• Jacquelyn R Evans, Billie Lou Short, Krisa Van Meurs, and Hari Cheryl Sachs.
• Division of Neonatology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. evans@email.chop.edu
• Clin Ther. 2006 Sep 1;28(9):1366-84.

BackgroundDespite increasing investigation in the area of cardiovascular instability in preterm infants, huge gaps in knowledge remain. None of the current treatments for hypotension, including the use of inotropic agents, have been well studied in the preterm population, and data regarding safety and efficacy are lacking. Thus, the labeling information regarding the use of inotropes as therapeutic agents in this population is inadequate.ObjectiveThis article reviews the current deficiencies in knowledge with respect to measuring and achieving normal organ perfusion; summarizes the clinical, methodological, and ethical issues to consider when designing trials to evaluate medications for hemodynamic instability in the preterm neonate; and proposes 2 possible trial designs. Unanswered questions and potential obstacles for the systematic study of drugs to treat cardiovascular instability in preterm neonates are discussed.MethodsThe neonatal Cardiology Group was established in 2003 by the US Food and Drug Administration (FDA) and the National Institute of Child Health and Human Development (NICHD) as part of the Newborn Drug Development Initiative. The Cardiology Group conducted a number of teleconferences and one meeting to develop a document addressing gaps in knowledge regarding cardiovascular drugs commonly used in low-birth-weight neonates and possible approaches to investigate these drugs. This work was presented at a workshop cosponsored by the NICHD and the FDA held in March 2004 in Baltimore, Maryland. Information for this article was gathered during this initiative.ResultsTo develop rational, evidence-based guidelines corroborated by robust scientific data for cardiovascular support in newborns, well-designed and adequately powered pharmacologic studies and clinical trials are needed to evaluate the safety and efficacy of inotropic agents and to determine the short- and long-term effects of these drugs. Trials investigating the currently available and novel therapies for cardiovascular instability in neonates will provide information that can be incorporated into product labeling and a scientific framework for cardiovascular management in critically ill neonates. The Cardiology Group identified and prioritized 2 conditions for investigation of therapeutic options for the management of neonatal cardiovascular instability: (1) cardiovascular instability in preterm neonates; and (2) cardiac dysfunction in neonates after cardiopulmonary bypass surgery. Key research questions in the area of cardiovascular instability in the preterm infant include determining optimal blood pressure (BP) in preterm infants; identifying better measures than BP to determine organ perfusion; optimizing hemodynamic treatments; and clarifying any associations between BP or therapy for low BP and mortality, intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, retinopathy of prematurity, and neurodevelopmental outcome. The Cardiology Group concluded that the study of inotropic agents in neonates using outcomes of importance to patients will require a complicated trial design to address the elements discussed. The group proposed 2 clinical trial designs: (1) a placebo-controlled trial with rescue therapy for symptomatic infants; and (2) a targeted BP trial.ConclusionThis summary is intended to stimulate and assist future research in the area of cardiovascular support for preterm infants.

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