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 25–28 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, 4–7)
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 hyper-bilirubinemia.(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-acetyl-p-benzoquinoneimine (NAPQI) produced by hepatic cytochrome P450 (CYP) as metabolite production -dependent 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. (18–20)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.