Should a prolonged or short course of indomethacin be used in preterm infants to treat patent ductus arteriosus?

A 27 week gestation infant is diagnosed to have a significant patent ductus arteriosus (PDA) on echocardiography on day 2. The infant is ventilator dependent. You decide to treat with indomethacin. The resident suggests that it would be better if prolonged indomethacin therapy could be administered over 5–7 days to ensure that the PDA remains closed. What evidence did she have?

In preterm infants with patent ductus arteriosus [patient], is prolonged course indomethacin [intervention] better than short course conventional therapy [comparator] in preventing recurrences and decreasing the need for surgical ligation [outcomes]?

Medline (1966–Dec 2002): “indomethacin” AND “patent ductus arteriosus” AND “infant, newborn”; LIMIT to “english language” …

I n order to give the best care to patients and families, paediatricians need to integrate the highest quality scientific evidence with clinical expertise and the opinions of the family. 1 Archimedes seeks to assist practising clinicians by providing ''evidence based'' answers to common questions which are not at the forefront of research but are at the core of practice. In doing this, we are adapting a format which has been successfully developed by Kevin Macaway-Jones and the group at the Emergency Medicine Journal-''BestBets''.
A word of warning. The topic summaries are not systematic reviews, through they are as exhaustive as a practising clinician can produce. They make no attempt to statistically aggregate the data, nor search the grey, unpublished literature. What Archimedes offers are practical, best evidence based answers to practical, clinical questions.
The format of Archimedes may be familiar. A description of the clinical setting is followed by a structured clinical question. (These aid in focusing the mind, assisting searching, 2 and gaining answers. 3 ) A brief report of the search used follows-this has been performed in a hierarchical way, to search for the best quality evidence to answer the question. 4 A table provides a summary of the evidence and key points of the critical appraisal. For further information on critical appraisal, and the measures of effect (such as number needed to treat, NNT) books by Sackett 5 and Moyer 6 may help. To pull the information together, a commentary is provided. But to make it all much more accessible, a box provides the clinical bottom lines.
The electronic edition of this journal contains extra information to each of the published Archimedes topics. The papers summarised in tables are linked, by an interactive N Is melatonin likely to help children with neurodevelopmental disability and chronic severe sleep problems?

Hierarchical searches
Archimedes wants to answer clinical questions using a hierarchical search process. What exactly does this mean? And why is it important anyway?
The hierarchical search aims to look for the best quality evidence first, and work downwards if insufficient research is discovered. Secondary sources are looked through in the first instance. These sources have done some of the work of critical appraisal already. An excellent secondary resource is the Cochrane Library. This database contains a large number of systematic reviews of the effects of healthcare interventions, both ''Cochrane'' reviews, and in collaboration with the NHS York Centre for Reviews and Dissemination, other published systematic reviews. Other secondary sources include the EBM Journal, which takes good quality studies published in other journals, creates an independent abstract of the paper, and is accompanied by a critical analysis and commentary. Some guidelines are excellent sources of information, and the authors may have done the job of collating and appraising all relevant evidence for you.
Searching in secondary sources is relatively easy: the Cochrane library is all in one place, 1 EBM Journal lives elsewhere, 2 and a very large number of guidelines are available at the redeveloped (US) National Guidelines Clearinghouse. 3 Where a secondary resource doesn't provide enough of an answer, Archimedes authors look back to the primary literature and perform a systematic, but limited, review of the studies they find. For interventions, randomised controlled trials (RCTs) are the preferred source of evidence. For medical interventions, there are empirical observations which show that non-randomised studies tend to exaggerate treatment effects. 4 If these can't be found, it may be useful to look for large cohort studies. These have many more problems than RCTs, with difficulty assessing the presence of extraneous (confounding) factors which provide an alternative explanation for the outcomes observed. However, they are more likely to estimate the true effect than most casecontrol studies. In turn, a case-control study has a jump on the case study (which is, after all, a posh way of saying ''anecdote'').
How do you search for these studies though? Typing ''heart attack'' into Medline may induce one. There are a few ways to assist the practicing clinician in their searching, by filtering out methodologically poor studies and presenting those with a greater chance of success. If you have the opportunity, many health information specialists (a.k.a. librarians) run courses on searching for clinical information.
Readers wishing to submit their own questions-with best evidence answers-are encouraged to review those already proposed at www.bestbets.org. If your question still hasn't been answered, feel free to submit your summary according to the Instructions for Authors at www.archdischild.com. Three topics are covered in this issue of the journal.
N Is indomethacin or ibuprofen better for medical closure of the patent ductus arteriosus? N Should a prolonged or short course of indomethacin be used in preterm infants to treat patent ductus arteriosus?
N What is the use of the glass test?
Should a prolonged or short course of indomethacin be used in preterm infants to treat patent ductus arteriosus? Report by Sachin Shah, Hospital for Sick Children and University of Toronto; sshahdoc@hotmail.com A 27 week gestation infant is diagnosed to have a significant patent ductus arteriosus (PDA) on echocardiography on day 2. The infant is ventilator dependent. You decide to treat with indomethacin. The resident suggests that it would be better if prolonged indomethacin therapy could be administered over 5-7 days to ensure that the PDA remains closed. What evidence did she have?  (1980( -Dec 2002, CINAHL (1982-Dec 2002, abstracts published in Pediatric Research (1990Research ( -2002. Five relevant trials were identified. See table 2.

Commentary
The five RCTs comparing prolonged versus short course indomethacin differ in the dosage regimes (for both prolonged and short course groups), diagnosis of PDA, and onset of treatment. Also there is a wide variation in the gestational age and birth weight.
In all but one study (Rennie et  There is significant ''in between study heterogeneity'' as far as outcomes like failure of PDA closure, need for surgical ligation, recurrence of PDA, and mortality rates are concerned.
In the majority of studies, the incidence of renal side effects was less in the prolonged indomethacin group compared to the short course group. There were no significant differences in the other co-morbidities.
In theory, short term indomethacin therapy suppresses dilator prostanoids and facilitates ductal constriction. This transient suppression may not allow sufficient time for anatomic ductal closure in many infants. This may be especially true for the extremely low birth weight infant whose PDA is more sensitive to prostaglandins and whose PDA does not constrict as tightly as the more mature infant. Also the ductus tends to retain its sensitivity for a longer duration, making it more susceptible to reopening.
This theoretical advantage has not translated into clinical practice in all the studies. The evidence is inconclusive as to which is the superior regimen. Further trials are needed to determine the optimum regimen and dose of indomethacin, especially in extremely low birth weight infants (,1000 g). A four arm trial where infants are randomised and allocated at birth, either to prolonged therapy or to short course therapy, may be the most efficient trial design. Within the prolonged and short course treatment arms, the infants would then be randomised to receive indomethacin on echocardiographic determination of PDA within the first seven days or when the PDA becomes clinically symptomatic. The outcomes assessed should be mortality and need for surgical ligation.

Clinical bottom line
N The evidence is inconclusive as to which is the superior regimen.
N The prolonged course regime may have a role in those with borderline impairment of renal function.  RR 0.14 (95% CI 0.02 to 1.00); RD 20.32 (20.56 to 0.08); NNT 3.0 (95% CI 2 to 12) Rennie and Cooke (1991) Total of 121 infants ,2500 g with clinical signs of PDA were randomised to receive either prolonged course indomethacin (0.1 mg/kg once daily 6 6 days; n = 59) or short course (0.2 mg/kg 12 hourly 6 3 doses; n = 62).  Tammela et al (1999) 61 infants of gestational ages 24-32 wk with a PDA confirmed with echocardiography were randomised to receive short course indomethacin (3 doses of 0.2, 0.1, and 0.1 mg/kg in 24 hours; n = 31) or prolonged course (0.1 mg/kg q 24 hourly 6 7 days). Echocardiography was performed 3, 9, and 14 days after starting treatment. A preterm baby of 28 weeks gestation with respiratory distress syndrome is admitted to the neonatal intensive care unit. On day 2 of life, the characteristic murmur of a patent ductus arteriosus (PDA) is heard, with the diagnosis confirmed by Doppler echocardiography. The attending neonatologist orders a course of indomethacin in an attempt to treat the PDA. The astute paediatric resident has just taken two tablets of ibuprofen to treat his post-call headache, and wonders whether this alternative non-steroidal anti-inflammatory drug might be just as efficacious, with less side effects.

Structured clinical question
In a preterm baby of gestational age less than or equal to 34 weeks [patient] is ibuprofen [intervention] compared with indomethacin [comparison intervention] equally efficacious at treating echocardiographically proven patent ductus arteriosus and have fewer side effects [outcomes]?
Search results-two systematic reviews: nil relevant. Two protocols for a Cochrane review: one relevant. Nine clinical studies found, four of which were relevant. See table 1.

Commentary
All four studies were randomised, controlled trials; however, the methods of randomisation were not reported. All used cards in sealed envelopes as the system of allocation concealment. Furthermore, there is no evidence that neonatologists, nurses, or pharmacists were blinded in any study. Echocardiographers were blinded in two of the studies.
Each study clearly shows the equivalence of ibuprofen and indomethacin in the treatment of patent ductus arteriosus. In addition, three studies showed a significant increase in oliguria among patients treated with intravenous indomethacin, and two studies showed a significant increase in serum creatinine. No study showed a difference in death, necrotising enterocolitis, or progression of intracranial haemorrhage between the two groups. All trials used a ''high'' dose of The recent Thai study attempts to compare oral ibuprofen with indomethacin; however, analysis is very difficult as patients in the indomethacin group received the drug by different routes of administration (some oral, some intravenous). Further trials with oral ibuprofen would be very helpful, especially for clinicians in countries where this is the only form of the drug available. Unfortunately, the intravenous preparation of ibuprofen is not easily available in North America.