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Published Online, 15 August 2006, www.theannals.com, DOI 10.1345/aph.1G212a.
 The Annals of Pharmacotherapy: Vol. 40, No. 9, pp. 1697. DOI 10.1345/aph.1G212a
© 2006 Harvey Whitney Books Company.
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Comment: Recent Advances in Neonatal Pharmacotherapy

Robert J Holt, PharmD MBA

Vice President, Medical Affairs Ovation Pharmaceuticals 4 Parkway North Deerfield, Illinois 60015-2502 fax 847/282-1003 Rholt{at}ovationpharma.com

Published Online, August 15, 2006. www.theannals.com, DOI 10.1345/aph.1G212a

TO THE EDITOR: In a recent issue of The Annals, Calhoun et al.1 reviewed the use of intravenous ibuprofen for treatment of patent ductus arteriosus (PDA) and stated that ibuprofen may cause pulmonary hypertension based on 2 citations, one of which was a comment on the other.2,3 The trial that prompted the earliest report was carried out in very preterm infants (<6 h after birth) who received ibuprofen for the prevention of PDA and were at high risk for pulmonary hypertension.4 The difference between the treatment and placebo groups was not statistically significant (double-sided p value = 0.0809), but because of the seriousness of the event, the trial was stopped prematurely. Additionally, the formulation (ibuprofen trishydroxyaminomethane, or THAM) used in the study is different from the one recently approved for use in the US (ibuprofen lysine). As noted by Mosca et al.,2 no unexpected worsening of oxygenation occurred after ibuprofen lysine administration in 227 mechanically ventilated infants and no association between ibuprofen lysine administration and pulmonary hypertension was found. The researchers concluded that ibuprofen lysine as a treatment for PDA is safe and effective. As Aranda et al.5 have pointed out, this adverse effect has not been associated with ibuprofen lysine, and they have called for further safety studies on ibuprofen THAM after Gournay et al.3 suggested that acidification by the ibuprofen THAM formulation may have precipitated pulmonary microembolization. Bellini et al.6 published a case report of pulmonary hypertension following the use of another formulation of ibuprofen lysine used in Italy. This single case occurred among 169 mechanically ventilated, ibuprofen lysine-treated, preterm infants treated over an 8 year period. Within an hour of the second dose, hypoxemia was noted and echocardiography showed closing of the ductus and findings consistent with right to left shunting. As the authors of this case report pointed out, pulmonary hypertension after ibuprofen lysine administration has not been reported in any multicenter, randomized, double-blind, controlled trial. In a systematic review of the use of intravenous ibuprofen for the treatment of PDA in preterm and/or low birth weight infants that provides the largest collective published experience to date, 11 studies with 620 infants showed no cases of pulmonary hypertension-induced severe hypoxemia.7

Finally, the 2 formulations available in the US for treating PDA (Indocin and NeoProfen, both manufactured by Ovation Pharmaceuticals) are not indicated in the extreme preterm study population in which these events occurred.

References

  1. Calhoun DA, Murthy SN, Bryant BG, Luedtke SA, Bhatt-Mehta V. Recent advances in neonatal pharmacotherapy. Ann Pharmacother 2006; 40: 710-9. Epub 28 March 2006. DOI 10.1345/aph.1G212[Abstract/Free Full Text]
  2. Mosca F, Milena B, Stucchi I, Fumagalli M. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet 2002;360:1023-4.[Medline]
  3. Gournay V, Savagner C, Thiriez G, Kuster A, Roze JC. Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants.Lancet 2002;359:1486-8.[CrossRef][Medline]
  4. Gournay V, Roze JC, Kuser A, et al. Prophylactic ibuprofen versus placebo in very premature infants: a randomized, double-blind, placebo-controlled trial. Lancet 2004;364:1939-44.[CrossRef][Medline]
  5. Aranda JV, Thomas R. Intravenous ibuprofen for preterm newborns.Neoreviews 2005;6:c516-22.
  6. Bellini C, Campone F, Serra G. Pulmonary hypertension following L-lysine ibuprofen therapy in a preterm infant with patent ductus arteriosus.CMAJ 2006;174:1843-4.[Abstract/Free Full Text]
  7. Ohlsson A, Walia R, Shah S. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. The Cochrane Database of Systematic Reviews 2005, issue4 . art. no.: Cochrane Database Syst Rev 2005(4): CD003481.pub2. DOI 10.1002/14651858.CD003481.pub2




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