10

review Article

Current evidence on the safety profile of NSAIDs for the treatment of PDA

costantino romagnoli1,2, iliana Bersani1,2, Serena Antonia rubortone1,2, Serafina lacerenza1,2 & Maria Pia De carolis1,2

1Department of Paediatrics and 2Division of Neonatology, Catholic University of Sacred Heart, Rome, Italy

The Journal of Maternal-Fetal and Neonatal Medicine

2011

24

S(3)

10

13

© 2011 Informa UK, Ltd.

10.3109/14767058.2011.604987

1476-7058

1476-4954

The Journal of Maternal-Fetal and Neonatal Medicine, 2011; 24(S(3)): 10–13Copyright © 2011 Informa UK, Ltd.ISSN 1476-7058 print/ISSN 1476-4954 onlineDOI: 10.3109/14767058.2011.604987

Correspondence: Prof. C. Romagnoli, Department of Paediatrics and Division of Neonatology, Policlinico “A. Gemelli”, Catholic University of Sacred Heart, Largo Gemelli 8, 00168 Rome, Italy, Tel: +39 06 30154786. E-mail: cromagnoli@rm.unicatt.it

Patent ductus arteriosus (PDA) complicates the clinical course of preterm infants. Nonsteroidal anti-inflammatory drugs, especially Indomethacin and Ibuprofen, have been widely used for both prevention and treatment of PDA. Short-term efficacy of Indomethacin or Ibuprofen is equivalent, while Ibuprofen results show a higher safety profile. Ibuprofen is associated with fewer clinical gastrointestinal and renal side effects with respect to Indomethacin even if subclinical potential effects are reported. When administered as prophylaxis, Ibuprofen has no effects on prevention of intraventricular haemorrhage unlike Indomethacin. Considering the potential adverse effects of both these drugs, a careful monitoring during and after the treatment period is highly recommended.

Keywords: Patent ductus arteriosus, non steroidal anti-inflammatory drugs, ibuprofen, indomethacin, neonate

IntroductionTreatment of patent ductus arteriosus (PDA) remains one of the most worrisome problems in the clinical management of preterm newborn infants.

Nonsteroidal anti-inflammatory drugs (NSAIDs), especially Indomethacin and Ibuprofen, have been widely used for both prevention and treatment of PDA [1–4]. Indomethacin repre-sented the standard drug for the treatment of PDA from 1976 up to 2004, when Ibuprofen-Sodium was introduced for neonatal use. Differences exist between these two molecules. First, these drugs belong to two different chemical classes: Indomethacin derives from the arylacetic acid, while Ibuprofen, a chiral compound, derives from the arylpropionic acid. They also bind in a different way to Cyclo-oxigenase (COX): Indomethacin through a competitive, time-dependent and slowly reversible mechanism, while Ibuprofen by a simple competitive one. Finally, they act differently towards COX, Indomethacin being more specific for COX-1 and Ibuprofen for COX-2 [5].

COX is the first enzyme involved in the synthesis pathway of prostaglandins (PG) and tromboxane from arachidonic acid. COX metabolites have a wide variety of physiological and pathophysi-ological effects and are involved in a number of homeostatic processes. In particular, COX-1 and COX-2 are expressed in the ductus and produce PGE2, thereby playing an essential role in ductus patency. Pharmacological inhibition of PG synthesis is associated with a functional ductus constriction, which precedes the anatomic remodeling.

Recent reviews showed effectiveness of both prophylactic and therapeutic use of Indomethacin and Ibuprofen in reducing the incidence of PDA and the need for rescue treatment with COX inhibitors and surgical ligation [1–4].

Adverse effects

Since COXs, especially COX-1, are constitutively expressed in different tissues, all NSAIDs can determine many side effects, mainly in cerebral, gastrointestinal and renal districts.

Cerebral nervous system

Indomethacin is a known vasoconstrictor and has been proven to decrease cerebral blood flow (CBF) in preterm neonates [6]. In the year 2000, a randomized controlled trial carried out in preterm infants treated for PDA demonstrated that Ibuprofen, unlike Indomethacin, does not cause any reduction in CBF and cerebral blood volume [7]. Also during prophylactic treatment, Ibuprofen did not show any direct effect on CBF in neonates; haemodynamic changes, related to ductus closure induced by the drug, were observed only in neonates with open ductus and left to right shunt before the treatment [8].

Although in response to a reduction of CBF after Indomethacin, an increased cerebral oxygen extraction is reported [9], but how this protective response is actually effective in the context of a vulnerable preterm brain has not been investigated. Both the degree of hypoxia and its duration are important when consid-ering possible brain damage. Nevertheless, at present time it is still uncertain whether Indomethacin treatment is associated with increased risk of ischaemic brain damage. In a recent study [10], an increased incidence of periventricular leukomalacia (PVL) associated with repeated courses of Indomethacin was reported, whereas in neonates with gestational age (GA) <28 weeks a decrease of both PVL and neurodevelopmental abnormalities was detected [11]. These controversial results could be related to different instrumental investigations (Ultrasound vs Magnetic Resonance Imaging), total amount of Indomethacin administered (1.7 mg/Kg vs 0.6 mg /Kg), and long-lasting PDA, that, on its own, can increase the risk of PVL. Otherwise, no statistically significant differences in the incidence of PVL were found between Ibuprofen and Indomethacin treatment [4].

Regarding intraventricular haemorrhage (IVH), it is known that prophylactic administration of Indomethacin reduces the incidence of severe IVH [1], thanks to germinal matrix microve-ssel maturation and reduction of vascular permeability. In contrast, prophylactic Ibuprofen results ineffective in preventing IVH [12].

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Safety of NSAIDs for the treatment of PDA 11

Copyright © 2011 Informa UK, Ltd.

Recent data on neurodevelopmental outcome highlighted that the use of either Ibuprofen or Indomethacin for the closure of a PDA did not influence two year neurodevelopmental outcomes in very low birth weight (VLBW) infants [13]. Moreover, Ibuprofen treatment is not associated with any alterations of brain growth and development in animal models [14].

Gastrointestinal system

The NSAIDs-related gastric complications are principally related to COX-1 inhibition, even if also COX-2 is present in the gastric mucosa and throughout the gastrointestinal tract.

The severity of gastric damage ranges from frequent asymp-tomatic inflammation, erosions and ulcers to the rare but serious ulcer complications such as perforation and clinically evident bleeding. NSAIDs-induced short-term gastric damage is related to drug affinity for COX-1, doses and physicochemical features such as acidity (pKa) and lipophilicity. The gastric Lanza Score, obtained in volunteer endoscopy studies, includes all these factors and results, higher for Indomethacin than for Ibuprofen (1.8–2.5 vs 0.2–1.88) [15].

Furthermore, Indomethacin lowers blood supply to the bowel, similarly to its action on cerebral blood flow, since it leads to a significant decrease of mean flow velocity in the superior mesen-teric artery [16].

Neonatal gut injuries, as isolated intestinal perforation (IIP) or necrotizing enterocolitis (NEC), are serious complications of prematurity. Indomethacin exposure has been implicated as one of the risk factors for neonatal gut injury [17]. Recently, it was found that the rate of IIP was greater among infants who received early Indomethacin treatment for IVH prophylaxis than among those receiving a later treatment for a PDA. It was hypothesized that early Indomethacin exposure may have decreased intes-tinal circulation during the critical period of adaptation, thus weakening the intestinal wall. Conversely, late Indomethacin administration, affecting ductus closure, might have normalized intestinal blood flow by reducing the “diastolic steal” due to a hemodynamically significant PDA, thereby resulting protection against NEC [18].

A recent meta-analysis showed that Ibuprofen treatment compared to Indomethacin, reduced the risk of NEC develop-ment [4]. It is known that Ibuprofen, unlike Indomethacin, does not significantly reduce mesenteric blood flow [19] and does not induce any macroscopically visible damage of the intestinal mucosa. However, early Ibuprofen treatment is reported to be associated with an increased risk of IIP in more immature infants (GA ≤26 weeks) [20], and enteral ibuprofen administration seems to increase the rate of NEC, probably as a consequence of the hyperosmolarity of the most currently available oral formula-tions [21].

Lung

During fetal life COX concentration gradually increases with the increase of GA. PGI2 synthesis plays a major role during changes in pulmonary vascular resistance at birth, contributing to vasodilation of pulmonary arterioles. In newborn animals, COX-inhibition prevents the normal decrease in pulmonary vascular resistance associated with the rhythmic lung distension at birth.

PPHN was also observed, soon after the administration of ibuprofen, in the context of a randomized prophylactic trial which was prematurely discontinued before full enrolment due to the development of this adverse effect [22]. Gournay et al [22] have alerted neonatologists about the possible occurrence of PPHN after the loading dose of ibuprofen, and hypothesized that

PPHN could be related either to the early drug administration or to a drug-induced pulmonary microembolism. The very early administration of the drug (within the first 6 hours of life) might prevent the normal decrease in pulmonary vascular resistance and thereby interfere with the physiologic peak of prostaglandin activity, markedly high in early postnatal period among very preterm infants. On the other hand, PPHN could be a consequence of acidification of the Ibuprofen-THAM solution (buffered with tromethamine) used by Gournay, and of a subsequent precipita-tion and microembolization to the lungs. However, against the hypothesis of early administration as causative factor, Schmidt et al registered only one case of PPHN during a randomized trial using Indomethacin prophylaxis within 6 hours after birth [23], while supporting the hypothesis of microembolization, Mosca et al giving Ibuprofen-Lysine, reported no acute hypoxaemia or unexpected worsening of oxygenation [24]. Consequently, we agree with Thomas et al that “caution is required in the case of Ibuprofen-THAM administration” [25].

In our experience, PPHN occurred exclusively in neonates with other concomitant risk factors predisposing to this compli-cation, regardless of the type of Ibuprofen formulation. Among the 11 neonates with PPHN, 7 treated with Ibuprofen-Lysine and four with Ibuprofen-Sodium, we observed that four neonates also had twin-to-twin transfusion syndrome and five were born to mothers with severe oligohydramnios, suggesting that, in addi-tion to ibuprofen administration, also other factors could play a role in determining this severe complication [26].

Kidney

Kidneys constitutively express COX-2 localized in renal vascular tissues, macula densa and podocytes, and COX-1 in tubule cells.

PGs, particularly PGI2 and PGE2, are of major importance in maintaining the Glomerular Filtration Rate (GFR), since they directly vasodilate the afferent arteriole and dampen the renal vasoconstrictor effects of both angiotensin II and sympathetic nervous stimulation.

PGs, mainly PGE2, inhibit Arginine Vasopressin (AVP)-stimulated water reabsorption in collecting ductus via water channel aquaporin-2 (AQP2), the main target for AVP.

PGs also increase sodium excretion via epithelial sodium chan-nels (ENaC). Consequently, COX inhibitors reduce glomerular blood flow, GFR, and both renal water and sodium excretion in adults. In premature neonates, COX inhibitors can significantly reduce glomerular blood flow and GFR, but the role of PG synthesis inhibition in renal water [27] and sodium [28] homeo-stasis is minimal.

It has been widely demonstrated that Indomethacin induces a significant reduction in renal blood flow velocity measured by Doppler Ultrasonography [16], unlike Ibuprofen which does not significantly affect it [19].

Renal clinical side effects (oliguria, increased serum creatinine) are reported both for Indomethacin and Ibuprofen [29, 30, 31]. However, as a consequence of the different renal vasoconstrictor action, Ibuprofen results associated with significantly less impair-ment of renal function [4,32].

Attempts have been made to reduce renal side effects of Indomethacin by the contemporary administration of Furosemide [33], but no satisfactory results were obtained [34]. Since both Indomethacin and Furosemide are secreted by the organic anions tubular mechanism at the proximal tube, when these drugs are administered together, the diuretic effect of Furosemide is blunted. Indomethacin, reducing the secretion of diuretic, decreases the amount of the Furosemide arriving in the lumen of the thick, ascending Henle’s loop, site of its action [35].

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12 C. Romagnoli et al.

The Journal of Maternal-Fetal and Neonatal Medicine

Although Ibuprofen showed fewer side effects than Indomethacin, renal function of infants receiving Ibuprofen should however be carefully monitored. The use of new suitable biomarkers of glomerular filtration such as cystatin C suggests that Ibuprofen may alter the glomerular filtration. It was shown that Ibuprofen treatment can induce a significant increase in serum levels of cystatin C without any alterations of serum creatinine levels. [30]. In addition, Vieux et al carried out a study specifically designed to determine renal effects of PDA treatment with Ibuprofen among very preterm infants. The authors high-lighted not only a significant reduction of urine output during the treatment period, but also decreased GFR and impaired tubular function during all the first month of life in neonates receiving Ibuprofen treatment compared to controls [36]. This issue should be properly considered in case of administration of other drugs, primarily eliminated by glomerular filtration, during or after the treatment with Ibuprofen. While it is already known that co-administration of Ibuprofen and Amikacin or Vancomycin reduces the antibiotic clearance by 21% and 18% respectively, and that the impact of Indomethacin on their clear-ance is more pronounced for both antibiotics (clearance reduc-tion of 46% and 28%, respectively) [37], after NSAIDs treatment the exact antibiotics dosing still needs to be checked and adjusted to the plasma level.

Long-term follow up is required to ensure that renal alterations, sustained up to one month of life, are the result of maturation delay and not of subtle lesions that could impact in these babies. In fact, it should be kept in mind that, when COX inhibitors are administered before the glomerulogenesis is completed (36 weeks), they could cause both glomerular and tubular injury [38].

Hematology

NSAIDs inhibit platelet adhesiveness leading to bleeding disorder. Indomethacin seems to prolong bleeding time without association with major hemorrhagic complications [39]. Dani et al. observed no differences in serial platelet number and in bleeding tendency (assessed by the detection of hematuria, gastric bleeding, blood detection in the endotracheal aspirate or stools, and oozing from puncture sites) between neonates receiving Ibuprofen treatment and controls [40]. Moreover, safety comparison of Ibuprofen versus Indomethacin did not show any increase in hemorrhagic complications [41].

Bilirubin

It is reported that Ibuprofen interferes with bilirubin transport and can potentially increase the risk of kernicterus, due to the increase of unbound bilirubin. In fact Ibuprofen, particularly at high plasma levels (>100 μg/mL), can interfere with bilirubin-albumin binding and increase unbound bilirubin [42,43].

Furthermore, Ibuprofen administration was associated with higher peak of total serum bilirubin levels, and the more-pro-nounced hyperbilirubinemia led to longer phototherapy [44]. Ibuprofen is known to be partially metabolized by uridinediphos-phateglucuronosyltransferase, which is also responsible for bilirubin glucuronidation. Competitive inhibition of 15%–30% between Ibuprofen and bilirubin was demonstrated in human liver microsomes. Very preterm infants have reduced hepatic glucuronidation activity, which can be even further decreased by Ibuprofen, potentially modifying an already weak and unstable equilibrium. This implies that Ibuprofen may be linked to increased neurologic risk, not only through the albumin-bilirubin displacement, but also through a direct competition with the enzyme responsible for bilirubin conjugation.

Adverse effects related to Ibuprofen formulation

Since Aranda’s pharmacokinetic study carried out in 1997, two intravenous Ibuprofen formulations (Ibuprofen-Lysine and Ibuprofen-THAM) have been used until 2004, when the ready-to-use formulation Pedea®, containing Ibuprofen-Sodium and specifically manufactured for intravenous administration in neonates, was commercialized.

Thomas et al in the year 2005 already identified PPHN as an adverse event of Ibuprofen-THAM [25]. In our experience we observed, during a prophylaxis study performed from 2000 to 2008, a higher efficacy of Ibuprofen-Lysine with respect to Ibuprofen-Sodium and a higher incidence of side effects such as pulmonary haemorrhage (during the prophylaxis period) and IIP (during the first 7 days of life) among neonates receiving Ibuprofen-Sodium. The different efficacy and safety of the two formulations may be related to their different pharmacokinetic properties, determining quantitative and temporal differences of the plasmatic peaks [45]. Higher lipophilicity of Ibuprofen-Lysine may determine a higher passage through the cellular membranes and a lower rate of drug removal, influencing drug bioavailability and, consecutively, plasma concentration-time curve areas under the curve (AUC). It was reported that Ibuprofen effectiveness is related to its plasmatic peaks and mostly to the AUC, although a large inter-patient variability exists so that a careful monitoring of plasma drug concentration is necessary, especially when the drug is administered at high doses.

ConclusionAs the short-term efficacy − defined as closure of PDA and decreased need for surgical closure − of Indomethacin or Ibuprofen is equivalent, the different safety profile of both these drugs can influence clinicians needing to weigh the potential side effects of one drug versus the other when choosing the most appropriate therapeutic strategy. From a strategic point of view, Ibuprofen should be the first choice due to its higher safety profile, as it is associated with fewer gastrointestinal and renal side effects than Indomethacin.

Nevertheless, it should be reminded that, when prophylacti-cally administered, Ibuprofen has no effects on IVH prevention unlike Indomethacin. Moreover, early Ibuprofen administration can increase the risk of kernicterus due to the rising levels of bilirubin typically present during the first days of life, the risk of PPHN mainly in neonates with concomitant risk factors predis-posing to this complication, and the risk of IIP especially in more premature neonates.

Considering the potential adverse effects of both these drugs, a careful monitoring during and after the treatment period is highly recommended. However, safety evaluation should also always consider long term consequences of clinical and subclin-ical side effects.

Declaration of interest: The authors declare no conflict of interest and are solely responsible for the content of their paper

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