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Three Part Question

In [preterm infants <32 weeks gestation with a patent ductus arteriosus], is [oral ibuprofen] as safe and effective as [intravenous ibuprofen], in [closure of the patent ductus arteriosus].

Clinical Scenario

You are a junior doctor in the neonatal intensive care unit. A preterm neonate has a loud murmur with bounding femoral pulse. Echocardiogram shows a haemodynamically significant patent ductus arteriosus. He is ventilated, but is otherwise well and has been tolerating full enteral feeds for a few days. A decision is made to commence intravenous Ibuprofen. You wonder whether oral Ibuprofen could be used and whether this would be as safe and efficacious as the intravenous route.

Search Strategy

Cochrane Register of Controlled Trials (CENTRAL)
Ovid interface for MEDLINE database (1946 to present), EMBASE (1980 to present) and CINAHL (1981 to present)
[exp neonate OR exp infant OR exp newborn OR exp neonat* OR exp ‘patent ductus arteriosus’ OR exp ‘ductus arteriosus’] AND [exp ‘cyclo-oxygenase inhibitor’ OR exp ibuprofen] LIMIT to studies on human

5 papers identified from Medline, 1 of which was published in an Italian journal and is not available via the British Library and no UK supplier for the article.

Search Outcome

4 papers of good methodological quality selected.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Olukman et al 2012 Turkey	66 infants <32 weeks and <1500g birth weight.	Retrospective cohort study	Closure of PDA without re-opening	100% and 97.6% closure rate (no difference) in oral and intravenous. Success with first dose 83% vs. 75% in oral and intravenous group respectively.	Retrospective design. Outcome assessors and data collectors not blinded to exposure. Significant exposure bias in the study- choice of oral or intravenous ibuprofen as well as decision to treat was left to clinician. Serum Ibuprofen levels not measured.
			Secondary outcomes- renal, metabolic, haematological, metabolica and gastrointestinal side effects.	Increased risk of sepsis (p= 0.04) and CLD (p=0.02) in the oral group. Increased risk of hypernatremia in intravenous group (p=0.01).
Erdeve et al 2011 Turkey	70 preterm infants <28 weeks and <1000g birth weight	Randomized controlled trial	Closure of the PDA	Higher in oral 83%vs. intravenous 61% (p value= 0.04)	Health workers not blinded to intervention. Safety parameters could have been predefined clearly to prevent overestimation. Side effects from preservatives i.e. Sodium benzoate in oral preparation not investigated.
			Safety of the oral administration	Reduction in bilirubin level (p=0.03) during first course and sodium level (p = 0.01)after 2nd course intravenous Ibuprofen.
			Need for a 2nd course	No difference
			Rates of surgical ligation	No difference
			Secondary outcomes: Mode and duration of ventilation, ROP, IVH, sepsis and death	No difference except for postnatal steroid use for CLD which was higher in the intravenous group ( p value 0.01)
Gokmen et al 2011 Turkey	102 premature babies< 32 weeks and <1500g	Randomized control trial	PDA closure rates	Higher in oral 82.6% vs intravenous 62% group p=0.01	Cys- C, which is the primary outcome in this study, has not been studied previously as a marker of renal tolerance in preterm infants. Larger number of babies >30 wks in oral group vs intravenous- may explain higher closure rates. Majority of babies are >30 wks gestation. Power calculation for study is inadequately explained. Study not powered to detect differences in complications.
			Renal tolerance	Cys-C level increased significantly after treatment in oral ibuprofen group (p = .001), the level after treatment did not differ significantly between the two groups (P = .4)
			Need for retreatment	No difference
			Need for surgical ligation	No difference
			Secondary outcome- mode and duration of ventilation, rise in bilirubin, surfactant treatment, pneumothorax, pulmonary hemorrhage, pulmonary hypertension, CLD, IVH, NEC , intestinal perforation, gastrointestinal bleeding, ROP, sepsis and death.	Mechanical ventilation longer in the intravenous group (p=0.02)
Cherif et al 2008 Tunisia	64 preterm infants <32 weeks gestation and birth weight <1500 grams	Randomized control trial	PDA closure rates	Higher in oral (84%) vs intravenous (62.5%) group with reliable confidence intervals (p= 0.04)	Babies who did not respond to first course of oral Ibuprofen were given intravenous Ibuprofen as rescue treatment- resulting in crossover and an effect on the primary and secondary outcomes.
			Number of doses required	No difference
			Secondary outcomes- mode and duration of ventilation, surfactant treatment, renal failure, NEC, IVH, NEC, CLD, PVL, nosocomial sepsis, duration of hospital stay, time to regain birth weight, time to full enteral feeds, and death	No difference

Comment(s)

The lower incidence of renal side effects with intravenous Ibuprofen as compared with indomethacin have made ibuprofen the more desirable alternative. It may be inferred that oral Ibuprofen would also be effective and safe. Due to higher cost and lack of availability of intravenous Ibuprofen, many European neonatal units are already using oral Ibuprofen. Results of the above studies indicate that oral Ibuprofen is more effective and as safe as intravenous Ibuprofen for PDA closure. The need for repeated courses is lower in the oral group and rates of surgical closure similar in both groups. Rates of renal and gastrointestinal side effects are similar in both groups. Single studies have shown a higher incidence of hypernatremia Olukman et al. 2012) and duration of mechanical ventilation (Gokmen et al. 2011) in the intravenous group. A higher risk of sepsis and CLD was shown in the oral group (Olukman et al. 2012) but confidence intervals and risk factors for sepsis have not been described. A larger sample size would be needed to confirm the accuracy of these findings as CLD is multi-factorial in origin. External validity and generalizability of these results is limited. Extremely preterm babies <28 weeks gestation have a higher incidence of PDA and are treated most commonly for ductal closure. An analysis of the literature shows little evidence to support the safety and efficacy of oral ibuprofen for the extremely low birth weight infant. The only study that addresses this included 80 infants with a mean birth weight of 880g (Erdeve et al. 2012). This study showed a higher PDA closure rate with oral Ibuprofen as compared to the intravenous form. A higher postnatal steroid use for CLD was seen in the intravenous group; however a larger sample size would be needed to confirm these findings due to the multi-factorial origins of CLD. None of these studies have measured Ibuprofen levels or adequately reported long term outcomes. Larger studies establishing safety and efficacy are needed in babies <28 weeks and <1250g in size before oral ibuprofen can be used in clinical practice. Renal function should be carefully monitored if oral ibuprofen is used.

Clinical Bottom Line

Oral ibuprofen appears to be as effective and safe as intravenous ibuprofen in closure of a PDA. Generalizability of these findings to the extremely preterm population is limited due to small sample size and lack of safety and pharmacokinetic data. As the oral preparation is cheaper and easily available, large scales studies are required in the extremely preterm population before oral ibuprofen can be used in clinical practice.

References

1. Olukman O, Calkavur S, Ercan G, Atlihan F, Oner T, Tavli V, Kultursay N Comparison of oral and intravenous Ibuprofen for medical closure of patent ductus arteriosus: which one is better? Congenital Heart Disease 2012: 534-43
2. Erdeve O, Yurttutan S, Altug N, Ozdemir R, Gokmen T, Dilmen U, Oguz SS, Uras N Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely Archives of Disease in Childhood Fetal & Neonatal Edition 97(4):F279-283
3. Tulin Gokmen, MD, Omer Erdeve, MD, Nahide Altug, MD, Serife Suna Oguz, MD, Nurdan Uras, MD, and Ugur Efficacy and Safety of Oral Versus Intravenous Ibuprofen in Very Low Birth Weight Preterm Infants with Patent Ductus Arteriosus Journal of Paediatrics 158; 549-554
4. Ahmed Cherif, MD, Naima Khrouf, MD, Sami Jabnoun, MD, Chahnez Mokrani, MD, Moez Ben Amara, MD, Nedia Randomized Pilot Study Comparing Oral Ibuprofen With Intravenous Ibuprofen in Very Low Birth Weight Infants With Patent Ductus Arteriosus Pediatrics 122(6); 1256–61