Overview of Patent Ductus Arteriosus, Diagnosis, Treatment Approaches

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1 Overview of Patent Ductus Arteriosus, Diagnosis, Treatment Approaches 1 Ahmad Jaber Aseeri, 2 Abdulrahman mohammed asiri, 3 Suliman Abdullah assri, 4 Turki Ali Abdullah AlElyani, 5 Mohammed Omar Mohammed Alsayed, 6 Ahmed Omar Al Khudhayr, 7 Faiz Jaber Hassan Sahari, 8 Abdullah Abdu Alasmari Abstract: In this review, we intended to overview the diagnosis and treatment options of Patent ductus arteriosus (PDA) by summarizing evidence for PDA diagnosis methods and the available therapeutic interventions for this heart congenital disease. Electronic Databases (MEDLINE, PubMed, and Emabse) were used to conduct a comprehensive review on Patent ductus arteriosus (PDA) in general and specifically the diagnostic approaches and treatment options. Restriction to English language published study up to December, 2016 was applied. Furthermore, references list of identified studies was searched for more relevant articles. Typical medical diagnosis among exceptionally premature infants, specifically in those with lung disease. Treatments are frequently utilized to close the PDA. Despite nearly 3 years of research, the question of whether the advantages of treatments to prevent ductal patency or promote closure surpass the threats of these treatments remains unanswered. The authors seldom utilize treatments created to close the PDA. Spontaneous closure of the patent ductus arteriosus (PDA) prevails. Therapy is normally sensible if considerable breathing distress or impaired systemic oxygen shipment is present. Intravenous (IV) indomethacin (or the more recent preparation of IV ibuprofen) is frequently efficient in closing a patent ductus arteriosus (PDA) if it is administered in the first days of life. I. INTRODUCTION Patent ductus arteriosus (PDA) is one of the most common hereditary heart defects. A PDA, defined as failure of the ductus arteriosus (DA) to close within 72 hours after birth (1), might lead to substantial infant morbidity and mortality rates that approach 30% (2). Possible complications of a persistently patent DA after birth include cardiac arrest, kidney dysfunction, necrotizing enterocolitis (NEC), intraventricular hemorrhage, and transformed postnatal nutrition and development. PDA is a common medical diagnosis in these infants. Approximately 65% of infants born at less than 28 weeks' pregnancy will have relentless patency of the ductus arteriosus and will be appointed the medical diagnosis of PDA at a long time during the early neonatal duration (3). PDA is associated with neonatal morbidities such as chronic lung disease (CLD) and necrotising enterocolitis (NEC) (4,5,6). Although a domino effect relationship in between PDA and these morbidities has not been developed, numerous neonatologists administer cyclo oxygenase (COX) inhibitors (eg, indomethacin or ibuprofen) to promote closure of the ductus arteriosus under the presumption that early closure reduces the probability of these and other morbidities (7). The reported incidence of PDA in term neonates is only 1 in 2,000 births, representing 5% - 10% of all congenital heart disease (8). The incidence of PDA in preterm neonates is far greater, with reports varying from 20% - 60% (depending upon population and diagnostic criteria) (9). The increased occurrence of PDA in the preterm infant is attributable to the absence of regular closure mechanisms due to immaturity. Gestational age and weight are intimately connected to PDA in preterm neonates. Particularly, PDA is present in 80% of infants weighing less than 1,200 g at birth, compared with 40% of infants weighing less than 2,000 g at birth (10). Physiological research studies have actually revealed a number of hemodynamic modifications that normalize after successful ductal closure. Epidemiological research studies have also demonstrated substantial associations between a Page 2114

2 large PDA and neonatal outcomes, consisting of intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and mortality. Trials of treatment to date have actually not revealed enhancements in results. Irregularity in techniques to evaluation and management of PDA has been suggested as one description for these irregular findings (7,9). In this review, we intended to overview the diagnosis and treatment options of Patent ductus arteriosus (PDA) by summarizing evidence for PDA diagnosis methods and the available therapeutic interventions for this heart congenital disease. II. METHODOLOGY Electronic Databases (MEDLINE, PubMed, and Emabse) were used to conduct a comprehensive review on Patent ductus arteriosus (PDA) in general and specifically the diagnostic approaches and treatment options. Restriction to English language published study up to December, 2016 was applied. Furthermore, references list of identified studies was searched for more relevant articles. Pathophysiology of PDA: III. RESULTS The DA is stemmed from the distal dorsal sixth aortic arch and is completely formed by the eighth week of pregnancy (8). Its role is to shunt the blood from the nonfunctional fetal lung through its connection between the primary lung artery and the proximal coming down aorta. This right-to-left shunt permits the blood with a relatively low oxygen concentration to be brought from the ideal ventricle through the coming down aorta and eventually to the placenta, where gas exchange will take place. Prior to birth, roughly 90% of right ventricular output circulations through the DA. (Figure 1) shows the function of the DA in redirecting fetal flow in contrast to neonatal circulation (11). Premature closure in the fetus is associated with considerable morbidities, consisting of right-sided cardiac arrest, which might lead to fetal hydrops (8). Generally, the DA closes within hours after a full-term birth; if after 72 hours the ductus cannot close, a diagnosis of relentless PDA may be made (12). Figure 1: Left The ductus arteriosus is an essential component of fetal circulation. It functions by shunting blood away from the nonfunctional fetal lung and into the systemic circulation through the aorta. Right After birth. The patency of the DA is primarily controlled by low fetal oxygen tension and the flow of prostanoids produced from the metabolic process of arachidonic acid by COX, with PGE2 producing the most extensive ductal relaxation amongst the prostanoids (12,13). Smooth muscle relaxation of the DA arises from the activation of the G-coupled prostaglandin receptor EP4 by PGE2. Following the activation of prostaglandin receptor EP4, a waterfall of occasions takes place, which Page 2115

3 includes the build-up of cyclic adenosine monophosphate, increased protein kinase A, and finally, decreased myosin light chain kinase, leading to vasodilation and eventually DA patency (11). The preterm ductus is specifically sensitive to the vasodilatory effects of prostaglandins, contributing to the failure of ductal closure (14). In term infants, as birth approaches, decreased level of sensitivity of the DA to prostaglandins and reduced distributing levels of PGE2 add to DA closure (15). Diagnosis procedures of PDA: Clinical Examination: A scientific diagnosis of PDA in preterm neonates is normally made inning accordance with a high index of suspicion and the presence of 1 or more particular scientific signs. In several cases, a PDA shunt has been shown to be already delegated right and of high volume as early as 6 hours of age (17). Typical clinical indications are absent at this early stage. Moreover, special use of medical signs for diagnosing PDA throughout the very first week after birth has limitations, with bad tomoderate interobserver arrangement (18,19,20,21). Lower high blood pressure are the only regularly reported medical finding related to a large PDA on day 1 after birth.4 This lag is because of the lower shunt velocity and delayed adaptation of the immature myocardium to modifications in preload. A boost in shunt speed coinciding with declining lung vascular resistance produces a particular systolic murmur (22). Subsequent myocardial adjustment results in tachycardia, increased stroke output, and contractility, which manifest clinically as hyper precordium, increased pulse volume, and large pulse pressure.a chest radiographmayalso expose indications of lung overcirculation and left heart dilatation. Amongst scientific signs, the existence of a murmur has the greatest uniqueness for the existence of a PDA but lacks sensitivity. The study (22) by Skelton et al reported that amurmurwas heard in 11% of neonateswith closed ducts and in 24% with a small PDA, indicating that isolated use of this clinical sign to diagnose a large PDA can result in significant misclassification. PDA Diameter and Shunt Pattern: Patent ductus arteriosus diameter is determined at its narrowest part in end systole and can be revealed either as an outright value in millimeters or indexed to the size of the left pulmonary artery (the ratio of PDA to LPA) or patient body weight (in millimeters per kg) (23,24). The relative advantage of each approach is unidentified. Shunt pattern evaluation consists of developing directionality and velocity throughout systole and diastole. For a PDA to cause substantial shunting from systemic to lung flow, the circulation has to be unrestrictive and entirely or almost totally delegated right; the latter is sometimes referred to as a growing pattern (25). The PDAs of less than 1.5 mm in size are thought about small due to the fact that they are commonly restrictive, cause a mild increase in lung circulation, and are rarely connected with echocardiographic markers of a high-volume shunt (26,27). Additional sub classification of PDAs of at least 1.5 mm as large or moderate is based upon incremental likelihood of a high-volume shunt. The diameter associates well with shunt volume, utilizing an outright cutoff to explain hemodynamic significance may be misleading offered the interobserver measurement variability (10%-15%) and its vibrant nature (26,27). Treatment options of PDA: Nonpharmacological Interventions: Suggested nonpharmacological interventions for PDA are restricted fluid intake, increasing end-expiratory pressure, and oxygen use, all of which need further assessment. Limited fluid intake has actually been connected with a decrease in PDA and BPD but has likewise been related to minimized systemic blood flow (28,29). A modest elevation of positive endexpiratory pressure can increase pulmonary vascular resistance and hence minimize lung blood flow, which might be useful in decreasing the shunt across a PDA (30). In the age of noninvasive respiratory management practices, determination of optimum end-expiratory pressure through ongoing evaluation of hemodynamic status would be practical. Oxygen is a potent stimulator of postnatal ductal tightness. Noori et al (31) reported a higher rate of PDA amongst neonates managed with a lower saturation target (83% -89%) vs a greater target (89%- 94%). However, a recent meta-analysis (32) of oxygen saturation targets reported no distinction in PDAs needing therapy (relative risk [ RR], 1.01; 95% CI, ). Pharmacological option of treatment of PDA: Pharmacological interventions for PDA consist of those that deal with the signs (eg, cardiac arrest) and those that promote PDA closure. Symptomatic treatments include diuretics (eg, furosemide and digoxin). 3 RCTs of furosemide showed no apparent benefit, (33) and digoxin is utilized rarely, (34) with no robust clinical studies of its results. Pharmacotherapy for Page 2116

4 PDA closure is based upon the role of prostaglandin in ductal tightness. The biochemical systems include results on cyclooxygenase and peroxidase enzymes. Indomethacin, the most widely utilized agent, is more prevalent in North America, and ibuprofen is more typically used in Europe and Asia (35). Indomethacin and Ibuprofen: Inhibition of prostaglandin synthesis with nonselective inhibitors of cyclooxygenase-1 and -2 (e.g., indomethacin and ibuprofen) appears to be a reliable alternative to surgical ligation (36). In most intensive care nurseries, indomethacin and ibuprofen have actually replaced surgical treatment as the favored treatment for closing a persistent PDA. Nevertheless, both have been related to a number of prospective adverse effects in the newborn. Indomethacin produces considerable decreases in renal, mesenteric, and cerebral blood circulation (37,38,39,40). Indomethacin likewise minimizes cerebral oxygenation (41). Modifications in creatinine clearance and oliguria (that are minimally responsive to dopamine or furosemide therapy (42) are common issues with the initial doses of indomethacin. Renal function returns to typical after the preliminary dosages of indomethacin or after drug discontinuation (43). A few of indomethacin's actions on these organ systems might not be because of its inhibition of prostaglandin synthesis (44,45). Although indomethacin produces considerable physiologic alterations, none of the controlled, randomized trials that have actually analyzed the relationship in between indomethacin and neonatal morbidity have discovered an increase in the occurrence of necrotizing enterocolitis, intestinal perforation, ROP, chronic lung disease, or cerebral white matter injury following indomethacin treatment (46). Indomethacin, by itself, has actually not been shown to increase the occurrence of gastrointestinal perforations, the mix of indomethacin and postnatal steroids, administered simultaneously, has actually been shown to increase the incidence of intestinal perforations/necrotizing enterocolitis (47). Indomethacin's cerebral vasoconstrictive effects are often mentioned as an issue for neonatologists (48) ; however, a Cochrane systematic review found that indomethacin prophylaxis is more likely to reduce rather than increase the incidence of periventricular leukomalacia (46). Although there is no proof that prophylactic indomethacin has any adverse or useful results on neurodevelopmental result at 18 months (49), there is evidence that there may be long term benefits at 4.5 and 8 years (50,51). Ibuprofen, another nonselective cyclooxygenase inhibitor, has actually been revealed to close the ductus in animals (52) and preterm infants. It seems as reliable as indomethacin in producing PDA closure in very low birthweight infants (a minimum of in infants with a mean gestational age of 28 weeks) (53). On the other hand, with indomethacin, ibuprofen does not appear to impact mesenteric blood flow (44,45) and has less of an impact on renal perfusion, oliguria (44,45), and cerebral blood flow (54). Animal studies suggest that ibuprofen may have some cytoprotective results in the intestinal system (55). Private studies have actually not discovered ibuprofen to be remarkable to indomethacin in the avoidance of NEC, a recent meta-analysis recommends that ibuprofen might be associated with a lower incidence of NEC than indomethacin (56). On the other hand, ibuprofen does not appear to have the exact same intracranial hemorrhage sparing impacts that are seen with indomethacin. The optimal age-appropriate dosing schedule for ibuprofen is still under consideration (57). Ibuprofen's impacts on overall and free serum bilirubin concentrations (58,59). Surgical closure of the ductus arteriosus: Surgical closure of the ductus arteriosus is generally booked for infants in whom medical treatment has actually stopped working. Infants who go through ligation are typically seriously ill. It is not surprising that result following surgical treatment is bad (60). In addition to high morbidity and mortality fundamental to the population, there are issues related to the procedure, such as reoccurring laryngeal nerve damage and pneumothorax. Current reports recommend that there is a duration of left ventricular dysfunction right away following ligation, (61) and that infants whose ductus arteriosus is ligated are at higher risk for bad developmental result compared to infants treated clinically (62). There have been no current regulated trials comparing results following ligation with outcomes following either placebo or medical treatment. The dangers and advantages of surgical ligation of the PDA are unknown. It is dissuading that after the conduct of many trials of treatments for closure of the ductus arteriosus over several years, we have little knowledge about their advantages and dangers. This lack of knowledge has actually resulted, in part, from limitations enforced by research study designs. Under the presumption that closure of a PDA is useful, almost all clinical trials in the modern-day era have actually concentrated on the most expeditious way in which to close a PDA. None have taken a look at the more fundamental question of whether closing the PDA improves result. Those trials that have actually included control groups treated with a placebo have actually allowed treatment of PDA that continued after reaching a specified study endpoint, typically just days after enrolment. This study design has led to high rates of treatment in the "placebo" group (usually in the range of Page 2117

5 40%) and has significantly disabled our capability to answer the fundamental concern of whether closure of the PDA influences result. In addition, our capability to discover negative effects of treatment is similarly compromised. In spite of these handicaps, the message from medical trials is not motivating. There is no proof that using medical treatments for the avoidance and treatment of PDA reduces mortality or severe morbidity, in spite of success in closure of the PDA (63,64). IV. CONCLUSION Patent ductus arteriosus (PDA) is a typical medical diagnosis among exceptionally premature infants, specifically in those with lung disease. Treatments are frequently utilized to close the PDA. Despite nearly 3 years of research, the question of whether the advantages of treatments to prevent ductal patency or promote closure surpass the threats of these treatments remains unanswered. The authors seldom utilize treatments created to close the PDA. Spontaneous closure of the patent ductus arteriosus (PDA) prevails. Therapy is normally sensible if considerable breathing distress or impaired systemic oxygen shipment is present. Intravenous (IV) indomethacin (or the more recent preparation of IV ibuprofen) is frequently efficient in closing a patent ductus arteriosus (PDA) if it is administered in the first days of life. REFERENCES [1] Clyman RI. Ibuprofen and patent ductus arteriosus. New Engl J Med. 2000;343: [2] Pegoli W. Pericardium and great vessels. In: Oldham KT, Colombiani PM, editors. Principles and Practice of Pediatric Surgery. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; p et al., editors. [3] Costeloe K, Hennessy E, Gibson A T. et al The EPICure study: outcomes to discharge from hospital for infants born at the threshold of viability. Pediatrics [4] Marshall D D, Kotelchuck M, Young T E. et al Risk factors for chronic lung disease in the surfactant era: a North Carolina population based study of very low birth weight infants. North Carolina Neonatologists Association. Pediatrics [5] Rojas M A, Gonzalez A, Bancalari E. et al Changing trends in the epidemiology and pathogenesis of neonatal chronic lung disease. J Pediatr [6] Dollberg S, Lusky A, Reichman B. Patent ductus arteriosus, indomethacin and necrotizing enterocolitis in very low birth weight infants: a population based study. J Pediatr Gastroenterol Nutr [7] Clyman R I. Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. J Pediatr (5 Pt 1) [8] Schneider DJ, Moore JW. Patent ductus arteriosus. Circulation. 2006;114: [9] Hajjar ME, Vaksmann G, Rakza T. Severity of the ductal shunt: a comparison of different markers. Arch Dis Child Fetal Neonatal Ed. 2005;90:F419 F422. et al. [10] Hammerman C. Patent ductus arteriosus. Clinical relevance of prostaglandins and prostaglandin inhibitors in PDA pathophysiology and treatment. Clin Perinatol. 1995;22: [11] Ivey KN, Srivastava D. The paradoxical patent ductus arteriosus. J Clin Invest. 2006;166: [12] Hermes-DeSantis ER, Clyman RI. Patent ductus arteriosus: pathophysiology and management. J Perinatol. 2006;26:S14 S18. [13] Van Overmeire B, Chemtob S. The pharmacologic closure of the patent ductus arteriosus. Semin Fetal Neonatal Med. 2005;10: [14] Clyman RI, Campbell D, Heymann MA. Persistent responsiveness of the neonatal ductus arteriosus in immature lambs: a possible cause for reopening of patent ductus arteriosus after indomethacin-induced closure. Circulation. 1985;71: et al. [15] Clyman RI, Mauray F, Rudolph AM. Age dependent sensitivity of the lamb ductus arteriosus to indomethacin and prostaglandins. Circulation. 1980;93: et al. [16] Groves AM, Kuschel CA, Knight DB, Skinner JR. Does retrograde diastolic flow in the descending aorta signify impaired systemic perfusion in preterm infants? Pediatr Res. 2008;63(1): Page 2118

6 [17] Alagarsamy S, Chhabra M, Gudavalli M, Nadroo AM, Sutija VG, Yugrakh D. Comparison of clinical criteria with echocardiographic findings in diagnosing PDA in preterm infants.j Perinat Med. 2005;33(2): [18] Davis P, Turner-Gomes S, Cunningham K, Way C, Roberts R, Schmidt B. Precision and accuracy of clinical and radiological signs in premature infants at risk of patent ductus arteriosus. Arch Pediatr Adolesc Med. 1995;149(10): [19] Evans N, Moorcraft J. Effect of patency of the ductus arteriosus on blood pressure in very preterm infants. Arch Dis Child. 1992;67(10, spec no): [20] Han UJ, Cho HJ, Cho YK, Choi YY, Ma JS. Change in blood pressure and pulse pressure in preterm infants after treatment of patent ductus arteriosus with indomethacin. Korean Circ J. 2011;41(4): [21] Lubetzky R, Mandel D, Mimouni FB, et al. Indomethacin-induced early patent ductus arteriosus closure cannot be predicted by a decrease in pulse pressure. Am J Perinatol. 2004;21 (5): [22] Skelton R, Evans N, Smythe J. A blinded comparison of clinical and echocardiographic evaluation of the preterm infant for patent ductus arteriosus.j Paediatr Child Health. 1994;30(5): [23] El Hajjar M, Vaksmann G, Rakza T, Kongolo G, Storme L. Severity of the ductal shunt: a comparison of different markers. Arch Dis Child Fetal Neonatal Ed. 2005;90(5):F419-F422. [24] Harling S, Hansen-Pupp I, Baigi A, Pesonen E. Echocardiographic prediction of patent ductus arteriosus in need of therapeutic intervention. Acta Paediatr. 2011;100(2): [25] Su BH, Watanabe T, Shimizu M, Yanagisawa M. Echocardiographic assessment of patent ductus arteriosus shunt flow pattern in premature infants. Arch Dis Child Fetal Neonatal Ed. 1997;77(1):F36-F40. [26] Evans N, Iyer P. Longitudinal changes in the diameter of the ductus arteriosus in ventilated preterm infants: correlation with respiratory outcomes. Arch Dis Child Fetal Neonatal Ed. 1995;72 (3):F156-F161. [27] Iyer P, Evans N. Re-evaluation of the left atrial to aortic root ratio as a marker of patent ductus arteriosus. Arch Dis Child Fetal Neonatal Ed. 1994; 70(2):F112-F117. [28] Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2008;2008(1):CD [29] De Buyst J, Rakza T, Pennaforte T, Johansson AB, Storme L. Hemodynamic effects of fluid restriction in preterm infants with significant patent ductus arteriosus.j Pediatr. 2012;161(3): [30] Shekerdemian L, Bohn D. Cardiovascular effects of mechanical ventilation. Arch Dis Child. 1999;80(5): [31] Noori S, Patel D, Friedlich P, Siassi B, Seri I, Ramanathan R. Effects of low oxygen saturation limits on the ductus arteriosus in extremely low birth weight infants.j Perinatol. 2009;29(8): [32] Saugstad OD, Aune D. Optimal oxygenation of extremely low birth weight infants: a meta-analysis and systematic review of the oxygen saturation target studies. Neonatology. 2014;105(1): [33] Brion LP, Campbell DE. Furosemide for symptomatic patent ductus arteriosus in indomethacin-treated infants. Cochrane Database Syst Rev. 2001;2001(3):CD [34] Tripathi A, Black GB, Park YM, Jerrell JM. Prevalence and management of patent ductus arteriosus in a pediatric Medicaid cohort. Clin Cardiol. 2013;36(9): [35] Irmesi R, Marcialis MA, Anker JV, Fanos V. Non-steroidal anti-inflammatory drugs (NSAIDs) in the management of patent ductus arteriosus (PDA) in preterm infants and variations in attitude in clinical practice: a flight around the world. Curr Med Chem. 2014;21(27): [36] Gersony WM, Peckham GJ, Ellison RC, et al. Effects of indomethacin in premature infants with patent ductus arteriosus: results of a national collaborative study. J Pediatr. 1983;102: [37] Rennie JM, Doyle J, Cooke RWI. Early administration of indomethacin to preterm infants. Arch. Dis. Child. 1986;61: Page 2119

7 [38] Pezzati M, Vangi V, Biagiotti R, et al. Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus. J Pediatr. 1999;135: [39] Coombs RC, Morgan MEI, Durin GM, et al. Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin. Arch. Dis. Child. 1990;65: [40] Van Bel F, Van Zoeren D, Schipper J, et al. Effect of indomethacin on superior mesenteric artery blood flow velocity in preterm infants. J Pediatr. 1990;116: [41] Laudignon N, Chemtob S, Bard H, et al. Effect of indomethacin on cerebral blood flow velocity of premature newborns. Biol Neonate. 1988;54: [42] Brion LP, Campbell DE. Furosemide for symptomatic patent ductus arteriosus in indomethacin- treated infants (Cochrane Review) Cochrane Database Syst Rev. 2001;3 [43] Barrington K, Brion LP. Dopamine versus no treatment to prevent renal dysfunction in indomethacin-treated preterm newborn infants. Cochrane Database Syst Rev CD [44] Seyberth HW, Rasher W, Hackenthal R, et al. Effect of prolonged indomethacin therapy on renal function and selected vasoactive hormones in very low birth weight infants with symptomatic patent ductus arteriosus. J Pediatr. 1983;103: [45] Malcolm DD, Segar JL, Robillard JE, et al. Indomethacin compromises hemodynamics during positive-pressure ventilation, independently of prostanoids. J Appl Physiol. 1993;74: [46] Fowlie PW, Davis PG. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev CD [47] Watterberg KL, Gerdes JS, Cole CH, et al. Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial. Pediatrics. 2004;114: [48] Leffler CW, Busija DW, Fletcher AM, et al. Effects of indomethacin upon cerebral hemodynamics of newborn pigs. Pediatr Res. 1985;19: [49] Schmidt B, Davis P, Moddemann D, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birthweight infants. N Engl J Med. 2001;344: [50] Vohr BR, Allan WC, Westerveld M, et al. School-age outcomes of very low birth weight infants in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics. 2003;111:e340 e346. [51] Ment LR, Vohr B, Allan W, et al. Outcome of children in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics. 2000;105: [52] Coceani F, White E, Bodach E, et al. Age-dependent changes in the response of the lamb ductus arteriosus to oxygen and ibuprofen. Can J Physiol Pharmacol. 1979;57: [53] Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev CD [54] Mosca F, Bray M, Lattanzio M, et al. Comparative evaluation of the effects of indomethacin and ibuprofen on cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus. J Pediatr. 1997;131: [55] Chemtob S, Laudignon N, Beharry K, et al. Effects of prostaglandins and indomethacin on cerebral blood flow and cerebral oxygen consumption of conscious newborn piglets. Dev Pharmacol Ther. 1990;14:1 14. [56] Grosfeld JL, Kamman K, Gross K, et al. Comparative effects of indomethacin, prostaglandin E1, and ibuprofen on bowel ischemia. J Pediatr Surg. 1983;18: [57] Hirt D, Van Overmeire B, Treluyer JM, et al. An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study. Br J Clin Pharmacol. 2008;65: [58] Zecca E, Romagnoli C, De Carolis MP, et al. Does Ibuprofen increase neonatal hyperbilirubinemia? Pediatrics. 2009;124: Page 2120

8 [59] Ahlfors CE. Effect of ibuprofen on bilirubin-albumin binding. J Pediatr. 2004;144: [60] Lee L C, Tillett A, Tulloh R. et al Outcome following patent ductus arteriosus ligation in premature infants: a retrospective cohort analysis. BMC Pediatr [61] Moin F, Kennedy K A, Moya F R. Risk factors predicting vasopressor use after patent ductus arteriosus ligation. Am J Perinatol [62] Kabra N, Schmidt B, Roberts R. et al Surgical closure of a patent ductus arteriosus (PDA) is associated with increased neurosensory impairment in extremely low birth weight (ELBW) infants. PAS [63] Fowlie P W, Davis P G. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 20023CD [64] Van Overmeire B, Allegaert K, Casaer A. et al Prophylactic ibuprofen in premature infants: a multicentre, randomised, double blind, placebo controlled trial. Lancet Page 2121