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.
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.
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.