Different approaches for patent ductus arteriosus in premature infants using acetaminophen

Aimann Surak · Amish Jain 2 · Abbas Hyderi

Abstract Background Acetaminophen use for pharmacological treatment of hemodynamically significant patent ductus arteriosus(hsPDA) in preterm infants is becoming more popular with emerging evidence that it is effective as well as safe alternative for other agents used to close hsPDA.

Keywords Acetaminophen · Ligation · Patent ductus arteriosus · Preterm

Introduction

Acetaminophen may facilitate ductus arteriosus closure via inhibition of the peroxidase moiety, acting as a reducing co-substrate, so that less prostaglandin G2 is converted to prostaglandin H2 [ 1]. This is opposed to non-selective cyclooxygenase (COX) inhibitors which inhibit the COX site. [ 2- 4]. In addition, peroxidase is induced in hypoxic conditions, which may make paracetamol more effective in these conditions.

A recent national survey from UK found 33% of units used acetaminophen with variable courses in terms of dosing (15 mg/kg 6 hourly in 62% of the units) and the length of treatment (between 3 and 5 days). Approximately, 44%of the units routinely monitored blood levels [ 5]. The low incidence of acetaminophen short-term toxicity is probably related to decreased CYP2E1 enzyme activity conferring some level of protective benefit in the event of an overdose[ 6].

There are different approaches to close the hemodynamically significant patent ductus arteriosus (hsPDA)described in literature. This could be a symptomatic approach, conservative, combination therapy, prophylactic or a rescue prior to surgical closure. In terms of defining those approaches to help selecting and categorizing different studies: a symptomatic approach is when the pharmacological treatment was initiated based on suspected or confirmed hsPDA based on clinical, laboratory or echocardiographic data; conservative approach is when the treatment focuses on the non-pharmacological measures to limit the ductal shunt (fluids restriction, optimizing mean airway pressure, diuretics, etc.); combination therapy is when two agents are combined in attempt to close the hsPDA (most commonly combining acetaminophen with ibuprofen); prophylactic approach is when pharmacological agent is administered afterbirth regardless of PDA status (not knowing in advance whether it is closed or patent and if it is patent whether it is hemodynamically significant); rescue therapy approach is when pharmacological treatment was attempted with no success closing the duct with potential need for surgical closure.In this article, we did a literature review for the use of acetaminophen in different approaches to closing PDA in preterm infants.

Acetaminophen in the symptomatic approach

Acetaminophen was used in attempt to close PDA either as a first line therapy or as an alternative second line due to failure or contraindication of other agents. Many nonrandomized trials reported the use of acetaminophen for ductal closure in preterm infants with safe side effect profile. Table 1 summarizes those trials with not a high level of evidence. However, Subsequently, multiple randomized controlled trials were conducted for the use of acetaminophen for the purpose of ductal closure in preterm infants. These studies reported a good efficacy for acetaminophen closing the ductus with no significant side effects reported. Table 2 summarizes these trials.

Higher level of evidence was seen in few systematic reviews as well. A systematic review by Hammerman et al.suggested that acetaminophen can be used for ductal closure in both aggressive and gentler PDA approach with minimal potential toxicity [ 40].

Another systematic review by Ohlsson et al. reviewed eight studies with a total 916 infants. The efficacy was equal between acetaminophen (oral or intravenous) and ibuprofen in achieving PDA closure. Also, there was less gastrointestinal bleed [risk ratio = 0.28, 95% confidence interval (CI) 0.12-0.69], lower serum levels of creatinine,lower serum levels of bilirubin and higher platelet counts.There was no difference in the neurological outcomes at 18-24 months [ 41]. Ohlsson in an updated review with more mature preterm infants (＜ 34 weeks), concluded that acetaminophen appears to be a promising alternative to indomethacin and ibuprofen for the closure of a PDA with possibly fewer adverse effects [ 42].

More recently, Pranata et al., in a systematic review and meta-analysis analyzed 10 with total of 1547 infants from the 10 selected studies with comparable closure rate.Further subgroup analysis for babies ≤ 30 weeks’ gestation revealed superiority of ibuprofen [odds ratio (OR) = 0.52(0.31-0.90),

I

2 = 0%]. However, acetaminophen was. more effective in neonates ≤ 34 weeks’ gestation [OR = 1.73(1.01-2.94),

I

2 = 30%]. When assessing other outcomes including re-opened ducts, need for surgical ligation,death, intraventricular hemorrhage and necrotizing enterocolitis, these were similar in both groups. Also, the rates of renal dysfunction and gastrointestinal bleeding were lower in acetaminophen group. Another analysis confirmed that the closure rate was not impacted by gestational age, birth weight, and gender [ 43].A recent meta-analysis compared the efficacy of oral acetaminophen and intravenous acetaminophen for ductal closure in preterm infants. Hossain et al. included 14 studies (total of 454 premature infants) with hsPDA and used either oral or intravenous acetaminophen for the treatment.Pooled proportion of PDA closure with oral acetaminophen was 77.79% (95% CI 72.92-82.15) in fixed effect and 75.77% (95% CI 65.48-84.74) in random effect model.In case of intravenous acetaminophen group, pooled portion of PDA closure was 81.52% (95% CI 74.00-87.64)and 81.52% (95% CI 74.62-87.55) in fixed and random model, respectively. The difference of proportion in the fixed effect model was 3.75% (95% CI - 5.08 to 11.64)(

P

= 0.37), and in the random effect model, it was 5.75%(95% CI 3.14-13.74) (

P

= 0.181) [ 44].

Xiao et al. in a systematic review concluded that acetaminophen could induce early ductal closure without significant side effects but that its efficacy is not superior to that ofindomethacin [ 45]. This included relatively more mature neonates (＞ 30 weeks).

Acetaminophen as a prophylactic approach

Despite using different agents (ibuprofen, ethamsylate and even ligation), indomethacin was the most commonly agent to be used for PDA prophylaxis. Acetaminophen was used as a prophylactic approach to hsPDA. A randomized control trial by Akbari Asbagh et al. found acetaminophen not to be effective when used as a prophylaxis in infants ＜ 32 weeks’gestational age [ 46].

However, other studies found different results. In a controlled, double-blinded trial by Härkin et al., infants ＜ 32 weeks’gestation, were randomly assigned to receive intravenous acetaminophen or placebo. The intervention group received a loading dose of acetaminophen 20 mg/kg within 24 hours of birth,followed by a maintenance dose of 7.5 mg/kg every 6 hours for 4 days. In the acetaminophen group, there was earlier closure of the ductus (hazard ratio = 0.49, 95% CI 0.25-0.97,

P

= 0.016) with no concerns regarding acetaminophen serum levels and no adverse effects were evident [ 47]. Höck et al.report a retrospective cohort of premature infants ＜ 32 weeks’(476 infants) [ 48] comparing intravenous acetaminophen in the intervention group and no preventive treatment in the control group. The intervention group had less PDAs (13.6% vs. 38.2%,

P

＜ 0.001), less severe and moderate bronchopulmonary dysplasia (2.7% vs. 7.4%,

P

= 0.023), less severe retinopathy of prematurity (0% vs. 4.4%,

P

= 0.002) and less length of stay(2.7% vs. 8.3%,

P

= 0.009). However, the intervention group had 1.5-fold increased risk for hyperbilirubinemia (86.0% vs.77.6%,

P

= 0.035).The EPAR study (Early PARacetamol Trial) randomized 58 preterm infants ＜ 29 weeks’ gestation to prophylactically receive either intravenous acetaminophen or placebo for 5 days. Less infants in the intervention group required intervention for PDA up to 5 days [6 (21%) vs.17 (59%) infants;

P

= 0.003]; relative risk reduction 0.35(95% CI 0.16-0.77; numbers needed to treat = 2.6). The intervention group had a higher rate of ductal closure [20(69%) vs. 8 (28%) infants;

P

= 0.002] and smaller ductal size (1.0 ± 0.8 mm vs. 1.4 ± 0.9 mm;

P

= 0.04). No other adverse events were reported [ 49].

Table 1 Non-randomized trials reporting acetaminophen use for ductal closure-symptomatic approach

Authors Study type GA (wk)(range or average)Dose Route Duration Efficacy Hammerman et al.[ 7]Case series (5 infants)26-32 15 mg/kg/dose every 6 h Oral 7 d 100%Jasani et al. [ 8] Case series (6 infants)28-31 15 mg/kg/dose every 6 h Oral 7 d 100%Kessel et al. [ 9] Case series(7 infants)26-30 15 mg/kg/dose every 6 h Oral 3 d in 5 infants 7 d in 1 infant 10 d in 1 infant 100%Tofé Valera et al.[ 10]Case series(3 infants)28, 31 and 32 15 mg/kg/dose every 6 h Intravenous 3 d in 2 infants 6 d in 1 infant 100%Sinha et al. [ 11] Case series (10 infants)27-33 15 mg/kg/dose every 6 h Oral 4 doses in 4 infants 5 doses in 5 infants 6 doses in 1 infant 100%Terrin et al. [ 12] Case series (8 infants)24-28 7.5-15 mg/kg/dose every 6 h Not reported Not reported 75%Roofthooft et al.[ 13]Prospective observational (33 infants)23.6-26.6 15 mg/kg/dose every 6 h Intravenous 3-7 d Variable efficacy ranging from 0-100%Yurttutan et al. [ 14] Prospective observational(6 infants)Nadir et al. [ 15] Prospective observational(6 infants)26-32 15 mg/kg/dose every 6 h 24-27 15 mg/kg/dose every 6 h Oral 3 d 83%Oral 5-7 d 71%El-Khuffash et al.[ 16]Prospective observational 24-28 +2 15 mg/kg/dose every 6 h Oral and intravenou 2-7 d Variable(21 infants)Sunil et al. [ 17] Prospective cohort(36 infants)27-31 15 mg/kg/dose every 6 h Intravenous 3 d 75%Tekgündüz et al.[ 18]Retrospective review(13 infants)24-31 30 mg/kg/d Oral 1-5 d ＞ 75%Lu et al. [ 19] Retrospective review 24-32 15 mg/kg/dose every 6 h Oral 3 d 37.9% (inferior to oral ibuprofen)(255 infants)Dimiati et al. [ 20] Prospective cohort(72 infants)34.26 15 mg/kg/dose every 6 h Intravenous 3 36.1%Vakiliamini et al.[ 21]Case series(18 infants)32 Loading dose of 25 mg/kg followed by maintenance dose 15 mg/kg every 8 h Rectal 3 d 95%Oshima et al. [ 22] Case series(16 infants)23-29 15 mg/kg/dose every 6 h Intravenous 3 88%Memisoglu et al.[ 23]Case series(11 infants)23-30.3 15 mg/kg/dose every 6 h Intravenous 3 d 90.9%Mohanty et al. [ 24] Prospective cohort(40 infants)Cakir et al. [ 25] Retrospective review(137 infants)23-29 15 mg/kg/dose every 6-8 h 23.8-31 Intermittent standard regimen as 15 mg/kg/dose every 6 h or as a continuous infusion 60 mg/kg/d Oral 3-5 72.5%Intravenous 5 d 86.8%

Table 1 (continued)

Authors Study type GA (wk)(range or average)Dose Route Duration Efficacy Peña-Juárez et al.[ 26]Pilot study (10 infants)30-36 15 mg/kg/dose every 6 h Oral 2-4 d About 70%Sancak et al. [ 27] Prospective comparison(18 infants)24.1-30 15 mg/kg/dose every 6 h Oral or intravenous 3 88% oral 70% intravenous

Table 2 Randomized trials reporting acetaminophen use for ductal closure-symptomatic approach

Authors Population Number of patients in acetaminophen arm Regimen used (dose,route, duration)Control arm Efficacy Dang et al. [ 28] ＜ 34 wk 80 15 mg/kg/dose, oral,for 3 d Babaei et al. [ 29] ＜ 34 wk 36 15 mg/kg/dose, oral,for 3 d Oncel et al. [ 30] ＜ 30 wk 40 15 mg/kg/dose, oral,for 3 d Oral ibuprofen 81.2%No intervention 94.4%Oral ibuprofen 77.5%Dash et al. [ 31] Preterms ＜ 1500 g 36 15 mg/kg/dose, oral,for 7 d Intravenous (IV) indomethacin 100%Valerio et al. [ 32] ＜ 32 wk 40 15 mg/kg/dose, IV,for 7 d Yang et al. [ 33] ＜ 37 wk (33.6 ± 2.1) 44 15 mg/kg/dose, oral,for 3 d Bagheri et al. [ 34] ＜ 37 wk 67 60-80 mg/kg/d, for 3 d and after that,it was increased by increments of to a maximum of 150 mg/kg/d IV ibuprofen Cumulative efficacy up to 77.8%Oral ibuprofen 70.5%Oral ibuprofen 82.1% after the first 3 d El-Mashad et al. [ 35] ＜ 28 wk 100 15 mg/kg/dose, IV,for 3 d IV ibuprofen and IV indomethacin 80%Kumar et al. [ 36] ＜ 32 wk 81 15 mg/kg/dose, oral,for 3 d Al-Lawama et al. [ 37] ＜ 32 wk 13 10 mg/kg/dose, oral,for 3 d Kluckow et al. [ 38] ＜ 33 wk 27 Loading dose of 25 mg/kg, followed by a maintenance dose of 15 mg/kg/dose every 8-12 h for 5 d Dani et al. [ 39] 25-31 +6 52 15 mg/kg/dose, IV,for 3 d Oral ibuprofen ＞ 90%Oral ibuprofen 69%Placebo 63%IV ibuprofen 52%

Acetaminophen in combination therapy

Acetaminophen was used in combination with other agents in attempt to close hsPDA. In a small double-blind, randomized, placebo-controlled pilot study, Hochwald et al.reported a higher overall ductal closure when intravenous acetaminophen was combined with intravenous ibuprofen with no evidence of increase in the side effects profile[ 50]. The study was limited by a small sample size which could explain non-statistical difference between the two groups. In the same year, an observational study by Yurttutan et al. revealed that combining oral acetaminophen with oral ibuprofen was successful in closing the ductus in 9 out of 12 infants who had failed two previous courses with no increase in the side effects [ 51].

A Canadian retrospective cohort by Kimani et al. compared the efficacy and safety of combination therapy to monotherapy [72 (58.5%) indomethacin, 29 (23.6%) acetaminophen and 22 (17.9%) ibuprofen]. Rate of ductal closure was not statistically different between indomethacin (41.7%),acetaminophen (37.9%), ibuprofen (31.8%) and combination therapy (41.2%) (

P

= 0.100). There were no differences in adverse effects were comparable between the groups [ 52].

Acetaminophen as a rescue approach prior to surgical closure

Acetaminophen was used as a late intervention or rescue attempt prior to PDA surgical closure. Late administration of oral acetaminophen for infants with persistent hsPDA was associated with reduced surgical ligation, but with increased chronic lung disease in a recent study from Toronto, Canada(2018) by Mashally et al. This was a retrospective cohort of preterm infants ＜ 29 weeks’ gestation with persistent hsPDA being considered for surgical ligation after unsuccessful pharmacological therapy. Infants in epoch 1 were immediately referred for ligation and infants in epoch 2 were given oral acetaminophen and then referred for ligation in the absence of improvement. Infants who received a rescue treatment were less likely to require surgical ligation [26(53%) vs. 31 (72%)]; however, they had more chronic lung disease and mortality rates [ 53].

Also, late medical therapy using intravenous acetaminophen was reported by El-Khuffash et al. in a retrospective review of infants with a hsPDA being considered for surgical ligation. Thirty-six infants with a median gestation of 26.1 weeks’ gestation received intravenous acetaminophen at a median age of 27 days. Acetaminophen administration resulted in ductal closure in 25% of the infants with no response in 11% who subsequently underwent a ligation[ 54].

Discussion

As a summary, the evidence is not the strongest for acetaminophen use for PDA closure, when it comes to efficacy,side effect profile, pharmacokinetics and comparison with nonsteroidal anti-inflammatory drugs (NSAIDs), especially in very preterm infants below [ 55]. Bouazza et al. pointed out a lower effect of acetaminophen on extremely preterm neonates (below 27 weeks), therefore, a study focusing specifically on extremely preterm infants is needed [ 55]. This is important as it appears that patient size is the major covariate of clearance variance in neonates [ 56].

Acetaminophen was used in literature in various approaches to PDA management with potential favorable short-term side effects profile even though there are only few studies directly comparing acetaminophen to ibuprofen especially in very immature infants [ 28, 30, 32- 34, 36, 37,39, 57]. There are many limitations as most of the studies are very small; even the largest studies, have the least effectiveness [ 19, 20]. Also, most of the studies comparing acetaminophen to ibuprofen were conducted in more mature infants where short-term safety profile appears to be more favourable which should not simply rationalize its use as a first line therapy (Table 2).

There is also not enough clarity regarding the definitions of symptomatic, conservative, prophylactic, and therapeutic approaches. Other pitfalls in literature include relative lack of pharmacodynamics and pharmacokinetic data about the use of acetaminophen, and relative lack of efficacy especially at lower gestations [ 16, 58]. There also exists a lot of uncertainty regarding the best route, dosage, duration, and therapeutic levels of acetaminophen [ 16, 58- 63].

Concerns have arisen regarding long term effects of neonatal acetaminophen exposure especially neurotoxicity.Several ecological and cohort studies have highlighted such concerns suggesting an ecological links between acetaminophen exposure during neonatal period and some longterm outcomes including autism spectrum disorder [ 64,65], attention-deficit hyperactivity disorder [ 66] and lower IQ [ 67], cognitive function [ 68]. Only one randomized trial by Oncel et al. reported neurodevelopmental outcomes for preterm infants (gestational age 30 weeks) comparing oral paracetamol versus oral ibuprofen for the closure of PDA. The developmental assessment was done by using“Bayley Scales of Infant Development, Second Edition”at 18-24 months’ corrected age. There was no significant difference in neurodevelopmental outcomes between the two groups [ 69]. Further research is needed to establish that association.

Conclusions

It is possible to use acetaminophen in case of contraindications for more traditional therapy with NSAIDs. The first-line therapy is pharmacologic, and ibuprofen is the most used agent. Acetaminophen recently gained attention, appearing as effective in ductal closure, with more favorable short-term side effects profile. Further research is needed to establish long-term effects of early exposure to acetaminophen.

Author contributions

SA and JA reviewed literature and drafted the manuscript. HA reviewed literature and supervised the manuscript. All authors approved the final version of the manuscript.

Funding

None.

Data availability

All data and articles supporting the findings of this study are available within the article in the reference section.

Declarations

Ethical approval

Not needed.

Conflict of interest

No financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. No conflict of interest to declare for all authors.