Haemodynamic insufficiency after birth is seen commonly in babies born prematurely and is associated with adverse outcomes. In current clinical practice, a combination of blood pressure and clinical signs is used to guide therapy. However, blood pressure is a poor surrogate of systemic and organ (brain) blood flow distribution during transitional circulation. This state is characterised by increased peripheral vascular resistance and increased afterload causing myocardial depression and impaired blood flow distribution in spite of 'normal' blood pressure. Echocardiography-Doppler (Echo-D) measurement of superior vena cava (SVC) flow has been proposed as a more clinically relevant marker of circulatory impairment shortly after birth than systemic hypotension. When there is low SVC flow, several small-scale clinical trials have suggested dobutamine as the optimal therapeutic option. However the associations between SVC flow and short- and long- term outcomes are not strong enough to allow SVC flow alone to be the basis for the inclusion of patients into a confirmatory trial to demonstrate the efficacy and safety of dobutamine. NeoCirc-001 - The primary objective is to answer some important questions required for the design of a subsequent placebo-controlled trial (NeoCirc-003), which will evaluate the effectiveness of a new neonatal formulation of dobutamine to treat haemodynamic insufficiency in the first 72 hours after birth in babies born at less than 33 weeks' gestation. Observational data will be collected from this population with a view to determining the degree to which diagnostic measures influence treatment decisions. The primary outcome is death or worst cranial ultrasound (CUS) appearance at or before 36 weeks' gestation. NeoCirc-001A - The primary objective is to estimate the elimination half-life, and consequently the time to steady-state of dobutamine in extremely premature neonates. NeoCirc-001B - The primary objective is to construct a population pharmacokinetic pharmacodynamic model that will be validated using samples collected during the confirmatory trial (NeoCirc-003).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
15
Infants who meet the definition of poor perfusion state will be treated at the discretion of the responsible physician following the standard local policies. The interventions will be dobutamine from a new neonatal formulation developed for NeoCirc and/or other treatments (including any other cardiovascular drug or volume replacement with normal saline).
La Paz University Hospital, Department of Neonatology
Madrid, Spain
Mortality, or intraventricular haemorrhage (IVH) grades 3 or 4, or cystic and non-cystic periventricular leukomalacia (PVL), or porencephalic cysts, ventriculomegaly, or cerebellar haemorrhage.
A composite endpoint is defined as follows: treatment failure is when one of the following is true at or before gestational age 36 (+/-2 weeks), when all surviving patients will have a cranial ultrasound (CUS)- 1. Neonate dies, or 2. Intraventricular haemorrhage (IVH) grades 3 or 4, or 3. cystic and non-cystic periventricular leukomalacia (PVL), or 4. porencephalic cysts, ventriculomegaly, or cerebellar haemorrhage.
Time frame: at 36 (+/-2 weeks) postmenstrual age
Half-life of the neonatal formulation of dobutamine.
NeoCirc-001A: Half-life of the neonatal formulation of dobutamine. The first sample will be drawn after the end of the infusion, at the time when dobutamine ceases reaching the systemic circulation of the neonate, defined as time end (te). To calculate the end of infusion (te) the dead space used in each unit will be taken into account (see below). The second sample will be taken at different study time points after the end of infusion: * 5 min after te * 15 min after te * 45 min after te * 2 hours after te * 6 hours after te Two infants will be allocated to each time point. Sampling times will be assigned randomly to the patients.
Time frame: The first sample will be drawn after the end of the infusion, at the time when dobutamine ceases. The second sample will be taken at different study time points after the end of infusion (from 5 min to 6 hours).
Arterial blood pressure
Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support
Time frame: First 72 hours of life (data collection every 9 ±3 hrs)
Capillary refill time
Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support
Time frame: First 72 hours of life (data collection every 9 ±3 hrs)
Urine output
Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support
Time frame: First 72 hours of life (data collection every 9 ±3 hrs)
Blood lactate concentration
Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support
Time frame: First 72 hours of life (data collection every 9 ±3 hrs)
Base excess
Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support
Time frame: First 72 hours of life (data collection every 9 ±3 hrs)
cerebral regional tissue oxygen saturation (rStO2)
Cerebral regional tissue oxygen saturation (rStO2) measured by means of near-infrared spectroscopy
Time frame: First 72 hours of life (data collection every 6 ±1 hrs)
Background pattern
Background pattern measured by means of Amplitude-integrated electroencephalography (aEEG/EEG)
Time frame: First 72 hours of life (data collection every 6 ±1 hrs)
Superior vena cava flow
Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support
Time frame: First 72 hours of life (data collection every 9 ±3 hrs)
Right cardiac output
Short-term outcomes of biomarkers for circulatory assessment while a patient is receiving cardiovascular support
Time frame: First 72 hours of life (data collection every 9 ±3 hrs)
Cerebral fractional oxygen extraction (FOE)
FOE= \[peripheral oxygen saturation (SaO2)-rStO2\] /SaO2
Time frame: First 72 hours of life (data collection every 6 ±1 hrs)
Interburst interval (IBI)
Interburst interval (IBI) measured by means of Amplitude-integrated electroencephalography (aEEG/EEG)
Time frame: First 72 hours of life (data collection every 6 ±1 hrs)
Discontinuity
Discontinuity measured by means of Amplitude-integrated electroencephalography (aEEG/EEG)
Time frame: First 72 hours of life (data collection every 6 ±1 hrs)
Amplitude
The amplitude measured by means of aEEG/EEG
Time frame: Fist 72 hours of life (data collection every 6 ±1 hrs)
Presence of abnormal transients
The presence of abnormal transients measured by means of aEEG/EEG
Time frame: First 72 hours of life (data collection every 6 ±1 hrs)
Synchrony
The synchrony measured by means of aEEG/EEG
Time frame: First 72 hours of life (data collection every 6 ±1 hrs)
Mortality
Time frame: From birth to 36 (+/-2 weeks) postmenstrual age
Intraventricular haemorrhage 2-4
Time frame: From birth to 36 (+/-2 weeks) postmenstrual age
Survival free of severe brain injury
Survival free of severe brain injury measured by means of cranial ultrasound studies
Time frame: From birth to 36 (+/-2 weeks) postmenstrual age
Hypotension
Time frame: From birth to 36 (+/-2 weeks) postmenstrual age
Hypertension
Time frame: From birth to 36 (+/-2 weeks) postmenstrual age
Necrotizing enterocolitis
Time frame: From birth to 36 (+/-2 weeks) postmenstrual age
Patent ductus (PDA)
Time frame: From birth to 36 (+/-2 weeks) postmenstrual age
Retinopathy of prematurity
Time frame: at 36 (+/-2 weeks) postmenstrual age
Chronic lung disease
Time frame: at 36 (+/-2 weeks) postmenstrual age
Oxygen-dependency at discharge
Time frame: At discharge
early infection
Time frame: From birth to 72 hours after birth
Nosocomial infection
Time frame: From birth to 36 (+/-2 weeks) postmenstrual age
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