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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
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