Randomized Trial of Prolonged Low-Dose Versus Conventional-Dose Indomethacin for Treating Patent Ductus Arteriosus in Very Low Birth Weight Infants
* Departments of Neonatology
Pediatrics, KK Women’s and Children’s Hospital, Singapore, Singapore
Clinical Trials and Epidemiology Research Unit, Singapore, Singapore
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Objective. 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.
Methods. 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.
Results. 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%.
Conclusions. 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.
Key Words: patent ductus arteriosus • prolonged • indomethacin • premature infants • very low birth weight • randomized trial
Abbreviations: PDA, patent ductus arteriosus • VLBW, very low birth weight • NEC, necrotizing enterocolitis
Indomethacin, a nonselective prostaglandin inhibitor, has been used to treat the patent ductus arteriosus (PDA) in premature infants since the early 1970s.1 Conventional-dose indomethacin remains ineffective in 10% to 30% of cases,2 and the best dosing regimen is still debatable. Prolonged low-dose indomethacin might improve PDA closure rates because theoretically, extended muscular constriction (functional closure) causes persistent hypoxia of the inner vessel wall which induces permanent anatomic closure of the ductus.3 The doses used range from 0.1 to 0.2 mg/kg daily for up to a week, whereas the conventional dose regimen is usually completed within a day.
Three randomized trials looking at prolonged low-dose indomethacin have been conducted.4–6 The largest (n = 121) by Rennie and Cooke4 found that it reduced the number of relapses and caused fewer rises in serum urea. Documentation of ductus closure or relapse in that study was, however, based on clinical signs and not by echocardiography. The other 2 trials were limited mainly by small sample sizes and had different conclusions. In view of the existing contradictory results, we conducted this trial to compare the efficacy and side effects of prolonged low-dose versus conventional-dose indomethacin for treating early symptomatic PDA.7 To improve the validity of the conclusions, we confirmed the presence of a hemodynamically significant PDA with echocardiography in all cases before starting treatment. Posttreatment status of the ductus was also determined echocardiographically for all.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Trial Design
This was a 2-arm randomized trial conducted in the neonatal intensive care unit from April 20, 1998 to July 24, 2000. The study was approved by the hospital’s ethics committee. About 15 000 newborns are delivered in our hospital each year, of which
200 (or 1.3%) are very low birth weight (VLBW) infants, ie, birth weight under 1500 g. Criteria for enrollment were any VLBW infant who had a hemodynamically significant PDA, defined as the presence of any one of these signs: systolic murmur, hyperactive precordium, wide pulse pressure (diastolic pressure less than half systolic), hypotension, apnea or rising PCO2, plus a PDA of >1.5 mm in diameter on 2-dimensional echocardiogram.8 Exclusion criteria were major congenital malformations and necrotizing enterocolitis (NEC). Informed formal written consent was obtained from either parent of all the enrolled infants.
Randomization
Stratified blocked randomization was used with birth weight (<1000 g and 1000–1499 g) as the stratification factor. Randomization was generated using a computer program and conducted through the central randomization office of the National Medical Research Council, Clinical Trials and Epidemiology Research Unit, Singapore, by means of a telephone call during office hours. After office hours, sequentially numbered sealed envelopes were used. The assigned treatment was concealed in the envelope until the point of allocation.
Treatment Schedule
Treatment began as soon as possible after randomization, usually within an hour. Each infant received either conventional dose indomethacin (Indocid I.V.; Merck, West Point, PA), given as 0.2 mg/kg body weight per dose every 12 hours for 3 doses, or prolonged low-dose, given as 0.1 mg/kg body weight per dose every 24 hours for 6 doses. The doses were checked by 2 people before infusion, which was given over half an hour. If the ductus failed to close or relapsed after the first course and was hemodynamically significant, a second course was given after an interval of at least 48 hours from the last dose. The dosing regimen of the second course was the same as that for the first. Surgical ligation was conducted if both courses failed. The enrolled infants were followed up until death or discharge from hospital.
Indomethacin was delayed for the following: platelet count <60 000 per cubic millimeter, intraventricular hemorrhage within the past 12 hours, active bleeding, urine output <1 mL/kg body weight per hour over the preceding 8 hours, serum creatinine concentration of >140 µmol/L, and significant hyperbilirubinemia with a serum bilirubin concentration within 35 µmol/L of exchange transfusion level (birth weight dependent as per unit protocol).
Indomethacin was not used for tocolysis in any of the mothers of the infants enrolled.
2-Dimensional Echocardiogram
This was performed by cardiologists who were blinded to the treatment allocation, using color Doppler echocardiography (Sonos 2000 imaging system; Hewlett-Packard, Andover, MA; using a 7.5 MHz transducer). Minimal diameter, ie, point of maximal constriction of the ductus, was measured. All the scans were recorded on videotapes. To document response, scans were repeated 24 to 72 hours after the last dose of the drug. Additional scans were done at the discretion of the physician-in-charge.
Primary and Secondary Outcomes
The response to the first course of indomethacin was identified as the primary endpoint of the study and was defined echocardiographically as 1) closed if the ductus was closed (without relapse) and needed no further treatment, 2) open if the ductus was still open and hemodynamically significant, and 3) relapsed if the ductus relapsed and was hemodynamically significant. Failure of response would mean that the status of the ductus was either open or relapsed after treatment.
Secondary outcome measures were the need for a second course of indomethacin, the number of surgical ligations and side effects. Anticipated side effects were oliguria (urine output <1 mL/kg body weight per hour for the preceding 24 hours), serum creatinine >140 µmol/L, serum sodium <130 mmol/L and <5 mmol/L of pretreatment value, brownish gastric aspirates needing treatment with ranitidine, fresh gastric bleeding, and focal gastrointestinal perforation. These side effects were considered to be attributable to indomethacin if it occurred within a week of starting treatment.
Potential Confounders
Data on these parameters were collected: daily fluid intake for the first 2 weeks, surfactant use, mean airway pressure and fraction of inspired oxygen at 24 and 72 hours, pulmonary pathology, antenatal steroids, and culture-proven sepsis.
Various clinical outcomes were recorded. These were days on supplemental oxygen, continuous positive airway pressure, intermittent mechanical ventilation and high frequency oscillatory ventilation, chronic lung disease (oxygen dependency at 28 days and/or at 36 weeks postconceptional age), retinopathy of prematurity, intraventricular hemorrhage, cystic periventricular leukomalacia, and NEC stages II and III.9
Feeding Protocol
Feeds, preferably fresh expressed breast milk, were started early (nonnutritive, 1 mL every 6 hours). When cardiovascularly stable, feed volume was increased by 10 mL/kg/d. For infants at risk of NEC (small for gestational age, Apgar score <5 at 5 minutes of life, hypotension requiring inotropes or abnormal prenatal Doppler studies), feeding might be increased on alternate days rather than daily. Feeds were not withheld when indomethacin was used.
Data Collection
Data were collected on printed case record forms. We had endeavored to obtain complete information on all subjects, and every attempt was made to resolve any missing or inconsistent information.
Independent Data Monitoring and Safety Committee
This comprised 2 neonatologists and a statistician from Australia. Interim analysis was done after completion of 50 cases, and the recommendation was that the trial be continued without major modifications.
Sample Size and Statistical Analysis
Previous data from our unit using conventional-dose indomethacin suggested a PDA closure rate of 70%. A sample size of 140 infants was based on testing for a 20% difference in ductal closure rates between the 2 dosing regimens, with 80% power, and a 2-sided significance level of 5%. Data were analyzed according to the intention-to-treat principle. The 
2 test was used to test for difference in proportions. The P values for the 6 side effects considered were adjusted for multiple testing using Holm’s multiple testing procedure. Exploratory subgroup analysis for infants with birth weights under 1000 g was also performed on the primary and secondary endpoints. All analyses were performed using SPSS for Windows Version 8 (SPSS, Inc, Chicago, IL) and confidence intervals obtained using the Confidence Interval Analysis program.10
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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During the study period, 442 VLBW infants were born. Of the 158 (35.7%) that were eligible, 140 were enrolled into the study. Eighteen (or 11.4%) of the eligible infants were not enrolled because 8 parents refused consent, 4 were uncontactable, 2 infants needed urgent treatment, 2 had potential medico-legal problems, and 2 were missed. The characteristics and outcomes of the eligible but not enrolled infants were similar to those enrolled. Figure 1 shows the trial profile of the 140 subjects.
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Patient Characteristics
Table 1 shows that the infants in both groups were comparable in terms of demographic and clinical characteristics. Their mean birth weight was 955 g and mean gestational age 27.4 weeks. Fifty-eight percent were extremely low birth weight infants, ie, birth weight under 1000 g. Nearly 80% of infants received partial or complete course of antenatal dexamethasone. Sixty-one percent received surfactant therapy for respiratory distress syndrome. The median age at the start of the first course was 53 hours.
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Treatment Response
Sixty-nine infants were randomized to the conventional dose and 71 to the prolonged low-dose group. Two infants in the conventional group and 4 in the low-dose group died before the evaluation of response after the first course of indomethacin. Hence, treatment response was evaluated in 67 infants in the conventional group and also 67 in the low-dose group.
Incomplete Course
Two infants in the conventional group received 2 instead of the full 3 doses because of contraindications, but their ductus was closed at discharge. Similarly, 11 infants in the low-dose group received an average of 3.3 instead of the full 6 doses because of contraindications. The ductus in 7 of the infants in this group were also closed at discharge despite the incomplete course; 3 had surgical ligation, and in the remaining 1 the ductus closed after a second course of indomethacin.
Response to First-Course Indomethacin (Table 2)
The closure rates were similar between the 2 groups (mean difference –3.7%, 95% confidence interval: –18.6% to 11.3%, P = .713). The number of infants requiring a second course or surgical ligation after 1 course was also comparable. Three infants had their ductus ligated at this stage because further indomethacin was contraindicated (focal intestinal perforation in 2 and acute renal failure in 1).
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Response to Second-Course Indomethacin (Table 2)
Seventeen in the conventional group and 14 in the low-dose group were given a second course. Again, the closure rates were not different. Eighteen (or 58%) of the 31 infants underwent surgical ligation. One infant in the prolonged low-dose group died before ligation.
Table 2 also summarizes the final closure rates with indomethacin and the total number that needed surgical ligation. Subgroup analysis of infants under 1000 g showed no significant differences between the groups on all outcomes considered.
Side Effects
Table 3 shows the side effects seen after the first course of indomethacin. Infants in the conventional group had significantly more oliguria (mean difference 22.6%, 95% confidence interval: 9.3% to 35.4%, P = .006). This effect was, however, transient in nature. On the other hand, for the subgroup of infants under 1000 g, the incidence of oliguria was similar between the groups (conventional-dose group 15.8%, prolonged low-dose group 10.3%).
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Neonatal Morbidities and Outcome
Short-term morbidities, death rates, ventilatory support, and feeding tolerances were very similar between the 2 groups (Table 4). Of note, however, was the fivefold higher incidence of NEC (7% vs 1.4%) in the prolonged low-dose group. Sepsis accounted for all 5 infant deaths in the conventional-dose group. There were 10 deaths in the prolonged low-dose group. They were attributable to sepsis (4 infants), NEC (3 infants), extreme prematurity (2 infants), and pulmonary hemorrhage (1 infant).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Various dosing strategies have been tried since indomethacin was used >20 years ago for treating the PDA. A significant proportion of the ductus in preterm infants still do not seem to respond to cyclo-oxygenase inhibition. Clyman11 has suggested that there may be other factors involved such as nitric oxide inhibition.
Three randomized-controlled trials comparing prolonged versus conventional regimens for treating symptomatic PDA reported contradictory findings. Hammerman5 studied 39 infants in whom the prolonged-dose group received a total of 1.6 mg/kg body weight of indomethacin over 6 days (compared with 0.6 mg/kg in our study), starting at about the ninth day of life. The prolonged-dose group had significantly fewer surgical ligations. It could be that this was a chance occurrence given the small sample size, or the relatively high dose of indomethacin given over a prolonged period indeed had a superior ductal closure effect. We would be wary of using such doses routinely in view of the possible deleterious effects on gastrointestinal and cerebral blood flow. Rennie and Cooke4 studied 121 infants using dosing regimens similar to ours and reported higher initial response and lower relapse rates in the prolonged low-dose group. However, retreatment rates and deaths were higher in this group. Larger preterm infants (birth weight up to 2500 g) were included and documentation of ductus closure or relapse was based on clinical signs alone. The latest trial by Tammela6 on 61 infants concluded that prolonged low-dose indomethacin offered no advantage.
In contrast to the above studies, we enrolled a larger number of infants, the majority (58%) of whom were under 1000 g, and performed echocardiography for all both before and at various points after treatment. Our results clearly showed that prolonged low-dose indomethacin was equally, but not more, effective than the conventional dose. We speculate that this might be because even short periods of prostaglandin inhibition, as found in the conventional-dose regimen, was effective in closing the PDA. This applied also to the period of increased drug clearance after 1 week of age because the closure rates for a second course of indomethacin (started at a median age of 16 days) was not different between the 2 groups. This too was in concordance with the observation that inhibition of prostaglandin synthesis in the newborn could be achieved even with low serum levels of indomethacin.12
The only side effect that occurred more frequently in the conventional group was oliguria. This effect of indomethacin is well-described, transient, and does not seem to have long-term sequelae.13 Therefore, it should not deter one from using the conventional regimen. One interesting phenomenon was that for the subgroup of infants under 1000 g, the incidence of oliguria was similar between the 2 regimens. The renal vascular beds of these extremely preterm infants seemed to be resistant to vasoconstriction by indomethacin, not unlike the poorer ductal constrictive effect of indomethacin in this group of infants.
There is also concern about the reduction in mesenteric blood flow with indomethacin14 and its possible relationship to NEC and focal gastrointestinal perforation.15 In our study, there was a higher incidence of definite NEC (stage II and III) in the prolonged low-dose group, although this was not statistically significant. However, our sample size was not designed to detect a significant difference in the incidence of NEC between the 2 groups. It is conceivable that reduced mesenteric blood flow over 6 days in the low-dose group might increase the risk of NEC through the action of ischemia. We acknowledge that this observed association could well have occurred by chance, and NEC is also a disease with many possible causes. Nevertheless, NEC is a devastating condition, and this observation would make one pause and consider if prolonged low dose should be used at all, especially if it had no clear-cut advantage.
A recent trial by Schmidt et al16 showed that prophylactic indomethacin did not have an effect on 18-month neurodevelopmental outcome, although indomethacin does reduce cerebral blood flow and can potentially cause brain ischemia. We did not demonstrate any difference in short-term neurologic sequelae between the groups. We plan to study the 2-year neurodevelopmental outcome in our cohort.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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There was no practical advantage in administering indomethacin over 6 days. In view of this as well as the trend toward a higher incidence of NEC if the drug was given over an extended period, prolonged low-dose indomethacin cannot be recommended for the treatment of the PDA in VLBW infants.
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ACKNOWLEDGMENTS |
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We thank Drs David Henderson-Smart, Victor Yu, and Val Gebski for their contribution as members of the data monitoring and safety committee.
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FOOTNOTES |
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Received for publication Jan 13, 2003; Accepted Feb 27, 2003.
Reprint requests to (J.L.) Department of Neonatology, KK Women’s and Children’s Hospital, 100 Bukit Timah Rd, Singapore, Singapore 229899. E-mail: ljiun{at}kkh.com.sg
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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