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ARTICLE: Jiun Lee, Victor Samuel Rajadurai, Keng Wee Tan, Keng Yean Wong, Ee Hwee Wong, and Joy Yoke Ngan Leong Randomized Trial of Prolonged Low-Dose Versus Conventional-Dose Indomethacin for Treating Patent Ductus Arteriosus in Very Low Birth Weight Infants Pediatrics 2003; 112: 345-350 [Abstract] [Full text] [PDF]

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Two dosing regimens for Indomethacin (RCT) , What is the evidence for change in practice?

Samir Gupta, Sanjay Gupta   (11 September 2003)

Actually we recommend no change in practice

Jiun Lee, Victor S. Rajadurai, Keng Wee Tan, Keng Yean Wong, Ee Hwee Wong, and Joy YN. Leong   (29 October 2003)

Two dosing regimens for Indomethacin (RCT) , What is the evidence for change in practice? 11 September 2003
Samir Gupta, Neonatal Fellow James Cook University Hospital, Marton road, Middlesbrough, TS4 3BW, Cleveland, UK, Sanjay Gupta Send letter to journal: Re: Two dosing regimens for Indomethacin (RCT) , What is the evidence for change in practice? neokids2002{at}hotmail.com Samir Gupta, et al.	Randomised Control Trial of Two dosing Regimens of Indomethacin for Treatment of Patent Ductus Arteriosus - Is there evidence for change in practice? Dear Sir, We read with interest the trial of two dosing regimens of Indomethacin for treatment of patent ductus arteriosius (PDA) by Dr Lee and colleagues in the recent issue of your journal¹. Although an interesting study the authors’ recommendation for not using the prolonged low-dose course of indomethacin is not warranted from their data and their interpretation is open to challenge. They based their conclusion on the basis of no significant difference in the closure rates of PDA between the two groups, and a higher incidence of necrotising enterocolitis (NEC) in babies on the prolonged low-dose course, which is inappropriate as NEC was secondary outcome data and the study was not adequately powered to say so. Moreover, the authors could have expressed the results better by analysing their data in terms of absolute risk increase (ARI) for NEC. For example, if we consider the low-dose regimen as experimental therapy, it is easy to calculate the number of babies that need to be treated with low -dose regimen to harm one extra baby, i.e., number needed to harm (NNH) (Table 1). Similarly, the effect on closure of PDA can be expressed as absolute benefit increase (ABI) and number needed to treat (NNT) to benefit one extra baby by using the low-dose regimen(Table 1). We have calculated this on the results of their study, based on the control event rate (CER) and experimental event rate (EER) using 67 babies in each arm, excluding the babies who died before evaluation of response to therapy. Table 1: Statistical calculations for PDA closure and NEC based on data from the article(1) ------------------------------------------------------------ OUTCOME CER EER ARR* NNT** (conventional) (low dose) (95%CI) (95%CI) ------------------------------------------------------------ PDA closure 0.701 0.761 9% 17 after 1st (-29%to12%)(12-infinity course NEC 0.014 0.07 0.0056 18 (-0.12-0.01)(9-infinity ------------------------------------------------------------ *ABI for PDA and ARI for NEC **NNH for NEC Looking at these calculations, it is quite obvious that there was no significant difference in the rates of closure of PDA or incidence of NEC between the two groups. Thus, the conclusions drawn from the article may be misleading and there is no valid reason as to why the current practice of using low dose indomethacin (0.1 mg per kg per dose daily for 6 days) regimen be stopped in favour of 3 dose conventional regimen (0.2 mg per kg per dose every 12 hours for 3 doses) for closing patent ductus arteriosus in very low birth weight babies. REFERENCES 1. Lee J, Rajadurai VS, Tan KW, Wong KY, Wong EH, Leong JYN. Randomised trial of prolonged low-dose versus conventional-dose indomethacin for treating patent ductus arteriosus in very low birth weight infants. Pediatrics 2003;112(2):345-350 AUTHORS 1. Samir Gupta, MRCPI, Neonatal Fellow 2. Sanjay Gupta, MRCPCH, Sp. Registrar Directorate of Neonatology, The James Cook University Hospital, Middlesbrough, TS4 3BW, Cleveland, UK CORRESPONDANCE TO: Samir Gupta Email: neokids2002@hotmail.com
Actually we recommend no change in practice 29 October 2003
Jiun Lee, Consultant Neonatologist KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Victor S. Rajadurai, Keng Wee Tan, Keng Yean Wong, Ee Hwee Wong, and Joy YN. Leong Send letter to journal: Re: Actually we recommend no change in practice ljiun{at}kkh.com.sg Jiun Lee, et al.	Dear Sir, Dr Gupta has, with impressive statistics, shown that prolonged low dose indomethacin has no significant advantage over conventional dosing, nor did it cause significant harm. This was something that we had made very clear in our article. Prolonged low dose indomethacin is however an experimental therapy. Necrotizing enterocolitis is a devastating condition and prolonged low dose indomethacin administration probably induces a state of prolonged gut ischemia, potentially setting off the chain of events leading to NEC. Tammela et al [1] had demonstrated a significantly higher incidence of NEC in their long course indomethacin arm, albeit using a different definition for NEC (they included stage 1 NEC). Using Dr Gupta’s statistics, there will be at least 5 more cases of NEC per year in our NICU (assuming 90 VLBW infants need indomethacin) had we administered the experimental therapy. To prove conclusively the association between prolonged indomethacin and NEC will probably require more than one thousand infants. We are prepared to continue with the present practice of using conventional dosing and not harm more infants unnecessarily. 1. Tammela O, Ojala R, Iivainen T, et al. Short versus prolonged indomethacin therapy for patent ductus arteriosus in preterm infants. J Pediatr 1999; 134: 552-7.