Inadvertent Relaxation of the Ductus Arteriosus by Pharmacologic Agents that are Commonly Used in the Neonatal Period

Abstract

Premature birth and disruption of the normal maturation process leave the immature ductus arteriosus unable to respond to postnatal cues for closure. Recent strategies that advocate conservative management of the patent ductus arteriosus (PDA) in premature infants are dependent on identification of the symptomatic PDA and understanding the risk factors that predispose to PDA. Exposure of premature infants to unintended vasodilatory stimuli may be one of the risk factors for PDA that is under-recognized. In this paper, we summarize the clinical factors that are associated with PDA and review commonly used neonatal drugs for their vasodilatory properties. Data demonstrating relaxation of the ductus arteriosus by gentamicin and other aminoglycoside antibiotics, by cimetidine and other H2 receptor antagonists, and by heparin are provided as examples of neonatal therapies that have unanticipated effects that may promote PDA.

Diagnosis and Management of Patent Ductus Arteriosus

“…Certain diuretics, such as furosemide, can prevent a ductus from closing (42) and are not recommended in the first 1 to 3 weeks, when the greatest decrease in ductus diameter occurs spontaneously. Conservative measures also include avoidance of other drugs that promote ductus arteriosus relaxation (43) and proactive use of agents like caffeine that are associated with lower rates of PDA. (44)…”

Congenital Heart Disease Requiring Maintenance of Ductus Arteriosus in Critically Ill Newborns Admitted at A Tertiary Neonatal Intensive Care Unit

“…Sixty to eighty percent of PEG1 is metabolized on first passing through the lungs and so must be administered by continuous infusion. At a starting dose of 0.025 to 0.1 microgram/ kg/minute, the ductus usually reopens within thirty minutes to two hours of initiating PGE1, with the clinical response usually being instant [11,[13][14][15].…”

Patent Ductus Arteriosus – A Complex Problem in Need of a Solid Conceptual Foundation –

“…j-circ.or.jp contrast, among premature infants, premature birth interrupts the normal maturation of ductal contractile mechanisms, leaving the ductus more susceptible to vasodilatory factors. 7 Although prostaglandins (PGs) are considered the dominant vasodilators opposing ductal constriction in the later part of gestation, 6 Kajimura et al suggest an even greater complexity in the mechanisms regulating ductus arteriosus, wherein • NO also plays an critical role in ductal patency, particularly in the setting of maternal chorioamnionitis. Another important finding in the present study by Kajimura et al is that use of a NOS inhibitor precursor, L-N G -nitroarginine methyl ester hydrochloride (L-NAME, which undergoes hydrolysis in vivo to produce L-N G -nitroarginine, the functional NOS inhibitor) prevented delayed closure of the ductus after birth in pups from LPS-injected rats.…”

“…7 Although prostaglandins (PGs) are considered the dominant vasodilators opposing ductal constriction in the later part of gestation, 6 Kajimura et al suggest an even greater complexity in the mechanisms regulating ductus arteriosus, wherein • NO also plays an critical role in ductal patency, particularly in the setting of maternal chorioamnionitis. 5 Consistent with work by Bustmante et al showing that injection of lipopolysaccharide (LPS) to pregnant dams inhibits postnatal decreases in the diameter of the ductus via mechanisms related to • NO release, 8 Kajimura et al show that LPS injection increases expression of inducible nitric oxide synthase (NOS), but not PG expression, in delayed closure of the ductus.…”

“…10 However, • NO blockade may not be therapeutically beneficial, because of the nonspecific nature of currently available treatments. 7 Although a phase I and II study by Keller et al showed higher rates of ductal closure with combined L-N G -monomethyl Arginine citrate (L-NMMA, a he ductus arteriosus (DA) is an essential component of the fetal circulation, shunting blood away from the high-resistance pulmonary vascular bed toward the placenta. At birth, the placental circulation is removed, and the lungs become the source of oxygenated blood; thus, shunting through the ductus becomes potentially harmful.…”