Journal of Perinatology (2014), 1–2 © 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
ORIGINAL ARTICLE
Paracetamol treatment of patent ductus arteriosus in preterm infants E Nadir1, E Kassem2, S Foldi1, A Hochberg1 and M Feldman1 OBJECTIVE: To determine the effectiveness of paracetamol in closing patent ductus arteriosus (PDA) in preterm infants of our population. STUDY DESIGN: Infants with symptomatic PDA who failed or could not get ibuprofen treatment, and who were candidates for surgical ligation, were administered oral paracetamol 15 mg kg–1 every 6 h, for up to 7 days and were monitored for clinical, echocardiographic and laboratorial courses. RESULT: Seven infants, between 24–27 weeks’ gestation, were included. In four the DA was closed while treated by paracetamol— in one of them the DA reopened, treated with paracetamol again, and closed. In one infant, the DA almost closed, symptoms disappeared, and the DA subsequently closed spontaneously later. Two needed surgical ligation. There were no hematologic or biochemical abnormalities. CONCLUSION: Although there is the possibility that PDA may have closed spontaneously, it is proposed that paracetamol could contribute to the closure of PDA in preterm infants. Journal of Perinatology advance online publication, 22 May 2014; doi:10.1038/jp.2014.96
INTRODUCTION Patent ductus arteriosus (PDA) is a common problem among premature infants. Current therapeutic interventions for PDA include nonselective cyclooxygenase inhibitors, which interfere with the production of prostaglandins. Indomethacin, the older inhibitor, may reduce cerebral oxygenation, thrombocytopenia, bleeding and lead to deterioration of renal function thrombocytopenia and bleeding; and the newer one, ibuprofen, has fewer adverse effects and appears to be the drug of choice. Surgical ligation is another option, but it is associated with some morbidity, including pneumothorax, chylothorax, scoliosis, infection and unilateral vocal cord paralysis, as well as anesthetic complications. Noteworthy, there is a high likelihood that the PDA will close spontaneously during the neonatal period. Several small series raised the possibility that paracetamol may be an effective medical alternative for closure of the PDA (Table 1).1–6 We now report our experience. METHODS Ours was an observational, non-randomized, non-controlled open-labeled study, started on January 2013. Echocardiography was performed on each preterm infant with either relevant obstetric history or cardiac murmur after the first day of life, or symptoms consistent with PDA, including either the need for assisted ventilation or feeding intolerance. As natural history of PDA is its spontaneous closure, planned closure was indicated only for symptomatic PDA, which was defined as PDA together with a need for assisted ventilation or feeding intolerance in a preterm infant. Preterm infants with symptomatic PDA who failed ibuprofen treatment or could not be treated with ibuprofen because of thrombocytopenia and/or acute renal failure, and to whom surgical closure was considered, were included. Our regimen consisted of oral paracetamol (Acamoli; Teva Pharmaceuticals, Petah-Tikva, Israel) 15 mg kg − 1 every 6 h for up to 7 days. We monitored the treated infants clinically and echocardiographically as well as the results
of their hematologic and biochemical analyses. Treatment was considered successful if the DA was closed during the treatment period. Closure of the DA after the treatment period was considered spontaneously. Other studies described detailed echocardiographic characteristics of the patients.1–6 As we believe that the important finding is not the closure of the DA per se, but rather, the disappearance of the accompanying symptomatology, we did not use these echocardiographic criteria for the decision of planned closure of PDA, but rather we planned closure of PDA for every preterm infant with symptomatic PDA. The study was approved by the Israeli Ministry of Health board for human research. The parents of all the participating infants provided informed consent before study entry (ClinicalTrials.gov identifier NCT1755728).
RESULTS From January 2013 to October 2013, 19 preterm infants (birth weight 656 to 2415 g and delivered at gestation week 24 to 33) underwent echocardiography. Two of them had no PDA, seven with PDA did not need any treatment because they were asymptomatic, three with PDA were successfully treated by ibuprofen and seven were treated by paracetamol with varying success and they comprise the study group whose gestational age, birth weight, therapeutic course and outcome are described in detail in Table 2. All seven patients in our study group met the criteria for large PDA in echocardiography. None of them displayed abnormalities in their hematologic and biochemical analyses, including liver function tests. DISCUSSION Paracetamol has been proposed to be a safe and promising alternative treatment of PDA, although it is not always successful. No randomized-control trial regarding paracetamol for closure of PDA has been published yet, and neither the patient selection
1 Department of Neonatology, Hillel Yaffe Medical Center, Hadera, Israel and 2Unit of Pediatric Cardiology, Hillel Yaffe Medical Center, Hadera, Israel. Correspondence: Dr E Nadir, Department of Neonatology, Hillel Yaffe Medical Center, POB 169, Hadera 38100, Israel. E-mail: [email protected] Received 9 March 2014; revised 13 April 2014; accepted 15 April 2014
Paracetamol for PDA in preterms E Nadir et al
2 Table 1.
Regimens and success rate of previous attempt series of paracetamol therapy for closure of PDA
Dosage 15 mg kg − 1 15 mg kg − 1 15 mg kg − 1 15 mg kg − 1 15 mg kg − 1 15 mg kg − 1 15 mg kg − 1
per per per per per per per
Treatment interval
Route
Number of treatment days
PDA closure success rate
Reference
6h 6h 6h 6h 6h 8h 6h
Oral Oral Intravenous Intravenous Oral Oral Oral
Up to 7 days Up to 6 days 3 days or 6 days Up to 19 days 3 days or 6 days 2 Days Up to 7 days
5/5 5/6 10/10 0/3 5/7 10/10 4/7
Hammerman et al.1 Yurttutan et al.2 Oncel et al.3 Alan et al.4 Özmert et al.5 Sinha et al.6 Current report
dose dose dose dose dose dose dose
Abbreviation: PDA, patent ductus arteriosus.
Table 2. GA
Description of the study infants diagnosed as having PDA and treated by paracetamol 15 mg kg − 1 every 6 h BW
Day of detection of PDA
Ibuprofen therapy (or C/I)
Paracetamol start day
Paracetamol result
Remarks
C/I: PLT↓
14th D
18th D—failed
18th D—surgically closed
B 26 951
4th D; 14th D—symptomatic 4th D
14th D
18th D—failed
21st D—surgically closed
C 26 880
4th D
There was—almost closed 14th D—reopened C/I: ARF C/I: PLT↓ and ARF
4th D
10th D—closed
40th D—closed (follow-up) 68th D—reopened—small Infant asymptomatic → no treatment 87th D—closed spontaneously
D 24 660
19th D—reopened 3rd D
C/I: Still PLT↓ There was—almost closed 22nd D—reopened. C/I: ARF There was—failed (on 5th D) Then C/I: ARF C/I: PLT↓ After one dose → ARF
19th D 22nd D
23rd D—closed 24th D—closed
5th D
10th D—closed
27th D—death d/t pulmonary hemorrhage
2nd D 4th D
5th D—closed 7th D—almost closed
12th D—closed (follow-up) 22nd D—reopened 28th D—still open Infant asymptomatic → no treatment. 35th D—closed spontaneously
A 24 656
E
25 853
3rd D
F 27 759 G 26 866
2nd D 3rd D
27th, 41st, 49th Ds—closed (follow up)
Abbreviations: ARF, acute renal failure; BW, birth weight (g); C/I, contraindication; D, day of life; GA, gestational age (weeks); PDA, patent ductus arteriosus; PLT↓, thrombocytopenia.
method, nor the best regimen, nor the treatment success rate are clear. Even if the DA has closed during the paracetamol treatment period, there is always the possibility of its spontaneous closure, so its success is doubtful. Although our study bears the limitations of being a descriptive, non-controlled, non-randomized and small-sample report, it adds the experience of seven new cases to the 41 that had been reported earlier. It is our impression that at least in a portion of the cases, paracetamol should be considered for treatment of PDA, especially in light of its having so few side effects compared with other medications and invasive procedures. A larger randomizedcontrolled multicenter study is warranted to establish its efficacy and safety for PDA closure in this patient population. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We thank Esther Eshkol for editorial assistance.
Journal of Perinatology (2014), 1 – 2
REFERENCES 1 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(6): e1618–e1621. 2 Yurttutan S, Oncel MY, Arayici S, Uras N, Altug N, Erdeve O et al. A different firstchoice drug in the medical management of patent ductus arteriosus: oral paracetamol. J Matern Fetal Neonatal Med 2013; 26(8): 825–827. 3 Oncel MY, Yurttutan S, Degirmencioglu H, Uras N, Altug N, Erdeve O et al. Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants. Neonatology 2013; 103(3): 166–169. 4 Alan S, Kahvecioglu D, Erdeve O, Atasay B, Arsan S. Is Paracetamol a Useful Treatment for Ibuprofen-Resistant Patent Ductus Arteriosus? Concerning the Article by M.Y. Oncel et al.: Intravenous Paracetamol Treatment in the Management of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants [Neonatology 2013;103:166–169]. Neonatology 2013; 104(3): 168–169. 5 Özmert MA, Özdemir OM, Doğan M, Küçüktaşçi K, Ergin H, Şahin Ö. Paracetamol therapy for patent ductus arteriosus in premature infants: a chance before surgical ligation. Pediatr Cardiol 2013; 35(2): 276–279. 6 Sinha R, Negi V, Dalal SS. An interesting observation of PDA closure with oral paracetamol in preterm neonates. J Clin Neonatol 2013; 2(1): 30–32.
© 2014 Nature America, Inc.
ORIGINAL ARTICLE
Paracetamol treatment of patent ductus arteriosus in preterm infants E Nadir1, E Kassem2, S Foldi1, A Hochberg1 and M Feldman1 OBJECTIVE: To determine the effectiveness of paracetamol in closing patent ductus arteriosus (PDA) in preterm infants of our population. STUDY DESIGN: Infants with symptomatic PDA who failed or could not get ibuprofen treatment, and who were candidates for surgical ligation, were administered oral paracetamol 15 mg kg–1 every 6 h, for up to 7 days and were monitored for clinical, echocardiographic and laboratorial courses. RESULT: Seven infants, between 24–27 weeks’ gestation, were included. In four the DA was closed while treated by paracetamol— in one of them the DA reopened, treated with paracetamol again, and closed. In one infant, the DA almost closed, symptoms disappeared, and the DA subsequently closed spontaneously later. Two needed surgical ligation. There were no hematologic or biochemical abnormalities. CONCLUSION: Although there is the possibility that PDA may have closed spontaneously, it is proposed that paracetamol could contribute to the closure of PDA in preterm infants. Journal of Perinatology advance online publication, 22 May 2014; doi:10.1038/jp.2014.96
INTRODUCTION Patent ductus arteriosus (PDA) is a common problem among premature infants. Current therapeutic interventions for PDA include nonselective cyclooxygenase inhibitors, which interfere with the production of prostaglandins. Indomethacin, the older inhibitor, may reduce cerebral oxygenation, thrombocytopenia, bleeding and lead to deterioration of renal function thrombocytopenia and bleeding; and the newer one, ibuprofen, has fewer adverse effects and appears to be the drug of choice. Surgical ligation is another option, but it is associated with some morbidity, including pneumothorax, chylothorax, scoliosis, infection and unilateral vocal cord paralysis, as well as anesthetic complications. Noteworthy, there is a high likelihood that the PDA will close spontaneously during the neonatal period. Several small series raised the possibility that paracetamol may be an effective medical alternative for closure of the PDA (Table 1).1–6 We now report our experience. METHODS Ours was an observational, non-randomized, non-controlled open-labeled study, started on January 2013. Echocardiography was performed on each preterm infant with either relevant obstetric history or cardiac murmur after the first day of life, or symptoms consistent with PDA, including either the need for assisted ventilation or feeding intolerance. As natural history of PDA is its spontaneous closure, planned closure was indicated only for symptomatic PDA, which was defined as PDA together with a need for assisted ventilation or feeding intolerance in a preterm infant. Preterm infants with symptomatic PDA who failed ibuprofen treatment or could not be treated with ibuprofen because of thrombocytopenia and/or acute renal failure, and to whom surgical closure was considered, were included. Our regimen consisted of oral paracetamol (Acamoli; Teva Pharmaceuticals, Petah-Tikva, Israel) 15 mg kg − 1 every 6 h for up to 7 days. We monitored the treated infants clinically and echocardiographically as well as the results
of their hematologic and biochemical analyses. Treatment was considered successful if the DA was closed during the treatment period. Closure of the DA after the treatment period was considered spontaneously. Other studies described detailed echocardiographic characteristics of the patients.1–6 As we believe that the important finding is not the closure of the DA per se, but rather, the disappearance of the accompanying symptomatology, we did not use these echocardiographic criteria for the decision of planned closure of PDA, but rather we planned closure of PDA for every preterm infant with symptomatic PDA. The study was approved by the Israeli Ministry of Health board for human research. The parents of all the participating infants provided informed consent before study entry (ClinicalTrials.gov identifier NCT1755728).
RESULTS From January 2013 to October 2013, 19 preterm infants (birth weight 656 to 2415 g and delivered at gestation week 24 to 33) underwent echocardiography. Two of them had no PDA, seven with PDA did not need any treatment because they were asymptomatic, three with PDA were successfully treated by ibuprofen and seven were treated by paracetamol with varying success and they comprise the study group whose gestational age, birth weight, therapeutic course and outcome are described in detail in Table 2. All seven patients in our study group met the criteria for large PDA in echocardiography. None of them displayed abnormalities in their hematologic and biochemical analyses, including liver function tests. DISCUSSION Paracetamol has been proposed to be a safe and promising alternative treatment of PDA, although it is not always successful. No randomized-control trial regarding paracetamol for closure of PDA has been published yet, and neither the patient selection
1 Department of Neonatology, Hillel Yaffe Medical Center, Hadera, Israel and 2Unit of Pediatric Cardiology, Hillel Yaffe Medical Center, Hadera, Israel. Correspondence: Dr E Nadir, Department of Neonatology, Hillel Yaffe Medical Center, POB 169, Hadera 38100, Israel. E-mail: [email protected] Received 9 March 2014; revised 13 April 2014; accepted 15 April 2014
Paracetamol for PDA in preterms E Nadir et al
2 Table 1.
Regimens and success rate of previous attempt series of paracetamol therapy for closure of PDA
Dosage 15 mg kg − 1 15 mg kg − 1 15 mg kg − 1 15 mg kg − 1 15 mg kg − 1 15 mg kg − 1 15 mg kg − 1
per per per per per per per
Treatment interval
Route
Number of treatment days
PDA closure success rate
Reference
6h 6h 6h 6h 6h 8h 6h
Oral Oral Intravenous Intravenous Oral Oral Oral
Up to 7 days Up to 6 days 3 days or 6 days Up to 19 days 3 days or 6 days 2 Days Up to 7 days
5/5 5/6 10/10 0/3 5/7 10/10 4/7
Hammerman et al.1 Yurttutan et al.2 Oncel et al.3 Alan et al.4 Özmert et al.5 Sinha et al.6 Current report
dose dose dose dose dose dose dose
Abbreviation: PDA, patent ductus arteriosus.
Table 2. GA
Description of the study infants diagnosed as having PDA and treated by paracetamol 15 mg kg − 1 every 6 h BW
Day of detection of PDA
Ibuprofen therapy (or C/I)
Paracetamol start day
Paracetamol result
Remarks
C/I: PLT↓
14th D
18th D—failed
18th D—surgically closed
B 26 951
4th D; 14th D—symptomatic 4th D
14th D
18th D—failed
21st D—surgically closed
C 26 880
4th D
There was—almost closed 14th D—reopened C/I: ARF C/I: PLT↓ and ARF
4th D
10th D—closed
40th D—closed (follow-up) 68th D—reopened—small Infant asymptomatic → no treatment 87th D—closed spontaneously
D 24 660
19th D—reopened 3rd D
C/I: Still PLT↓ There was—almost closed 22nd D—reopened. C/I: ARF There was—failed (on 5th D) Then C/I: ARF C/I: PLT↓ After one dose → ARF
19th D 22nd D
23rd D—closed 24th D—closed
5th D
10th D—closed
27th D—death d/t pulmonary hemorrhage
2nd D 4th D
5th D—closed 7th D—almost closed
12th D—closed (follow-up) 22nd D—reopened 28th D—still open Infant asymptomatic → no treatment. 35th D—closed spontaneously
A 24 656
E
25 853
3rd D
F 27 759 G 26 866
2nd D 3rd D
27th, 41st, 49th Ds—closed (follow up)
Abbreviations: ARF, acute renal failure; BW, birth weight (g); C/I, contraindication; D, day of life; GA, gestational age (weeks); PDA, patent ductus arteriosus; PLT↓, thrombocytopenia.
method, nor the best regimen, nor the treatment success rate are clear. Even if the DA has closed during the paracetamol treatment period, there is always the possibility of its spontaneous closure, so its success is doubtful. Although our study bears the limitations of being a descriptive, non-controlled, non-randomized and small-sample report, it adds the experience of seven new cases to the 41 that had been reported earlier. It is our impression that at least in a portion of the cases, paracetamol should be considered for treatment of PDA, especially in light of its having so few side effects compared with other medications and invasive procedures. A larger randomizedcontrolled multicenter study is warranted to establish its efficacy and safety for PDA closure in this patient population. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS We thank Esther Eshkol for editorial assistance.
Journal of Perinatology (2014), 1 – 2
REFERENCES 1 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(6): e1618–e1621. 2 Yurttutan S, Oncel MY, Arayici S, Uras N, Altug N, Erdeve O et al. A different firstchoice drug in the medical management of patent ductus arteriosus: oral paracetamol. J Matern Fetal Neonatal Med 2013; 26(8): 825–827. 3 Oncel MY, Yurttutan S, Degirmencioglu H, Uras N, Altug N, Erdeve O et al. Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants. Neonatology 2013; 103(3): 166–169. 4 Alan S, Kahvecioglu D, Erdeve O, Atasay B, Arsan S. Is Paracetamol a Useful Treatment for Ibuprofen-Resistant Patent Ductus Arteriosus? Concerning the Article by M.Y. Oncel et al.: Intravenous Paracetamol Treatment in the Management of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants [Neonatology 2013;103:166–169]. Neonatology 2013; 104(3): 168–169. 5 Özmert MA, Özdemir OM, Doğan M, Küçüktaşçi K, Ergin H, Şahin Ö. Paracetamol therapy for patent ductus arteriosus in premature infants: a chance before surgical ligation. Pediatr Cardiol 2013; 35(2): 276–279. 6 Sinha R, Negi V, Dalal SS. An interesting observation of PDA closure with oral paracetamol in preterm neonates. J Clin Neonatol 2013; 2(1): 30–32.
© 2014 Nature America, Inc.
