔDHb (as a marker of changes in cerebral blood flow will be monitored continuously by NIRS. | From birth to 24 hours of life | 
| Doppler-cranial ultrasonography (PD-CUS) variables. | Doppler-cranial ultrasonography (PD-CUS) variables. Changes in cerebral blood flow velocities and the resistance index in cerebral arteries will be evaluated. The effect of SVCF changes on these variables will be analysed. | From birth to the 4th day of postnatal life | 
| Invasive or non-invasive arterial blood pressure | Invasive or non-invasive arterial blood pressure | From birth to the 4th day of postnatal life | 
| Central and peripheral temperature | Central and peripheral temperature | From birth to the 4th day of postnatal life | 
| Heart rate | Heart rate | From birth to the 4th day of postnatal life | 
| Respiratory rate | Respiratory rate | From birth to the 4th day of postnatal life | 
| Other echocardiographic variables | Right and left ventricular output Pulmonary pressure Patent ductus arteriosus | From birth to the 4th day of postnatal life | 
| Biochemistry markers | Arterial, venous or capillary gasometry, serum lactate Hemogram, ions, glycemia, creatinine, proteins, Troponine I, N-terminal probrain natriuretic peptide(NT-proBNP) | From birth to the 4th day of postnatal life | 
| Structural brain damage markers: | Intraventricular hemorrhage (IVH) grade 1. IVH grade 2. IVH grade 3. Periventricular hemorrhagic infarction. Moderate or severe periventricular echogenicity. Persistent periventricular echogenicity. Cyst periventricular echogenicity. | From birth to discharge (approximately around 10-15 weeks) | 
| Mortality and neurodevelopment variables | Mortality rate Cerebral palsy Neurodevelopmental delay | From birth until 2 years of corrected age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Low superior vena cava flow, Functional echocardiography