persistent patent ductus arteriosus

International Journal of Technology Assessment In Health Care, 7:Suppl. 1 (1991), 70-78.Copyright © 1991 Cambridge University Press. Printed in the U.S.A.

PERSISTENT PATENTDUCTUS ARTERIOSUS

Ronald I. ClymanMt. Zion Hospital and Medical Center, San Francisco

Two observations about the ductus arteriosus are established: most normally devel-oped infants will have a patent ductus arteriosus (PDA) at the time of delivery, andmost fullterm infants will have anatomic obliteration of the ductus lumen by 3-6 monthsof age. Studies designed to determine how a PDA contributes to an infant's morbidityor when a PDA becomes a persistently patent ductus arteriosus have been hamperedby the lack of consistent diagnostic criteria for defining the condition. Ellison et al.(22) attempted to evaluate several commonly used criteria for diagnosing a large left-to-right shunt through the ductus arteriosus by noting the occurrence of each sign bothbefore and 36-48 hours after surgical ligation. No single criterion sufficed as an indi-cator of PDA. Certain signs, such as continuous murmur or hyperactive left ventric-ular impulse, were specific for a PDA, but lacked sensitivity; conversely, M-modeechocardiography and ventilatory support criteria were very sensitive but lacked speci-ficity.

The combination of two-dimensional echocardiographic visualization of the ductuswith either pulsed, continuous wave, or color Doppler measurements appears to benot only very sensitive but also specific for identifying ductus patency (20;27;33;42;62),this combination may also be useful in determimng pressure gradients across the ductus(46). However, its usefulness in determining the magnitude of the ductus shunt hasnot yet been convincingly demonstrated (20). Attempts to correlate echocardiographicor angiographic findings with the presence of a "symptomatic" patent ductus arteri-osus have been hampered by the lack of a "gold standard" measurement for symptom-atic PDA (21;22;42). In addition, the presence of a significant ductus shunt may berequired for several days before symptoms develop (21;42). Thus, we have the abilityto determine whether some degree of ductus patency exists but no clear consensuson how to decide which patent ductus is a potential source of problems.

If we cannot agree on the diagnostic criteria necessary to define a patent ductusarteriosus, deciding when patency becomes problematic or persistent is even harder.Pulsed Doppler echocardiographic assessments of fullterm infants indicate that func-tional closure of the ductus has occurred in almost 50% by 24 hours, in 90% by 48hours, and in all by 96 hours (27). In contrast, the ductus of many preterm infantswill remain open for many days or weeks (20;42). Twelve flours following delivery, ductusshunts in preterm infants can be shown to be greater than those in term infants (20).However, not all infants with angiographic or Doppler demonstrable ductus patencywill develop clinical symptomatology (21;42): the more mature the infant, the less thelikelihood that ductus patency within the first 48 hours after delivery will require sub-sequent therapeutic intervention (21;42). In one study of 1,689 infants with birth weights

Persistent patent ductus arteriosus

less than 1,750 g, a large "hemodynamically significant" PDA was noted in 42% ofinfants with birth weights less than 1,000 g, in 21% of infants between 1,000-1,500 g,and in 7% of those between 1,500-1,750 g (22). The incidence of PDA is also muchhigher in infants with respiratory distress syndrome (13;59;64;65). Furthermore, an in-creased incidence of symptomatic PDA has been noted in preterm infants who ex-perience perinatal asphyxia (18). The rate of fluid administration during the initialseveral days after birth may influence the incidence of symptomatic PDA (6) or mayonly alter its detection (4).

Since the initial studies of Kennedy and Clark (36), many investigators have demon-strated that oxygen is responsible for constricting the ductus arteriosus after birth.However, the biochemical basis for the oxygen response has never been fully explained(16;23). Although neural and hormonal factors possibly contribute to the closure ofthe ductus under physiological conditions, they do not mediate oxygen-induced vesselclosure. Oxygen has a greater constrictor effect in ductus from older than in thosefrom younger fetuses (10). Studies in fetal animals indicate that the increased contrac-tile response of the mature ductus arteriosus to oxygen is due to a developmental alter-ation in the sensitivity of the vessel to locally produced prostaglandins: ductus smoothmuscle from animals near term is less sensitive to the dilating action of prostaglandin(PG) E2 than that from younger fetuses (10). There is some evidence to suggest thatPGE2 production by the ductus after delivery may be stimulated by reactive oxygenmetabolites (15). The factors that alter the sensitivity of the ductus to locally producedPGE2 are unknown. Elevated cortisol concentrations in the fetus have been found todecrease the sensitivity of the ductus to PGE2 (13), consistent with these findings,prenatal administration of glucocorticoids causes a significant reduction in the inci-dence of PDA in premature human and animal infants (11;13;17;45;64;67).

In normal, fullterm animals, loss of responsiveness to PGE2 shortly after birthprevents the ductus arteriosus from reopening once it has constricted. In prematureinfants, once the ductus has closed (either spontaneously or as a result of indometh-acin administration), it may reopen at a later date, with recurrence of the left-to-rightshunt (41). The incidence of ductus reopening is inversely related to birth weight: 33%of infants with a birth weight less than 1,000 g reopened their ductus after initial clo-sure, while only 8% of infants with birth weights greater than 1,500 g reopened theirductus (12). Premature animals' persistent responsiveness to PGE2 after ductus con-striction may account for the high rate of ductus reopening observed in preterm in-fants after successful indomethacin-induced closure. Of those infants whose ducti re-open after initial closure, 80% apparently remain responsive to indomethacin (12). Thefactors that maintain ductus responsiveness to PGE2 in immature animals after post-natal ductus constriction are unknown, as is the reason that a premature ductus failsto develop the normal anatomic obliteration of its lumen.

Indomethacin appears to be an effective alternative to surgery for treatment ofa PDA (28). Its efficacy and toxicity have been explored extensively, and it appearsto be comparable to surgical ligation in preventing the complications associated witha PDA: bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), in-tracranial hemorrhage (ICH), and intolerance of enteral feedings (28). In most inten-sive care nurseries, indomethacin has replaced surgery as the preferred therapy for apersistent PDA, probably because the most frequently occurring risks associated withligation (increased incidence of cicatricial retinopathy of prematurity and need forthoracotomy) seem more serious than those associated with indomethacin (decreasedurine output and increased bleeding other than ICH) (28). While there may be generalconsensus on the efficacy of indomethacin for treatment of a PDA, questions about

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Clyman

proper dosage, treatment duration, and optimal timing of treatment remain quite con-troversial.

When treating 8-10-day-old infants with left-to-right shunts that are causing car-diovascular compromise, the response of the ductus to indomethacin depends on thesize of the dose (0.3 mg/kg vs. 0.1 mg/kg) (69), as well as on the number of dosesadministered (1 vs. 2 or 3) (69;70). Because drug clearance depends on postnatal age(9;12;60;63;68;69), one can envision that using the same indomethacin dosage regimerecommended for infants at 8-10 days (when the half life of the drug is 21 hrs) (68;69)in infants who are treated on day 1 (when the half life is 71 hrs) (60) may lead to elevatedand prolonged plasma concentrations. Not surprisingly therefore, Krueger et al. (37)found a single loading dose of indomethacin (0.2 mg/kg) without subsequent main-tenance doses effective in preventing clinical symptoms associated with a PDA whenadministered to very low birth weight (VLBW) infants within the first 24 hours fol-lowing delivery.

The age at which infants are treated with indomethacin is another important vari-able in the treatment's overall effectiveness (25). Several investigators have suggestedthat the relative ineffectiveness of indomethacin in treating infants of advanced post-natal age may be due to rapid drug clearance and a resultant inability to maintain"desired" plasma concentrations (9;63). In general, however, the response of the ductusand the side effects of indomethacin do not correlate with the peak concentration ofthe drug (4;7;8;9;28;47;69). Thus, in most infants the failure of indomethacin to pro-duce ductus constriction is not due to lowered drug concentrations alone. In addition,there has been no consistent correlation between ductus closure after treatment withindomethacin and either the area under the curve or the plasma concentrations at 6,12, or 24 hours (l;9;28;51;52;53;70). Even when indomethacin concentrations have beenmaintained in the "desired" range, the drug's ability to produce ductus closure remainsinversely proportional to the postnatal age at the time of treatment (1;52;53). Thisdecreasing effectiveness of indomethacin to produce ductus closure with advancingpostnatal age has been shown to be due to the diminishing ability of PGE2 to main-tain ductus patency (14). Thus, patency of the ductus arteriosus becomes independentof dilator prostaglandins with advance in postnatal age (1;29).

A second type of indomethacin treatment failure is found in patients whose ductiinitially constrict when treated with indomethacin only to reopen several days later.Recurrence of a symptomatic PDA after initial successful treatment is independentof initial plasma indomethacin concentrations (9;28;51). Prolonged treatment with in-domethacin may delay reopening of the PDA as long as the drug administration con-tinues (24;57); however, the ultimate rate of reopening remains constant whether indo-methacin treatment is administered for 5-7 days or only for 36 hours (24;57). The rateof reopening, which is greatest among the most immature infants, may also be relatedto the timing and completeness of initial ductus closure after delivery (12;14). Infantswith spontaneous closure during the first 3 postnatal days do not have subsequentsigns of a symptomatic PDA (21;43). Similarly, those infants whose ducti are closedwith indomethacin during the first 2 days after delivery (35;39;40;61) appear to havea lower incidence of reopening when compared with those treated between 8-10 days(9;28;32;41;51;54) or after 20 days (34). Because of the lower incidence of indometh-acin failure and ductus reopening when indomethacin is administered within the first48 hours, there is less need for surgical ligation than when it is given after the firstweek (28;32;39;40;61). In summary, indomethacin is most effective when administeredwithin the first days after delivery; not only can the total dose be lower (although there

7 2 INTL. J. OF TECHNOLOGY ASSESSMENT IN HEALTH CARE


are probably equal plasma concentrations), but also the overall success rate is greaterthan when indomethacin is given after the first week.

Indomethacin treatment may be most effective in the first 24-48 hours after delivery,but is that necessarily the best time to administer it? Of infants with severe respiratorydistress, 90% have evidence of a PDA on contrast echocardiogram within the first24 hours; however, only 40% subsequently will develop symptoms of hemodynami-cally large left-to-right shunt that will require intervention with indomethacin or sur-gery (21). In addition, most infants will not develop the symptoms of cardiovascularcompromise before 7 days, (4;19;28). Therefore, treating infants within the first 24-48hours implies that approximately 60% of the infants treated would never have devel-oped symptoms of cardiovascular compromise. Because indomethacin has been as-sociated with several frequent as well as infrequent complications (2;5;26;28;37;38;52;69),such an aggressive approach to therapy can be justified only if early treatment canbe demonstrated to alter outcome significantly in these infants.

Cotton et al. (19) demonstrated that failure to close the ductus after significantclinical symptoms of cardiovascular compromise have developed (approximately 7-10days) significantly increases neonatal morbidity. Similarly, treating infants after signsof a hemodynamically significant PDA develop (2-3 days), but before the presenceof cardiovascular compromise (7-10 days), leads to a reduction in mortality and BPD(35;44).

If infants receive indomethacin treatment at the first clinical sign of a PDA (anasymptomatic murmur) instead of after the symptoms of a hemodynamically signifi-cant shunt are apparent, they demonstrate a significant reduction in the developmentof large shunts and in the number of surgical ligations required, as well as in the totalduration of oxygen therapy and time to regain birth weight (39;40). In addition, thefrequency of complications does not increase significantly with this approach (39;40).However, the effectiveness of indomethacin treatment as soon as clinical signs of aPDA become apparent, but before a major shunt has developed, can be demonstratedonly among infants weighing less than 1,000 g. These small premature infants withasymptomatic murmurs are at high risk (80%) (39;40;55) for developing large ductusshunts and appear to benefit from early indomethacin treatment (39;40). In contrast,only 30% of infants with birth weights greater than 1,000 g who have an asymptom-atic murmur will subsequently develop symptoms of a major shunt. These larger in-fants have a high rate of spontaneous closure; as a result, early treatment of an asymp-tomatic murmur in these infants offers no advantage over initiating therapy only aftersymptoms of a significant hemodynamic shunt have developed (40).

Even less evidence supports treating infants with indomethacin before clinical signsof a PDA develop. Hammerman et al. (32) treated infants with birth weights less than1,000 g who had no clinical evidence of a PDA, but who had evidence of left-to-rightductal flow on contrast echocardiogram (Day 2-3). Prophylactic closure in these in-fants with "silent" PDA decreased the incidence of clinically symptomatic PDA andthe need for ultimate ligation; however, it did not affect the development of BPD (aswas seen in the studies discussed earlier) or the incidence of ICH or NEC.

To date, at least nine centers have performed controlled studies to examine theeffects of prophylactic indomethacin treatment during the first 24 hours after delivery(30;37;39;43;48;49;50;52;55;56;61;66). Although most reports are still in abstract form,some preliminary conclusions can be made. Results from 622 infants with birth weightsless than 1,500 g (mean = 1,100 g) and gestational age of 28.5 weeks have been reported.More than 85% had respiratory distress at the time of entry, which was between 6-24

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Clyman

hours after delivery. Only 6% of the infants who received prophylactic indomethacin,compared with 40% of those in the control group, developed a hemodynamically sig-nificant PDA (p < 10~6). Two (43;56) of the nine centers reported a significant reduc-tion in the incidence of ICH; however, no significant reduction could be found whencombining results from all the studies (ICH 3* grade I: control = 120/288 [42%] vs.indomethacin = 99/282 [35%]). If one considers just the frequency of bleeds greateror equal to grade II, then there was still a significant difference between the two treat-ment groups when all the studies were combined (ICH > grade II: control = 107/266[40%] vs. indomethacin = 67/256 [26%], p < 0.001) (14;22;29;31;33;43; 44;46;47). Therewere no significant differences between the two groups in the total duration of oxygentherapy or ventilatory support (30;37;39;43;44;45;46;47;48;49;50; 52;56;61;66), nor werethere significant differences in the incidence of BPD, NEC (37;39;50;52;55;61;66), ortime to regain birth weight (37;39). Four of five studies reported a transient but signifi-cant alteration in renal function in the prophylactic treatment group (30;37;39;48;52).One study (52) found a significant increase in the incidence of gastrointestinal hemor-rhage in the prophylactic treatment group. These findings are not at all surprising,especially when one considers that only 40% of the infants who were eligible for treat-ment within the first 24 hours ultimately would have developed a hemodynamicallysignificant PDA (30;37;39;43;50;52;55;61;66). The chances of this occurring would beeven less (14%) among the infants with birth weight greater than 900 g (55). The findingsin these nine studies are also consistent with the increasing number of animal studiesthat suggest that during the first day after birth, a PDA does not alter the course ofhyaline membrane disease (3;49;58).

At this time, the available information does not support routine indomethacintreatment on the first day of life in small premature infants; most of these infants willnever have signs of a hemodynamically significant PDA. Except for decreasing theincidence of symptomatic PDA and the need for surgical ligation, routine first-daytreatment does not significantly decrease morbidity. Rather, in infants who weigh lessthan 1,000 g at birth, it would seem appropriate to treat a PDA when it first becomesclinically apparent and before signs of a large shunt are evident; 80% of these infantswill develop a large shunt, and treatment at this time has been associated with botha decreased need for surgical ligation and decreased neonatal morbidity. There ap-pears to be no advantage in treating infants with birth weights greater than 1,000 gbefore they develop signs of a hemodynamically significant shunt; however, once thisdoes occur, prompt treatment rather than conservative management will significantlydiminish later morbidity.

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persistent patent ductus arteriosus

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