Persistent responsiveness of the neonatal ductus arteriosus in immature lambs : a possible cause for reopening of patent ductus arteriosus after indomethacin - induced

Reopening of the ductus arteriosus after successful indomethacin-induced closure has become a major problem with indomethacin treatment. In full-term human newborns and lambs, the ductus behaves like ischemic tissue after its initial constriction. Its ability to continue to relax or contract depends on the amount of left-to-right shunt through the ductus lumen. To see if ductus constriction in preterm lambs would produce the same loss of ductus responsiveness, we delivered 42 lambs by cesarean section and ventilated them for 6.6 + 0.5( + SE) hr. We measured ductus arteriosus resistance and left-to-right shunt with the use of radionuclide-labeled microspheres. After the hemodynamic measurements were obtained, the ductus was studied in vitro. Immature lambs were more likely to have reactive ductus (after their initial ductus constriction) than were more mature lambs. This was due to a diminished degree of ductus constriction as well as persistence of ductus responsivenes in immature lambs when compared with more mature lambs. This persistence of ductus responsiveness in immature lambs after ductus constriction may account for the high reopening rate in preterm infants after successful indomethacin-induced closure. Circulation 71, No. 1, 141-145, 1985. SEVERAL recent controlled trials have demonstrated that indomethacin is effective in treating the patent ductus arteriosus (PDA)'-' in preterm infants. However, it has become apparent that once the ductus arteriosus has been closed by indomethacin, it may reopen at a later date, with recurrence of the left-to-right shunt. The reported incidence of reopening of the ductus arteriosus after successful indomethacin treatment has varied from 20% to 100%.' 2,4, 6`0 These studies are difficult to compare since indomethacin was given at different postnatal ages to infants of different gestational ages and in different amounts per dose. However, reopening of the ductus arteriosus did not appear to be associated with excessive fluid therapy before or after treatment7 or with low plasma concentrations of indomethacin during the initial therapy.'0 The mechanisms regulating patency and closure of From the Department of Pediatrics, Mt. Zion Hospital and Medical Center, and the Cardiovascular Research Institute and Department of Pediatrics. University of California, San Francisco. Supported by grants from the United States Public Health Service Program Project HL24056 and SCOR HL27356. Address for correspondence: Ronald Clyman, M.D., 1403 HSE, University of California, San Francisco, San Francisco, CA 94143. Received Aug. 17, 1984; accepted Sept. 20, 1984. Vol. 71, No. 1, January 1985 the ductus arteriosus are only partially understood. There appears to be a balance between the constricting effect of oxygen and the vasodilating effect of prostaglandins. The marked sensitivity of the lamb ductus to prostaglandin E, (PGE,) suggests that this is the most important prostanoid for regulation of vessel patency in this species." However, within a few days after birth the relaxing effects of PGE, and hypoxia are lost and the ductus remains "irreversibly" closed thereafter. 12-15 Fay and Cooke'3 have proposed that irreversibility reflects a mechanical restraint imposed by cellular necrosis, loss of an intact endothelium, and intermingling of cells from opposing walls such that there was no longer an anatomic lumen. Because necrosis and cell dislocation are limited to the central regions of the ductus, several authors have suggested that these processes result from interruption of luminal blood flow. 3' 16-1 We have previously observed a decrease in the ability of the ductus arteriosus to dilate and contract that occurs within the first hours after postnatal ductus constriction and before the loss of an anatomically patent lumen in human newborns and in full-term lambs.'2 141 by gest on N ovem er 2, 2017 http://ciajournals.org/ D ow nladed from