Is high dose intravenous acetaminophen affect liver function in premature neonates with patent ductus arteriosus?

The aim of this study was to collect consistent data on the efficacy and safety and evaluation hepatotoxicity of intravenous acetaminophen for the treatment of PDA in preterm infants. Methods This is an observational longitudinal prospective study on 46 preterm infants with PDA who treated with high dose of acetaminophen and evaluated with echocardiography and serum liver enzymes at Hafez and Zeinabiyeh hospitals from January 2016 to December 2019. Result Forty-six preterm infants with PDA treated with intravenous acetaminophen. Rate of closure of PDA was 82.6. There was no significant difference after treatment regarding AST, ALT, Albumin, total and direct bilirubin (P value > 0.05) and no adverse side effects were observed in association with intravenous acetaminophen.


Introduction
A common complication in preterm neonates is patent ductus arteriosus (PDA). PDA is a congenital heart defect that communicate aorta into the pulmonary artery. patency of PDA is necessary for fetal circulation. In healthy term neonates spontaneous PDA closure happen normally 24-72 hours after birth because of increase pressure of oxygen in artery. (1) Incidence of PDA in preterm neonates between 30-37 week gestational age is 10%, those delivered in [25][26][27][28] week of GA is 80% and 90% is the percentage of infants born before 24 week GA that after a week would reduce to 2%, 65% and 87%. (2,3) Hypoxia, acidosis, raised pulmonary pressure and increasing prostaglandin level are risk factors that contributing to ductal patency. Shunt of blood from the aorta into the pulmonary artery can promote pulmonary over circulation that lead to significant clinical consequence such as vital organ perfusion impairment for example pulmonary hypertension, heart failure, intra ventricular hemorrhage and respiratory disease, periventricular leukomalacia, cerebral palsy or death. (2,(4)(5)(6)(7) PDA intervention is controversial, and there is limitation of evidence to guide treatment. There is 3 strategies for closure of PDA in prelatures: Prophylactic management, treatment of clinically detected asymptomatic PDA, and treatment when the PDA is symptomatic neonates. Management of ductal closure include conservative treatments (i.e. fluid restriction, diuretics, etc and waiting for spontaneous closure), pharmacological management and surgical ligation. (1,3,8,9) FDA approved intravenous (IV) indomethacin and ibuprofen (cyclooxygenase inhibitors) as first drug use for treatment of PDA. These drug reduce the levels of prostaglandin that promote ductus arteriosus muscular wall constriction lead to fibrosis as anatomical ductal closure. Prenominated NSAIDs were successful in closure of PDA. (10) Indomethacin decrease incidence of intraventricular hemorrhage, pulmonary hemorrhage and in extremely premature neonate reduce development BPD and death. (2) Ibuprofen has same mechanism action and efficacy for closure of PDA as indomethacin (success rate 70-85%) but less impairment of renal function because of lower vasoconstrictor effect. However, ibuprofen has significant side effects, such as nephrotoxicity, pulmonary hypertension and hyperbilirubinemia. (2,3,5,11) NSAID adverse effect include renal function impairment, GI bleeding, necrotizing enterocolitis, intestinal perforation, thrombocytopenia, pulmonary hypertension and hyperbilirubinemia and etc. (1,2) In recent years increasing acetaminophen administration for PDA treatment because this drug is has same efficacy as NSAIDs with fewer side effects because acetaminophen is prostaglandin synthesis inhibitor with affect at peroxidase site of prostaglandin H synthetase (POX) that differs from COX inhibitor. (1,2) In neonates who have contraindication for treatment with indomethacin and ibuprofen or the NSAIDs have failed in closure of PDA administration of acetaminophen suggested as a choice before surgical ligation. (2) Evaluating of advantages and disadvantages of pharmacological treatment by assessment of following outcomes: PDA closure failure (according to clinical evaluation or echocardiography criteria) as primary outcome; require surgical ligation of PDA, death, and selected any untoward medical occurrence, as secondary outcomes., not certainly having a causal association with treatment (8) Prospective trials may support more perception of acetaminophen effectiveness and safety as a further or even as a first-line option for closure of PDA in neonates (12) Some hepatic side effects have been happened after usage of iv acetaminophen, which may determine a transient raise in liver enzymes or more serious acute liver toxicity. (13,14) acetaminophen itself not directly cause of hepatotoxicity in neonates but can be caused by N-acetylp-benzoquinoneimine (NAPQI) produced by hepatic cytochrome P450 (CYP) as metabolite productiondependent mixed function oxidase enzyme. The action of NAPQI formation, sulphate elimination, and glucuronide production rate are not known in preterm neonates exactly. (15,16) The hepatic metabolism of acetaminophen happens through sulphation, glucuronidation, and oxidation. Usage therapeutic doses of acetaminophen produces nontoxic metabolites through glucuronidation, or sulphation activation as first mechanism. CYP1A2, 3A4, and 2E1 induce acetaminophen oxidation that generates the highest reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI).
Glutathione conjugate it into a renal metabolite that is safe. Sulphation and glucuronidation pathways saturate after an high dose of acetaminophen and lead to excessive dose of NAPQI use glutathione resource and Becomes toxic as a results. the toxic acetaminophen dose is higher than therapeutic concentration about ten times in adults and the growth changes acetaminophen metabolism. (17) The rate of glucuronidation in neonates is variable and the ability of glutathione conjugation is limited with the sulphation pre dominancy, and the expression of CYP is early in postnatal life in full-term neonates while this is unknown exactly in preterms. (18)(19)(20)However, the existence of a large therapeutic serum concentration range for acetaminophen suggested by clinical evidence that demonstrate a low or absent hepatic toxicity in neonates. (2,10,18,21) In this study we use high dose acetaminophen in infants with a clinically significant PDA to determine efficacy and hepatic side effects of iv acetaminophen.

Methods
This is an observational longitudinal prospective study.
The study involved 46 preterm infants (gestational age < 37 weeks, mean birth weight 1099.3 g) with hemodynamically significant patent ductus arteriosus (HsPDA) born at our hospitals (Hafez and Zeinabiyeh) hospitals with the approval of the local ethics committee from January 2016 to December 2019 Exclusion Criteria Preterm neonates with complex congenital heart disease, those were PDA as life saving for them, the cases who ibuprofen or indomethacin administrated before treatment with acetaminophen, and if the parents did not accept to enroll in this study.

Treatment Eligibility Criteria And Drug Administration Protocol
Infants with a gestational age < 37 weeks and who Had clinical signs of significant PDA within the first week of life, diagnosed by pediatric cardiologist were enrolled in the study after obtaining written consent from their parents.
Echocardiography for diagnosis of PDA was done by pediatric cardiologist.
Treatment with high dose of i.v route acetaminophen was started at a dose 20 mg/kg every 6 h for 4 d, with echocardiographic evaluation performed at the end of the treatment.
Treatment success was defined as complete ductal closure on echocardiography. Pre-and posttreatment levels of liver enzymes (alanine transaminase (ALT), aspartate aminotransferase (AST), albumin, total and direct bilirubin) were measured for evaluation liver toxicity.
Data and analysis done with SPSS version 19 and p value < 0.05 consider as significant.
Result 46 preterm infants were included in this study (January 2016 to December 2019). The median gestational age was 30.1 weeks (minimum-maximum: 25.5-36) and the median birth weight was 1099.3 g (800-3300) were PDA positive born at our institution began "first-line" i.v acetaminophen treatment (dose 20 mg/kg every 6 h for 4 d). PDA echocardiographic parameters before starting any i.v acetaminophen treatment are given in Table 1. Pre-and post-treatment levels of liver enzymes and bilirubin levels of all infants for the purpose of assessing the treatment's safety are summarized in Table 2.
There was no significant difference after treatment regarding AST, ALT, Albumin, total and direct bilirubin (P value > 0.05). Pre-and post-treatment levels of liver enzymes and bilirubin levels were normal in all patients, and no adverse side effects were observed in association with iv acetaminophen. The liver size and clinical examination of the 46 infants during and after treatment were normal. No sign and symptom of hepatotoxicity such as Jaundice, yellowish sclera and hepatomegaly were seen during and after treatment with high dose acetaminophen. Bleeding tendency, GI complication and oliguria did not detect. 39 cases cured in first course of acetaminophen administration and improved signs and symptoms due to PDA. PDA closure improves dynamic compliance and increases tidal volume in preterm neonates receiving mechanical ventilation and a significant decrease in ventilator setting in our patients with PDA closure than those with failure of PDA closure.7 infants failed in closure of PDA treated with second course combination acetaminophen and ibuprofen.  and hyperbilirubinemia showed after ibuprofen therapy However, an appropriated monitoring in order to early detect acetaminophen toxicity is recommended. All these authors agree with the possibility of using acetaminophen in case of ibuprofen or indomethacin contraindications and/or failure.GI bleeding was significantly more observed in the indomethacin group followed by the ibuprofen group.
In our study bleeding tendency and GI complication did not detect. GI bleeding never seen that went with the results of other investigators. A safer profile in terms of gastrointestinal bleeding and hyperbilirubinemia after acetaminophen administration instead of ibuprofen has been described by Evans (5)

Conclusion
The goal of the studies on PDA management would be to perform an individualized therapy, choosing the for each of the patient characteristics, which could be the most effective as much as possible, personalized, and with the lowest side effects. acetaminophen is as effective as indomethacin and ibuprofen in closure of PDA in preterm neonates with less side effects than both. Our data suggest that acetaminophen is an effective and safe therapeutic without hepatotoxicity side effects option for PDA closure. Our results support previous reports that proposed the use of acetaminophen as an alternative treatment for PDA. Between the available drugs for PDA treatment, acetaminophen seems to be a promising alternative and most authors agree with the necessity of more trials to establish the safer dose in preterms and its efficacy. If acetaminophen is shown to be effective in a large series, because of low risk of side effects, low cost it may be an advantageous alternative at PDA treatment. Ethical approval and consent to participate: The study was explained for the patients or guardians and informed consent forms were signed by them.

Availability of Data and Materials:
We state that the data used and/or analyzed during the current study are available from the corresponding author on reasonable request. Data sharing is applicable to this article and datasets were generated and analyzed during the current study and data sharing is allowed.

Funding:
This article was funded by Shiraz University of Medical Sciences. All of the Echocardiographic evaluations were performed in this university. The funder had no impact on study design, analysis, or result interpretation.

Acknowledgment:
We would like to thank doctor M.Rezayi and Dr H.Arabi for their support and suggestions. We