Cierre farmacologico pca


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Cierre farmacologico pca

  1. 1. pharmacology reviewsPharmacologic Closure ofPatent Ductus Arteriosus inthe NeonateMeera Narayanan-Sankar MD*, Ronald I. Clyman MD†Objectives After completing this article, readers should be able to:1. Delineate the factors regulating patent ductus arteriosus (PDA) and the two stages of closure of PDA.2. Detail the medical treatment of PDA with indomethacin.3. Explain the role of ibuprofen in treating PDA.4. Discuss other agents and novel therapeutic approaches for PDA.Introduction left-to-right shunt in preterm infants.PDA is a common complication This has resulted in a greater per-that occurs in more than 70% of ceived need by physicians to treatvery low-birthweight infants who PDA.have respiratory distress syndrome The clinical consequences of(RDS). Burnard initially noted in PDA are related to the degree of1939 that murmurs were more left-to-right shunting through thecommon among infants who had ductus. The blood flow distributionrespiratory distress, and he sug- is altered by the decrease in dia-gested the possibility of PDA in stolic pressure and localized vaso-affected infants. The presence of a constriction. The reduced organductal left-to-right shunt shortly af- perfusion contributes to some ofter birth in normal term infants was the morbidity caused by PDA, in-inferred from dye dilution studies cluding feeding intolerance, necro-by Prec and Cassels and from car- tizing enterocolitis, and decreaseddiac catheterization studies by glomerular filtration rate. PDA alsoAdams and Lind and by Rowe and exposes the pulmonary microvascu-James. The first reported catheter- lature to systemic blood pressureization proof of PDA in preterm and increased pulmonary bloodinfants who had RDS was provided flow. Because the preterm infantby Rudolph and coworkers in who has RDS frequently has low1961. plasma oncotic pressure and in- Exogenous surfactant therapy has creased capillary permeability, analtered both the incidence and pre- increase in pulmonary microvascu-sentation of PDA. Although surfac- lar pressures increases interstitialtant has no effect on the contractile and alveolar lung fluid. The in-behavior of the ductus, its effects on crease in oxygen concentration andpulmonary vascular resistance lead to mean airway pressures needed toan earlier clinical presentation of the overcome these changes in lung compliance may be important fac-*Fellow in Pediatrics, Division of Neonatal-Perinatal tors in the development of chronicMedicine, University of California, Davis, Davis, CA. lung disease.† Professor of Pediatrics, Division of Neonatal-Perinatal Medicine, University of California, San The incidence of PDA is inverselyFrancisco, San Francisco, CA. related to the maturity of the infant. NeoReviews Vol.4 No.8 August 2003 e215
  2. 2. pharmacology reviewsIn term newborns, the ductus closes growth factor-beta, which play early lumen and those of the vasa vasorumwithin 24 to 48 hours after delivery. roles in ductal remodeling. invading its outer muscle media. TheHowever, in preterm newborns, the In contrast to term infants, the relative importance of the two vaso-ductus frequently fails to close. As a ductus in preterm infants frequently dilators, PGE2 and NO, in maintain-result, 70% of preterm newborns de- remains open for several days after ing ductal patency changes afterlivered before 28 weeks’ gestation birth. Even when it does constrict, birth. With advancing postnatal age,require either medical or surgical clo- profound hypoxia and anatomic re- dilator PGs no longer may be thesure of PDA. In this review, we sum- modeling often fail to develop, which dominant factor in maintaining pa-marize factors that regulate patency leads to subsequent ductal reopen- tency. These findings are consistentof the ductus arteriosus, describe the ing. Preterm infants require more with recent clinical observations thatstandard pharmacologic treatment of ductal constriction to produce the the PG inhibitor indomethacin isPDA with indomethacin, and com- same level of ductal wall hypoxia as is much more likely to close the ductuspare standard treatment with the re- found at term. If the same level of if administered on the first day aftercent use of ibuprofen. Finally, we hypoxia can be induced in the pre- birth. In preterm baboons, the com-describe novel approaches to PDA term ductus, most of the anatomic bined use of an NO inhibitor andtreatment that are in the investiga- changes that occur in term infants indomethacin produced a muchtional stage. will occur in preterm infants. greater degree of ductus constriction Closure of the ductus arteriosus at than indomethacin alone. Drugs thatFactors Regulating Patency birth depends on an alteration in the interfere with NO synthesis couldof the Ductus Arteriosus balance between dilating and con- become a useful adjunct, especially inIn the term infant, closure of the stricting factors. Since the initial situations where indomethacin hasductus arteriosus occurs in two studies of Kennedy and Clark, many proved to be ineffective.phases. Initial smooth muscle con- investigators have demonstrated thatstriction produces a “functional” clo- oxygen plays an important role insure of the lumen within hours after ductus arteriosus constriction after Indomethacin: An Alternativebirth. This is followed by “anatomic” birth. However, the biochemical ba- to Surgical Ligationocclusion of the lumen over the next sis of the oxygen response never has Surgical ligation of a symptomaticseveral days caused by extensive neo- been explained fully. PDA in preterm infants can be per-intimal thickening and loss of We have a much better under- formed in the neonatal intensive caresmooth muscle cells from the inner standing of the factors that oppose unit with low mortality and morbid-muscle media. This initial functional ductus constriction. The ductus pro- ity. However, respiratory compro-constriction of the ductus produces a duces several vasodilator substanceszone of ischemic hypoxia in the mus- that inhibit the ability of oxygen to mise, blood pressure fluctuations, in-cle media of the ductus that appears constrict the ductus. Vasodilator tracranial hemorrhage, infection,to be the necessary signal for irrevers- prostaglandins (PGs), PGE2 and chylothorax, recurrent laryngealible anatomic closure. This hypoxic PGI2, play significant roles in main- nerve paralysis, and death remainzone is associated with local produc- taining ductal patency during fetal risks associated with surgical closure,tion of hypoxia-inducible growth and neonatal life. PGE2 appears to be especially among infants born at lessfactors, such as vascular endothelial the most important prostanoid regu- than 28 weeks of gestation. Inhibi-growth factor and transforming lating ductal patency. Inhibition of tion of PG synthesis with nonselec- PG synthesis by inhibition of the en- tive inhibitors of COX appears to be zyme cyclooxygenase (COX) pro- an effective alternative to surgery for duces constriction of the ductus in closure of PDA. Over the years, ther- Abbreviations both animals and humans. In addi- apy with indomethacin, a nonselec- CBF: cerebral blood flow tion to PGs, the ductus arteriosus tive COX inhibitor, has been ac- COX: cyclooxygenase produces a nitric oxide (NO)-like va- cepted as effective in mediating NO: nitric oxide sodilator after birth. Only one of the ductal closure in preterm neonates. PDA: patent ductus arteriosus three isoforms of nitric oxide syn- However, there is little consensus re- PG: prostaglandin thase (ecNOS) appears to be located garding proper dosage, treatment RDS: respiratory distress syndrome in the ductus wall. This is restricted duration, and optimal timing of to endothelial cells lining the ductus treatment with indomethacin.e216 NeoReviews Vol.4 No.8 August 2003
  3. 3. pharmacology reviews Dose sure rate and to decrease the relapse III/IV intracranial hemorrhage andMany variations in dosage regimens rate when compared with a shorter pulmonary hemorrhage, its use mayare reported. In most instances, a course (2 to 3 doses over 24 h). be appropriate in infants who are atsingle dose has not resulted in persis- However, this dosage regimen needs high risk for developing these com-tent contraction of the ductus arteri- further evaluation. In some reports, a plications.osus. The response of the ductus to higher mortality rate was observedindomethacin depends on the size of among infants receiving prolonged Factors Affecting Ductalthe dose and the number of doses indomethacin. In summary, al- Reopeningadministered. Because the plasma though use of a prolonged low-dose Several studies have shown that theclearance of indomethacin depends indomethacin course is controversial, more immature infant has a greateron the infant’s postnatal age, a dos- an initial standard three-dose course chance of ductus reopening. Animalage regimen recommended for in- followed by an additional course may studies have shown that vasa vasorumfants at the end of the first postnatal be therapeutically advantageous in are less well developed in the pretermweek (when the half-life is 21 h) may preventing reopening of a PDA in ductus compared with the term duc-lead to elevated plasma concentra- very low-birthweight infants of less tus. Although the reduction in lu-tions when used in infants on day 1 than 28 weeks’ gestation. men area in preterm animals is similar(when the half-life is 71 h). to that seen in 1- and 2-day-old term In addition to its effects on the Timing of Treatment animals, the increase in thickness ofductus, indomethacin also is associ- The effectiveness of indomethacin in the avascular ductus wall (0.47 toated with vasoconstriction of cere- permanently closing the ductus is a 0.67 mm) is only one third of thatbral, renal, and mesenteric vascular function of the infant’s postnatal age seen at term. As a result, the diffusionbeds. Indomethacin causes reduction at the start of treatment. Indometh- path for oxygen is much less in thein cerebral blood flow (CBF) and acin is more effective when used dur- preterm ductus than it is at term.CBF velocity ranging from 25% to ing the first days after birth than Consequently, the immature ductus60%. Prolonging the rate of indo- when used several days later. This is seems to be more resistant to devel-methacin infusion (20 to 30 min) consistent with studies that demon- oping hypoxia during postnatal con-alleviates some of the decrease in strate a waning role of PGs in main- striction. Without this hypoxic stim-CBF, but it does not totally eliminate taining ductal patency with ad- ulus, there is neither cell death northe reduction in CBF velocity. vancing postnatal age. Prophylactic vessel remodeling, making the vesselA continuous indomethacin infusion indomethacin treatment within the more susceptible to later reopening.(17 mcg/kg per hour over 36 h) of first 15 hours after birth leads to a If the preterm ductus has completethe same total daily dose appears to higher rate of permanent ductal clo- obstruction of luminal blood flow, iteliminate any reduction in CBF ve- sure, primarily by causing a greater can develop the same degree of hyp-locity and decrease its adverse effects degree of initial ductal constriction. oxia as found at term. This under-further. Renal vasoconstriction also It does not affect the remodeling scores the critical importance of thehas been eliminated by continuous process or alter the inverse relation- initial constrictive phase of ductusinfusion. ship between infant maturity and closure in triggering the subsequent subsequent reopening. steps of ductus remodeling. Duration Although prophylactic indometh- Posttreatment echocardiographyPG production is suppressed only acin reduces the chances of develop- with Doppler seems to be the mosttransiently following indomethacin ing a symptomatic PDA and the need useful test for predicting ductal re-therapy. Circulating PGE2 concen- for surgical ligation, it does not ap- opening. If no evidence of luminaltrations return to the normal range pear to offer any additional advan- patency is found on the Dopplerwithin 6 to 7 days of completing tage in reducing pulmonary mor- study, the chance of later reopeningtherapy. This interval may not allow bidity or necrotizing enterocolitis is less than 20% in infants youngersufficient time for ductal remodeling compared with an approach that than 27 weeks’ gestation. However,in the most immature infants. A pro- waits for the first symptoms of a PDA if any evidence of luminal patency islonged maintenance course of low- to appear (around day 3) before ini- found, more than 90% of infantsdose indomethacin (0.1 mg/kg ev- tiating treatment. Because prophy- eventually reopen their ductus. Mak-ery 24 h for 5 to 7 d) appears both to lactic indomethacin has been shown ing distinctions in the amount of lu-increase the success of the initial clo- to reduce the incidence of grade minal flow is not important because NeoReviews Vol.4 No.8 August 2003 e217
  4. 4. pharmacology reviewseven intermittent, clinically insignifi- transient decrease in the urine output Ibuprofen appears to be effective incant degrees of luminal blood flow after the overdose. It is interesting to mediating ductal closure while possi-uniformly are associated with ductal note that there was a 10-fold differ- bly causing less vascular compromise.reopening. ence in dosage between the two It does not appear to reduce mesen- groups that initially reported the use teric blood flow, and it has a smallerComplications of of indomethacin for PDA closure in effect than indomethacin on renalIndomethacin Treatment 1976, with little difference in adverse perfusion. Ibuprofen does not re-Most infants treated with indometh- effects. duce CBF and even may extend theacin develop a transient decrease in range of blood pressures for whichglomerular filtration rate, urine out- Concurrent Use of CBF is autoregulated. Studies in an-put, fractional excretion of sodium Furosemide imals suggest that ibuprofen mayand chloride, and serum sodium con- Because furosemide increases PG have cytoprotective effects in the in-centration. Many centers do not use production, it has the potential to testinal tract.indomethacin if the serum creatinine help prevent indomethacin-related Ibuprofen is administered intrave-is above 1.2 to 1.7 mg/dL (106.1 to toxicity, but it also could decrease nously at a dose of 10 mg/kg, fol-150.3 mcmol/L) or if the urine out- ductal response to indomethacin. lowed at 24-hour intervals by twoput is less than 1 mL/kg per hour. Consequently, furosemide may have doses of 5 mg/kg each. Several re-The reasoning behind this caveat is conflicting physiologic effects in the cently published controlled, ran-that indomethacin may decrease the preterm infant who has PDA. A re- domized trials have compared theurine output further and cause signif- cent Cochrane review reported that safety and efficacy of ibuprofen withicant water and electrolyte problems. there was insufficient evidence to indomethacin in closing a PDA inA critical value of serum creatinine is support the administration of furo- preterm infants who had RDS. Ibu-not available. semide to preterm infants treated profen had less of an effect on urine Indomethacin, in adequate doses, with indomethacin for symptomatic output and fluid retention than didinhibits platelets and prolongs the PDA. Furosemide appears to be con- indomethacin, but it had a similarbleeding time. This effect lasts 7 to traindicated in the presence of dehy- effect on ductal closure. Ibuprofen9 days, until the affected platelets are dration in these infants. also had less of an effect on mesen-replaced by new ones not exposed to teric blood flow velocity comparedindomethacin. Frank renal or gastro- Prenatal PG Inhibition and with indomethacin. There was nointestinal bleeding are contraindica- the Ductus difference between the two groups intions to the use of indomethacin. Indomethacin has been used as a to- the onset of enteral feedings, rate of Isolated cases of localized intesti- colytic because PGs play a role in weight gain, or incidence of necro-nal perforation following indometh- uterine contractility. However, indo- tizing enterocolitis. Nor was there aacin treatment have been described, methacin readily crosses the placenta difference in the rate of intracranialbut an increased frequency of this and may inhibit fetal PG synthesis. hemorrhage or periventricular leu-lesion has not been observed in any Although fetal ductus constriction komalacia between the two groups.of the controlled treatment trials. may occur in as many as 60% of fe- In contrast to the previously citedThe National Collaborative study tuses exposed to indomethacin in information, some animal studiesdid observe an increased incidence of utero, these same infants have a have shown that ibuprofen and indo-occult blood loss from the gastroin- higher incidence of persistent PDA methacin cause similar decreases intestinal tract (Gersony and associ- postnatally. Indomethacin produces renal blood flow. Speziale and col-ates), but there was no increased in- constriction and ischemic hypoxia of leagues reported that both indo-cidence of necrotizing enterocolitis, the fetal ductus, which impairs the methacin and ibuprofen significantlyretinopathy of prematurity, or sepsis. future ability of the ductus to con- increased renal vascular resistance in A recent report of four infants strict after birth. newborn piglets. Chamaa and associ-weighing less than 1,000 g at birth ates demonstrated in newborn rab-who received a 10-fold overdose of Ibuprofen bits that intravenous ibuprofenindomethacin found no evidence of Ibuprofen, another nonselective caused a dose-dependent, significantmajor morbidity; 50% had a transient COX inhibitor, is emerging rapidly reduction in urine volume, glomeru-increase in serum creatinine and as a potential alternative to indo- lar filtration rate, and renal bloodblood urea nitrogen and 75% had a methacin in the treatment of PDA. flow; a decrease in filtration fraction;e218 NeoReviews Vol.4 No.8 August 2003
  5. 5. pharmacology reviewsa steep increase in renal vascular re- therapeutic approach may offer hope Brion LP, Campbell DE. Furosemide forsistance; and a decrease in urinary in the future for immature infants symptomatic patent ductus arteriosus in indomethacin-treated infants.sodium excretion. whose ductus fails to remodel after CD001148. The Cochrane Library; Ox- Cooper-Peel and coworkers have indomethacin therapy. ford, England: Update Software 2000raised questions concerning a possi- Burnard ED. The cardiac murmur in rela-ble undesirable adverse effect of Selective COX Inhibitors tion to symptoms in the newborn. Bribuprofen. They demonstrated that Two isoforms of COX have been de- Med J. 1939;1:134 Clyman RI. Medical treatment of patentibuprofen serum concentrations scribed. COX-1 is expressed consti- ductus arteriosus in premature infants.achieved during current dosing regi- tutively by most tissues and seems to In: Long WA, ed. Fetal and Neonatalmens can increase the free fraction of be responsible for the majority of PG Cardiology. 1st ed. Philadelphia, Pa: WBbilirubin by a factor of four. In con- production in the adult. COX-2 is an Saunders; 1990:682– 690trast, at therapeutic indomethacin inducible form of the enzyme that Chamaa NS, Mosig D, Drukker A, Guig- nard JP. The renal hemodynamic effectsconcentrations, there is no measur- is stimulated by proinflammatory of ibuprofen in the newborn rabbit. Pe-able displacement of bilirubin from agents. Animal studies have shown diatr Res. 2000;48:600 – 605albumin. Ibuprofen may increase the that both isoforms of COX are ex- Clyman RI, Chan CY, Mauray F, et al. Per-risk of bilirubin encephalopathy pressed in the fetal and neonatal duc- manent anatomic closure of the ductuswhen used in sick preterm infants. tus. Therefore, the applicability of arteriosus in newborn baboons: the roles of postnatal constriction, hypoxia and The use of prophylactic ibuprofen selective COX inhibition to the treat- gestation. Pediatr Res. 1999;45:19 –29has been found to be as effective as ment of PDA does not seem to be Clyman RI, Chen YQ, Chemtob S, et al. Inprophylactic indomethacin, with no very promising at the moment. utero remodeling of the fetal lamb duc-significant difference in the incidence tus arteriosus: the role of antenatal indo-of adverse effects between the two PGE2 Receptor Manipulation methacin and avascular zone thickness on vaso vasorum proliferation, neoin-agents. The vascular effects of prostaglandins tima formation, and cell death. Circula- are mediated by specific prostanoid tion. 2001;103:1806 –1812Other Agents receptors. Manipulating these recep- Clyman RI, Narayanan M. Patent ductusMefenamic acid is an anthranilic acid tors with agonists and antagonists arteriosus: a physiologic basis for currentderivative that both inhibits PG syn- may offer interesting avenues for fu- treatment practices. In: Hansen TN, McIntosh N, eds. Current Topics in Neo-thesis and reduces PG activity, possi- ture therapeutic investigations. natology Number 4. London, England:bly by blocking PG receptors. How- WB Saunders, Harcourt Publishers Lim-ever, it appears to be associated with Conclusion ited; 2000:72–91more serious gastrointestinal adverse Future studies will focus on the po- Clyman RI, Waleh N, Black SM, Riemereffects than some of the other non- tential role of combination treatment KR, Mauray F, Chen YQ. Regulation of ductus arteriosus patency by nitric oxidesteroidal anti-inflammatory agents. with indomethacin and NO inhibi- in fetal lambs: the role of gestation, ox- Aspirin (acetylsalicylic acid) had tion, the use of PG receptor antago- ygen tension and vasa vasorum. Pediatrbeen considered as an alternative to nists, and manipulation of mediators Res. 1998;43:633– 644indomethacin treatment of PDA. of vascular remodeling to produce Cooper-Peel C, Brodersen R, Robertson A.However, at the doses used, it ap- permanent ductus closure. Recent Does ibuprofen affect bilirubin-albumin binding in newborn infant serum? Phar-pears to be less effective than indo- studies have shown that ibuprofen macol Toxicol. 1996;79:297–299methacin. may be an alternative therapy for Dani C, Bertini G, Reali MF, Fabris C, PDA in infants who have decreased Vangi V, Rubaltelli FF. Prophylaxis ofFuture Directions renal function. However, potential patent ductus arteriosus with ibuprofen NO Inhibition problems arising from its interaction in preterm infants. Acta Paediatr. 2000; 89:1369 –1374Recent studies in preterm animals with bilirubin and albumin will need Gersony WM, Peckham GJ, Ellison RC,and humans have shown that al- to be avoided. Miettinen OS, Nadas AS. Effects of in-though indomethacin may not con- domethacin in premature infants withstrict the premature ductus suffi- patent ductus arteriosus: results of a na-ciently to develop tissue hypoxia, a Suggested Reading tional collaborative study. J Pediatr. Adams FH, Lind J. Physiologic studies on 1983;102:895–906combination of indomethacin and an the cardiovascular status of normal new- Hammerman C, Kaplan M. Comparativeinhibitor of NO can produce a con- born infants (with special reference to tolerability of pharmacological treat-striction that limits oxygen delivery the ductus arteriosus). Pediatrics. 1957; ments for patent ductus arteriosus. Drugand causes vessel remodeling. This 19:431– 437 Safety. 2001;24:537–551 NeoReviews Vol.4 No.8 August 2003 e219
  6. 6. pharmacology reviewsHammerman C, Glaser J, Schimmel MS, et patent ductus arteriosus: a randomized indomethacin therapy. Pediatrics. 2002; al. Continuous vs. multiple rapid infu- controlled trial. Eur J Pediatr. 2002; 110:e10. Available at www.pediatrics. sions of indomethacin: effects on cere- 161:202–207 org/cgi/content/full/110/1/e10 bral blood flow velocity. Pediatrics. Ment LR, Oh W, Ehrenkranz RA, et al. Rowe RD, James LS. The normal pulmo- 1995;95:244 –248 Low-dose indomethacin therapy and ex- nary arterial pressure during the first yearKajino H, Goldbarg S, Clyman RI, et al. tension of intraventricular hemorrhage: of life. J Pediatr. 1957;51:1–3 Vaso vasorum hypoperfusion is respon- a multicenter randomized trial. Pediat- Rudolph AM, Drorbaugh JE, Auld PAM, et sible for medial hypoxia and anatomic rics. 1994;124:951–955 al. Studies on the circulation in the neo- remodeling in the newborn lamb ductus Narayanan M, Cooper B, Weiss H, Clyman natal period. Pediatrics. 1961;27: arteriosus. Pediatr Res. 2002;51: RI. Prophylactic indomethacin: factors 551–556 228 –235 determining permanent ductus arterio- Scholz TD, McGuinness GA. Localized in-Hammerman C, Kaplan M. Patent ductus sus closure. J Pediatr. 2000;136: testinal perforation following intrave- arteriosus in the premature neonate: 330 –337 nous indomethacin for patent ductus ar- current concepts in pharmacological Narayanan M, Schlueter M, Clyman RI. teriosus. J Pediatr Gastroenterol Nutr. management. Pediatr Drugs. 1999; Incidence and outcome of a 10-fold in- 1988;7:773–775 1(2):81–92 domethacin overdose in premature in- Speziale MV, Allen RG, Henderson CR,Hammerman C, Glaser J, Kaplan M, Schim- fants. J Pediatr. 1999;135:105–107 Barrington KJ, Finer NN. Effects of ibu- mel MS, Ferber B, Eidelman AI. Indo- Patel J, Roberts I, Azzopardi D, Hamilton profen and indomethacin on the re- methacin tocolysis increases postnatal P, Edwards DA. Randomized double- gional circulation in newborn piglets. patent ductus arteriosus severity. Pediat- blind controlled trial comparing the ef- Biol Neonate. 1999;76:242–252 rics. 1998;102:e56. Available at: fects of ibuprofen with indomethacin on Van Overmeire B, Follens I, Hartmann S, cerebral hemodynamics in preterm in- Creten WL, Van Acker KJ. Treatment of 102/5/e56 fants with patent ductus arteriosus. Pe- patent ductus arteriosus with ibuprofen.Keller R, Tacy T, Clyman RI. Combined diatr Res. 2000;47:36 – 42 Arch Dis Child Fetal Neonatal Ed. 1997; inhibition of nitric oxide and prostaglan- Pezzati M, Vangi V, Biagottic R, Bertini G, 76:179 –184 din synthesis for refractory patent ductus Cianuiulli D, Rubaltelli FF. Effects of Van Overmeire B, Smets K, Lecoutere D, et arteriosus. Presented at the Annual indomethacin and ibuprofen on mesen- al. A comparison of ibuprofen and indo- APS–SPR meeting, Seattle, Washing- teric and renal blood flow in preterm methacin for closure of patent ductus ton, May 3– 6, 2003 infants with patent ductus arteriosus. arteriosus. N Engl J Med. 2000;343:Kennedy JA, Clark SL. Observations on the J Pediatr. 1999;135:733–738 674 – 681 physiological reactions of the ductus ar- Prec KJ, Cassels DE. Dye dilution curves Varvarigou A, Bardin CL, Beharry K, teriosus. Am J Physiol. 1942;136: and cardiac output in newborn infants. Chemtob S, Papageorgiou A, Aranda 140 –147 Circulation. 1955;11:789 –798 JV. Early ibuprofen administration toLago P, Bettiol T, Salvadori S, et al. Safety Quinn D, Cooper B, Clyman RI. Factors prevent patent ductus arteriosus in pre- and efficacy of ibuprofen versus indo- associated with permanent closure of the mature newborn infants. JAMA. 1996; methacin in preterm infants treated for ductus arteriosus: A role for prolonged 275:539 –544e220 NeoReviews Vol.4 No.8 August 2003
  7. 7. pharmacology reviewsNeoReviews Quiz 3. Several factors contribute to the regulation of patency of the ductus arteriosus in the fetus and the newborn. Of the following, the most accurate statement regarding ductal patency is that: A. Advancing postnatal age reduces the effect of vasodilating prostaglandins in maintaining ductal patency. B. All three isoforms of nitric oxide synthase are located in the ductal wall. C. Exogenous surfactant treatment promotes constriction of the ductus. D. Preterm neonates require lesser ductal constriction than term infants to produce ductal wall hypoxia. E. The zone of ischemic hypoxia in the muscle media of the ductus is larger in preterm than in term neonates. 4. Indomethacin, a nonselective cyclooxygenase inhibitor, is effective in mediating closure of the ductus arteriosus in preterm neonates. Of the following, the most accurate statement regarding indomethacin use is that: A. A single dose of indomethacin results in persistent constriction of the ductus. B. Circulating prostaglandin E2 concentration returns to normal within 24 hours of indomethacin treatment. C. Indomethacin is more effective when used during the first few days after birth than later. D. Prolonged infusion of indomethacin eliminates any reduction of cerebral blood flow. E. The half-life of indomethacin is positively related to postnatal age. 5. Prophylactic administration of indomethacin reduces the occurrence of symptomatic patent ductus arteriosus and the need for surgical ligation of the ductus in preterm neonates, and it may have other beneficial effects. Of the following, prophylactic indomethacin treatment is most likely to reduce the incidence of: A. Chronic lung disease. B. Disseminated intravascular coagulopathy. C. Intraventricular hemorrhage. D. Necrotizing enterocolitis. E. Retinopathy of prematurity. 6. Ibuprofen, a nonselective cyclooxygenase inhibitor, is emerging as a potential alternative to indomethacin in the treatment of patent ductus arteriosus in preterm neonates. Of the following, the potential risk most associated with ibuprofen treatment is: A. Bilirubin encephalopathy. B. Gastrointestinal perforation. C. Intraventricular hemorrhage. D. Periventricular leukomalacia. E. Renal failure. NeoReviews Vol.4 No.8 August 2003 e221