PDA was considered hemodynamically significant with at least two of the following criteria: left atrial/aortic root ratio >1.5, reverse end-diastolic flow in descending aorta, pulsatile transductal flow (Vmax) <1.8m/s, ductus diameter >1.5 mm. Fluid intake and surfactant administration were provided according to our standard protocols [3]. During prophylaxis period, urine output, serum creatinine, the occurrence of necrotising enterocolitis (NEC), spontaneous intestinal perforation (SIP), PPHN, pulmonary hemorrhage (PH), intraventricular hemorrhage (IVH) and hypocoagulability were encountered.

Statistical analysis was performed using the Stata Statistical Software: Release 10 (StataCorp LP, College Station, Tx). Univariate statistical analysis was performed using Student’s t test for continuous variables, Wilcoxon rank-sum test (Mann Whitney U test) for non-parametric continuous variables and Fisher’s exact test for categorical variables. Logistic regression analysis was built to verify the independence of treatment effect on ductus closure. Prenatal/neonatal variables were included in the model if significant at a 0.10 level at univariate analysis. A P<0.05 was considered significant.

Overall, 216 neonates received IV ibuprofen prophylaxis: 156 Ibu-Lys (Group I) and 60 Ibu-Na (Group II). Maternal/neonatal characteristics were similar between the groups, except for a higher rate of IUGR, twins, lower birthweight and need for surfactant therapy in Group II (Table I ). Ductus closure rate after prophylaxis was significantly higher (73.1% vs 50%; P=0.002) and surgical ligation significantly lower (8.2% vs 23.3%; P=0.005) in Group I. Logistic regression analysis showed that Ibu-Na was significantly associated with higher unsuccessful prophylaxis rate, independently on gender, IUGR, and twins. Surfactant therapy and lower birthweight were also significantly and independently associated with higher prophylaxis failure rate (Table II). A smaller number of neonates of Group I versus Group II showed oliguria (20/156 vs 14/60; P=0.064) and hemorrhagic diseases, such as severe IVH (7/156 vs 7/60; P=0.067) and PH (4/156 vs 6/60, P=0.029), despite more neonates with hypocoagulability in Group I (29/156 vs 3/60; P=0.011). No differences were found between the groups in PPHN (7/156 vs 4/60; P=0.503), NEC (2/156 vs 1/60; P=0.187) and SIP (1/156 vs 0/60; P=1.000). Nevertheless, considering the first week of life, a lower number of SIP was observed in Group I (1/156 vs 4/60; P=0.021).

TABLE I	Baseline Clinical Characteristics of the Study Groups

	  	  

Table II	Ductus Patency Models (Adjusted for the Statistically Significant Variables) 

Our study highlights higher efficacy and safety of Ibu-Lys compared to Ibu-Na for PDA prophylaxis. Only three variables (birthweight, surfactant treatment, Ibu-Na) were significantly and independently associated with higher unsuccessful prophylaxis rate. It is known that birthweight and RDS affect ibuprofen efficacy [4], while difference in effectiveness related to type of compound has never been reported.

The recent Cochrane review on the topic [1], including six trials, analyzed the prophylaxis efficacy regardless the kind of formulation, although four studies used IV Ibu-Lys (Arfen), one IV ibuprofen-THAM (Orphan-Europe, France) and one oral ibuprofen suspension (Junifen, Boots Company, Thailand). The highest rate of prophylaxis failure (27.7%) was with ibuprofen-THAM [5], and the lowest (9.1%) using Ibu-Lys [6].

Ibuprofen is a weak acid, used as salt with different bases: sodium hydroxide, tris (hydroxymethyl) aminomethane (THAM), amines such as Lysine. During neonatal period, Ibu-Lys IM formulations (Arfen, Imbun) were off-label intravenously utilized [4,6-9] because no neonatal IV compounds existed. The IV ibuprofen formulation specifically manufactured for neonatal period (Pedea) was approved in 2004 and adopted by us from 2006. The only study on bioequivalence of two Ibuprofen formulations intravenously adminis-tered was performed in healthy male adults with a single 5 mg/kg dose: Ibu-Lys (Imbun) was bioequivalent to Ibu-Na (Pedea) [10].

Since we found higher efficacy of Ibu-Lys versus Ibu-Na, presumably biochemical properties of Ibu-Lys influence its effectiveness. Ibu-Lys higher lipophilicity determines higher transmembrane passage and tissue concentrations, and less drug removal, probably influencing its bioavailability and plasma concentration-time curve areas under the curve (AUC). A study showed that higher AUC values are associated with higher ductus closure rate; neonates with closed ductus versus neonates with persisting PDA had significantly higher values of either AUC after the first dose of ibuprofen or cumulated AUC after the three doses [11], prolonging the contact-time between drug and ductus wall [12].

We are aware that our study was retrospective, at different time-points, and with different samples-size, although the main treatment protocols (ibuprofen, fluids and surfactant administration) remained unchanged [3]. Further prospective randomized trials need to confirm our data. Since a new IV Ibu-Lys (Neoprofen) was recently commercialized for neonatal use [13], a prospective head-on comparison with Ibu-Na (Pedea) should be performed to define the optimal regimen.

Acknowledgments: Dr Francesca Paola Fusco, Dr Serafina Lacerenza and Dr Luca Maggio, Department of Pediatrics, Division of Neonatology, Catholic University of Sacred Heart.

Funding: None; Competing interests: None stated.

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