Systematic Review: Intravenous Ibuprofen in Preterm Newborns

doi:10.1053/j.semperi.2006.04.003

Seminars in Perinatology

Volume 30, Issue 3, June 2006, Pages 114-120

https://doi.org/10.1053/j.semperi.2006.04.003 Get rights and content

Ibuprofen, a nonsteroidal antiinflammatory drug, widely used as antipyretic, antiinflammatory, and analgesic agent and for therapy of arthritis, exerts a dose-dependent constriction of the ductus arteriosus in newborn lambs. Two intravenous preparations, namely ibuprofen lysine and ibuprofen-THAM, have been studied in preterm newborns with patent ductus arteriosus. Clinical trials have compared IV ibuprofen to placebo, or to indomethacin. Pharmacodynamic effects of this drug before and after its administration have also been evaluated. Compared with placebo, IV ibuprofen effectively closed PDA with minimal effect on renal function. One study using intravenous ibuprofen-THAM showed decreased renal function and increased risk of NEC and PPHN. Compared with indomethacin, IV ibuprofen lysine exerted similar efficacy (75% to 93% closure). However, indomethacin increased abnormal renal function and decreased mesenteric and cerebral blood flow and bio-energetics. Two clinical trials showed that ibuprofen did not reduce the incidence of intraventricular hemorrhage compared with placebo. The drug has prolonged elimination (plasma half-life = ca 23 hours), suggesting that once daily dosing is appropriate. Dose finding studies indicate that a starting dose of 10 mg/kg followed by 5 mg/kg/d for 2 more days provides optimal efficacy with the least adverse effects. Neonatal data on ibuprofen and indomethacin indicate that, on the first day of life when IVH prevention is desired, indomethacin and not ibuprofen should be used since ibuprofen has no effect on IVH risk. On or after the second day of postnatal life, when early or therapeutic PDA closure is needed, ibuprofen and not indomethacin is probably the first choice due to its better adverse event profile.

Section snippets

Clinical Studies

Clinical trials have compared IV Ibuprofen to placebo, or to indomethacin, or evaluated the pharmacodynamic effects of this drug before and after its administration. Compared with placebo, IV ibuprofen lysine decreased PDA with minimal effect on renal function.4, 7, 8 One study using another formulation of IV ibuprofen (ibuprofen-THAM) showed decreased renal function and increased risk of NEC, and PPHN.5, 6 Compared with indomethacin, IV ibuprofen exerted similar efficacy (75% to 93% closure).

Ibuprofen: Pharmacodynamics (Pre- and Post-Drug Dose Studies)

The efficacy and pharmacodynamic studies on IV ibuprofen using Doppler blood flow and near infrared spectroscopy on cerebral, renal, and/or mesenteric hemodynamics showed that this drug has minimal effects on organ blood flow of these systems.21, 22, 23 Ibuprofen also attenuated cerebral hemodynamic changes associated with withdrawal, but not infusion, from umbilical venous and arterial catheters,⁵³ suggesting improved autoregulation at lower perfusion pressures.

Pharmacokinetics, Metabolism, and Disposition

The pharmacokinetics of ibuprofen in adults has been reviewed.³⁶ Ibuprofen is extensively metabolized to two major metabolites: 2-[4-(2-hydroxy-2-methyl propyl) phenyl] propionic acid (2-hydroxy ibuprofen) and 2-[3-(2-carboxypropyl) phenyl]propionic acid (carboxy ibuprofen). Recent evidence suggests that CYP 2C9 is the major CYP mediating the 2- and 3-hydroxylations of R- and S-ibuprofen in the liver of Caucasians. Other CYPs, particularly CYP 2C8, may play a role in these biotransformations

Adverse Effects and Potential Drug–Drug Interactions

Ibuprofen, like all NSAIDs, exerts many pharmacologic effects resulting in adverse events leading to gastrointestinal and hematologic side effects. Some potential drug interactions are also noted below.

Aminoglycosides Interaction and Other Renal Effects

Retrospective calculations of the pharmacokinetics of amikacin in 72 preterm newborns <31 weeks gestation who received either placebo or ibuprofen showed that the median serum half-life (16.4 versus 12.4 hour) of amikacin was significantly longer (P < 0.02), and the clearance (0.36 versus 0.6 mL/kg/min; P < 0.005) of amikacin was significantly lower in infants who received ibuprofen-lysine.⁵² The renal effects of ibuprofen in the human newborn appears to be less compared with neonatal

Therapeutic Strategy for Ibuprofen and Indomethacin Use in Newborns

Data described above indicate that ibuprofen has no effect on IVH prevention. Thus, when NSAID is indicated at age 1 day where IVH prevention is timely, indomethacin but not ibuprofen should be used. After days 2 and 3, when early therapy of pharmacologic closure of a hemodynamically significant PDA is desired, ibuprofen should be the first choice due to its better safety profile.

In summary, clinical trials have compared IV Ibuprofen to placebo, or to indomethacin, and have shown efficacy of

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Cited by (83)

Concentration of carprofen in the milk of lactating bitches after cesarean section and during inflammatory conditions
2022, Theriogenology
Citation Excerpt :
It has been found that the use of indomethacin and ibuprofen to treat patent ductus arteriosus in preterm infants carries the known risk of causing a decreased GFR. The doses used in those patients are clinical doses (10 mg/kg/day for ibuprofen), which are half the recommended dose for an adult and the treatment is usually not longer than three days [4,5]. It must be taken into consideration that these premature infants are often critically ill with other comorbidities and are, therefore, also exposed to other potentially nephrotoxic drugs that increase the risk of side effects [5].
Pain treatment of lactating bitches is a clinically relevant, but complicated issue. Published scientific studies regarding the excretion of drugs in canine milk are scarce. When considering the risk of side effects in their offspring, lactating bitches have traditionally received very restricted analgesic and anti-inflammatory therapy. Our aim was to quantify the concentrations of carprofen in milk from lactating bitches and relate those to potential risks for the puppies. A second aim was to evaluate the impact mastitis may have on the concentration of carprofen in milk. A population of 100 bitches was enrolled in the study, among which 88 were bitches treated with carprofen after cesarean section (Group CS), eight were bitches with painful inflammatory conditions (Group I) and four were bitches with mastitis (Group M). The patients enrolled in the study received carprofen 4 mg/kg sc at day 1 followed by 2 mg/kg po every 12 h for the following 2–5 days. Owners were instructed to collect milk once a day for five days. The concentration of carprofen in the milk was quantified with ultra-performance liquid chromatography-tandem mass spectrometry. The data obtained were statistically analyzed as repeated-measures data with a mixed-model approach. Data were used to calculate the theoretical maximum total daily intake of carprofen by the puppies in order to perform a computerized simulation of the plasma concentration of carprofen in the puppies. Follow-up telephone interviews to check the status of the enrolled bitches and their litters occurred at one week and three-six months after treatment with carprofen. The major finding of the study was that the concentration of carprofen in the milk was <700 ng/mL from bitches undergoing CS or suffering painful conditions other than mastitis. In comparison, administration of 2 mg/kg of carprofen sc or po to adult dogs, results in mean maximal plasma concentrations of 19480 ± 5420 ng/mL (mean ± SD). Moreover, data suggests that inflammation of the mammary gland results in a higher concentration of carprofen in milk (up to 1300 ng/mL). In the computerized simulation, the plasma concentrations of carprofen in puppies in group CS and in group I are one tenth of the concentration in adult dogs receiving carprofen at standard doses. Considering the low excretion into milk, carprofen provides an analgesic alternative to lactating bitches without mastitis.
Non-steroidal Anti-inflammatory Drugs in Newborns and Infants
2017, Pediatric Clinics of North America
Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns
2016, Jornal de Pediatria
Citation Excerpt :
Both have side effects, but ibuprofen seems to have fewer negative effects on the cerebral and renal blood flow and also possibly fewer gastrointestinal side effects.15–17 The recommended standard dose of intravenous ibuprofen for patent ductus arteriosus closure is 10 mg/kg/dose on the first day and 5 mg/kg/dose on the second and third days.18,19 However, Dani et al.16 demonstrated that the use of ibuprofen at high doses (20-10-10 mg/kg/day) is more effective than the standard regimen for PDA in preterm newborns with a gestational age <29 weeks, without increasing the rate of adverse effects.
To compare the efficacy of intravenous ibuprofen at high (20-10-10 mg/kg/dose) and low doses (10-5-5 mg/kg/dose) the closure of patent ductus arteriosus in preterm newborns.
A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death.
Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8%) low-dose patients and in 17 (51.5%) high-dose patients (p > 0.99). Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p > 0.99). Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p = 0.22). Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p > 0.99). Twenty-two (50%) low-dose patients died vs. 15 (45.5%) high-dose patients (p = 0.86).
There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens.
Comparar a eficácia do ibuprofeno endovenoso em doses altas (20, 10 e 10 mg/kg/dose) e em doses baixas (10, 5 e 5 mg/kg/dose) para o fechamento do canal arterial em recém-nascidos pré-termo.
Estudo de coorte com controle histórico pesquisando recém-nascidos que receberam ibuprofeno endovenoso, no período de 2010 à 2013 na unidade de internação neonatal, em doses altas e baixas para o fechamento do canal arterial, documentado por ecocardiograma. Como desfechos secundários foram avaliados o número de ciclos de ibuprofeno realizados, a incidência de displasia broncopulmonar, enterocolite necrosante, alteração de função renal e óbito.
77 pacientes receberam 3 doses de ibuprofeno para tratamento do canal arterial, sendo que 33 dose alta e 44 dose baixa. 25 (56.8%) dos que receberam dose baixa fecharam o canal após o 1° ciclo e 17 (51,5%) fecharam após receberem dose alta (p > 0.99). 16 pacientes receberam o 2° ciclo, destes 50% fecharam o canal após uso de dose baixa e 60% após o uso de dose alta (p > 0.99). 7 pacientes foram à cirurgia para fechamento do canal, sendo 13,6% do grupo que recebeu dose baixa e 3% dose alta (p = 0.22). 39 pacientes desenvolveram displasia broncopulmonar, 50% do grupo de dose baixa e 51,5% do grupo de dose alta (p > 0.99). 22 (50%) dos pacientes do grupo dose baixa evoluiu a óbito versus 15 (45,5%) dos pacientes do grupo de dose alta (p = 0.86).
Não encontramos diferença em relação ao fechamento do canal arterial, assim como ocorrência de efeitos adversos, quando comparamos os dois esquemas posológicos.
Impact of patient selection on outcomes of PDA in very low birth weight infants
2013, Early Human Development
Citation Excerpt :
No infant received prophylactic treatment for PDA. Throughout the study, oral ibuprofen was prescribed at 10 mg/kg of ibuprofen as an initial dose, followed by two additional doses of 5 mg/kg on consecutive days [13,14]. We excluded subjects with other congenital heart diseases or chromosomal abnormalities, as well as, infants who weighed greater than 1500 g.
The aim of this study was to observe whether our patient selection maximized the benefits of PDA ligation by comparing the outcomes in a surgically ligated group of PDA to a medically closed group.
If a hemodynamically significant ductus arteriosus (HSDA) was found to meet both clinical and echocardiographic criteria (stage ≥ 3), as proposed by NcNamara and Hellman, medical treatment was initiated with oral ibuprofen (maximum 2 courses). If the PDA of these patients failed to close medically, timed surgical closure was performed.
Medical treatment was effective in 75 (72%) cases, and 29 (28%) patients required surgical ligation. The mean gestational age and birth weight were each significantly lower and the initial PDA shunt size was significantly larger in the surgically treated group. Additionally, the mean durations of mechanical ventilation, oxygen dependence and hospital admission were significantly longer in the surgically ligated group. However, our logistic regression analysis demonstrated no statistically significant difference in the outcomes of hospitalization (CLD, NEC, ARF, sepsis, IVH, ROP, PVL and death) between the two groups.
Comprehensive HSDA patient selection may maximize the benefits of timed PDA ligation without adverse outcomes in very low birth weight infants.
The Influence of Short Chain Alcohols on the Aggregation and Physicochemical Interaction between Sodium Dodecyl Sulfate and Ibuprofen Drug
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Investigating multifaceted action of ibuprofen derivatives towards cox isozymes and interleukin-6 (IL-6) site correlating with various target sites
2024, Journal of Biomolecular Structure and Dynamics

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Systematic Review: Intravenous Ibuprofen in Preterm Newborns

Section snippets

Clinical Studies

Ibuprofen: Pharmacodynamics (Pre- and Post-Drug Dose Studies)

Pharmacokinetics, Metabolism, and Disposition

Adverse Effects and Potential Drug–Drug Interactions

Aminoglycosides Interaction and Other Renal Effects

Therapeutic Strategy for Ibuprofen and Indomethacin Use in Newborns

Lancet

Lancet

Lancet

Lancet

J Pediatr

J Pediatr

J Pediatr

J Pediatr

Lancet

Semin Perinatol

Age dependent changes in the response of the lamb ductus arteriosus to oxygen and ibuprofen

Can J Physiol Pharmacol

Prostanoids determine the range of cerebral blood flow autoregulation of newborn piglets

Stroke

Differences in the effects in the newborn piglet of various nonsteroidal antiinflammatory drugs on cerebral blood flow but not on cerebrovascular prostaglandins

Pediatr Res

Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants

J Am Med Assoc

Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants

Eur J Pediatr

Ibuprofen and cerebral oxygenation and circulation

Arch Dis Child Fetal Neonatal Ed

Prophylaxis of patent ductus arteriosus with ibuprofen in preterm infants

Acta Paediatr

Rndomized double-blind controlled trial comparing the effects of ibuprofen with Indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus

Pediatr Res

Treatment of patent ductus arteriosus with ibuprofen

Arch Dis Child Fetal Neonatal Ed

A comparison of ibuprofen and Indomethacin for closure of patent ductus arteriosus

N Engl J Med

Safety and efficacy of ibuprofen versus Indomethacin in preterm infants treated for patent ductus arteriosusa randomized controlled trial

Eur J Pediatr

Ibuprofen vs indomethacin in the treatment of patent ductus arteriosus in very premature neonates

Pediatr Res

Comparison of ibuprofen and Indomethacin therapy for patent ductus arteriosus in preterm infants

Pediatr Int

Effects of prophylactic ibuprofen on cerebral and renal hemodynamics in very preterm neonates

Clin Pharmacol Ther

Prophylactic ibuprofen therapy of patent ductus arteriosus in preterm infants

Eur J Pediatr

A comparison of oral ibuprofen and intravenous Indomethacin for closure of patent ductus arteriosus in preterm infants

J Med Assoc Thai

Oral ibuprofen and Indomethacin for treatment of patent ductus arteriosus in premature infantsa randomized trial at Ramathibodi Hospital

J Med Assoc Thai