|Year : 2021 | Volume
| Issue : 2 | Page : 79-87
Paracetamol for closure of patent ductus arteriosus in preterm babies born before 32-week gestational age: academic unit experience
Nagwa Sabry Mahmoud1, Hany Asklany2
1 Department of Pediatric, Faculty of Medicine, Minia University, Minya, Egypt
2 Department of Cardiology, Faculty of Medicine, Minia University, Minya, Egypt
|Date of Submission||27-Nov-2020|
|Date of Decision||31-Dec-2020|
|Date of Acceptance||03-Jan-2021|
|Date of Web Publication||15-May-2021|
Nagwa Sabry Mahmoud
Lecturer of Pediatric, Department of Pediatric, Faculty of Medicine, Minia University
Source of Support: None, Conflict of Interest: None
Background: It remains unclear which treatment approach is most advantageous for closure of patent ductus arteriosus (PDA) in preterm infants. Despite the presence of previous trials and meta-analysis, a correct and univocal strategy for closure of PDA is still under debate. Till now, standard medical treatment for PDA closure has been indomethacin/ibuprofen, percutaneous transcatheter closure, or surgical ligation. Up to date, new strategies have been reported with paracetamol. The aim of this study was to present our experience with intravenous (IV) and oral paracetamol for closing PDA in preterm neonates born before 32-week gestational age (GA). Patients and Methods: We conducted a prospective study in a neonatal intensive care unit (NICU) from a tertiary hospital in Minia University; Egypt. Eighty-seven preterm neonates born before 32-week GA with hemodynamically significant PDA (hsPDA) were enrolled. They received 15 mg/kg/6 h for 5 days IV or oral paracetamol for ductal closure. Our NICU guidelines before the current study state that only hsPDA is treated with oral ibuprofen based on the decision of the neonatologist after discussion with pediatric cardiologist. The study aims to vary the practice to use IV or oral paracetamol instead of ibuprofen to avoid side effects of nonsteroidal drugs in preterm babies. Results: During the study period, 140 babies <32 weeks admitted to the NICU assessed for eligibility to the study, 87 of them received IV or oral paracetamol for the treatment of hsPDA for a total of 5 days. Forty-five babies received IV paracetamol, while 42 received oral form with closure rate of 82.22% and 80.95%, respectively. Successful closure on paracetamol was achieved in 71 of 87 babies (81.6%). Conclusion: This study concluded that paracetamol is not only an alternative treatment in closing PDA but also may be the treatment of choice in future.
Keywords: Paracetamol, patent ductus arteriosus, preterm, treatment
|How to cite this article:|
Mahmoud NS, Asklany H. Paracetamol for closure of patent ductus arteriosus in preterm babies born before 32-week gestational age: academic unit experience. J Clin Neonatol 2021;10:79-87
|How to cite this URL:|
Mahmoud NS, Asklany H. Paracetamol for closure of patent ductus arteriosus in preterm babies born before 32-week gestational age: academic unit experience. J Clin Neonatol [serial online] 2021 [cited 2021 Dec 6];10:79-87. Available from: https://www.jcnonweb.com/text.asp?2021/10/2/79/316180
| Introduction|| |
Ductus arteriosus (DA) is the vascular communication between pulmonary artery and aorta. It represents one of the fundamental shunts of fetal circulation., DA may be pathologically or physiologically patent. The conditions of “Patent DA (PDA)” and “Persistent DA” are often defined as “PDA,” even if they differ in terms of morphology, clinical effects, and management.,, Preterm infants may experience PDA with a higher rate, but the correlation between gestational age (GA) at birth and PDA is not absolute. There are other clinical risk factors rather than GA predisposing to PDA including sepsis, respiratory distress syndrome (RDS), intrauterine growth restriction, and others. Genetic variability has an influence on PDA incidence and treatment. PDA is a frequent, complex, and difficult to treat clinical syndrome among preterm babies in the neonatal intensive care unit (NICU). Clinical response and toxicity from drugs used to treat PDA are highly variable. Given the variable efficacy and toxicity of known drug therapies, novel therapeutic drugs for the treatment of PDA offer the promise of precision medicine. Vascular smooth muscle relaxation occurs under the effect of prostaglandin E2 (PGE2), resulting in maintenance of ductal patency and occurs through the activation of adenylate cyclase, leading to increase in cyclic adenosine monophosphate, through interaction with G-protein receptors., Anatomical closure of DA is generally complete in a few weeks, replaced by ligamentum arteriosum., Because of persistence of high levels of circulating PGE2, spontaneous DA closure often fails or is delayed in preterm babies, and this condition has been associated with severe short- and long-term complications. On the 4th day of life, PDA would persist in about 10% of babies with GA between 30 and 37 weeks, in 80% of those with GA between 25 and 28 weeks, and in 90% of preterms born at 24 weeks of GA. From the 7th day of postnatal life, the percentage of infants with PDA in these groups will be reduced, respectively, to about 2%, 65%, and 87%. DA will be spontaneously closed in 73% of babies with more than 28 weeks of GA and in 94% of infants with birth weight (BW) >1000 g.
| Patients and Methods|| |
Babies born before 32 weeks GA between July 2017 and November 2019 were recruited from NICU, Minia university hospital for obstetrics and gynecology and pediatrics. This study was approved by the research committee at Faculty of Medicine, Minia University, Egypt. A written consent was taken from the parents of all neonates participated in the study. Our NICU guidelines before the current study state that only hemodynamically significant PDA (hsPDA) is treated with oral ibuprofen based on the decision of the neonatologist after discussion with pediatric cardiologist. Intravenous (IV) ibuprofen and indomethacin are not available in our unit. The aim of this study is to change the practice to use IV or oral paracetamol instead of ibuprofen to avoid side effects of nonsteroidal drugs in preterm babies.
- Informed parental consent
- Babies born before 32-week GA with clinical, laboratory manifestations, and echocardiographic findings of PDA in the form of:
- Evidence of a PDA >1.5 mm with left-to-right shunt by echocardiography
- Hyperdynamic precordium or prominent precordial pulsation
- Wide pulse pressure (>25 mmHg) and blood pressure instability on two consecutive blood pressure measurements
- Systolic/continuous murmur at left parasternal area
- Bounding peripheral pulses
- Poor peripheral perfusion and prolonged capillary refill time
- Decreased urine output and deranged renal function tests
- Metabolic acidosis (not due to other causes such as sepsis or hypoperfusion)
- Abnormal weight gain
- Increase in liver size
- Deteriorating respiratory status and increase in oxygen requirements
- Difficulty in weaning from the ventilator or increased ventilatory support
- Frequent episodes of apnea
- Carbon dioxide retention
- Feeding intolerance
- Occurrence of pulmonary hemorrhage
- Inotrope-resistant hypotension.
We selected oral route for babies who were in partial or complete feeding.
Babies were excluded if parents refused to sign the study consent or there was already evidence of congestive heart failure with multiorgan affection, antenatally, or postnatally suspected or diagnosed structural heart disease, sepsis, perinatal asphyxia, chromosomal, or congenital abnormalities, and abnormal baseline liver function.
- Echocardiogram (Echo)
Echocardiogram was done routinely at 72 h of life for all preterm babies born before 32 weeks GA with brain ultrasound. Specialized pediatric cardiologist was responsible for doing detailed initial and serial follow-up echos for all recruited cases.
Echo will determine whether PDA is hemodynamically significant or not by measuring:
- Size of the PDA (by 2D and color doppler). The size of the PDA measured by echocardiography is generally used to determine whether or not a PDA is hemodynamically significant in preterm infants <32 weeks. One commonly used measure is a transductal diameter that exceeds 1.5 mm/kg body weight and according to the size PDA is classified into:
- Small PDA: Transductal diameter <1.5 mm
- Moderate PDA: Transductal diameter 1.5–3 mm
- Large PDA: Transductal diameter more than 3 mm.
Color and spectral Doppler will determine whether PDA is shunting left to right, bidirectional or right to left, reversal/no-reversal of postductal descending aortic diastolic flow, is PDA restrictive or nonrestrictive, and is there pulmonary hypertension or notEcho will also show PDA's hemodynamic effect by:
- Ductal velocity <2 m/s
- Evidence of left atrial enlargement (left atrium: aortic root diameter ratio ≥1.4)
- Increased velocity in the left pulmonary artery (diastolic >0.2 m/s, mean >0.45 m/s)
- Dilation of the left atrium and/or left ventricle (>1.4:1)
- E wave: A wave ratio >1
- Isovolumic relaxation time ≤45 ms.
A blood sample of 0.5 mL was collected to exclude abnormal liver function/abnormally raised bilirubin before the commencement of study medicationThe research team agreed that all neonates with hsPDA should receive the following supportive care once diagnosed:
- Neutral thermal environment
- Respiratory support (if required) including ventilator support or continuous positive airway pressure (CPAP) to achieve adequate oxygenation that minimizes demands on left ventricular function
- Minimal respiratory support ensuring adequate oxygenation (target pulse oximetry saturation between 90% and 95%) and allowing permissive hypercapnia (partial pressure of carbon dioxide 55–60 mmHg) as long as pH remains in the accepted range (i.e., 7.25–7.45). For infants who are mechanically ventilated, gentle ventilation with small tidal volume to minimize further pulmonary injury and positive end-expiratory pressure of 5–8 cmH2O to prevent atelectasis are recommended
- Maintenance of the hematocrit at 35%–40% which may increase pulmonary vascular resistance and reduce left-to-right shunting
- Daily Fluid restriction between 120 and 130 mL/kg while providing adequate nutrition of at least 120 kcal/kg/day. The desired nutrients may need to be contained in a reduced volume of feeding to deliver the necessary daily caloric intake for growth and maintain fluid restriction. Mother's milk is preferred but if not available milk formula suitable to the baby should be used
- Furosemide or any other loop diuretic is not recommended, as loop diuretics stimulate renal synthesis of PGE2, a potent vasodilator that maintains PDA patency
- Thiazide diuretic (e.g., hydrochlorothiazide) may be used in infants who become fluid overloaded or with signs of increased interstitial pulmonary fluid.
After routine assessment of all recruited cases at 72 h of life with cranial and echocardiography, the results were communicated to the treating team who will decide whether hsPDA requires intervention or not. If there is evidence of significant pulmonary hypertension (defined by either suprasystemic pulmonary pressures > 30% or there is right to left ductal shunt), no treatment is required. Babies who meet all the inclusion criteria and who have a demonstrable DA with left-to-right shunt and did not respond to conservative management for 72 h confirmed by another echo, received IV paracetamol (Perfalgan 100 ml, Bristol Mayers Squibb, Egypt) at a dose of 15 mg/kg every 6 h for 5 days or oral paracetamol at the same dose regimen (Abimol 120 mg/5 ml, Glaxo Smithkline, Egypt). Another echo was done 72 h after starting paracetamol therapy and final assessment will be performed at the end of the treatment course (5 days). Additional interim assessments may be performed as clinically indicated. At all times, babies will remain under the care of the treating neonatologist. Clinical decisions, including PDA management, will always be at the discretion of the treating team. Ongoing management of the PDA after 5 days will continue as per the treating team. Paracetamol oral suspension would be administered through an orogastric tube in a dose of 15 mg/kg every 6 h for 5 days. The drug would be filled in 5 mL plastic syringes and would be gently pushed through the orogastric tube, followed by a flush of 1 mL of sterile water for injection.
Dosing and preparation of paracetamol were performed by clinical pharmacists in charge of NICU. The research team selected the dose regimens as most published data investigating treatment of PDA using IV or oral paracetamol started with nearby dose regimens. IV paracetamol was selected if there is contraindication to oral feeding. Cases with impaired liver functions were excluded as with regular high-dose paracetamol, the potential for hepatotoxicity due to accumulation of toxic metabolites, particularly in the immediate neonatal period when paracetamol clearance may be low. Based on pharmacokinetic prediction modeling, it is likely that a modest loading dose followed by a more conservative regular dose will quickly achieve a good median paracetamol concentration at levels that will optimize safety. It is important to acknowledge, however, that the target concentration for ductal closure is unknown.
Follow-up of recruited cases
A repeat echo by a pediatric cardiologist was performed after 72 h of medication administration and again 24 h after completion of the 5-day course documenting the ductal parameters. Respiratory parameters of oxygen requirement, type of respiratory support, and maximum appropriate mean airway pressure were collected before, throughout, and after the treatment. Changes in feed amounts and intolerance of feeds were also recorded. Blood (0.5 mL) was collected in a lithium heparin tube to assess for elevated liver function tests (LFTs). These were repeated at completion of the study medication on day 5.
Safety of the drugs was assessed daily during the course of treatment, including 24 h urine output calculation, bleeding tendency, interventricular hemorrhage (IVH) grade, and serum creatinine and bilirubin levels. An eye examination was conducted according to unit guidelines for retinopathy of prematurity (ROP). The occurrence of any of the following conditions would prompt stopping of treatment: renal failure, necrotizing enterocolitis (NEC), IVH Grade 3–4, and gastrointestinal bleeding.
Babies could be withdrawn from the trial for the following reasons: withdrawal of parental consent, or potential complications of paracetamol treatment such as raised serum alanine transaminase, raised aspartate transaminase, or a conjugated serum bilirubin >80 mmol/L.
The following variables will be recorded for babies included in the study: demographic data, GA, BW, sex, mode of delivery, exposure to antenatal steroids, and maternal history of hypertensive disease of pregnancy. Clinical outcomes will be assessed at discharge.
- Closure of DA at 3 and 5 days of therapy
- Size of DA at 3 and 5 days of therapy
- Ductal reopening during admission
- DA parameters
- Systemic blood flow measurements
- Adverse events during the treatment period.
Clinical outcomes include mortality and significant morbidities (early-onset sepsis, late-onset sepsis, IVH, periventricular leukomalacia [PLV], chronic lung disease, ROP, and hepatic impairment).
Participants in the study may receive any medications required, either routine medications given in the context of prematurity or medications for comorbid conditions. Any medication known to cause liver dysfunction should be used with caution while participants are receiving paracetamol.
| Results|| |
During the study period, 140 babies <32 weeks admitted to the NICU at Minia university hospital for Obstetrics and Gynecology and Pediatrics assessed for eligibility to the study, 87 of them, received IV or oral paracetamol for the treatment of PDA for total 5 days.
Paracetamol treatment was initiated at a median of 7 days of life (interquartile range [IQR] 5–10 days). IV paracetamol was given for 45 babies, while oral paracetamol was given for 42 babies.
Echocardiographic evaluation before the initiation of paracetamol treatment revealed a large PDA in 57 neonates (65.52%) and moderate PDA in thirty neonates (34.48%). Paracetamol was used for all recruited cases.
The demographics, perinatal characteristics, and vital signs of the recruited babies are shown in [Table 1]. There was no significant difference between IV group and oral group regarding demographic and perinatal data. Furthermore, there was no significant difference in the blood pressure of the neonates within IV and oral paracetamol groups before and after treatment; no significant difference was observed between the two groups in terms of the heart rate, a significant decrease was observed within each group after the treatment with a significant difference (P < 0.001), while the comparison of the groups showed no significant difference in this regard (P > 0.05). Moreover, respiratory rate reduced within both groups with a significant difference before and after the treatment (P < 0.001), while comparison of the groups showed no significant difference in this regard (P > 0.05). In this study, no complications were observed in both groups. At the time of initiation, six neonates (6.89%) were receiving supplemental oxygen through high-flow nasal cannula; 11 (12.65%), CPAP; and 70 (80.46%), conventional mechanical ventilation.
|Table 1: Baseline characteristics of neonates who received paracetamol for patent ductus arteriosus|
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Neonates were treated with paracetamol for a total duration of 5 days. Seventy-one neonates (81.61%) responded to paracetamol therapy and no further treatment for PDA was required. Posttreatment echocardiograms were performed for all patients. Of these, posttreatment echocardiogram documented PDA closure in 31 neonates (43.66%) and a significant reduction in ductal size in forty neonates (56.34%), both groups did not require further treatment. Sixteen patients (18.39%) did not have significant improvement in PDA with paracetamol. Surgical ligation was considered for PDA closure in this group.
With the exception of GA and BW, responders and nonresponders had similar baseline and treatment characteristics [Table 2].
There was a statistically significant increase in median alanine aminotransferase but no significant increase in any other marker of hepatic injury [Table 3]. Although serum creatinine differed significantly before and during treatment, the magnitude and direction of this change reflects no clinical difference or an improvement in renal function. No clinical signs of paracetamol toxicity were observed in any patients at any point during or immediately after therapy.
|Table 2: Patient characteristics of responders and nonresponders to paracetamol|
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|Table 3: Safety laboratory parameters for intravenous and oral paracetamol|
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Safety of treatment
There were no significant differences between the two groups in the incidence of oliguria, NEC, IVH grades (1–2 and 3–4), gastrointestinal bleeding, spontaneous intestinal perforation, serum creatinine concentration, and hyperbilirubinemia. Furthermore, there were no significant differences between the two groups in adverse events including bronchopulmonary dysplasia (BPD), PVL, sepsis, ROP, and death from 1 week after treatment onward during the hospitalization period [Table 4].
[Table 5] shows that the ductus was closed in 37 babies (82.22%) of the IV paracetamol group compared with 34 (80.95%) of the oral paracetamol group, and there was no significant difference between the two treatment protocols (P = 0.94). Meanwhile, the 95% confidence interval for the difference between the two groups was (−0.079, 0.129). Thus, the efficacy of oral paracetamol group was not inferior to the IV group. Reopening of the ductus after closure occurred in three babies (10%) of the IV paracetamol group and in three of the oral group (11.11%). After continuing to receive the assigned drug treatment for another 5 days, the ductus closed again in two patients of each group.
| Discussion|| |
During fetal life, the DA diverts blood from the pulmonary artery to the aorta bypassing the lungs. Functional closure of the DA occurs by about 15 h of life in healthy term babies.
DA starts to close immediately after birth due to sudden increase of the arterial oxygen and reduction of the endogenous prostaglandins. Synthesis of prostaglandins is possible through the cyclooxygenase (COX) and peroxidase pathways. Indomethacin and ibuprofen inhibit COX3 in a nonselective manner. The mechanism of PDA closure by paracetamol still obscure, but it is known that it inhibits prostaglandin synthetase. Alternatively, paracetamol may selectively inhibit a central isoform of COX3, but the existence of a functional human COX3 is not well established.
There are few studies on PDA spontaneous closure in newborns with lower GA and BW, or in infants with RDS, because a PDA therapeutic closure is often performed in these categories of patients. Prolonged condition of PDA in preterm babies can be associated with important complications such as severe RDS, prolonged need for assisted ventilation, pulmonary hemorrhage, BPD, NEC, renal function damage, IVH, PLV, cerebral palsy, or death. These conditions depend on the magnitude of left-to-right shunt volume through PDA, regulated by the balance between PDA dimension and arterial resistance fall in the pulmonary circle during early hours of postnatal life and resulting in lung hyperflow and development of pulmonary congestion and edema. If this condition persists, deterioration of respiratory function can occur. The impact of this “ductal steal” on systemic circulation causes a reduction in cardiac output increasing, the mechanism that allows facing the rising in systemic resistances of postnatal period. This condition can lead to vital organs perfusion impairment such as brain, kidney, and bowel. To prevent such complications, the practice of DA closure is common, and it is performed at first pharmacologically, but, in case of drugs failure or contraindication, with surgical ligation. Despite years of researches and clinical experience on PDA management, many unresolved issues about its evaluation and treatment, with consequent heterogeneity of clinical practices in different centers, still remain, particularly regarding timing and modality of intervention. In fact, the available strategies vary from prophylactic treatment to early or delayed therapy., Recent studies, however, do not recommend prophylaxis in case of non-hsPDA, because it exposes the infants to indomethacin or ibuprofen adverse effects, without substantial short-term or long-term benefits., The most reasonable strategy seems to be, nowadays, reserving the treatment only to hsPDA. For this purpose, the first-line therapy is medical and nonsteroidal anti-inflammatory drugs are drugs of choice, preventing the conversion of arachidonic acid into prostaglandins through COX inhibition, in both the existing isoforms COX-1 (constitutive) and COX-2 (inducible).,, Reduction in prostaglandin levels leads to DA muscular wall constriction through the hypoxia of ductal vasa vasorum and consequent local angiogenesis, formation of neointimal tissue, and apoptosis. These mechanisms, in conjunction with platelet recruitment and activation, lead to processes of obstruction and fibrosis and as a result, anatomical ductal closure.
In this study, no increase was observed in the blood urea nitrogen and creatinine; this is in agreement with the results of Ghaderian et al., who studied the effect of low-dose IV acetaminophen versus oral ibuprofen for the closure of PDA in premature neonates. There was a statistically significant increase in median alanine aminotransferase but no significant increase in any other marker of hepatic injury. These results are in agreement with Luecke et al., who stated that, although there was a statistically significant increase in alanine aminotransferase in their study, the finding was not clinically significant as no other signs or symptoms of hepatotoxicity were observed in their patient group. Furthermore, Tekgündüz et al. and Sinha et al. reported a high level of transaminases caused by IV paracetamol treatment for PDA closure in premature babies and they found that a lower dose of paracetamol also is effective., Therefore, the dose and dose interval of IV paracetamol treatment might require revision in future studies. The single adverse event noticed by Tofe et al. was a transient elevation in liver enzymes in two patients of their studied nine preterm babies <32 weeks and they required no treatment. This is in agreement with our results.
In this study, we observed the relation between paracetamol therapy and NEC, spontaneous intestinal perforation, and BPD in all recruited babies. We did not notice any significant morbidities related to paracetamol use in preterm babies <32 weeks.
There is not difference in the side effects comparing the two administration routes, but it cannot affirm with certainties that such effects are not related to paracetamol.
These results are in agreement with Luecke et al. and Ohlsson et al.,
Dang et al. found that there were no significant adverse events including BPD, PVL, and NEC, sepsis, ROP and death from 1 week after treatment with oral paracetamol and onward during the hospitalization period. These results are in agreement with our study.
As the previous studies lacked sufficient sample sizes for analysis of efficacy and safety-related factors such as gastrointestinal bleeding, NEC, IVH, hyperbilirubinemia, and death, they cannot be used to support paracetamol as a first-line drug for PDA in preterm newborns. Therefore, we conducted the present study to evaluate and compare the efficacy and safety of IV or oral paracetamol on the closure of DA in premature babies born before 32 weeks GA. The efficacy of paracetamol in the current study was estimated to be 82.22% for IV paracetamol and 80.95% for oral paracetamol.
The first use of successful ductal closure by paracetamol was reported by Hammerman et al. in 2011. They studied five preterm babies (GA: 26–32 weeks; postnatal age: (3–35 days) with large, hsPDA who had either failed or had contraindications to ibuprofen therapy. Those five babies were treated with oral paracetamol in a dose of 15 mg/kg/dose 6 h for 48 h. Ductal closure was achieved in all the treated babies, and no toxicity was observed. Futhermore, Oncel et al. used IV paracetamol in ten premature babies born before 30-week GA with a 100% of effectiveness. Nevertheless, Roofthooft et al. used paracetamol for closure of PDA in ten preterm babies < 27 weeks with a high failure rate (around 70%) compared to other results. They explained paracetamol failure by the relatively old postnatal age in their patients (median 22 days and IQR: minimum 13 and maximum 30). The most common dosage used is 15 mg/k/dose/q6 h.
Among 13 previous observational studies, paracetamol was given orally (112 premature infants), and in another 12 observational studies, paracetamol was given IV (150 premature infants) with a closing rate up to a 72.2% in oral route versus 66% with iv paracetamol.,,,, We have reported a higher average ductal closure than the previously published studies probably because paracetamol was given earlier, in the 1st week of life. Other observational studies showed that paracetamol is more effective when there has been no exposure to ibuprofen and less effective when it is administered later., Average of spontaneous ductal closure is higher at higher GAs. The median GA among our premature babies with hsPDA and spontaneous closure was 28 weeks for the IV group and 29 weeks for the oral group, so we truly believe that the spontaneous closure among our population cannot be due to higher GAs. This is in agreement with Tofe et al.
In the current study, we used oral paracetamol for ductal closure and we did not face any gastrointestinal problems rather than the known morbid conditions for the same group with same weight and GA, but one limitation to this study we do not have control to compare these conditions.
The main difference between the present research and other studies is the doses of prescribed medications. In previous studies, paracetamol was administered as one to two courses which each course of drug was administered with the dosage of 15 mg/kg/6 h for 3 days, while we administered the drug for a longer duration (5 days for one course). Dang et al. studied 160 infants with GA ≤ 34 weeks treated with 15 mg/kg every 6 h for 3 days of paracetamol. They found that the ductus was closed in 81.2% of infants in the paracetamol group compared with 78.8% of infants in the ibuprofen group. In this regard, using the binomial test and considering the chance of success rate of 81.22% for IV group and 80.95% for oral group in the study, there was no significant difference in the closed PDA between the current study and the standard dose. In the present study, patients who did not respond to paracetamol were considered for surgical ligation based on the NICU guidelines.
This study is a single unit experience, and multicenter studies are needed to elaborate more on use of paracetamol for PDA closure. Another limitation is that no controls were used in the study to compare the side effects and complications of paracetamol.
| Conclusion|| |
This study concluded that paracetamol is not only an alternative treatment in closing PDA but also may be the treatment of choice in future. Multicenter studies are needed to know the long-term consequences of using paracetamol for closing PDA and to determine the optimal dose, the best route of administration, safety, and the implications in motor and neurodevelopmental growth.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Fanos V, Pusceddu M, Dessì A, Marcialis MA. Should we definitively abandon prophylaxis for patent ductus arteriosus in preterm new-borns? Clinics 2011;66:2141-9.
Mitra S, Florez ID, Tamayo ME, Aune D, Mbuagbaw L, Veroniki AA, et al
. Effectiveness and safety of treatments used for the management of patent ductus arteriosus (PDA) in preterm infants: A protocol for a systematic review and network meta-analysis. BMJ Open 2016;6:e011271.
Gittenberger-De Groot AC. Persistent ductus arteriosus: Most probably a primary congenital malformation. Br Heart J 1977;39:610-8.
Chuaqui BJ, Piwonka GC, Farr ÚO. The wall in persistent ductus arteriosus. Virchows Arch A Pathol Anat Histol 1977;372:315-24.
Reese J, Veldman A, Shah L, Vucovich M, Cotton RB. Inadvertent relaxation of the ductus arteriosus by pharmacologic agents that are commonly used in the neonatal period. Semin Perinatol 2010;34:222-30.
Lewis TR, Shelton EL, Van Driest SL, Kannankeril PJ, Reese J. Genetics of the patent ductus arteriosus (PDA) and pharmacogenetics of PDA treatment. Semin Fetal Neonatal Med 2018;23:232-8.
Tan ZH, Baral VR. Principles of clinical management of patent ductus arteriosus in extremely preterm neonates. Curr Pediatr Rev 2016;12:83-97.
Waleh N, Kajino H, Marrache AM, Ginzinger D, Roman C, Seidner SR, et al
. Prostaglandin E2-mediated relaxation of the ductus arteriosus: Effects of gestational age on G protein-coupled receptor expression, signaling, and vasomotor control. Circulation 2004;110:2326-32.
Antonucci R, Bassareo P, Zaffanello M, Pusceddu M, Fanos V. Patent ductus arteriosus in the preterm infant: New insights into pathogenesis and clinical management. J Matern Fetal Neonatal Med 2010;23:34-7.
Evans N. Preterm patent ductus arteriosus: A continuing conundrum for the neonatologist? Semin Fetal Neonatal Med 2015;20:272-7.
Benitz WE. Committee on Fetus and Newborn, American Academy of Pediatrics. Patent Ductus Arteriosus in Preterm Infants. Pediatrics 2016;137(1):e20153730. [doi: 10.1542/peds. 2015-3730].
Abdel-Hady H, Nasef N, Shabaan AE, Nour I. Patent ductus arteriosus in preterm infants: Do we have the right answers? Biomed Res Int 2013;2013:15.
Dani C, Poggi C, Mosca F, Schena F, Lista G, Ramenghi L, et al
. Efficacy and safety of intravenous paracetamol in comparison to ibuprofen for the treatment of patent ductus arteriosus in preterm infants: Study protocol for a randomized control trial. Trials 2016;17:182.
El-Khuffash A, Jain A, Corcoran D, Shah PS, Hooper CW, Brown N, et al
. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: Evidence from human and murine studies. Pediatr Res 2014;76:238-44.
Schena F, Francescato G, Cappelleri A, Picciolli I, Mayer A, Mosca F, et al
. Association between hemodynamically significant patent ductus arteriosus and bronchopulmonary dysplasia. J Pediatr 2015;166:1488-92.
Bagheri, MM, Niknafs, P, Sabsevari F, Torabi MH, Bijari BB, Noroozi E, et al
. Comparison of oral acetaminophen versus ibuprofen in premature infants with patent ductus arteriosus. Iran J Pediatr. 2016;26:3975.
Van den Anker JN, Allegaert K. Acetaminophen to prevent symptomatic patent ductus arteriosus: Another drug bites the dust? J Pediatr 2016;177:7-9.
Demirel G, Erdeve O, Dilmen U. Pharmacological management of PDA: Oral versus intravenous medications. Curr Clin Pharmacol 2012;7:263-70.
Allegaert K, Anderson B, Simons S, Van Overmeire B. Paracetamol to induce ductus arteriosus closure: Is it valid? Arch Dis Child 2013;98:462-6.
Ghaderian M, Armanian AM, Sabri MR, Montaseri M. Low-dose intravenous acetaminophen versus oral ibuprofen for the closure of patent ductus arteriosus in premature neonates. J Res Med Sci 2019;24:13.
] [Full text]
Luecke CM, Liviskie CJ, Zeller BN, Vesoulis ZA, McPherson C. Acetaminophen for patent ductus arteriosus in extremely low-birth-weight neonates. J Pediatr Pharmacol Ther 2017; 22:461-6.
Tekgündüz KS, Ceviz N, Caner I, Olgun H, Demirelli Y, Yolcu C, et al
. Intravenous paracetamol with a lower dose is also effective for the treatment of patent ductus arteriosus in pretermin fants. Cardiol Young 2015;25:1060-4.
Sinha R, Negi V, Dalal SS. An interesting observation of PDA closure with oral paracetamol in preterm neonates. J Clin Neonatol 2013;2:30-2.
] [Full text]
Tofe I, Ruiz-González, MD, Cañete MD, Pino A, Rueda RL, Parraga MJ, et al
. Efficacy of paracetamol in closure of ductus arteriosus in infants under 32 weeks of gestation. Frontiers in Pediatrics. Recuperado 2018. 10.3389/fped.2018.00025/full.
Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants. Cochrane Database Syst Rev. 2015 Mar 11;(3):CD010061. doi: 10.1002/14651858.CD010061.pub2.
Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: A randomized controlled trial. PLoS One 2013;8:e77888.
Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Ductal closure with paracetamol: A surprising new approach to patent ductus arteriosus treatment. Pediatrics 2011; 128:e1618-21.
Oncel MY, Yurttutan S, Uras N, Altug N, Ozdemir R, Ekmen S, et al
. An alternative drug (paracetamol) in the management of patent ductus arteriosus in ibuprofen-resistant or contraindicated preterm infants. Arch Dis Child Fetal Neonatal Ed 2013;98:F94.
Roofthooft DW, van Beynum IM, Helbing WA, ReissI K, Simons SH. Paracetamol for ductus arteriosus closure: Not always a success story. Neonatology 2013;104:170.
Jasani B, Kabra N, Nanavati RN. Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates. J Postgrad Med 2013;59:312-4.
] [Full text]
Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, et al
. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: A randomized controlled trial. J Pediatr 2014;164:510-40.
Yang B, Gao X, Ren Y, Wang Y, Zhang Q. Oral paracetamol vs. oral ibuprofen in the treatment of symptomatic patent ductus arteriosus in premature infants: A randomized controlled trial. Exp Ther Med 2016;12:2531-6.
El-Mashad AE, El-Mahdy H, El Amrousy D, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. Eur J Pediatr 2017;176:233-40.
Valerio E, Valente MR, Salvadori S, Frigo AC, Baraldi E, Lago P. Intravenous paracetamol for PDA closure in the preterm: A single-center experience. Eur J Pediatr 2016;175:953-66.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]