Patent ductus arteriosus, treatment

An apparent association between severe retinopathy of prematurity and dexamethasone therapy has been shown in a retrospective study (SEDA-20, 372 76). Infants treated with dexamethasone required longer periods of mechanical ventilation (44 versus 26 days), had a longer duration of supplemental oxygen (57 versus 29 days), had a higher incidence of patent ductus arteriosus (28/38 versus 18/52), and required surfactant therapy more often for respiratory distress syndrome (17/38 versus 11/52). Prospective, randomized, controlled studies are needed to correct for differences in severity of cardiorespiratory disease. Until such studies are available, careful consideration must be given to indications, dosage, time of initiation, and duration of treatment with dexamethasone in infants of extremely low birthweight. 

Oral ibuprofen is often prescribed in lower doses (< 2400 mg/d), at which it has analgesic but not anti-inflammatory efficacy. It is available over the counter in low-dose forms under several trade names. A topical cream preparation appears to be absorbed into fascia and muscle an (S)( ) formulation has been tested. Ibuprofen cream was more effective than placebo cream for the treatment of primary knee osteoarthritis. A liquid gel preparation of ibuprofen 400 mg provided faster relief and superior overall efficacy in postsurgical dental pain. In comparison with indomethacin, ibuprofen decreases urine output less and also causes less fluid retention than indomethacin. Ibuprofen has been shown to be effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin. Oral ibuprofen is as effective as intravenous administration in this condition. 

Enalapril, captopril, and lisinopril (and presumably other ACE inhibitors) cross the placenta in pharmacologically significant amounts (17). There is clear evidence of fetotoxicity when ACE inhibitors are used beyond the first trimester of pregnancy. Since continuation of treatment beyond the first trimester carries an excess risk of low fetal birth weight and other more severe complications, it is important to withdraw the ACE inhibitor at this time. Intrauterine growth retardation, oligohydramnios, and neonatal renal impairment, often with a serious outcome, are characteristic (98) failure of ossification of the skuU or hypocalvaria also appear to be part of the pattern (17). There is also evidence that persistence of a patent ductus arteriosus is also more likely to occur. 

Ng PC, So KW, Fok TF, To KF, Wong W, Liu K. Fatal haemorrhagic gastritis associated with oral sulindac treatment for patent ductus arteriosus. Acta Paediatr 1996 85(7) 884-6. 

Indomethacin is FDA approved for closure of persistent patent ductus arteriosus. Successful closure is obtained in >70% of neonates treated with the drug. Such therapy is indicated primarily in premature infants who weigh between 500 and 1750 g, who have a hemodynamically significant patent ductus arteriosus, and in whom other supportive maneuvers have been attempted. Unexpectedly, treatment with indomethacin also may decrease the incidence and severity of intraventricular hemorrhage in low-birth-weight neonates. The principal limitation of treating neonates is renal toxicity, and therapy is stopped if urine output falls to <0.6 mL/kg/h. Renal failure, enterocolitis, thrombocytopenia, or hyperbilirubinemia are contraindications to the use of indomethacin. 

Indomethacin is available for the short-term treatment of acute gouty arthritis, acute pain of ankylosing spondylitis, and osteoarthritis. An injectable form to be reconstituted also is available as the sodium trihydrate salt for IV use in premature infants with patent ductus arteriosus. Because of its ability to suppress uterine activity by inhibiting prostaglandin biosynthesis, indomethacin also has an unlabeled use to prevent premature labor. 

The potent vasodilatory effects of PGE, have been used with success in treatment of severe forms of Raynaud s disease as well as vascular insufficiency in systemic sclerosis and other connective tissue diseases [168], PGE, and PGE2 also relax the ductus arteriosus of newborns. Infusions of PGE, (50 ng/kg/min) to newborns with certain cardiac malformations, which make the persistence of the ductus essential for the systemic or pulmonary circulation, improves the clinical condition and allows surgery to be delayed to a more suitable time (see ref. 169 for a review). The tone of the ductus arteriosus seems to be balanced between the constrictor effects of oxygen, possibly also other vasoconstrictor substances, and the dilatory effects of prostaglandins formed intramurally [170], Inhibitors of prostaglandin biosynthesis have been used to induce closure of patent ductus arteriosus of newborns, and in most cases the conventional surgical treatment could be omitted [171], For reviews on the role of prostaglandins in the vascular system see refs. 133, 165, 172 and 173. 

In vitro, eicosanoids are produced by all layers of the arterial wall (see above). Endogenous production of prostaglandins by smooth muscle is related partly to tone, for example gut, umbilical artery, ductus arteriosus and coronary artery (Eckenfels and Vane 1972, Tuvemo and Wide 1973, Coceani et al. 1975, Kalsner 1975). Clinically this has led to the successful use of indomethacin for the treatment of patent ductus arteriosus. To what extent do changes in smooth muscle contraction modulate endogenous production of eicosanoids by the smooth muscle cells Does generation of eicosanoids within the arterial wall either mediate or modulate the actions of other vasoactive agents on arterial smooth muscle Clearly these questions are interlinked. 

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