Introduction of plasma indomethacin level monitoring and evaluation of an effective threshold level in very low birth weight infants with symptomatic patent ductus arteriosus

First results are described of individually tailored indomethacin dose rates employing on-line drug level monitoring for pharmacologically induced ductal constriction in very low birth weight infants with symptomatic patent ductus arteriosus (sPDA). In addition prolonged indomethacin therapy was introduced. From our data it appears that the effective threshold indomethacin level for the induction of ductus constriction has to be about 1000 ng/ml 10 h postdosing, while ductus closure can be maintained with a dose rate that exceeds a plasma level of 500 ng/ml for at least 1 week. These maintenance levels were also effective in completely suppressing the urinary metabolite excretion rates of PGI₂ and PGE₂, which are potential mediators of ductal relaxation. On-line indomethacin level monitoring appears to be practically essential for prolonged indomethacin therapy to overcome the marked variation of indomethacin disposition in preterm infants with sPDA.Abbreviations sPDA symptomatic patent ductus arteriosus - PDA-MUR patent ductus arteriosus murmur - PGE-M 7-hydroxy-5,11-diketotetranorprostane-1,16-dioic acid - IMV intermittent mandatory ventilation - R/F retrograde and forward flow ratio - HPLC high pressure liquid chromatography - GC-MS gas chromatography-mass spectrometry Dedicated to Prof. Dr. H. Bickel on the occasion of his 65th birthday     

Diastolic flow velocity of the left pulmonary artery of patent ductus arteriosus in preterm infants

BACKGROUND: The usefulness of diastolic pulmonary flow velocity determined by echocardiography in the assessment of symptomatic patent ductus arteriosus (sPDA) in preterm infants has not been confirmed. METHODS: Echocardiography was performed daily in infants ranging from 23 to 31 gestational weeks of age, and diastolic flow velocity of the left pulmonary artery (DFLPA) was measured. The DFLPA data before indomethacin administration for sPDA were compared with data obtained after indomethacin administration. The normal range of DFLPA was also determined from serial measurements performed in infants who did not develop sPDA during the first 7 days of life. Then, this range was compared with data from infants who did develop sPDA during this time. RESULTS: In infants who underwent indomethacin treatment, DFLPA increased with the development of sPDA and decreased when the symptoms of sPDA disappeared. On the basis of results from serial DFLPA measurement, the sensitivity and specificity of DFLPA for assessing sPDA was found to be 0.82 and 0.83, respectively. CONCLUSIONS: Measurement of DFLPA by echocardiography is a useful method for assessing sPDA in preterm infants.     

血N端脑钠肽前体在早产儿症状性动脉导管未闭诊治中的应用价值

目的探讨血浆N端脑钠肽前体(NT-pro BNP)在早产儿症状性动脉导管未闭(s PDA)诊治中的临床应用价值。方法选取2013年10月—2014年9月入住新生儿重症监护病房、胎龄28~32周、出生体质量??1 500 g的早产儿107例,分别于生后第4、7天检测NT-pro BNP,采血后30 min内行超声心动图检查。根据生后第4天超声心动图检查结果分PDA组(39例)与对照组(68例);PDA组根据有无超声血流动力学显著改变及临床表现分为症状性PDA(s PDA组,20例)和无症状性PDA(as PDA组,19例);s PDA组再根据是否服用布洛芬分为治疗组(13例)与非治疗组(7例)。结果生后第4天,s PDA组患儿血浆NT-pro BNP水平高于as PDA组,as PDA组高于对照组,差异均有统计学意义(P??0.05);生后第7天,s PDA组患儿血浆NT-pro BNP水平高于as PDA组和对照组,差异有统计学意义(P??0.05),as PDA组与对照组的差异则无统计学意义(P??0.05)。治疗组生后第7天血浆NT-pro BNP水平较第4天显著下降,差异有统计学意义(P??0.05);非治疗组生后第7天与第4天血浆NT-pro BNP水平的差异无统计学意义(P??0.05)。PDA患儿生后第4天血浆NT-pro BNP水平与动脉导管(DA)直径、左心房/主动脉根部内径比值(LA/AO)及DA直径与左肺动脉内径比值(TDD/LPA)呈正相关(r=0.498~0.670,P均??0.05)。生后第4天血浆NT-pro BNP水平预测s PDA的ROC曲线下面积(AUC)为0.969(95%CI:0.938~1.000),NT-pro BNP水平在13 964 pg/m L时,诊断s PDA的灵敏度为95%,特异度为95.4%。结论 s PDA早产儿血浆NT-pro BNP水平明显增高,治疗后下降。第4天血浆NT-pro BNP是预测s PDA的敏感指标,动态监测血浆NT-pro BNP水平变化对指导早产儿PDA治疗策略的选择有重要临床价值。     

Late closure of the ductus arteriosus using indomethacin in the preterm infant

Several studies have shown a lack of effect of indomethacin therapy for the closure of a patent ductus arteriosus (PDA) in premature infants over 14 days of postnatal age. In this report we describe two cases in which a hemodynamically significant PDA was closed with indomethacin in preterm infants over 20 days of age. The response to indomethacin may be more related to postconceptual age than to actual postnatal age. We suggest that intravenous indomethacin therapy should be attempted before surgical ligation is performed in those premature infants under 34 weeks postconceptual age who have a hemodynamically significant patent ductus arteriosus.     

Abnormal blood flow patterns in renal arteries of small preterm infants with patent ductus arteriosus detected by Doppler ultrasonography

Blood flow velocities and pulsatory indices in both renal arteries (RAs) and in the internal carotid artery (CAI) were measured by pulsed Doppler ultrasonography in ten preterm infants with patent ductus arteriosus (PDA), before and after surgical ligation. The results obtained in the RAs were compared to those found in a reference group of 22 stable preterm infants. In the RAs the diastolic steal volume of the PDA led to a marked decrease in diastolic blood flow velocity (range 3 to-23 cm/s). Seven infants showed retrograde diastolic flow, whereas only three infants had these flow patterns in the CAI. In the RAs, the peak systolic blood flow velocities (range 56 to 135 cm/s) exceeded the values found in the reference group by 85% on average. The pulsatility indices reached values of above 1,00. In spite of the increase in systolic flow velocities before surgery, the time mean of maximum velocities was significantly lower than those measured after surgery and in the reference group. After PDA ligation, blood flow velocities normalized. The present study shows that a large PDA may induce abnormal flow patterns even in the RAs. These flow patterns may predispose to renal hypoperfusion and subsequent impairment of renal function.Abbreviations CAI internal carotid artery - NFC necrotizing enterocolitis - PDA patent ductus arteriosus - PI pulsatility index - RA renal artery - Vd end-diastolic velocity - V_max time mean of maximum velocity - Vs peak systolic velocity     

Angiotensin II type 1 receptor A1166C polymorphism and prophylactic indomethacin treatment induced ductus arteriosus closure in very low birth weight neonates

Altered pulmonary vascular resistance might be a factor for delayed closure of the ductus arteriosus (DA) in preterm infants. Angiotensin II plays a central role in the elevation of pulmonary vascular resistance. Angiotensin II exerts its vasoconstrictor effect on the angiotensin II type 1 receptor (AT1R). Homozygous carriers of the AT1R A1166C genetic variant present an exaggerated vasoconstrictor response to angiotensin II. We have investigated whether the presence of AT1R CC1166 influences the effect of prophylactic indomethacin treatment on the closure of DA until the fifth postnatal day in preterm infants. In this retrospective study detailed medical history of the first postnatal week was obtained in 159 infants born before the 33rd gestational week. All were treated by prophylactic indomethacin to induce permanent closure of the DA. On the sixth postnatal day the DA was still open in 56, whereas it was permanently closed in 103. The AT1R A1166C genotype of the infants was determined from Guthrie spots. Stepwise binary logistic regression analysis was used to assess the effect of medical conditions and genotype on the risk of patent DA (PDA). Birth weight, infantile respiratory distress, and severe hypotension were independent risk factors for PDA (p < 0.01, p < 0.05, p < 0.05, respectively). The carrier state of AT1R CC1166 was protective against PDA (p < 0.05; odds ratio, 0.067). AT1R AC1166 genotype was not associated with PDA. Our results indicate that the risk of PDA might be lower in infants of AT1R CC1166 than in those with AC or AA genotypes.     

Recovery of prostaglandin production associated with reopening of the ductus arteriosus after indomethacin treatment in preterm infants with respiratory distress syndrome

Increased PGE production has been demonstrated in 9 of 17 preterm infants with patent ductus arteriosus (PDA) associated with respiratory distress syndrome (RDS). Inhibition of PGE production in eight preterm infants with PDA and RDS was associated with marked improvement in the respiratory and circulatory function of all of them. However, in six of them this effect was only transient. In the posttreatment period of five and a half days reopening of the ductus arteriosus was frequently associated with increased PGE production and a drop of indomethacin serum levels. Three of these six infants were transferred for surgical ligation whereas the other three were successfully treated with a second course of indomethacin. However, the margin between closure of the ductus arteriosus and the deterioration of kidney function in preterm infants treated with a presently recommended indomethacin dosage was narrow. In conclusion, until an acceptable therapeutic serum level of indomethacin for ductal closure in preterm infants has been established and the duration of effective prostaglandin synthesis inhibition is known, it is too early for a general recommendation of a dosage regime of indomethacin for the pharmacological closure of PDA in infants with RDS.     

Sensitivity,specificity and predictive value of clinical findings,m-mode echocardiography and continuous-wave Doppler sonography in the diagnosis of symptomatic patent ductus arteriosus in preterm infants

By means of probability analysis we have compared the diagnostic value of clinical symptoms, m-mode echocardiographic measurements and peripheral arterial flow, assessed by continuous-wave Doppler, in preterm infants with symptomatic patent ductus arteriosus (PDA). Data were obtained in 29 infants with PDA and in 29 controls. The most sensitive clinical finding was a hyperactive precordium. Bounding pulses and a heart murmur were absent in 15% and 20%, respectively of the patients with PDA. M-mode echocardiographic measurements were rather specific for the detection of a PDA but less sensitive. Diastolic backflow in the brachial and femoral arteries was present in the majority of patients with PDA and absent in about 67% of the controls. The values in probability analysis, however, were too low to base a therapy on these findings. The highest sensitivity and specificity (100% each) was found for a disturbed cerebral blood flow with absent or retrograde diastolic perfusion estimated by Doppler sonography.Abbreviations PDA patent ductus arteriosus - cw-Doppler continuous-wave Doppler - SF shortening fraction - LPEP/LVET, RPEP/RVET left and right ventricular systolic time intervals - R/F retrograde/forward flow Dedicated to Professor Dr. E. Kleihauer on the accasion of his 60th birthday     

Response of the patent ductus arteriosus to indomethacin treatment

The purposes of this study were to examine the response of the patent ductus arteriosus (PDA) to indomethacin, using serial two-dimensional and pulsed Doppler echocardiographic studies, and to correlate the response to treatment with serum indomethacin levels. Nineteen preterm infants (gestational age, 26 to 31 weeks [mean, 28 weeks]; weight, 600 to 1680 g [mean, 1060 g]) were treated with indomethacin. Two-dimensional and pulsed Doppler echocardiograms were obtained before administration of indomethacin and daily thereafter until the day after the last dose. Ductal responses to treatment were graded as open, constricted, or closed, and serum indomethacin levels were obtained 24 hours after the last dose. The PDA initially closed in 11 (58%) of 19 infants; however, in four of the 11, PDA reopened and three of four required surgical ligation. In seven (37%) of 19 patients, the PDA initially constricted, but five of seven subsequently reopened and required ligation. In one patient, indomethacin had no effect on the PDA. The mean indomethacin level for the whole group was 622 ng/mL. There was no difference in indomethacin level between the group with initial closure vs those with constriction (580 vs 590 ng/mL), nor between those who eventually required ligation and those who did not. This study demonstrates that the majority of premature infants respond to indomethacin treatment with ductal constriction or closure but that reopening occurs frequently. The initial response does not mean that the ductus will remain constricted or closed, and surgical intervention may still be necessary. A serum indomethacin level of more than 250 ng/mL does not ensure ductal closure.     

口服消炎痛和布洛芬治疗早产儿动脉导管未闭的比较

目的：静脉注射消炎痛是早产儿动脉导管未闭的常规治疗方法,但治疗过程中常出现一些副作用,如少尿、消化道出血、脑血流灌注减少。近年来,静脉注射布洛芬已用于治疗早产儿动脉导管未闭。布洛芬治疗不会减少脑血流灌注,也不会影响胃肠道和肾脏的血流动力学。伊朗目前尚无消炎痛和布洛芬的静脉制剂供应。该研究旨在比较这两种药的口服制剂治疗早产儿动脉导管未闭的疗效和安全性。方法：36例胎龄小于34周经超声心动图确诊患有动脉导管未闭的早产儿被随机分为两组,每组18人。一组给予消炎痛口服,每次0.2 mg/kg,24 h给药 1 次,共3次。另一组给予布洛芬口服,共 3 次,间隔时间为24 h,首剂为 10 mg/kg,随后两次各 5 mg/kg。用药后观察导管闭合率、副作用、并发症及临床过程。结果：用药后布洛芬组18例患儿动脉导管都闭合（100％）,而消炎痛组18例中有15例患儿动脉导管闭合（83.3%）（P＞0.05）。两组疗效差异统计学无显著性意义。治疗前后两组的血清尿素氮和肌酐含量差异也无显著性意义。消炎痛组发生了3例（16.6%）坏死性小肠结肠炎,布洛芬组则无,差异有显著性意义 (P＜0.05)。治疗1个月后两组成活率均为 94%（17／18）。消炎痛组1例死于坏死性小肠结肠炎,布洛芬组1例死于败血症。结论：口服布洛芬治疗早产儿动脉导管未闭和口服消炎痛治疗一样有效,而且坏死性小肠结肠炎的发生率较口服消炎痛治疗低。［中国当代儿科杂志,2007,9（5）：399-403］     

Indomethacin and cerebral blood flow in premature infants treated for patent ductus arteriosus

Central blood flow (CBF) was estimated by an intravenous 133-xenon technique in six preterm infants before and after administration of indomethacin for closure of patent ductus arteriosus. CBF fell in all infants (range 12%–40%), the mean fall was 24% (P<0.005). Though none of the infants showed signs of impaired cerebral function during or following the injections, the results do not indicate whether or not the use of indomethacin is a potential hazard.Abbreviations PDA patent ductus arteriosus - CBF cerebral blood flow - PaCO₂ arterial carbon dioxide tension - MAP mean arterial blood pressure     

A meta-analysis of ibuprofen versus indomethacin for closure of patent ductus arteriosus

Ibuprofen (IBU) has previously been shown to be as effective as indomethacin (INDO) in closing the patent ductus arteriosus (PDA) of preterm infants, without severely affecting renal hemodynamics or basal cerebral blood flow. We conducted a meta-analysis of randomized trials to compare the efficacy and safety of IBU and INDO for treatment of PDA. Data from the nine relevant trials ( n =566), showed no significant difference in the efficacy of IBU and INDO in PDA closure ( P =0.70). However, five trials ( n =443) provided serum creatinine concentration data that revealed a significantly lower increase favoring IBU ( P < 0.001), and urine output data that showed a significantly lower decrease favoring IBU ( P < 0.001). In two trials ( n =188) the proportion of infants who required postnatal oxygen therapy at 28 days (defined as chronic lung disease) was significantly higher with IBU (52/94; 55.3%) than with INDO (38/94; 40.4%, P < 0.05). No statistically significant differences were found in mortality, intraventricular hemorrhage, necrotizing enterocolitis, surgical ligation, sepsis, retinopathy of prematurity, periventricular leukomalacia, length of hospital stay, gastrointestinal bleeding, re-opening of PDA, back-up treatment, surfactant therapy, or days on a ventilator. Conclusion:ibuprofen and indomethacin have similar efficacy in patent ductus arteriosus closure, but preterm infants treated with ibuprofen experience lower serum creatinine values, higher urine output, and less undesirable decreased organ blood flow and vasoconstrictive adverse effects.     

The relationship between the continuous opening of arterial catheters and platelet parameters in preterm infants北大核心CSCD

Objective To analyze the correlation between the continuous opening of patent ductus arteriosus (PDA) in preterm infants and platelet parameters in the first 24 hours of life. Methods The preterm infants (gestational age <34 weeks) admitted to Neonatal Intensive Care Unit(NICU)of the Affiliated Xuzhou Hospital of Southeast University from November 2012 to July 2018 were enrolled. The following data were collected retrospectively: the platelet parameters in the first 24 hours of life, clinical factors possibly related to continuous opening of PDA, and echocardiography examination fin-dings on the 4 -7 day after birth. According to the diagnostic criteria of PDA, all preterm infants were divided into symptomatic PDA (sPDA) group, non - sPDA (nsPDA) group, and non - PDA (nPDA) group. SPSS 20.0 software was used for data analysis. Data were analyzed by Chi -square test,LSD or Tambane's T2 of One - Way analysis of variance, and binary Logistic regression analysis of the receiver operating characteristic (ROC) curve. Results Totally 760 preterm infants were chosen, and among them there were 67 cases (8. 8%) in sPDA group, 106 cases (14. 0%) in nsPDA group,and 587 cases (77. 2%) in nPDA group. There were significant differences in the terms of gestation age,birth weight,platelet counts (PLT),and plateletcrit (PCT) in the first 24 hours of life among 3 groups (all P < 0. 05). The smaller gestation age, the lower birth weight, the lower PLT and PCT in the first 24 hours of life,and the higher incidence of PDA in preterm infants. There were no significant differences in the platelet distribution width,mean platelet volume,and platelet large cell ratio in the first 24 hours of life among 3 groups (all P >0. 05). The low lower birth weight and PCT in the first 24 hours of life were independent risk factors for the occurrence of sPDA in preterm infants (P =0. 013,0. 000). The risk of occurrence of sPDA in preterm infants will be increased by 3.279 -fold (95% CI;2. 369 -4.479) if PCT in the first 24 hours of life is decreased by 0. 10%. The area under the ROC curves of PCT and PLT in the first 24 hours of life for prediction of sPDA in preterm infants was 0. 757 (95%C/:0.712 -0.814) and 0.718 (95%C/:0.671 -0.768),respectively. The best cutoff values of PCT and PLT were 0. 178% (sensitivity was 75. 7%, specificity was 71. 9%) and 207. 5 x 10 /L (sensitivity was 71. 4% specificity was 63. 2%). Conclusions The continuous opening of PDA in preterm infants may have correlation with the platelet. The low PCT, rather than PLT, in the first 24 hours of life was an independent risk factor and has medium predictive value for the occurrence of sPDA in preterm infants on the 4 - 7 day after birth. © 2019 Authors. All rights reserved.     

Longitudinal changes in the diameter of the ductus arteriosus in ventilated preterm infants: correlation with respiratory outcomes.

This study aimed to examine the early natural history of ductal shunting in ventilated preterm infants (< 1500 g) and to document the association between this shunting and respiratory outcomes. The size of the ductal shunt was assessed in 48 infants using serial echocardiographic measurement of colour Doppler internal ductal diameter and pulsed Doppler postductal aortic diastolic flow (PADF). At all postnatal ages, normal antegrade PADF was invariably seen when the ductal diameter was 1.5 mm or less, and was usually abnormal (absent or retrograde) when more than 1.5 mm. Longitudinal progress of ductal diameter fell into three groups: (i) asymptomatic spontaneous closure (n = 31)--in 20 of these infants closure occurred within 48 hours; (ii) symptomatic PDA which enlarged after a postnatal constriction (n = 9); and (iii) symptomatic PDA that showed minimal postnatal constriction (n = 8). Infants in group 2 were significantly less mature and had PDAs which became symptomatic significantly later than those in group 3. Logistic regression showed that ductal shunting had a significant correlation with mean oxygenation index over the first five days but not with ventilator or oxygen days. Gestation had the most significant association with the latter two variables, with atrial shunting also being related to days in oxygen. The preterm duct displays a wide spectrum of postnatal constrictive activity. Symptomatic PDAs usually showed slower early postnatal constriction. Ductal shunting independently related to short term but not long term respiratory outcomes.     

Changes in cerebral,renal and mesenteric blood flow velocity during continuous and bolus infusion of indomethacin

Vasoconstriction induced by bolus injection of indomethacin reduces organ perfusion and has been related to the well-known side effects of indomethacin given for closure of the patent ductus arteriosus (PDA). The aim of the study was to compare the changes in cerebral, renal and mesenteric blood flow velocities after continuous infusion versus bolus injection of indomethacin for closure of the PDA. Thirty-two preterm infants (range 26-35 wk gestational age) with PDA were randomly assigned to receive the same amount of indomethacin either as three bolus injections (n = 14) or as a continuous infusion (n = 18) over 36 h. Blood flow velocities were measured in the internal carotid, right renal and superior mesenteric arteries at baseline and serially at 10, 30, 60 and 120 min and 12, 24, 36 and 48 h after the start of indomethacin treatment. There were no differences in blood flow velocities between both groups at baseline. During continuous infusion of indomethacin there was no significant change in the cerebral, renal and mesenteric blood flow velocities, whereas the flow velocities in the infants receiving bolus injections decreased significantly during the first 2 h after indomethacin administration in all arteries measured. There was a transient, but significant reduction in urine output after bolus injection of indomethacin. Conclusion: In contrast to bolus injections, decrease of organ blood flow and impairment of urine output do not accompany continuous infusion of indomethacin over 36 h.     

Management of the patent ductus arteriosus in preterm infants

Management of the patent ductus arteriosus (PDA) is one of the most contentious topics in the care of preterm infants. PDA management can be broadly divided into prophylactic and symptomatic therapy. Prophylaxis with intravenous indomethacin in extremely low birth weight infants may reduce severe intraventricular hemorrhage. Echocardiography should be routinely used to confirm the presence of a PDA before considering symptomatic therapy. A symptomatic PDA can be managed conservatively, using pharmacotherapy or with procedural closure. Ibuprofen should be considered as the pharmacotherapy of choice for a symptomatic PDA. High-dose ibuprofen may be preferable, especially for preterm infants beyond the first 3 to 5 days of age. If pharmacotherapy fails (after two courses) or is contraindicated, procedural closure may be considered for infants with a persistent PDA with significant clinical symptoms in addition to echocardiographic signs of a large PDA shunt volume and pulmonary over-circulation.     

Skin reflectance changes in preterm infants with patent ductus arteriosus

INTRODUCTION: Patent ductus arteriosus (PDA) is a common complication in preterm infants. While two-dimensional echocardiography is the method of choice for diagnosing a PDA, clinical signs are known to be of limited value. STUDY DESIGN: Haemodynamically significant PDA (hs-PDA) was defined as a ductal left-to-right shunt with elevated left atrial/aortic root ratio ( > 1.6:1), a ductal diameter > 2 mm, retrograde diastolic flow exceeding 30% of the anterograde flow and anterograde peak diastolic flow velocity in left pulmonary artery > 50 cm/s. A hs-PDA may affect the cerebral circulation and skin color is known to be related to local perfusion. In this study, we tested the value of a caudal-to-cephalic skin reflectance differential in detecting preterm infants with hs-PDA. The study was blinded and prospective. SUBJECTS: Fifteen infants with a hs-PDA (M: 8, F: 7; gestational age: 28.0 +/- 2.0 weeks, birth weight: 880 +/- 130 g) and 15 gender- and gestational age-matched infants without a haemodynamically significant PDA (M: 8, F: 7; gestational age: 28.2 +/- 2.3 weeks, birth weight: 885 +/- 135 g) participated to the study. OUTCOME MEASURE: Skin reflectance measurements were performed using a reflectance spectrophotometer (CM-2600d/2500d, Minolta, Osaka, Japan). Sole ("postductal" site) to forehead ("preductal" site) skin reflectance ratio (caudal-to-cephalic ratio). RESULTS: hs-PDA infants showed significantly lower forehead light reflectance values on for the whole visible spectrum (p < or = 0.043) with the exception of 580-590 nm (p = 0.058), whereas no statistically significant differences were observed for the sole skin reflectance between the two groups in the examined visible spectrum. Consequently, hs-PDA infants showed a significantly higher caudal to cephalic ratio in the 410-430 nm (p < or = 0.042), 460-530 nm (p < or = 0.027) and 590-700 nm (p < or = 0.011) wavelength ranges. CONCLUSIONS: These findings may provide a previously unrecognised clinical marker for haemodynamically significant PDA in preterm infants, thus predicting those preterm infants who may require intervention for PDA.     

Controlled trial of intravenous lyophilized indomethacin in the treatment of persistent ductus arteriosus in premature infants

As a result of randomized assignment, 24 premature infants with symptomatic patent ductus arteriosus (PDA) were either treated by 0,2 mg I.V. indomethacin just after diagnosis (12) or left untreated for 48 hours (12). Clinical, radiological, and biological data before trial were remarkably similar. In the 12 "treated" infants, the DA closed within 4 to 26 hours of the first dose in 8 cases. In all 12 "non-treated" infants, PDA persisted for at least 48 h, then 10 infants were treated ad libitum by I.V. (5) or oral (5) indomethacin. Three deaths (late) did not appear to be associated with either PDA or treatment. Two surgical closures were required (1 in each group). Four spontaneous closures occurred after more or less delay: 2 in the 2 never treated infants, and 2 after a double failure of I.V. or oral indomethacin. Treatment (even when unsuccessful) was usually followed by some water retention and blood dilution, sometimes of striking magnitude but always transient. To date, I.V. indomethacin can be given earlier than orally and offers slightly better chances for closure of PDA, thereby reducing the needs for surgical closure which should be reserved for badly tolerated failures of pharmacologic closure.     

Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus

OBJECTIVE: To evaluate the effect of intravenous ibuprofen and indomethacin for treatment of patent ductus arteriosus (PDA) on mesenteric and renal blood flow velocity in preterm infants. STUDY DESIGN: Seventeen mechanically ventilated preterm infants (<33 weeks' gestation) with PDA received either 0.2 mg/kg indomethacin (n = 8) or 10 mg/kg ibuprofen (n = 9), infused over 15 minutes. Mesenteric and renal blood flow velocity were measured by using Doppler ultrasonography. RESULTS: Indomethacin caused a significant reduction in mesenteric and renal blood flow velocity 30 minutes after drug administration; mesenteric and renal blood flow velocity did not return to the pretreatment values by 120 minutes. Ibuprofen did not alter blood flow 30 minutes after treatment, and blood flow increased 120 minutes after treatment. Mesenteric and renal blood flow velocity changes were significantly different between the 2 treatment groups. CONCLUSIONS: Compared with indomethacin, ibuprofen did not significantly reduce mesenteric and renal blood flow velocity.     

Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants

BACKGROUND: Patent ductus arteriosus (PDA) is commonly found in very low-birthweight (VLBW) infants. The presence of respiratory distress syndrome (RDS) is also associated with increased frequency of significant PDA. Intravenous indomethacin has been used to treat and to prevent PDA in premature infants since 1976. However, concern remains regarding the safety of indomethacin, which affects renal, gastrointestinal and cerebral perfusion. Intravenous ibuprofen has recently been used to treat and to prevent PDA premature infants with PDA without reducing cerebral blood flow or affecting intestinal or renal hemodynamics. The aim of the present study is to compare intravenous ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of PDA in preterm infants. METHODS: A total of 63 preterm infants with RDS who had a birthweight of < or =1500 g and gestational age of < or =32 weeks, were enrolled in the present study. All patients were treated with nasal continuous positive airway pressure with additional oxygen supply in inspired air>30%, or with mechanical ventilation. The patients' serum platelet counts were>100,000/uL, and serum creatinine values were <1.5 mg/dL. There were no 3-4 grade intraventricular hemorrhages before randomization, and all patients were aged 2-7 days and had echo-cardio-graphic evidence of significant PDA. Patients were randomized into two groups: the first group of neonates (group A, n = 32) received intravenous ibuprofen lysine 10 mg/kg, followed by 5 mg/kg after 24 and 48 h; the second group (group B, n = 31) received intravenous indomethacin 0.2 mg/kg every 12 h for three doses. RESULTS: Patent ductus arteriosus closed in 27 patients from the ibuprofen group (84.4%) and in 25 patients from the indomethacin group (80.6%). PDA reopened in three patients from the ibuprofen group (9.4%) and in three patients from the indomethacin group (9.7%). One patient in the ibuprofen group and two patients in the indomethacin group required ductal ligation. Serum creatinine and blood urea nitrogen (BUN) concentrations were lower in the ibuprofen group than in the indomethacin group. Urine output and creatinine clearance values were higher in the ibuprofen group than in the indomethacin group. CONCLUSIONS: Ibuprofen therapy is as efficacious as indomethacin for the treatment of PDA in preterm infants. Infants treated with ibuprofen have higher creatinine clearance and urine output and lower serum creatinine and BUN values than infants treated with indomethacin.