L.Gagliardi¹, R. Bellù², R. Zanini², C.A. Rizzi³

¹ Dept. of Women and Children Health, Ospedale Versilia, Camaiore, Italy

² Neonatal Intensive Care Unit, Ospedale Manzoni, Lecco, Italy

³ Medineos srl, Milan, Italy

Introduction - Years 2000s have been largely characterised by big Randomised Controlled Trials (RCTs) based on head-to-head comparisons between pharmaceutical products, often with large sample sizes (megatrials) and very long of follow-ups, aimed at identifying new gold standards in various therapeutic fields. However, in spite of the big efforts and resources used, not always these big trials supported unequivocal conclusions (primary endpoints). Therefore, while leading to a better profile of the medications used  (secondary endpoints), such studies missed to establish the better standard for human health management. In the last years more creative study designs were proposed, in which therapeutic procedures rather than drugs were compared as RCTs, keeping in mind the clinical outcome of patients. Herewith, an RCT in very preterm neonates with hypotension is presented, in which two well established drugs (dopamine or dobutamine) are used. However, the goal is not to compare the two pharmaceutical principles at cardiovascular level, but rather to identify the better therapeutic approach to hypotension (and its consequences) in preterm newborns.

Methodology - Dopamine and dobutamine are both sympatho-mimetic drugs endowed with different properties at cardiovascular level. Dopamine indirectly increases blood pressure by stimulating norepinephrine release. On the contrary, the primary activity of dobutamine is a direct stimulation of the b₁-adrenoceptors of the heart and the increased contractility and cardiac output. It is the ideal drug to increase tissue perfusion with limited hypertensive effects.

The hypotension-induced damage in very preterm infants is believed to occur under a certain BP threshold, because of a perfusion reduction leading to cellular, organ and systemic  damage. Thus, the rationale for aggressively treating systemic hypotension in preterm infants has been either to increase blood pressure (dopamine) to preserve adequate organ perfusion or to act only against hypoperfusion (dobutamine) when clinical signs of it are evident. The HIPHOP study (Hypotension In Preterms: Health Outcome Protocol) is designed to evaluate which of the two approaches, using different drugs, is more appropriate in preterms (23-30 weeks) with hypotension.

This is a randomised, two parallel groups, multicentre study, which will enrol 600 preterm inpatients in 27 Neonatal Intensive Care. The primary objective will be the comparison of the policy of an immediate treatment using an anti-hypotensive drug (dopamine) with watchful waiting until occurence of hypoperfusion (treatment with dobutamine), on a combined endpoint of lethality, and severe clinical outcomes such as intraventricular haemorrhage and periventricular leukomalacia. A global picture of the different outcomes will be completed by a set of secondary objectives such as necrotizing enterocolitis, retinopathy, respiratory distress syndrome, bronchopulmonary dysplasia, renal failure and iperkalemia, arrhytmias, hypertension, convulsions, effects on tyrhoid hormones, in the two treatment groups. Outcomes will be collected at the discharge visit.

Start of enrolment is April 2011. Results will be available second quarter of 2013.

Conclusions - This study will compare two arms, both including the administration of a sympathomimetic drug, either dopamine or dobutamine. However, the goal of the study is not to compare the two drugs, but rather to shed a light on the potentially best therapeutic approach, by using the methodology of the RCTs. Whether this method in this specific field is reliable for the benefit of patients and public health operators in neonatology, will be shown by the reliability and strength of the results, available the second quarter of 2013.