PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1863 (doi:10.1542/peds.2005-3087)
High-Dose Indomethacin for Patent Ductus Arteriosus Closure: How Strong Is the Evidence?
Shabih Manzar, MDDivision of Neonatology
John Stroger Hospital of Cook County
Chicago, IL 60612
To the Editor.
This is in reference to the recent article by Sperandio et al,1 who described their successful experience of ductal closure with the use of high-dose indomethacin in preterm infants with minimal adverse effects. In their protocol for treatment of patent ductus arteriosus (PDA), instead of using the second course of indomethacin they used a stepwise increment in the dose using a high dose (0.4 to 1 mg/kg). The rationale for this protocol (see their Fig 1)1 was based on previous case reports of indomethacin overdose in premature infants that resulted in transient impairment in renal function without any other adverse effects. However, this dose-dependent closure of ductus was not supported by measuring the steady-state indomethacin serum concentration.
A recent study showed that the volume of distribution of indomethacin is 
0.26 L, with clearance of 0.0071 L/hour. It was observed that clearance from birth increased by 3.3% per day, whereas the volume of distribution increased by 1.47% per day, with 41% and 21% interindividual variability.2 These facts suggest that the indomethacin dose has to be adjusted on an individual basis with a predetermined target serum level. The present study lacked the important pharmacokinetic and pharmacodynamic information on the high-dose indomethacin. The authors' ongoing project on correlating serum indomethacin with the dose resulting in successful closure of PDAs would be very informative.
There is some controversy among neonatologists about treating asymptomatic PDA.3 The prophylactic use of indomethacin has also been debated.4 This dilemma is aggravated further by the observation of increased percentages of early and spontaneous closure of PDA. This is also evident from the results of the Sperandio et al study, which showed that 87% of PDAs were closed by relatively lower doses (57% by the conventional dose [0.2 mg/kg] and another 30% by the initial increment of <0.4 mg/kg; see their Fig 2).1 Only 13% of PDAs were closed by using the high-dose indomethacin, thus preventing the need for surgical ligation.
The concomitant use of steroids, furosemide, or dopamine with indomethacin has been shown to alter the effects and adverse effects of indomethacin.5–7 We assume that none of the infants in the study cohort received these medications. The use of steroids has shown to be associated with an increased risk of spontaneous gastrointestinal perforation.5 For that reason, in many centers, the concomitant use of indomethacin and dexamethasone is viewed very critically. On the other hand, many neonatologists prefer using furosemide and/or dopamine to prevent renal dysfunction during indomethacin therapy.
The question is: Would it be wise to use the high-dose indomethacin regimen for 13% of nonresponding echocardiographic PDAs? A judicious approach is advisable until a head-to-head randomized, controlled trial is conducted comparing the prolonged low-dose course and escalating high-dose course of indomethacin for the treatment of PDA in premature infants.
REFERENCES
- Sperandio M, Beedgen B, Feneberg R, et al. Effectiveness and side effects of an escalating, stepwise approach to indomethacin treatment for symptomatic patent ductus arteriosus in premature infants below 33 weeks of gestation.
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[Abstract/Free Full Text] - Smyth JM, Collier PS, Darwish M, et al. Intravenous indometacin in preterm infants with symptomatic patent ductus arteriosus: a population pharmacokinetics study.
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[Abstract/Free Full Text] - Cooke L, Steer P, Woodgate P. Indomethacin for asymptomatic patent ductus arteriosus in preterm infants. Cochrane Database Syst Rev. 2003;(2):CD003745
- Fowlie PW, Davis PG. Prophylatic indomethacin for preterm infants: a systematic review and meta-analysis.
Arch Dis Child Fetal Neonatal Ed. 2003;88
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[Abstract/Free Full Text] - Stark AR, Carol Wa, Tyson JE, et al. Adverse effects of early dexamethasone in extremely low birth weight infants. National Institute of Child Health and Human Development Neonatal Research Network.
N Engl J Med. 2001;344
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[Abstract/Free Full Text] - Barrington K, Brion LP. Dopamine versus no treatment to prevent renal dysfunction in indomethacin-treated preterm newborn infants. Cochrane Database Syst Rev. 2002;(3):CD003213
- Brion LP, Campbell DE. Furosemide for symptomatic patent ductus arteriosus in indomethacin-treated infants. Cochrane Database Syst Rev. 2001;(3):CD001148
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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Pediatrics 2006 117: 1863-1864.[Extract] [Full Text]
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