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Three Part Question

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

Clinical Scenario

A 27 week gestation infant is dignosed 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 we could administer prolonged indomethacin therapy over 5-7 days to ensure that the PDA remains closed. What evidence did she have?

Search Strategy

MEDLINE (1966-Dec 2002). Other databses searched were Cochrane Controlled Trials Register (Issue 4, 2002), EMBASE (1980-Dec 2002), CINAHL (1982-Dec 2002), abstracts published in Pediatric Research (1990-2002).
"indomethacin" AND "Patent ductus arteriosus" AND "infant, newborn"; LIMIT to "english language" and "human" - 375 references.

Search Outcome

Five relevant trials were identified.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Lee J et al 2001 Singapore	Infants less or equal to 1500 grams with a symptomatic PDA greater or equal to 1.5 mm on echocardiography were randomised to conventional indomethacin (0.2 mg/kg/dose q 12 hourly x 3 doses; n = 70) or prolonged low dose course indomethacin (0.1 mg/kg q 24 hourly x 6 doses; n = 70)	Prospective randomised controlled trial (level 1b)	Closure after first course	Relative risk (RR) 1.02; 95% CI 0.87, 1.27; Risk difference (RD) 0.01; 95% CI -0.14, 0.17.	No blinding of intervention Intention to treat analysis PDA diagnosis by echocardiography
			Need for surgical ligation of PDA	RR 0.62 (95% CI 0.27, 1.39); RD -0.07 (-0.19, 0.05)
				No difference in mortality rates
Tammela et al 1999 Finland	61 infants of gestational ages 24 - 32 weeks 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 x 7 days). Echocardiography was performed 3, 9 and 14 days after starting treatment.	Prospective randomised controlled trial (level 1b)	Closure after first course	RR 0.71 (95% CI 0.54, 0.93); RD -0.27 (-0.46, -0.08)	Only assessment was blinded
			Need for surgical ligation	Increased need for surgical ligation in the prolonged group [RR 4.65 (95% CI 1.09, 19.78); RD 0.24 (95% CI 0.05, 0.42); NNH 4.0 (95% CI 2, 20)]
			Recurrences needing treatment	RR 1.03 (95% CI 0.37, 2.85); RD 0.01 (-0.19, 0.21)
				No difference in mortality rates
Hammerman and Aramburo 1990 Israel	39 infants < 1500 grams with echocardiographically confirmed PDA were randomised to receive standard indomethacin therapy (0.2 mg/kg/dose q 8 hourly), followed by either maintenance indomethacin (0.2 mg/kg q 24 hourly x 5 days; n = 20) or equivalent volume of placebo for 5 days (n = 19)	Prospective double-blind randomised controlled trial (level 1b)	Closure after first course	RR 1.22 (95% CI 0.90, 1.66); RD 0.16 (-0.07, 0.40)
			Recurrence of PDA	RR 0.11 (95% CI 0.01, 1.84); RD -0.21 (95% -0.41, -0.01)
			Need for surgical ligation	RR 0.14 (95% CI 0.02, 1.00); RD -0.32 (-0.56, -0.08); NNT 3.0 (95% CI 2, 12)
				There was no increase in the toxic effects of indomethacin
Rennie and Cooke 1991 UK	Total of 121 infants < 2500 grams with clinical signs of PDA were randomised to receive either prolonged course indomethacin (0.1 mg/kg q 24 hourly x 6 days; n = 59) or short course (0.2 mg/kg q 12 hourly x 3 doses; n = 62)	Prospective randomised controlled trial (level 1b)	Closure after first course	RR 1.16 (95% CI 0.99, 1.36); RD 0.12 (95% CI -0.01, 0.25)	No blinding of intervention or assessment Echocardiography was not used for assessment of PDA
			Recurrence of PDA	RR 0.61 (95% CI 0.32, 1.17); RD -0.12 (95% CI -0.27, 0.03)
			Need for surgical ligation	RR 1.58 (95% CI 0.27, 9.10); RD 0.02 (95% CI -0.05, 0.09)
				Higher mortality rate in the prolonged indomethacin group, not directly related to treatment. Majority occurred after the first month
Rhodes et al. 1988 USA	70 preterm infants < 1500 grams with echocardiographically diagnosed PDA were randomised to either prolonged course indomethacin over 1 week or to short course (2 doses of indomethacin; n = 36). All infants were given 2 doses of indomethacin 0.15 mg/kg 12 hours apart. The prolonged course group (n = 34) received additional 0.1 mg/kg q 24 hourly x 5 days.	Prospective randomised controlled trial (level 1b)	Closure after first course	RR 1.11 (95% CI 0.77, 1.61); RD 0.06 (95% CI -0.16, 0.29)	No blinding of intervention
			Recurrence of PDA	RR 1.51 (95% CI 0.65, 3.52); RD 0.10 (95% CI -0.10, 0.30)
			Need for surgical ligation	RR 2.12 (95% CI 0.20, 22.30); RD 0.03 (95% CI -0.06, 0.13)
				No differences in mortality rates

Comment(s)

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 1 study (Rennie et al), PDA was diagnosed by echocardiography. In 2 studies (Lee et al; Rhodes et al), PDA was detected on echocardiographic screening at predermined intervals while in 2 studies (Tammela et al; Hammerman et al), a clinically symptomatic PDA was confirmed on echocardiography. 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 majority of the studies, the incidence of renal side-effects was less in the prolonged indomethacin group as compared to 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 (<1000g). 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 efficent trial design. Within the prolonged and short course treatment arms, the infants would then be randomised to receive indomethacin on echocardiograhic determination of PDA within the first seven days or when PDA becomes clinically symptomatic. The outcomes assessed should be mortality and need for surgical ligation.

Clinical Bottom Line

The evidence is inconclusive as to which is the superior regimen. The prolonged course regime may have a role in those with borderline impairment of renal function.

References

1. Lee J, Rajadurai S, Wong KY, et al. Comparing two indomethacin dosing regimes for treating patent ductus arteriosus (PDA): a randomised controlled trial. Pediatr Research 2001;49:387A
2. Tammela O, Ojala R, Iivainen T, et al. Short versus prolonged indomethacin therapy for patent ductus arteriosus in preterm infants. J Pediatr 1999;134(5):552-7.
3. Hammerman C, Aramburo MJ. Prolonged indomethacin therapy for the prevention of recurrences of patent ductus arteriosus. J Pediatr 1990;117(5):771-6.
4. Rennie JM, Cooke RWI Prolonged low dose indomethacin for persistent ductus arteriosus of prematurity. Arch Dis Child 1991;66(1 spec no):55-8.
5. Rhodes PG, Ferguson MG, Reddy NS. Effects of prolonged versus acute indomethacin therapy in very low birth infants with patent ductus arteriosus. Eur J Pediatr 1988;147(5):481-4.