Effect of fluid administration on the development of symptomatic patent ductus arteriosus and congestive heart failure in premature infants. Water balance in very low-birth-weight infants: relationship to water and sodium intake and effect on outcome. Early enteral feeding does not affect the incidence of necrotizing enterocolitis. A comparison of oral ibuprofen and intravenous indomethacin for closure of patent ductus arteriosus in preterm infants. Randomized trial of prolonged low-dose versus conventional-dose indomethacin for treating patent ductus arteriosus in very low birth weight infants. A randomized, controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth. Timing of patent ductus arteriosus treatment and respiratory outcome in premature infants: a double-blind randomized controlled trial. [Comparison of the efficacy of ibuprofen and indomethacin in the treatment of patent ductus arteriosus in prematurely born infants]. 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. Prophylactic indomethacin for prevention of intraventricular hemorrhage in premature infants. [Ibuprofen versus indomethacin in the treatment of patent ductus arteriosus in preterm infants].
We studied 170 premature infants with birth weights between 751 and 2000 g in a randomized sequential trial comparing "high" and "low" volumes of fluid intake. Beginning on the third day of life, the low-volume group received only enough water to meet average estimated requirements, and the high-volume group received an excess of at least 20 ml per kilogram of body weight per day (mean excess, 47 ml per kilogram per day). Sequential analysis showed that the risk of patent ductus arteriosus with congestive heart failure was greater in infants receiving the high-volume regimen. Thirty-five of 85 infants in the high-volume group acquired murmurs consistent with patent ductus arteriosus, and 11 of these 35 had congestive heart failure. Only nine of 85 infants in the low-volume group had murmurs consistent with patent ductus arteriosus, and two of these nine had congestive heart failure. More cases of necrotizing enterocolitis also occurred in the high-volume group. We conclude that limitation of fluid intake to amounts estimated to meet requirements for excretion, insensible loss, and growth can reduce the risks of patent ductus arteriosus and congestive heart failure in premature infants. The clinical effects of fluid therapy designed to maintain different degrees of negative water balance during the first five days of life were determined prospectively in 88 very low-birth-weight infants. Infants with birth weights of 750 to 1,500 gm were matched for birth weight in 250 gm increments. RDS or no RDS, asphyxiated or not, and inborn or outborn. Each infant was randomized to either Group 1--fluids managed to allow 1 to 2% loss of BW per day to a maximum loss of 8 to 10%, or Group 2--fluids managed to allow 3 to 5% loss of BW per day to a maximum loss of 13 to 15%. The mean five-day cumulative fluid input in Group 2 was 220 ml/kg less than in Group 1, yet Group 2 lost only 41 gm/kg more than did Group 1 (8.8% of BW lost in Group 1 vs 12.9% of BW lost in Group 2, P less than 0.001). There were no statistically significant differences between the groups in incidence of clinically significant patent ductus arteriosus, intracranial hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, dehydration, acute renal failure, or metabolic disturbances. There was no difference in duration of respiratory support required, in time to regain BW, or in time to discharge. There was no difference in the neonatal mortality rate. Fluid input in VLBW infants can be flexible to allow the gradual loss of 5 to 15% of birth weight during the first week of life without adversely affecting outcome. To begin to determine the optimal time for initiating enteral feedings, 34 sick, very low birth weight infants were prospectively selected from all neonates of less than 1,500 g (N = 116) and randomly divided into two groups. Infants were fed either on day 1 (early) or 7 (late) of life, according to a feeding protocol which included parenteral nutrition and a scheduled progression from sterile water to 2.5% dextrose, half-strength, and finally full-strength formula over seven days. The incidence of necrotizing enterocolitis and subsequent hospital course were compared. Initiating enteral feedings on day 1 did not significantly increase the incidence of necrotizing enterocolitis, produce a clustering of cases, or induce an earlier onset of necrotizing enterocolitis. The overall incidence of necrotizing enterocolitis in sick, very low birth weight neonates was 29% (5/17) and 35% (6/17) in the early and late groups, respectively, compared with 4.2% (2/47) in minimally sick, very low birth weight neonates. No significant differences between groups were seen in obstetrical complications, birth weight, gestational age, Apgar scores, presence of patent ductus arteriosus or intraventricular hemorrhage, use of umbilical catheterization, and respiratory or oxygen requirements. Infants fed enterally from day 1 did show a significantly higher energy and protein intake during the second week of life. These data show that providing dilute, early enteral calories does not adversely affect the incidence of necrotizing enterocolitis. Indomethacin is widely accepted as the treatment for patent ductus arteriosus (PDA) in preterm infants but it has various side effects. Ibuprofen is the alternative treatment and believed to be less likely to induce side effects.
                To compare efficacy and side effects of ibuprofen versus indomethacin treatment for symptomatic patent ductus arteriosus (PDA) in preterm infants.
                The authors studied 30 infants (gestational age < or = 35 weeks, aged < or = 10 days) who were diagnosed as having symptomatic PDA confirmed by echocardiogram. The infants were randomly assigned to receive three intravenous doses of indomethacin given at 12-hour intervals or three doses of ibuprofen given at 24-hour intervals, starting within ten days of life. The demographic data, rate of clinical closure, need for additional treatment, side effects, complications and the infants' clinical course were recorded within 28 days.
                The rate of ductal closure was similar with the two treatment regimes. Ductal closure occurred in 7 of 15 infants given ibuprofen (46.67%) and 10 of 15 infants given indomethacin (66.67%). (Relative risk 0.669; 95% confidence interval, 0.328 to 1.364; p = 0.462) The number of infants who needed a second pharmacologic treatment was not significantly different between the two groups, (6 cases in the ibuprofen group, 5 cases in the indomethacin group) but surgical ligation was performed in two cases in the indomethacin group. There was a significant difference in using the diuretic drug (furosemide) in the indomethacin group (11 cases), compared to the ibuprofen group (3 cases), (p = 0.009). More cases of necrotizing enterocolitis were seen in the indomethacin group (66.67% compared to 40% in the ibuprofen group) but there was no statistically significant difference.
                Ibuprofen has the same efficiency as indomethacin for the treatment of symptomatic patent ductus arteriosus in preterm infants and less likely to induce necrotizing enterocolitis and renal toxicity than indomethacin. Indomethacin is used for closing the patent ductus arteriosus in premature infants. Prolonged low-dose indomethacin given over 6 days could potentially improve closure rates because ductal constriction is maintained long enough for more effective anatomic closure. We compared the efficacy of this regimen to conventional dosing in a cohort of very low birth weight infants.
                In a 2-arm clinical trial, 140 infants were randomized to either conventional dose (0.2 mg/kg/dose every 12 hours for 3 doses) or prolonged low-dose indomethacin (0.1 mg/kg/dose daily for 6 doses). The primary outcome measure was ductal closure rate, and the secondary outcomes were the need for a second course of treatment, surgical ligation rates, and side effects.
                Ductal closure after 1 course of indomethacin was similar between the 2 groups: 68% for the conventional dose group and 72% for the prolonged low dose (mean difference -4%; 95% confidence interval: -19% to 11%). The incidence of transient oliguria was higher in the conventional dose group, 31% versus 9%. There was a trend toward more necrotizing enterocolitis in the prolonged low-dose group, 7.0% versus 1.4%.
                There was no difference in efficacy between the 2 dosing regimens. In view of this and with its higher incidence of necrotizing enterocolitis, we do not recommend using prolonged low-dose indomethacin for closing the patent ductus arteriosus in very low birth weight infants. We speculated that prophylactic ligation of the ductus arteriosus would reduce mortality and morbidity in very-low-birth-weight infants. To test this hypothesis, we randomly assigned 84 babies who weighed 1000 g or less at birth and required supplemental oxygen either to receive standard treatment (n = 44) or to undergo prophylactic surgical ligation of the ductus arteriosus on the day of birth (n = 40). The ductus was ligated in babies in the control group only if the shunt was hemodynamically important. All the babies were followed for one year. The incidence of necrotizing enterocolitis was reduced in the group that underwent prophylactic ligation (3 of 40 [8 percent]) as compared with the control group (13 of 44 [30 percent]; P = 0.002). The frequency of death, bronchopulmonary dysplasia, retinopathy of prematurity, and intraventricular hemorrhage was similar in both groups. Because early enteral feeding may have increased the incidence of necrotizing enterocolitis, we analyzed separately the babies who were fed early. Among the infants who were fed within 14 days of birth, those who underwent prophylactic ligation had a lower incidence of necrotizing enterocolitis (1 of 11 [9 percent]) than those who did not (13 of 24 [54 percent]; P = 0.001). Within the control group, the infants who were fed within 14 days of birth and whose ductus was ligated for medical reasons within 5 days of birth had a lower incidence of necrotizing enterocolitis (2 of 10 [20 percent]) than those whose ductus was ligated later or not at all (11 of 14 [79 percent]; P = 0.004). We conclude that early surgical closure of the ductus arteriosus reduces the risk of necrotizing enterocolitis in infants of very low birth weight who require supplemental oxygen. To determine whether "early" ibuprofen treatment, at the onset of subtle patent ductus arteriosus (PDA) symptoms, would improve respiratory outcome in premature infants compared with "expectant" management, with ibuprofen treatment only when the PDA becomes hemodynamically significant (HS).
                We conducted a randomized double-blind controlled trial of infants with gestational ages 23 to 32 weeks and birth weights 500 to 1250 g who had echocardiography for subtle PDA symptoms (metabolic acidosis, murmur, bounding pulses). Infants were then randomized to "early" treatment (blinded ibuprofen; n = 54) or "expectant management" (blinded placebo, n = 51). If the PDA became HS (pulmonary hemorrhage, hypotension, respiratory deterioration), infants received open label ibuprofen. Infants with HS PDA at enrollment were excluded from the study. Respiratory outcomes and mortality and major morbidities were determined.
                "Early" treatment infants received ibuprofen at median age of 3 days; infants in the "expectant group" in whom HS symptoms developed (20%) received ibuprofen at median of 11 days. A total of 49% of "expectant" infants never required ibuprofen or ligation. No significant differences were found in the primary outcome (days on oxygen [O(2)] during the first 28 days), death, O(2) at 36 weeks, death or O(2) at 36 weeks, intestinal perforation, surgical necrotizing enterocolitis, grades III and IV intracranial hemorrhage, periventricular leukomalacia, sepsis or retinopathy of prematurity.
                Infants with mild signs of PDA do not benefit from early PDA treatment compared with delayed treatment.
                Copyright © 2012 Mosby, Inc. All rights reserved. To assess the efficacy and safety of early treatment with ibuprofen (IBU) and indomethacin (INDO) of patent ductus arteriosus in preterm infants. Prospective study with blind trial.
                We studied 35 preterm infants (19 treated with INDO, 16 IBU) (gestation age <33 and birth weight < 1500 g), who had an echocardiographicaly confirmed patent ductus arteriosus (PDA). The infants were randomly assigned in two groups to receive INDO (0.2-0.2-0.2 mg/kg) or IBU (10-5-5 mg/kg) in first 72 hours of life (average 2 days of life). The rate of ductal closure, the need for surgical ligation, side effects, complications, and the infants clinical course were recorded.
                The rate of ductal closure was similar in two groups (15/19, 80% INDO; 11/16, 69% IBU). 27 infants (15 INDO, 12 IBU) were treated per protocol (3 doses). For remaining 8 infants we stopped treatment due to side effects. In the IBU group the main reason to stop treatment was pulmonary hemorrhage (3/16, 19%) and pulmonary hypertension (1/16, 6%), but in the INDO group it was increased serum creatinine and urea nitrogen concentrations (3/19, 16%) and intraventricular hemorrhage (IVH IV) grade (1/19 5%). In IBU group vs. INDO, urine output decreased (p=0.02), but never before below the level of oliguria (defined as urine output below 1 ml/kg/h). Risk of necrotizing enterocolitis (NEC) grade II was similar in two groups, but only patients treated with INDO showed intestinal perforations (p=ns). They received also postnatal hydrocortisone and we showed near significant tendency (p=0.06) for intestinal perforation in patients treated with INDO and hydrocortisone. There were no significant differences with respect to IVH or PVL between the groups.
                The efficacy of ibuprofen and indomethacin in PDA treatment is similar. Treatment of ibuprofen and indomethacin may cause transient renal dysfunction: diminished urine output and increase of serum creatinine and urea nitrogen concentrations. Indomethacin, especially with concomitant treatment with hydrocortisone, may increase the risk of intestinal perforation. To determine whether a course of low-dose indomethacin therapy, when initiated within 24 hours of birth, would decrease ductal shunting in premature infants who received prophylactic surfactant in the delivery room.
                Ninety infants, with birth weights of 600 to 1250 gm, were entered into a prospective, randomized, controlled trial to receive either indomethacin, 0.1 mg/kg per dose, or placebo less than 24 hours and again every 24 hours for six doses. Echocardiography was performed on day 1 before treatment and on day 7, 24 hours after treatment. A hemodynamically significant patent ductus arteriosus (PDA) was confirmed with an out-of-study echocardiogram, and the nonresponders were treated with standard indomethacin or ligation.
                Forty-three infants received indomethacin (birth weight, 915 +/- 209 gm; gestational age, 26.4 +/- 1.6 weeks; 25 boys), and 47 received placebo (birth weight, 879 +/- 202 gm; gestational age, 26.4 +/- 1.8 weeks; 22 boys) (P = not significant). Of 90 infants, 77 (86%) had a PDA by echocardiogram on the first day of life before study treatment; 84% of these PDAs were moderate or large in size in the indomethacin-treated group compared with 93% in the placebo group. Nine of forty indomethacin-treated infants (21%) were study-dose nonresponders compared with 22 (47%) of 47 placebo-treated infants (p < 0.018). There were no significant differences between both groups in any of the long-term outcome variables, including intraventricular hemorrhage, duration of oxygen therapy, endotracheal intubation, duration of stay in neonatal intensive care unit, time to regain birth weight or reach full caloric intake, incidence of bronchopulmonary dysplasia, and survival. No significant differences were noted in the incidence of oliguria, elevated plasma creatinine concentration, thrombocytopenia, pulmonary hemorrhage, or necrotizing enterocolitis.
                The prophylactic use of low doses of indomethacin, when initiated in the first 24 hours of life in low birth weight infants who receive prophylactic surfactant in the delivery room, decreases the incidence of left-to-right shunting at the level of the ductus arteriosus. The impact of early prophylactic use of intravenous indomethacin on the incidence and severity of periventricular-intraventricular hemorrhage and patent ductus arteriosus in 199 oxygen-requiring premature infants (less than or equal to 1300 g birth weight) was prospectively investigated. The trial was controlled, the infants were randomized, and the investigators were unaware of the group assignments. Patients with minimal (grade I) or no periventricular-intraventricular hemorrhage determined by prestudy echoencephalography were randomized within two birth weight subgroups (500 to 899 and 900 to 1300 g) to receive either prophylactic indomethacin (n = 99) or an equal volume of saline-vehicle placebo (n = 100). The first dose (0.2 mg/kg) was given within 12 hours of delivery and two subsequent doses (0.1 mg/kg) were administered at 12 hourly intervals. Prophylactic indomethacin significantly reduced the incidence of grades II to IV periventricular-intraventricular hemorrhage. Intraventricular hemorrhage was half as common in infants given prophylactic indomethacin as in control infants (23% v 46%, P less than .002). The reduction was manifested in both birth weight subgroups. Results of this study also confirmed a lower incidence of clinically significant patent ductus arteriosus in infants who received prophylactic indomethacin in contrast to those who received placebo (11% v 42%, P less than .001). No significant differences were found between treatment and control groups in the duration of oxygen therapy, mechanical ventilation, or hospitalization or in the incidence of pneumothorax, chronic lung disease, sepsis, necrotizing enterocolitis, retinopathy of prematurity, or death. Early prophylactic indomethacin initiated within 12 hours of delivery is effective in reducing the incidence of intraventricular hemorrhage as well as clinically significant patent ductus arteriosus in very low birth weight premature infants. Persistent patent ductus arteriosus (PDA) is a common entity in preterm infants. The most commonly used pharmacological treatment to close the ductus is indomethacin but it can affect cerebral, renal and mesenteric blood flow. Ibuprofen has recently been shown to be effective in closing PDA with fewer hemodynamic effects. In this study we compared the safety and efficacy of ibuprofen and indomethacin in the treatment of PDA in preterm infants.
                A randomized trial was performed. Premature infants with symptomatic PDA confirmed by echocardiography in the first week of life and who required respiratory support were included. The patients were randomly assigned to receive either intravenous indomethacin or ibuprofen. The rate of ductal closure, need for additional treatment, complications, and clinical course were evaluated.
                Twenty-four patients were treated with indomethacin and 23 with ibuprofen. The clinical characteristics before treatment were similar in both groups. Both treatments were effective in closing PDA (87.5% in the indomethacin group and 82.6% in the ibuprofen group). The two cohorts did not differ in the rate of reopening, need for a second pharmacologic treatment, or surgical ductal ligation. No patient in the ibuprofen group developed gastrointestinal adverse effects, but two infants in the indomethacin group had isolated bowel perforation and one had necrotizing enterocolitis. Transient renal dysfunction developed in seven patients (29%) in the indomethacin group versus two (9%) in the ibuprofen group. Transient renal insufficiency was found in one patient in the indomethacin group and in none in the ibuprofen group. The rate of other complications was similar in both groups.
                In our trial ibuprofen was as effective as indomethacin in closing PDA. No significant differences were found in the incidence of complications but fewer renal complications and no gastrointestinal complications were found in the ibuprofen group.
Based on this analysis, the most prudent prescription for water intake to premature infants would seem to be careful restriction of water intake so that physiological needs are met without allowing significant dehydration. This practice could be expected to decrease the risks of patent ductus arteriosus and necrotizing enterocolitis without significantly increasing the risk of adverse consequences.