NeoAdapt 2: An Observational Study Investigating Novel Biomarkers in the Evaluation and Treatment of Neonatal Circulatory Insufficiency

Research has shown that there is large difference in how doctors treat this circulatory failure. This is because there is no agreed definition for this condition. By investigating new methods of assessing a babies circulatory status we intend to help create a new definition of circulatory failure which will in turn help doctors create further studies to identify infants with circulatory failure and find the best ways of treating this condition in babies. So far research in this area has been confined to babies born at less than 33 weeks gestation. We intend to extend the knowledge in the area to infants older that 33 weeks gestation.

Dobutamine is a drug that does not have a license for use in premature infants. In the future all new drugs will need to be studied in children before a license for them is given. In addition the European Community are encouraging that research is undertaken to look into the use of old drugs which are used in babies. As mentioned previously there is very little data to show how dobutamine is handled by babies and this study will contribute to new information on how this drug should be given to babies safely.

This is a pilot observational study in infants older than 33 weeks gestational age. The population will be observed for the diagnostic measures used to trigger treatment for circulatory failure. Treatment decisions will be made according to the preference of the responsible doctors. The treatment decision will be documented by the research team and the effect of that treatment on diagnostic measures will be recorded.

There will be an additional sub study involving those infants who receive dobutamine. This study will look at how the babies handle this drug.

WHAT WILL HAPPEN TO RESEARCH PARTICIPANTS

Infants will receive the same care as any other infant admitted to the neonatal intensive care unit. If the attending medical team decide that the infant is suffering from circulatory failure then they will receive treatment in the same way as other babies not involved in the study would. This may involve the giving of fluid through a vein, or the use of drugs such as dobutamine.

All infants who are admitted to neonatal intensive care unit will have all the standard tests and observations that infants would have. For babies included in the study for the first three days of their lives all included infants will have two specific measurements once a day. These are known as:-

1. Superior vena cava flow assessment- This involves measuring the blood flow through one of large veins that is connected to the babies' heart using an ultrasound machine. It is a painless procedure that is well tolerated by infants.
2. Pleth variability index- This involves placing a small probe on the baby's hand or foot that will measure their oxygen levels. This will be done at the same time as the superior vena cava flow assessment is performed. Again this is a painless procedure that is well tolerated by infants.

The study will also record important relevant outcomes of routine tests performed on infants admitted other neonatal unit:

1. Brain ultrasound appearances during their stay on the unit.
2. Monitoring of clinical parameters, observations and laboratory tests.
3. Major clinical diagnoses.

If an infant receives dobutamine then they will have two small blood samples taken to investigate how drug is processed in babies. This will be done via methods that minimise pain and distress for the infants involved in the study.

This will be an observational pilot cohort study with the aim of improving the definition of circulatory failure in neonates and document current treatment strategies for haemodynamic insufficiency during the transitional circulation in infants greater than 33 weeks gestational age who are admitted to the neonatal unit (NICU) for intensive care.

Inclusion criteria will be

1. Neonates >33 weeks gestational age admitted to the neonatal intensive care unit
2. Postnatal age <72 hours;
3. Parental informed consent; This population will be observed with regard to which diagnostic measures lead to treatment decisions and what the effect of those decisions are on the various diagnostic measures. Decision-making for their treatment will be based on clinical guidelines in operation at Trevor Mann Bay Unit and clinician preference.

The assessment of SVC flow and PVI will only be done in every 24 hours for the first 72 hours of life in babies.

Primary Outcome Measure Values for SVCF and PVI in neonates aged older than 33 weeks gestational age receiving intensive care derived from Echo-D and plethysmographic studies .

Observed Clinical Outcome Measures

Cranial US appearances

The analysis of the findings on cranial ultrasound scan will be interpreted in the light of a baseline scan, to be performed as soon as possible after birth on enrolment, to avoid ascribing the effect of antenatal insults to postnatal events.

Treatments for Circulatory Failure Infants will receive treatment according to the preference of the responsible physician. As is common practice, dobutamine, dopamine and/or other treatments (including other cardiovascular drugs and/or volume replacement therapy with normal saline) will be administered.

Dose of administration The dose of administration of dobutamine will be at the discretion of the responsible physician. We envisage that dobutamine will typically be started between 2.5 and 5 mcg/kg/min and increased in steps of 5 mcg/kg/min to a maximum of 20 mcg/kg/min with a given time frequency if no response is seen.

Any changes to the treatment strategy will be documented by the responsible physician.

Criteria for Up-Titration of Medication Dose escalation will be guided by clinical judgment. Clinicians will be asked to record the criteria they used in order to make this decision.

Criteria for Down-Titration Dose reduction will be guided by clinical judgment. Clinicians will be asked to record the criteria they used in order to make this decision.

Further treatment If there is no response to dobutamine at 20 mcgg/k/min or the clinical response is considered by the attending physician to be inadequate, further treatment will be at the discretion of the attending physician who will be asked to record the reasons for the change in treatment strategy as well as the additional treatment that is given to the patient.

Concomitant therapy There will be no per-protocol concomitant medication or treatment. Accordingly, other important co-interventions will follow specific centre protocols and will be recorded in the case record form.

PHARMACOKINETICS (PK) SUB-STUDY

Aim of the PK sub-studies The aim of the sub-study is to give preliminary information in order to try and construct a population PK model. Given the uncertainties regarding the PK of dobutamine in infants receiving intensive care we shall assess its elimination half life. This is defined as the amount of time for the quantity of a concentration to fall by half.

Half-life sub-study We will perform a preliminary study on all the infants included in NeoAdapt 2 that receive dobutamine as treatment for haemodynamic insufficiency. Two blood samples, of 400 μl each, will be obtained from each of these patients. 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).

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.

Plasma samples will be sent to the laboratory for the quantification of dobutamine.