Management of Patent Ductus Arteriosus in Very Preterm Infants in the Post-surfactant Era
Current methods of diagnosis and treatment of patent ductus arteriosus in an era in which surfactant replacement therapy is being used routinely in respiratory distress syndrome are reviewed. Surfactant results in the early development of a left-to-right ductal shunt that affects the clinical presentation of the ductus in very preterm infants. The timing and indications for echocardiography in a cohort of very preterm infants at Monash Medical Centre were reported, and a comparison was made between those whose ductus was suspected and treated early within one week with those who presented later. Necrotising enterocolitis following indomethacin was seen only with early therapy, and treatment failure required surgical closure only with late therapy. The incidence of chronic lung disease was similar in the two groups. In the post-surfactant era, the optimal protocol for the management of the ductus requires further study in very preterm infants.
Keyword : Echocardiography; Indomethacin; Patent ductus arteriosus; Prematurity
In the first clinical report of successful surfactant replacement therapy in infants with respiratory distress syndrome (RDS) over two decades ago, there was a suggestion that surfactant was associated with an earlier development of patent ductus arteriosus (PDA).1 Surfactant has been shown to reduce pulmonary vascular resistance one hour after administration, which results in a decrease in pulmonary artery pressure and an increase in left-to-right shunting through the PDA.2,3 This may lead to haemorrhagic pulmonary oedema and the increased risk of 'pulmonary haemorrhage' in preterm infants following surfactant therapy.4 Prophylactic use of prostaglandin inhibitors has been recommended to close the PDA after surfactant therapy.5
Clinical features of PDA in preterm infants classically develop late towards the end of the first week after birth and into the second week as the infant recovers from RDS.6 Untreated, left-to-right shunting through the PDA reduces pulmonary compliance, contributing to their ventilator dependence7,8 and increasing their risk of developing chronic lung disease (CLD).9,10 The earlier improvement of RDS with surfactant therapy has an effect on the timing and presentation of PDA, and possibly on the response to indomethacin therapy and co-morbidities such as necrotising enterocolitis (NEC) and CLD. This review describes the current approach to the early diagnosis of PDA. Our experience in the management of PDA in a cohort of extremely preterm infants born at Monash Medical Centre over a three-year period is reported. Current options for effective and safe pharmacological closure of PDA are discussed.
A high parasternal systolic or continuous heart murmur is a common presenting sign. However, a murmur is audible in only 20-50% of infants with a documented PDA.11,12 The most sensitive clinical sign is a hyperactive precordium.13 Although a 'bounding pulse' may suggest a wide pulse pressure, the latter has not been substantiated by objective arterial blood pressure data.14,15 PDA is associated with a reduction in both the systolic and diastolic pressure, but there is no increase in pulse pressure. Tachycardia, tachypnoea, hepatomegaly and rales on auscultation are late and inconsistent signs. A deterioration of cardiorespiratory function is often heralded in by increasing frequency or severity in episodes of apnoea and bradycardia. Infants already on assisted ventilation often experience lack of progress in weaning or worsening oxygen and ventilatory requirements. However, clinical features are generally unreliable for the early diagnosis of PDA. Echocardiagraphic evidence of a PDA is known to precede the development of signs and symptoms by a mean of two days.16
The electrocardiogram is usually normal. The chest X-ray may show cardiomegaly, a 'hilar flare', hazy lung fields or a complete white-out. However, radiological abnormalities are difficult to interpret in the presence of parenchymal lung disease. In one study, pulmonary plethora and cardiomegaly were present in only 30% of infants with a symptomatic PDA prior to surgical ligation.17 Another study reported that cardiomegaly was absent in 22% of infants with symptomatic PDA.18
Even though clinical signs and symptoms provide important clues to the presence of a PDA, they cannot be relied upon to detect a large left-to-right ductal shunt in the preterm infant. Echocardiography is an essential tool in the diagnosis of PDA.19 M-mode echocardiography correctly identifies about half of the infants with PDA.20 The sensitivity of individual M-mode measurements in the diagnosis of PDA vary from 52% to 71%.11 The ratio of the diameter of the left atrium to that of the aortic root (LA:Ao ratio) is the most sensitive of the M-mode measurements.21 Left-to-right ductal shunting increases the volume load on the left side of the heart and dilates the left atrium. The LA:Ao ratio increases in infants with a large PDA and falls promptly after pharmacological closure.22 A LA:Ao ratio of >1.5:1 (>1.3:1 in fluid restricted infants), a ductal diameter >1.4 mm, and retrograde diastolic flow in the descending aorta exceeding 30% of the antegrade flow, are all indicative of a large left-to-right ductal shunt.23
Current clinical practice in extremely preterm infants managed in individual neonatal intensive care units (NICUs) varies from (1) prophylactic treatment with indomethacin in the first 24 hours in all extremely preterm infants, to (2) routine echocardiography in the first week and pre-symptomatic treatment on ultrasound evidence of PDA, to (3) echocardiography performed only on a clinical suspicion of PDA and treatment given if the PDA is considered 'haemodynamically significant' (hsPDA), a multifactorial decision based on a combination of clinical features and ultrasound data. In the NICU at Monash Medical Centre, we follow the third of the above protocols.
The Monash Experience
We reviewed a cohort of infants consecutively born at Monash Medical Centre in the three years, from January 2000 to December 2002, with a gestational age of less than 30 weeks or a birthweight of less than 1500 grams. Those without major congenital malformation and survived 28 days were included in the study. The indications for echo-cardiography were examined, as was the age at which the PDA was first suspected. A comparison was made between those who were investigated with an echocardiogram within one week after birth for a suspected PDA and those who presented late after one week. Infants considered to have an hsPDA were treated with intravenous indomethacin 0.1 mg/kg per dose given six times on a daily basis. Surgical closure of PDA was performed when the ductus failed to close after two courses of indomethacin or when indomethacin was contraindicated. Statistical analyses were performed using ANOVA, Kruskal-Wallis analysis of variance on ranks, chi square test, and Fisher exact test (Sigmastat).
Of the 272 extremely preterm infants, 124 infants (46%) had echocardiographic assessment for a suspected PDA, of whom 57 (47%) infants had their first study within one week after birth and 67 (53%) infants after one week. The suggestive clinical features that led to echocardiographic assessment were an audible heart murmur (54%), failure to wean from ventilation (35%), persistent hypotension (10%), blood in the endotracheal aspirate suggestive of pulmonary oedema or pulmonary haemorrhage (3%), and increased heart size on the chest X-ray (4%) (Table 1). Sixty-one (22%) of the 272 extremely preterm infants were treated with indomethacin. Only 15 (26%) of the 57 infants who had an early echocardiogram within one week had indomethacin therapy, in contrast to 46 (69%) of the 67 infants who had a late echocardiogram. Of the remaining 63 infants who did not receive indomethacin, 34 had only a small PDA and were not treated, and 29 did not have a PDA.
Comparison of Infants With and Without a hsPDA
Among the 95 infants who were diagnosed to have a PDA on echocardiogram, the 61 infants who had a hsPDA and were treated with indomethacin compared to the 34 infants who had a small PDA and were not treated with indomethacin, had a significantly lower birthweight and lower gestational age (Table 2). The LA:Ao ratio was >1.5 in 51 (84%) of the 61 infants who were treated with indomethacin. Infants who had a hsPDA, compared to those with a small PDA, had a significantly longer duration of oxygen therapy and assisted ventilation, and significantly more remained on assisted ventilation at 36 weeks post-conceptual age.
Comparison of Infants with Early and Late Treatment
Among the 61 infants who had indomethacin therapy, there was no significant difference in birthweight or gestational age between the 15 infants who had an echocardiogram early and were treated with indomethacin within one week after birth compared to the 46 infants who were investigated late and were treated after one week (Table 3). There was no significant difference in their LA:Ao ratios, duration of oxygen therapy and assisted ventilation, and the number who remained in oxygen or on assisted ventilation at 36 weeks post-conceptual age. Indomethacin therapy was successful in closing the PDA in 58 (95%) of the 61 infants. In the early treatment group, PDA closed with indomethacin therapy in all 15 infants, compared to 43 (93%) of 46 infants in the late treatment group. The three infants whose PDA remained opened after two courses of indomethacin had surgical closure of their PDA. In the early treatment group, transient abdominal distension developed in one infant and NEC in three infants after receiving indomethacin. One infant in the late treatment group developed transient abdominal distension.
Treatment Regime and Response Rate
Indomethacin is the most widely used prostaglandin synthetase inhibitor for the pharmacological closure of PDA. At Monash Medical Centre, we began to use indomethacin in 1977 in the oral dose of 0.3 mg/kg per dose given twice 24 hours apart.24 The response to oral or rectal indomethacin therapy is highly variable, with an overall response rate of about 60%.6 Intravenous indomethacin therapy has a higher and more consistent success rate of about 90% (range 75-96%). Absorption of orally administered indomethacin is relatively poor, and the variability in serum levels is greater with oral compared with intravenous therapy. The rate of PDA closure with indomethacin therapy improved at Monash Medical Centre following the change to the intravenous route.25 Our recent experience from 2000-2002 reported in this article has shown that treatment failure was confined to therapy after one week of age. It has been shown the poorer response in older infants is the result of pharmacokinetic differences at a greater postnatal age, and a larger dose or an increased number of doses may be required to achieve the same closure rate as in younger infants.26
Currently, many NICUs follow the indomethacin regime of 0.2 mg/kg per dose given three times every 8 or 12 hours. A randomised controlled trial (RCT) has reported that prolonged therapy (0.2 mg/kg per day given eight times once a day) resulted in a higher success rate (90% vs 53%), no increase in toxicity, and a lower incidence of CLD (35% vs 68%).27 A more popular alternative is to use a prolonged low-dose regime (0.1 mg/kg per dose intravenously given six times once a day), which has been shown in a RCT to result in a significantly higher initial closure rate (90% vs 77%), a lower subsequent relapse rate (21% vs 40%) and a lower incidence of renal dysfunction (29% vs 53%).28 Using this regime at Monash Medical Centre, indomethacin therapy was found to be successful in 90% of infants <1500 g birthweight after the first course with a recurrence rate of 3%.29 Our recent experience from 2000-2002 reported in this article has shown an overall success rate of 95%.
Adverse Effects of Treatment
The renal blood flow velocity decreases for about two hours,30 and dilutional hyponatraemia can result from a transient reduction in glomerular filtration rate and free water clearance.31 Frusemide given with indomethacin can prevent the reduction in urine output without affecting its therapeutic effectiveness,32 but this is contraindicated in the presence of dehydration.33 Low-dose dopamine has not been shown to reduce the magnitude of oliguria.34 Indomethacin is not contraindicated in infants with high serum creatinine and blood urea nitrogen levels, because they are often secondary to poor renal perfusion in infants with PDA and would improve following closure of the PDA with indomethacin therapy. Coagulation defects should be corrected before giving indomethacin, as it impairs synthesis of thromboxane A2, a potent inducer of platelet aggregation, and causes prolongation of the bleeding time. Indomethacin, though protein bound, does not affect the binding of bilirubin to protein and is safe to use in jaundiced infants.35 Although it had been suggested that indomethacin predisposes the preterm infant to the development of sepsis,36 this association has not be observed in other studies.
Gastrointestinal complications are associated with serious morbidity and mortality. A review of the literature had revealed 24 cases of gastrointestinal perforation, six of which were associated with NEC and the remainder were focal perforations with no other obvious pathology.25 These reported cases had a high mortality rate of 86%. The disturbance in mid-gut perfusion in PDA is known to be exacerbated by indomethacin37 although this can be minimised with a slow infusion over 30 minutes.38 A study in infants <1000 g birthweight has shown that when indomethacin was given as a slow infusion, the incidence of bowel perforation and NEC in infants treated for a hsPDA was not significantly different from infants without a hsPDA and not given indomethacin.29 Our recent experience from 2000-2002 reported in this article has shown that NEC following indomethacin therapy was seen only in the early treatment group (3 of 15 infants or 20%). This finding is similar to that from another study that reported a 20% incidence of NEC with bowel perforation when indomethacin was given during the first 48 hours after birth, but no NEC case was reported in the late treatment group.39 To avoid NEC with early indomethacin therapy, it has been suggested that the 0.1 mg/kg doses be discontinued as soon as the PDA has closed (mean cumulative dose at ductal closure was 0.35 mg/kg in that study),40 or that a continuous but slow infusion of indomethacin (0.004 mg/kg/h) be given until ductal closure.41
Indomethacin increases systemic blood pressure42 but causes a significant reduction in flow velocity in the anterior cerebral artery,43 which can be minimised with a slow infusion.44,45 Indomethacin has been shown to improve cerebral autoregulation so that cerebral oxygen metabolism is not compromised even at low cerebral perfusion pressures.46 A large RCT of early prophylactic indomethacin has reported a reduction in the incidence of PDA and severe periventricular haemorrhage.47 The latter finding could be explained by the fact that early ductal closure with indomethacin results in improved stability of arterial blood-gases and systemic blood pressure, which predispose to periventricular haemorrhage in preterm infants.48
Early versus Late Treatment
Neither natural or synthetic surfactant increases the incidence of PDA,49,50 but left-to-right ductal shunting occurs earlier within the first week following a more rapid recovery from RDS that results in an increase in pulmonary compliance and a decrease in pulmonary vascular resistance and pulmonary arterial pressure. The role of prophylactic indomethacin following surfactant therapy remains controversial. Although prophylactic treatment has been shown to reduce the incidence of PDA and periventricular haemorrhage, it does not improve short-term respiratory outcome or long-term neurodevelopmental outcome.47,51,52 A RCT comparing indomethacin therapy started on day three versus day seven in infants with a hsPDA confirmed by echocardiography, has shown no respiratory advantage but rather an increase in major complications such as NEC with early treatment.53 On the other hand, a hsPDA in extremely preterm infants can lead to serious respiratory, intestinal and neurological morbidities, and a delay in indomethacin therapy needs careful justification.54
Decisions on indomethacin therapy for hsPDA in the NICU at Monash Medical Centre during 2000-2002, as reported in this article, were individualised and based on clinical and echocardiographic assessment. This clinical practice is similar to that recommended in an overview of RCTs in the treatment of PDA in preterm infants.55 Even with this expectant and individualised approach to treatment, we have shown that in the post-surfactant era, almost one half of the extremely preterm infants developed clinical features within the first week that led to a suspicion of a PDA, and one quarter of the infants diagnosed to have a hsPDA had early indomethacin therapy in that first week. The complications experienced with early treatment could possibly be avoided with a different dosing regime, but alternative agents for pharmacological closure of PDA that result in less adverse effects have also been considered.
This is a non-steroidal anti-inflammatory agent which has been shown to be effective in closing the PDA but without affecting intestinal haemodynamics.56 It does not have a direct effect on cerebral and renal blood flow velocities, and haemodynamic changes are related to closure of the ductus induced by the drug.57 Ibuprofen is given intravenously at a dose of 10 mg/kg followed by 5 mg/kg 24 and 48 hours later.58 A RCT has shown that it is as efficacious as indomethacin and is significantly less likely to induce oliguria.59 However, this comparison was made with an indomethacin regime of 0.2 mg/kg at 12-hour intervals for three doses, and it is known from another RCT that an indomethacin regime of 0.1 mg/kg at 24-hour intervals for six doses results in a higher ductal closure rate with less renal side effects.28 Comparison of ibuprofen with this prolonged low-dose indomethacin regime has not been done. Day one prophylactic ibuprofen has been compared in a RCT with later expectant treatment for PDA diagnosed by echocardiography.60 Unlike when indomethacin was given prophylactically, early ibuprofen did not result in significant adverse effects.
This is a relatively renal-sparing cyclo-oxygenase prostaglandin inhibitor that has comparable anti-inflammatory property and potency to indomethacin. The limited clinical experience with sulindac, given orally at a dose of 3 mg/kg every 12 hours for four doses, suggested that it is as effective as indomethacin in closing PDA but without compromise of the renal function.61 However, its spectrum of gastrointestinal complications is similar to those described for indomethacin, and one infant was reported to have died from haemorrhagic gastritis following sulindac therapy.62 Until the question of safety could be adequately addressed, the use of sulindac in the treatment of PDA should remain experimental.
Clinically stable infants who do not require oxygen or ventilatory therapy generally do not have a PDA that is haemodynamically significant, and they do well even without treatment. However, the benefits of closing a PDA in infants with significant respiratory disease were first established in the first meta-analysis of RCTs published a decade ago.63 It showed that indomethacin therapy for asymptomatic PDA results in a significantly shorter duration of oxygen therapy and assisted ventilation and shorter time to regain birthweight. Indomethacin therapy for symptomatic PDA results in a significant improvement in cardiorespiratory status and reduction in mortality rate.
There is however no general agreement among neonatologists on the appropriate timing and indications of indomethacin therapy. The threshold for early indomethacin therapy has progressively been lowered in the post-surfactant era. It has been suggested that all infants <1500 g birthweight who are receiving oxygen and ventilatory therapy should be treated with indomethacin when their PDA becomes clinically apparent and is confirmed with an echocardiogram, even before signs of a large left-to-right shunt and evidence of a hsPDA are present.64 This recommendation was based on a meta-analysis showing that early treatment compared with delayed treatment beyond one week when symptoms other than a PDA murmur has developed, results in a significant reduction in the duration of assisted ventilation and the incidence of CLD. Some NICUs have extended this clinical protocol to performing a routine echocardiogram within a day after surfactant therapy, and giving indomethacin as pre-symptomatic treatment on ultrasound evidence of PDA alone. Evidence of benefit with this practice remains lacking. There may be a role for prophylactic indomethacin in some preterm infants in some NICUs within a few hours after birth immediately after surfactant therapy and without first doing an echocardiogram,65 but further RCTs have been recommended to assess more precisely its beneficial and adverse effects on short and long-term outcomes.66 Most neonatologists have been persuaded by recent RCT evidence47 that this protocol has less merit than previously claimed. However, the reduced need for surgical closure of PDA with prophylactic indomethacin (five infant avoiding surgery for every 100 infants treated) may be of particular importance in NICUs where infants need to be moved to another centre for surgery.67
Our recent experience at Monash Medical Centre from 2000-2002 reported in this article is based on a protocol adopted by most NICUs, that is, for echocardiography to be performed only on a clinical suspicion of PDA, and indomethacin therapy to be given only if the PDA is considered haemodynamically significant, a multifactorial decision based on a combination of clinical features and ultrasound data. However, the data presented suggest that this might not be the optimal practice in the post-surfactant era, and the ideal protocol for the management of PDA that gives the greatest effectiveness and safety in extremely preterm infants requires further study.
1. Fujiwara T, Maeta H, Chida S, Morita T, Watabe Y, Abe T. Artificial surfactant therapy in hyaline membrane disease. Lancet 1980;1:55-9.
2. Milner AD. How does exogenous surfactant work? Arch Dis Child 1993;68(3 Spec No):253-4.
3. Kaapa P, Seppanen M, Kero P, Saraste M. Pulmonary hemodynamics after synthetic surfactant replacement in neonatal respiratory distress syndrome. J Pediatr 1993;123:115-9.
4. Garland J, Buck R, Weinberg M. Pulmonary hemorrhage risk in infants with a clinically diagnosed patent ductus arteriosus: a retrospective cohort study. Pediatrics 1994;94:719-23.
5. Amato M, Huppi P, Markus D. Prevention of symptomatic patent ductus arteriosus with ethamsylate in babies treated with exogenous surfactant. J Perinatol 1993;13:2-7.
6. Yu VY. Patent ductus arteriosus in the preterm infant. Early Hum Dev 1993;35:1-14.
7. Jacob J, Gluck L, DiSessa T, et al. The contribution of PDA in the neonate with severe RDS. J Pediatr 1980;96:79-87.
8. Dudell GG, Gersony WM. Patent ductus arteriosus in neonates with severe respiratory disease. J Pediatr 1984;104:915-20.
9. Brown ER. Increased risk of bronchopulmonary dysplasia in infants with patent ductus arteriosus. J Pediatr 1979;95(5 Pt 2):865-6.
10. Reller MD, Lorenz JM, Kotagal UR, Meyer RA, Kaplan S. Hemodynamically significant PDA: an echocardiographic and clinical assessment of incidence, natural history, and outcome in very low birth weight infants maintained in negative fluid balance. Pediatr Cardiol 1985;6:17-23.
11. Knight DB, Yu VY. Contrast echocardiographic assessment of the neonatal ductus arteriosus. Arch Dis Child 1986;61:484-8.
12. Hirsimaki H, Kero P, Wanne O. Doppler ultrasound and clinical evaluation in detection and grading of patent ductus arteriosus in neonates. Crit Care Med 1990;18:490-3.
13. Kupferschmid C, Lang D, Pohlandt F. Sensitivity, specificity and predictive value of clinical findings, m-mode echo-cardiography and continuous-wave Doppler sonography in the diagnosis of symptomatic patent ductus arteriosus in preterm infants. Eur J Pediatr 1988;147:279-82.
14. Ratner I, Perelmuter B, Toews W, Whitfield J. Association of low systolic and diastolic blood pressure with significant patent ductus arteriosus in the very low birth weight infant. Crit Care Med 1985;13:497-500.
15. 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):1169-73.
16. 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;30:406-11.
17. Ellison RC, Peckham GL, Lang P, et al. Evaluation of the preterm infant for patent ductus arteriosus. Pediatrics 1983;71:364-72.
18. Higgins CB, Rausch J, Friedman WF, et al. Patent ductus arteriosus in preterm infants with idiopathic respiratory distress syndrome. Radiographic and echocardiological evaluation. Radiology 1977;124:189-95.
19. Evans N. Diagnosis of patent ductus arteriosus in the preterm newborn. Arch Dis Child 1993;68(1 Spec No):58-61.
20. Valdes-Cruz LM, Dudell GG. Specificity and accuracy of echocardiographic and clinical criteria for diagnosis of patent ductus arteriosus in fluid-restricted infants. J Pediatr 1981;98:298-305.
21. 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:F112-7.
22. Yu VY, Knight DB, Obeyesekere HI, Mitvalsky J. The management of patient ductus arteriosus in very low birthweight infants. J Singapore Paediatr Soc 1983;25:159-66.
23. Skinner J. Diagnosis of patent ductus arteriosus. Semin Neonatol 2001;6:49-61.
24. Obeyesekere HI, Pankhurst S, Yu VY. Pharmacological closure of ductus arteriosus in preterm infants using indomethacin. Arch Dis Child 1980;55:271-6.
25. Rajadurai VS, Yu VYH. Intravenous indomethacin therapy in preterm neonates with patent ductus arteriosus. J Paediatr Child Health 1991;27:370-5.
26. Shaffer CL, Gal P, Ransom JL et al. Effect of age and birth weight on indomethacin pharmacodynamics in neonates treated for patent ductus arteriosus. Cri Care Med 2002;30:343-8.
27. Hammerman C, Aramburo MJ. Prolonged indomethacin therapy for the prevention of recurrences of patent ductus arteriosus. J Pediatr 1990;117:771-6.
28. Rennie JM, Cooke RW. Prolonged low dose indomethacin for persistent ductus arteriosus of prematurity. Arch Dis Child 1991;66(1 Spec No):55-8.
29. Kumar RK, Yu VY. Prolonged low-dose indomethacin therapy for patent ductus arteriosus in very low birthweight infants. J Paediatr Child Health 1997;33:38-41.
30. van Bel F, Guit GL, Schipper J, van de Bor M, Baan J. Indomethacin-induced changes in renal blood flow velocity waveform in premature infants investigated with color Doppler imaging. J Pediatr 1991;118(4 Pt 1):621-6.
31. Betkerur MV, Yeh TF, Miller K, Glasser RJ, Pildes RS. Indomethacin and its effect on renal function and urinary kallikrein excretion in premature infants with patent ductus arteriosus. Pediatrics 1981;68:99-102.
32. Yeh TF, Wilks A, Singh J, Betkerur M, Lilien L, Pildes RS. Furosemide prevents the renal side effects of indomethacin therapy in premature infants with patent ductus arteriosus. J Pediatr 1982;101:433-7.
33. Brion LP, Campbell DE. Furosemide for symptomatic patent ductus arteriosus in indomethacin-treated infants. Cochrane Database Syst Rev 2001;CD001148.
34. Fajardo CA, Whyte RK, Steele BT. Effect of dopamine on failure of indomethacin to close the patent ductus arteriosus. J Pediatr 1992;121(5 Pt 1):771-5.
35. Lam BC, Wong HN, Yeung CY. Effect of indomethacin on binding of bilirubin to albumin. Arch Dis Child 1990;65:690-1.
36. Herson VC, Krause PJ, Eisenfeld LI, Pontius L, Maderazo EG. Indomethacin-associated sepsis in very-low-birth-weight infants. Am J Dis Child 1988;142:555-8.
37. Meyers RL, Alpan G, Lin E, Clyman RI. Patent ductus arteriosus, indomethacin, and intestinal distension: effects on intestinal blood flow and oxygen consumption. Pediatr Res 1991;29:569-74.
38. Coombs RC, Morgan ME, Durbin GM, Booth IW, McNeish AS. Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin. Arch Dis Child 1990;65(10 Spec No):1067-71.
39. Fujii AM, Brown E, Mirochnick M, O'Brien S, Kaufman G. Neonatal necrotizing enterocolitis with intestinal perforation in extremely premature infants receiving early indomethacin treatment for patent ductus arteriosus. J Perinatol 2002;22:535-40.
40. Dumas de la Roque E, Fayon M, Babre F, Demarquez JL, Pedespan L. Minimal effective dose of indomethacin for the treatment of patent ductus arteriosus in preterm infants. Biol Neonate 2002;81:91-4.
41. Nakamura T, Tamura M, Kadowaki S, Sasano T. Low-dose continuous indomethacin in early days of age reduce the incidence of symptomatic patent ductus arteriosus without adverse effects. Am J Perinatol 2000;17:271-5.
42. Evans N, Iyer P. Change in blood pressure after treatment of patent ductus arteriosus with indomethacin. Arch Dis Child 1993;68(5 Spec No):584-7.
43. Mardoum R, Bejar R, Merritt TA, Berry C. Controlled study of the effects of indomethacin on cerebral blood flow velocities in newborn infants. J Pediatr 1991;118:112-5.
44. Colditz P, Murphy D, Rolfe P, Wilkinson AR. Effect of infusion rate of indomethacin on cerebrovascular response in preterm neonates. Arch Dis Child 1989;64(1 Spec No):8-12.
45. Hammerman C, Glaser J, Schimmel MS, Ferber B, Kaplan M, Eidelman AI. Continuous versus multiple rapid infusions of indomethacin: effects on cerebral blood flow velocity. Pediatrics 1995;95:244-8.
46. Van Bel F, Bartelds B, Teitel DF, Rudolph AM. Effect of indomethacin on cerebral blood flow and oxygenation in the normal and ventilated fetal lamb. Pediatr Res 1995;38:243-50.
47. Schmidt B, Davis P, Moddemann D, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med 2001;344:1966-72.
48. Szymonowicz W, Yu VY. Periventricular haemorrhage: association with patent ductus arteriosus and its treatment with indomethacin or surgery. Aust Paediatr J 1986;23:21-5.
49. Soll RF. Prophylactic natural surfactant extract for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2000;CD000511.
50. Soll RF. Prophylactic synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2000;CD001079.
51. Couser RJ, Ferrara TB, Wright GB, et al. Prophylactic indomethacin therapy in the first twenty-four hours of life for the prevention of patent ductus arteriosus in preterm infants treated prophylactically with surfactant in the delivery room. J Pediatr 1996;128(5 Pt 1):631-7.
52. Narayanan M, Cooper B, Weiss H, Clyman RI. Prophylactic indomethacin: factors determining permanent ductus arteriosus closure. J Pediatr 2000;136:330-7.
53. Van Overmeire B, Van de Broek H, Van Laer P, Weyler J, Vanhaesebrouck P. Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory distress syndrome. J Pediatr 2001;138:205-11.
54. Wadhawan R, Rubin LP. Early versus late treatment of PDA with indomethacin. J Pediatr 2002;140:487-8.
55. Knight DB. The treatment of patent ductus arteriosus in preterm infants. A review and overview of randomized trials. Semin Neonatol 2001;6:63-73.
56. Grosfeld JL, Kamman K, Gross K, et al. Comparative effects of indomethacine, prostaglandine E1 and ibuprofen on bowel ischemia. J Pediatr Surg 1983;18:738-42.
57. Romagnoli C, De Carolis MP, Papacci P, et al. Effects of prophylactic ibuprofen on cerebral and renal hemodynamics in very preterm neonates. Clin Pharmacol Therap 2000;67:676-83.
58. Varvarigou A, Bardin CL, Beharry K, Chemtob S, Papageorgiou A, Aranda JV. Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants. JAMA 1996;275:539-44.
59. Van Overmeire B, Follens I, Hartmann S, Creten WL, Van Acker KJ. Treatment of patent ductus arteriosus with ibuprofen. Arch Dis Child Fetal Neonatal Ed 1997;76:F179-84.
60. Dani C, Bertini G, Reali MF, et al. Prophylaxis of patent ductus arteriosus with ibuprofen in preterm infants. Acta Paediatr 2000;89:1369-74.
61. Ng PC, So KW, Fok TF, et al. Comparing sulindac with indomethacin for closure of ductus arteriosus in preterm infants. J Pediatr Child Health 1997;33:324-8.
62. 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;85:884-6.
63. Nehgme RA, O'Connor TZ, Lister G, Bracken MB. Patent ductus arteriosus. In: Sinclair JC, Bracken MB, eds. Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992;281-324.
64. Clyman RI. Recommendations for the postnatal use of indomethacin: an analysis of four separate treatment strategies. J Pediatr 1996;128(5 Pt 1):601-7.
65. Fowlie PW, Davis PG. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 2000;CD000174.
66. Fowlie PW. Intravenous indomethacin for preventing mortality and morbidity in very low birth weight infants. Cochrane Database Syst Rev 2002;CD000174.
67. McGuire W, Fowlie PW. Treating extremely low birthweight infants with prophylactic indomethacin. Evidence for short term benefits only. BMJ 2002;324:60-1.
This web site is sponsored by Johnson & Johnson (HK) Ltd.