The pharmacologic closure of the patent ductus arteriosus
Introduction
Patent ductus arteriosus (PDA) is the most common cardiovascular abnormality of the preterm infant. Its incidence is inversely related to gestational age, such that it affects up to 60% of infants less than 28 weeks gestation. A patent ductus is essential for fetal well-being because it allows 90% of the right ventricular output to bypass the high-resistance pulmonary vascular bed in utero. Prostaglandins play a major role in maintaining ductal patency during fetal life1; of the prostaglandins, PGE2 is the most important ductus arteriosus relaxant. Postnatally, the ductus starts to close within the first few hours after birth and in the term infant is usually complete by 72 hours of age; in the preterm infant the closure usually takes longer. The increased postnatal oxygen tension, along with a decreased sensitivity of the ductus to PGE2 as the fetus approaches term, facilitates its closure. The preterm infant is more sensitive to PGE2, which makes cyclooxygenase (COX) inhibitors a feasible therapeutic modality. This chapter will address two interrelated aspects: (i) the basic mechanisms through which prostaglandins and, accordingly, COX inhibitors such as indomethacin function to elicit their effects on the ductus arteriosus; and (ii) the aspect related to efficacy of COX inhibitors in PDA closure by focusing on the more recent trials of indomethacin and ibuprofen.
Section snippets
Synthesis of prostanoids
PGE2 is the most potent ductal relaxant among the five major prostanoids, PGE2, PGF2α, PGD2, PGI2 and TXA2.2 COX enzymes are rate-limiting in converting arachidonic acid to prostanoids. The two separate genes encoding COX proteins are COX-1 and COX-2. Recently, a splice variant of COX-1, informally called COX-3, was also identified3; acetaminophen (paracetamol) has been proposed to target COX-3. COX-1 is mostly constitutive and COX-2 highly and readily expressed during inflammation. However,
Relative role of COX-1 and COX-2 in regulating DA tone
Three selective COX-2 inhibitors so far have been approved in the US by the Food and Drug Authority (FDA) for use in humans suffering from a variety of inflammatory conditions but only two selective COX-2 inhibitors are currently on the market. So far, few human studies using COX-2 inhibitors have examined their effects on ductal patency and these studies have not involved direct administration of COX-2 inhibitors to newborns. In animals, selective inhibition of COX-2 increases ductal tone in
Prostanoid receptors
Prostanoids exert their effects through receptors classified as DP, EP, FP, IP and TP, respectively, for PGD2, PGE2, PGF2α, PGI2 and TXA2; EP receptors are further divided into EP1, EP2, EP3 and EP4.4 The eight known types of prostanoid receptors are each encoded by an individual gene. Prostanoid receptors belong to the superfamily of G protein-coupled receptors. EP2, EP4, DP and IP induce smooth muscle relaxation and are more closely related to each other than to the other prostanoid
Decreased responsiveness of the preterm DA to indomethacin
Although indomethacin is very effective in closing the DA of preterm infants, its efficacy is limited in very immature infants weighing less than 1000 g at birth. This has led to the use of prophylactic indomethacin therapy or surgical ligation in the extremely low birth weight infant (see below).
A number of mechanisms seem to participate in this relative reduced responsiveness of the very preterm DA to indomethacin. As mentioned above, increased sensitivity of the immature DA to PGE2 is likely
Indomethacin
Until recently indomethacin was the only COX inhibitor approved for treatment of PDA; 70–90% of infants respond to indomethacin.19, 20 However, this response is variable due to physiological constraints of the more immature DA,21 and at gestations below 26 weeks its efficacy decreases to <60% and the risk of reopening increases to >20%.
The pharmacokinetic parameters vary widely in preterm infants due to physiological changes that occur after birth. Studies have shown large prolonged half-life
Surgical treatment
Although definitive closure of the PDA by surgical ligation is generally considered to be of low morbidity and mortality, it remains associated with a number of complications, such as pneumothorax, bleeding, IVH, chylothorax, hypotension, wound infection and vocal cord paralysis19, 47; the morbidity rate ranges from 1 to 16% and mortality from 0 to 10%. Since the widespread use of indomethacin in the 1980s, ligation has been reserved for infants with contraindications for pharmacological
Conclusion
Thus far, indomethacin remains the most frequently prescribed drug to facilitate PDA closure, either prophylactically or therapeutically. The most effective dosing regimen exhibiting the most favorable benefit/risk ratio has yet to be established. Ibuprofen is increasingly studied as a possible alternative, although more detailed data on cerebral and long-term effects are needed. Despite the relative lack of response of the very low birthweight infant to cyclooxygenase inhibitors, evidence to
Acknowledgements
B. Van Overmeire wishes to thank all collaborators, parents and infants that participated in the clinical trials supporting this review. S. Chemtob is recipient of a Canada Research Chair. He wishes to thank the following agencies that contributed to personal works presented: Canadian Institutes of Health Research, Fonds de la Recherche en Santé du Québec, Heart & Stroke Foundation of Québec, and the March of Dimes Birth Defects Foundation.
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Cited by (102)
Patent ductus arteriosus in preterm newborns: A tertiary hospital experience
2022, Revista Portuguesa de CardiologiaCitation Excerpt :However, it remains unclear whether the various comorbidities identified arise as a result of prematurity, the existence of PDA with hemodynamic significance, or the therapeutic interventions. Additionally, the optimal point for therapeutic intervention after PDA diagnosis remains uncertain, since waiting for spontaneous closure may prevent overtreatment and associated adverse effects, and ibuprofen treatment itself seems to be effective even when applied relatively later.7 Nevertheless, aggressive and early treatment of PDA has been recommended to prevent further complications.
An echocardiographic evaluation to determine the immediate and short-term changes in biventricular systolic and diastolic functions after PDA device closure-an observational analytical prospective study (echo- PDA study)
2021, Indian Heart JournalCitation Excerpt :Patent Ductus Arteriosus (PDA) is a commonly occurring acyanotic congenital heart disease resulting due to failure of physiological constriction of ductus in newborn. The overall prevalence of PDA as a congenital heart disease is around 6–11%.1–4 The isolated PDA is present in 1 in 2000 live term births.5
The molecular mechanisms of oxygen-sensing in human ductus arteriosus smooth muscle cells: A comprehensive transcriptome profile reveals a central role for mitochondria
2021, GenomicsCitation Excerpt :Therefore, understanding the physiology of DA closure becomes crucial in the development of therapeutic interventions in addition to nonsteroidal inflammatory drugs (NSAIDs), percutaneous DA closure devices, or surgery. Currently, treatments for PDA include invasive surgical intervention and percutaneous interventions [8] in infants who fail a trial of NSAIDs (neonates <32 week's gestational age) [9–11]. Intervention to close the patent DA includes risks of complications like recurrent laryngeal nerve damage whilst the use of NSAIDs may cause gastrointestinal, renal and cerebral side-effects [12–15].
Evidence-based use of acetaminophen for hemodynamically significant ductus arteriosus in preterm infants
2018, Seminars in Perinatology