Effectiveness of Dual Medication Therapy (Oral Acetaminophen and Oral Ibuprofen) for the Management of Patent Ductus Arteriosus in Extremely Premature Infants: A Feasibility Trial

Abstract

Objective The study aimed to evaluate the efficacy of dual medication therapy (DMT) with oral acetaminophen and oral ibuprofen for the closure of a hemodynamically significant patent ductus arteriosus (hsPDA). Study Design In a prospective case–control cohort study (July 2017–May 2019), infants <29 weeks' gestational age and birth weight <1,000 g at ≤14 postnatal days with hsPDA and ratio of the smallest ductal diameter to the ostium of the left pulmonary artery diameter >0.5 were eligible. Infants received 10 mg/kg oral ibuprofen followed by two additional doses of 5 mg/kg at 24 and 48 hours after the initial ibuprofen dose and concomitant treatment with 15 mg/kg oral acetaminophen every 6 hours for 3 days (12 doses). Success of PDA treatment was defined as a small or absent PDA as ascertained by echocardiographic measurements. The p-values of comparisons were adjusted for multiple comparisons to preserve an error rate of 5%. Results Overall, 20 infants received oral DMT and 11 infants received intravenous single medication therapy (SMT) with ibuprofen. The rates of successful PDA treatment following the first treatment in DMT and SMT groups were not statistically different (11/20 [55%] vs. 4/11 [36%], p = 0.46). However, DMT significantly decreased PDA size (mean difference = 0.54 mm, 95% confidence interval [CI]: 0.21–0.96, adjusted p-value = 0.0002) and PDA/LPA ratio (mean difference = 0.27, 95% CI: 0.10–0.47, adjusted p-value = 0.0004). We observed no evidence of hematologic, hepatic, or renal impairment. Conclusion DMT achieved a greater degree of PDA closure than SMT and did not result in abnormalities in hepatic and renal profile. Key Points

Dual medication therapy (acetaminophen and ibuprofen) for the management of patent ductus arteriosus in preterm infants: a systematic review and meta-analysis

“…Nine studies were considered to be relevant after initial screening. As described in the PRISMA ow diagram, three studies were excluded, leaving six (4 NRS [13,23,25,26] and 2 RCTs [22,24]) for inclusion in this systematic review. (Figure 1) We found one ongoing trial in a clinical trials registry (Clinical Trials # NCT03648437).…”

“…Four studies [22,23,24,26] reported no differences in liver function tests pre-and post-treatment with acetaminophen. Only two studies [13,23] reported acetaminophen levels; the mean/median value of acetaminophen level on day 3 of medication administration was less than 25 mcg/ml.…”

“…After their initial report, a few more studies have reported experience with DMT for PDA management in preterm infants. [13,[23][24][25][26] Each DMT study has used ibuprofen as the SMT and enrolled small number of infants. In order to synthesize the best available evidence for DMT for PDA management, we conducted the rst systematic review and meta-analysis of all published articles (both RCTs and NRS) that compared DMT with acetaminophen and ibuprofen with ibuprofen monotherapy to assess ductal closure after the rst treatment course.…”

Survey highlighting the lack of consensus on diagnosis and treatment of patent ductus arteriosus in prematurity

“…Current RCTs, like the Baby-OSCAR trial [ 35 ], management of the PDA trial (NCT03456336), and the BeNeDuctus trial [ 36 ], will hopefully add to the available knowledge and will guide our way either to more aggressive treatment with monotherapy (ibuprofen or paracetamol) or even combined therapy (ibuprofen and paracetamol) or to a more expectant approach [ 37 , 38 ]. Furthermore, advances in percutaneous ductal closure might lead to reconsideration of early invasive closure for a select group of patients [ 39 ].…”

The Effect of Dual (Combined) Treatment in Late Preterm Infants with Patent Ductus Arteriosus

“…We read the article written by Shah et al with interest and would like to share our opinion on it. 1 In the study in which the synchronous use of ibuprofen and paracetamol treatment was recommended in the article, successful closure rate was observed with dual therapy in 20 infants. In the discussion part of the article, its use was recommended due to the success of a highly effective treatment with combined therapy.…”