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Global shortage and rationing of indomethacin: need to refine approach

Journal of Perinatology volume 30, pages 384–387 (2010)Cite this article

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Global shortage of indomethacin has led to an unprecedented situation, which is likely to affect neonatal units around the world. The financial and logistic implications of this are likely to be quite significant. Without going into the reasons for and chronology of how this scenario came about, it is important that steps are taken to reassess and possibly refine our strategy. This letter briefly outlines factors that should be considered. Patent ductus arteriosus (PDA) is a common diagnosis in preterm infants. Approximately 65% of infants born at <28 weeks of gestation will have persistent patency of the ductus arteriosus and will be assigned the diagnosis of PDA at some time during the early neonatal period.1 Although most would be convinced about associations between a hemodynamically significant ductus arteriosus and postnatal morbidities, equipoise exists whether treatment makes a difference to outcomes.2, 3 Recent trials of nonsteroidal anti-inflammatory drugs have not led to any detectable reduction in neonatal morbidities or improvements in outcomes.4 The contribution of burden of disease, including its medical treatment, is extensive. A recent analysis from Australia showed that out of 11 330 preterm infants <32 weeks of gestation, 2506 (22.6%) were assigned the diagnosis of PDA. Of these, 2192 (87.5%) received indomethacin.5 It goes without saying that consumption of this medication worldwide is likely to be extensive. The one fact remains that indomethacin is the mainstay of medical treatment for medical closure of a symptomatic PDA. Lack of consensus plagues almost all other aspects.

The need to treat itself has been an unresolved dilemma. This stems from uncertain or unproven causal linkage between PDA and neonatal comorbidities, as well as lack of beneficial effects as outlined above. Some investigators rarely treat and virtually never ligate,2 whereas others treat early, that is on day 1.6 It is interesting that meta-analysis of early targeted therapy has not shown improvement in outcomes (morbidity or mortality), although demonstrating increasing primary closure rate.7 Spontaneous closure rate in preterm infants also cannot be ignored. Van Overmeire et al.8 reported spontaneous closure by 7 days of life in 80% of moderately sick preterm infants between 26 and 31 weeks of gestation. About 21% closure at 24 to 25 weeks of gestation has been reported, whereas for each week above 23 weeks, odds of spontaneous closure increase by 1.5.9, 10 These figures need to be considered while rationalizing the usage of indomethacin, keeping in mind its negative effects on intestinal, cerebral and lately coronary vasculature.11 Uniformity in dosage schedule also seems elusive. Although we use a dose of 0.1 mg kg−1 per dose intravenously daily for 6 days, 3-day courses (though similar cumulative dosage: 0.2 mg kg−1 once a day for 3 days, or 0.2 mg kg−1 every 12 h for three doses) are also widely prevalent. Is there a role for plasma concentration measurements to guide therapy? Pharmacokinetic studies have investigated correlation between indomethacin plasma concentration and efficacy. Although initial pharmacological studies failed to demonstrate a relationship between plasma concentrations and PDA closure, Thalji et al.12 showed a clear relationship between area under the plasma indomethacin concentration curves and patient response to treatment, although presence of a threshold indomethacin concentration was less clear. Other investigators have noted that closure occurred in 75% of infants with a plasma concentration of ⩾0.4 mg l−1 24 h after the last dose.13 Whether this information affects the dosing regimens used worldwide or makes the case for routine drug level monitoring in guiding therapy is still unclear. Vert et al.14 studied elimination and plasma half-lives of indomethacin in preterm infants and noted the plasma half-life seemed to be inversely correlated with gestational age (r=0.66, P<0.05). Once again, no relationship between peak plasma levels and ductal closure was established. Does this imply dosage should be gestation specific? It seems unclear on the basis of available evidence that titrating dosage regimens according to gestational age or for that matter chronological age carries any additional benefit.

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References

  1. Costeloe K, Hennessy E, Gibson AT, Marlow N, Wilkinson AR . The EPICure study: outcomes to discharge from hospital for infants born at the threshold of viability. Pediatrics 2000; 106: 659–671.

    Article  CAS  Google Scholar 

  2. Bose CL, Laughon MM . Patent ductus arteriosus: lack of evidence for common treatments. Arch Dis Child Fetal Neonatal Ed 2007; 92: F498–F502.

    Article  Google Scholar 

  3. McNamara PJ, Sehgal A . Towards rational management of patent ductus arteriosus—the need for disease staging. Arch Dis Child 2007; 92: F424–F427.

    Article  Google Scholar 

  4. Bose CL, Laughon M . Treatment to prevent patency of the ductus arteriosus: beneficial or harmful? J Pediatr 2006; 148 (6): 713–714.

    Article  Google Scholar 

  5. Santhanam S, Walker K, Shingde V, Bishuevel C, Halliday R, Badawi N et al. Patent ductus arteriosus in preterm babies &lt; 32 weeks in NSW and ACT over the period 1992–2005: risk factors, associated morbidities and outcome. 12th Annual Congress of Perinatal Society of Australia and New Zealand 2008. Queensland; abstract A41.

  6. Carmo KB, Evans N, Paradisis M . Duration of indomethacin treatment of the preterm patent ductus arteriosus as directed by echocardiography. J Pediatr 2009; 155 (6): 819–822.e1; e-pub ahead of print 29 July 2009.

    Article  Google Scholar 

  7. Jones LJ, Craven PD, Attia J, Wright I . Early targeted indomethacin: where is the evidence?. 12th Annual Congress of Perinatal Society of Australia and New Zealand 2008. Queensland; abstract A38.

  8. Van Overmeire B, Van de Broek H, Van Laer P, Weyler J, Vanhaesebrouck P . Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory distress syndrome. J Pediatr 2001; 138 (2): 205–211.

    Article  CAS  Google Scholar 

  9. Narayanan M, Cooper B, Weiss H, Clyman RI . Prophylactic indomethacin: factors determining permanent ductus arteriosus closure. J Pediatr 2000; 136 (3): 330–337.

    Article  CAS  Google Scholar 

  10. Koch J, Hensley G, Roy L, Brown S, Ramaciotti C, Rosenfeld CR . Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics 2006; 117: 1113–1121.

    Article  Google Scholar 

  11. Sehgal A, Ramsden A, McNamara PJ . Effect of indomethacin on cardiovascular and coronary haemodynamics in preterm infants. Pediatric Academic Societies Annual Meeting 2010, Vancouver; abstract E-PAS 2845.237.

  12. Thalji A, Carr I, Yeh TF, Raval D, Luken JA, Pildes RS . Pharmacokinetics of intravenously administered indomethacin in premature infants. J Pediatr 1980; 97: 995–1000.

    Article  CAS  Google Scholar 

  13. Smyth JM, Collier PS, Darwish M, Millership JS, Halliday HL, Peterson S et al. Intravenous indomethacin in preterm infants with symptomatic patent ductus arteriosus. A population pharmacokinetic study. Br J Clin Pharmacol 2004; 58: 249–258.

    Article  CAS  Google Scholar 

  14. Vert P, Bianchetti G, Marchal F, Monin P, Morselli PL . Effectiveness and pharmacokinetics of indomethacin in premature newborns with patent ductus arteriosus. Eur J Clin Pharmacol 1980; 18: 83–88.

    Article  CAS  Google Scholar 

  15. Konig K, Collins C, Casalaz D, Watkins A . Efficacy of a second course of indomethacin for treatment of patent ductus arteriosus in preterm infants. 12th Annual Congress of Perinatal Society of Australia and New Zealand 2008. Queensland; abstract A40.

  16. Moore GP, Lawrence SL, Maharajh G, Sumner A, Gaboury I, Lemyre B . Repeated indomethacin courses in &lt;27 week gestational age infants with patent ductus. Is it worthwhile? Pediatric Academic Societies Annual Meeting 2009; Baltimore; abstract E-PAS5511.183.

  17. Ojala TH, Lethonen L . a preliminary report: heparin counteracts indomethacin effect on ductus arteriosus in very low birth weight infants. Pediatr Crit Care Med 2007; 8 (3): 258–260.

    Article  Google Scholar 

  18. Silas R, Ramsden CA, Veldman A . Heparin administration with TPN during indomethacin therapy for PDA: a combination which deserves attention. 12th Annual Congress of Perinatal Society of Australia and New Zealand 2008. Queensland; abstract P109.

  19. Dagle JM, Lepp NT, Cooper ME, Schaa KL, Kelsey KJ, Orr KL et al. Determination of genetic predisposition to patent ductus arteriosus in preterm infants. Pediatrics 2009; 123 (4): 1116–1123.

    Article  Google Scholar 

  20. Noori S, Friedlich P, Seri I, Wong P . Changes in myocardial function and hemodynamics after ligation of the ductus arteriosus in preterm infants. J Pediatr 2007; 150 (6): 597–602.

    Article  Google Scholar 

  21. McNamara PJ, Teixiera L, Shivananda S, Sehgal A, Stephens D, Redington A . PDA ligation is associated with postoperative myocardial dysfunction in premature infants. J Thorac and Cardiovasc Surg. Accepted 2010.

  22. Francis JV, Padmanabhan S, Jacques L, Courtot J, Sehgal A . Respiratory and cardiovascular morbidity in the first 48 h post duct ligation surgery. Pediatric Academic Societies Annual Meeting 2010; Vancouver; E-PAS2835.236.

  23. Insoft RM, Filkins BA . Comparison of ibuprofen lysine versus indomethacin for the closure of patent ductus arteriosus: the results of a BWH NICU QI Project. Pediatric Academic Societies Annual Meeting 2009; Baltimore; E-PAS2009:430.

  24. Glenen L, Kirkby S, Turenne W, Dysart K, Philadelphia PA . Is indomethacin or ibuprofen more beneficial for treatment of patent ductus arteriosus? Pediatric Academic Societies Annual Meeting 2009; Baltimore; E-PAS2009:510.

  25. Ohlsson A, Walia R, Shah SS . Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. no.: CD003481. DOI: 10.1002/14651858.CD003481.pub3.

  26. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 2005; 365 (9460): 663–670.

    Article  Google Scholar 

  27. Sehgal A, McNamara PJ . Staging the ductus arteriosus facilitates identification of neonates at increased risk of respiratory morbidity. 13th Annual Congress of Perinatal Society of Australia and New Zealand 2009. Queensland; abstract A27.

  28. Sehgal A, McNamara PJ, Sehgal A, McNamara PJ . Echocardiographic markers of a haemodynamically significant ductus arteriosus. Eur J Pediatr 2009; 168 (8): 907–914.

    Article  Google Scholar 

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Authors and Affiliations

  1. Monash Newborn, Monash Children's, Melbourne, VIC, Australia

    A Sehgal

  2. Ritchie Centre for Baby Health Research, Melbourne, VIC, Australia

    A Sehgal

  3. Monash University, Melbourne, VIC, Australia

    A Sehgal

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Sehgal, A. Global shortage and rationing of indomethacin: need to refine approach. J Perinatol 30, 384–387 (2010). https://doi.org/10.1038/jp.2010.49

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