Oral Ibuprofen for Patent Ductus Arteriosus Closure in Preterm Infants: Does High Osmolality Matter?

Two studies suggesting that oral ibuprofen is an option in the management of patent ductus arteriosus (PDA) in preterm infants have been recently published in this journal.[1] [2] These are in accordance with the results of other trials[3] [4] that suggest oral ibuprofen may be as efficacious as indomethacin, with less risk of reducing renal and mesenteric blood flow. The oral form of ibuprofen has the particular advantages of being simpler to administer and less expensive than the intravenous form.[2]

The reduction of mesenteric perfusion may result from a hemodynamically significant PDA and/or be a side effect of indomethacin or ibuprofen, predisposing to necrotizing enterocolitis (NEC).[3] [5] Compared with indomethacin, it seems that intravenous ibuprofen does not reduce mesenteric blood flow velocity significantly in preterm infants with PDA.[6] When oral ibuprofen is preferred, its osmolality should be well known because most commercial suspensions have not been designed for neonatal use, and the enteral use of hyperosmolar solutions may also predispose to NEC in preterm infants.[7] The American Academy of Pediatrics recommends that 400 mOsm/kg should be the maximum osmolality for neonatal feedings.[8] To the best of our knowledge, there are no similar recommendations for drugs and solutions administered to neonates by enteral route.

Using a previously described methodology[9] we have measured, by the freezing point depression method, the osmolality of a convenience sample of ibuprofen suspensions commercially available in some European countries and in the United States. The osmometry was performed without previous knowledge of their osmolalities, and 10-fold dilutions of the suspensions in distilled water were used whenever the osmolality exceeded the range of the osmometer (> 2000 mOsm/kg). Such extrapolation assumes that the cryoscopic constant used for the automatic calculation is a characteristic of the solvent, which is independent of the solute concentration.[10] Intra-assay and interassay coefficients of variations were always less than 1.9% and 3.4%, respectively. The mean osmolalities of the ibuprofen suspensions analyzed, shown in increasing order in Table [1], varied from 1495.0 to 4221.7 mOsm/kg.

Table 1 Osmolality of Some Commercially Available Ibuprofen Suspensions Commercial Name and Manufacturer Concentration mg/mL Osmolality mOsm/kg Mean Standard Deviation Ibum Hasco-Lek, Wrockaw, Poland 20 1495.0 39.1 Motrin McNeil Consumer and Specialty Pharmaceuticals, Fort Washington, PA 40 2037.8 18.9 Ipren Pfizer AB, Sollentuna, Sweden 20 2350.0 69.0 Motrin McNeil Consumer & Specialty Pharmaceuticals, Fort Washington, PA 20 2397.2 32.4 Nurofen Crookes Healthcare, Nottingham, UK 20 2685.0 14.8 Calprofen Pfizer Consumer Healthcare, Surrey, UK 20 2912.2 20.0 Arfen Medinfar, Condeixa, Portugal 20 3332.8 26.1 Advil Wyeth Consumer Healthcare, Madison, WI 20 3391.7 15.9 Advil Wyeth Consumer Healthcare, Madison, WI 40 3546.1 62.9 Brufen Abbott S.p.A, Latina, Italy 20 4221.7 136.0

The commercial names and the osmolalities or osmolarities of ibuprofen suspensions used in the studies involving preterm infants have not been disclosed,[2] [3] [4] [11] [12] [13] [14] [15] except in the following two trials: Cherif et al[1] used Ibuphil (Simed Health Care Group, Sfax, Tunisia), a locally manufactured suspension with a stated osmolarity of 312 mOsm/L, and Heyman et al[16] used Nurofen (Boots Healthcare International, Nottingham, UK) stating an osmolarity of 320 mOsm/L. These values are unexpectedly low when compared with our osmolality measurements, namely of Nurofen (Table [1]). The excipient used in the suspensions may largely contribute to their elevated osmolality. This could explain how a less concentrated preparation made by the same manufacturer has higher osmolality than the more concentrated one, as is the case of the measured Motrin suspensions (Table [1]).

It is not known whether a small amount of an extremely high osmolal suspension given by enteral route may result in adverse gastrointestinal effects in preterm infants. However, gastrointestinal erosions and bleeding may result from a direct irritating effect of ibuprofen on gastric and duodenal mucosa.[17] In preterm infants, oral ibuprofen has been associated with significant delay in starting feeding when used for prophylaxis of PDA[14] and with spontaneous intestinal perforation when used for treatment of PDA.[13] In the studies published to date,[1] [2] [3] [4] [11] [14] [16] the rates of NEC or upper gastrointestinal bleeding do not seem negligible in preterm infants receiving oral ibuprofen for treatment or prevention of PDA.

To summarize, all the commercially available ibuprofen suspensions measured have high osmolality, raising concern over their enteral use in preterm infants. When the use of oral ibuprofen is considered in newborn infants, more isosmolar suspensions should probably be preferred. Only larger safety studies addressing the potential gastrointestinal adverse effects of oral ibuprofen will be able to clarify this issue.

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