|Year : 2022 | Volume
| Issue : 1 | Page : 19-22
Outcome of conservative and pharmacological treatment of hemodynamically significant patent ductus arteriosus in preterm infants less than 34 weeks
Tariq Alsafadi1, Hala Gabel1, Abdullghany Dowaikh1, Mohammed Albaloushi2, Abdulbaqi Suwaydi2, Asmaa Alzahrani2, Ebrahim Nooh2
1 East Jeddah Hospital, Jeddah, Saudi Arabia, Kingdom of Saudi Arabia
2 King Abdulaziz Hospital, Jeddah, Saudi Arabia, Kingdom of Saudi Arabia
|Date of Submission||10-Jan-2021|
|Date of Decision||10-Mar-2021|
|Date of Acceptance||06-Jul-2021|
|Date of Web Publication||03-Jan-2022|
Neonatologist Consultant, East Jeddah Hospital, Jeddah
Kingdom of Saudi Arabia
Source of Support: None, Conflict of Interest: None
Background: Preterm infants frequently have hemodynamically significant patent ductus arteriosus (PDA). Persistent ductal shunting may result in pulmonary hyper circulation, increasing the risk of mortality and morbidity. The effectiveness of active management, as well as the timing and modality of PDA treatment, is still debatable. Aim: The purpose of this study was to determine whether there was a difference in mortality and morbidity between conservative and pharmacological treatment of clinically significant PDA in preterm infants at <34 weeks. Design: Retrospective study. Setting: Comprised of two neonatal intensive care units (NICUs). Materials and Methods: NICUs medical records from 2017 to 2020. Statistical Analysis: Logistic regression analysis. Results: A total of 1059 medical records were screened for the study, with 106 preterm (PT) infants included. The mean gestational age was 29.2 ± 3.2 weeks, the mean birth weight (BW) was 1267 ± 485 g, and the mean length of stay in the hospital was 30 ± 20 days. Twenty patients (18.8%) received paracetamol, six patients (5.6%) received ibuprofen, one patient (0.9%) received surgical ligation, and one patient (0.9%) received indomethacin. Five patients (4.7%) received multiple courses of PDA medication. Nineteen patients (17.9%) received diuretics. [Table 1] also contains additional data characteristics. After adjusting the confounding variables, intraventricular hemorrhage (IVH) (odds ratio [OR]: 5 P: 0.04) and BW were found to increase mortality (OR: 0.87 P: 0.034). Conservative treatment (OR: 1.4, P = 0.38), paracetamol (OR: 0.87, P = 0.22), and ibuprofen (OR 1.2, P = 0.12) had no effect on mortality. None of the treatment modalities (conservative, paracetamol, or ibuprofen) has a significant effect on morbidities (IVH, bronchopulmonary dysplasia, retinopathy of prematurity, late onset sepsis, pulmonary hemorrhage, or necrotizing enterocolitis). Conclusion: In PT 34 weeks, there was no difference in mortality or morbidity between conservative and pharmacological treatment of hemodynamically significant PDA.
Keywords: Management, patent ductus arteriosus, preterm
|How to cite this article:|
Alsafadi T, Gabel H, Dowaikh A, Albaloushi M, Suwaydi A, Alzahrani A, Nooh E. Outcome of conservative and pharmacological treatment of hemodynamically significant patent ductus arteriosus in preterm infants less than 34 weeks. J Clin Neonatol 2022;11:19-22
|How to cite this URL:|
Alsafadi T, Gabel H, Dowaikh A, Albaloushi M, Suwaydi A, Alzahrani A, Nooh E. Outcome of conservative and pharmacological treatment of hemodynamically significant patent ductus arteriosus in preterm infants less than 34 weeks. J Clin Neonatol [serial online] 2022 [cited 2022 Jan 19];11:19-22. Available from: https://www.jcnonweb.com/text.asp?2022/11/1/19/334736
| Introduction|| |
The ductus arteriosus (DA) redirects blood from the pulmonary artery into the aorta during fetal life, bypassing the lungs. Following birth, the DA is actively constricted and eventually obliterated. When the DA does not completely close after delivery, this is referred to as patent DA (PDA). The reported incidence of PDA in very premature neonates varies according to the gestation and age of the newborns at assessment, as well as the characteristics of the population included in the trial but can be as high as 50%. PDA prevalence is inversely proportional to gestational age (GA) in general. Preterm infants who have moderate to large left-to-right shunts have a greater mortality rate than those who do not have a PDA. Furthermore, they are more likely to develop pulmonary edema, pulmonary hemorrhage, bronchopulmonary dysplasia (BPD), and decreased perfusion and oxygen delivery to the end organs, increasing the risk of necrotizing enterocolitis (NEC) and renal failure.,,,, To avoid such complications, surgical ligation and medications such as ibuprofen, indomethacin, and paracetamol have been used to close PDAs. However, conservative management of PDA without the use of pharmacological agents has increased in recent years., There are no randomized controlled trials comparing the mortality and morbidity associated with various treatment strategies. As a result, it is unknown which approach is the most beneficial for premature infants and whether certain clinical parameters or settings favor one approach over another. This uncertainty has resulted in a range of approaches to managing PDA in preterm infants. The purpose of this study is to determine whether there is a difference in mortality and morbidity between conservative and pharmacological treatment of clinically significant PDA in preterm infants below 34 weeks of gestation.
| Materials and Methods|| |
Retrospective study of all medical records for PT 34 < weeks admitted to two Neonatal Intensive Care Units (NICUs) from October 2017 to September 2020. Hemodynamically significant PDA was the criterion for inclusion. Cyanotic heart diseases and significant congenital abnormalities were both excluded. Excel 2013 and SPSS version 18 were used to code and enter data (SPSS Inc., Chicago, Ill., USA). Data were summarized using mean, standard deviation, and range for the quantitative variables and number and percent for the qualitative variables. The Chi-square test was used to compare the groups for the qualitative variables, the independent sample t-test for normally distributed quantitative data, and the Mann–Whitney test for nonnormally distributed qualitative variables. Hemodynamically significant PDA is defined as PDA that is associated with an increase in oxygen demand and was confirmed by an echocardiogram. Conservative care of PDA involves using measures to reduce the shunt volume and or the hemodynamic effects of PDA, such as increasing positive end-expiratory pressure in a ventilated newborn to limit left to right shunting and using diuretics carefully. The dose of paracetamol was 60 mg/kg per day, administered intravenously over a 2–7-day period. Ibuprofen was administered orally as two doses, the first dose of 10 mg/kg, with two further doses of 5 mg/kg given at a 24-h interval. The logistic regression model was used and it included birth weight (BW), GA, gender, mood of delivery, premature rupture of membrane, defined as rupture of membrane >18 h, antenatal corticosteroid, multiple births, and birth asphyxia, defined as Apgar score 5 at 5 min. High-frequency oscillation ventilation, conventional mechanical ventilation, pneumothorax, inotrope use, and surfactant use were all the factors in the logistic regression model that assessed severity of disease. It also included neonatal morbidities associated with PDA including intraventricular hemorrhage (IVH) ≥Grade 2. BPD defined as oxygen demand at 36 weeks, NEC defined as Stage 2 according to the modified Bell criteria, retinopathy of prematurity (ROP) (any stage), and late onset sepsis (LOS) defined as a positive blood, urine, or cerebrospinal fluid culture after the third postnatal day.
| Results|| |
A total of 1059 medical records were screened (on average, 353 PT infants <34 weeks per year were admitted to both NICUs), with 106 PT infants included in the study. Mean GA: 29.2 ± 3.2 weeks, mean BW: 1267 ± 485 g, mean length of stay: 30 ± 20 days. Twenty patients (18.8%) received paracetamol, six patients (5.6%) received ibuprofen, and one case (0.9%) was treated with surgical ligation and one patient (0.9%) received indomethacin. Five patients (4.7%) received multiple courses of PDA medication. Diuretics were administered to 19 patients (17.9%). Other data characteristics are shown in [Table 1]. After reviewing the confounding variables, the factors that increased mortality were IVH (odds ratio [OR]: 5 P: 0.04) and BW (OR: 0.87 P: 0.034). Conservative treatment (OR: 1.4, P = 0.38), paracetamol (OR: 0.87, P = 0.22), and ibuprofen (OR: 1.2, P = 0.12) had no effect on mortality. None of the treatment modalities (conservative, paracetamol, or ibuprofen) has a significant effect on morbidity (IVH, BPD, ROP, LOS, pulmonary hemorrhage, or NEC), as shown in [Table 2].
| Discussion|| |
Our study suggested that there was no difference in mortality or morbidity between conservative and pharmacological treatment of hemodynamically significant PDA in preterm infants <34 weeks. In preterm infants with PDA, conservative management with supportive therapy alone may be preferable to pharmacological treatment with ongoing assessment and intervention as needed., Numerous experts in the field advocate for conservative management of PDA in preterm infants based on evidence of a high rate of spontaneous closure, well-established adverse effects of both pharmacologic and surgical intervention, and evidence that treatment results in comparable rates of mortality and morbidity.,,, In a retrospective study, spontaneous PDA closure occurred in 237 of 280 infants (85%) treated conservatively; the median time to spontaneous PDA closure increased with decreasing GA and BW. Another study demonstrated that while conservative treatment was less effective than pharmacological treatment in closing PDAs, it had comparable outcomes in terms of mortality, NEC, or IVH, as reported in one meta-analysis. In a retrospective Korean study that reviewed the outcomes of two time periods from 2009 to 2011 (for mandatory closure either with medical or surgical treatment) and 2012–2014 (for supportive therapy alone), there were no differences in mortality, NEC, or IVH. In an exploratory trial of extreme preterm infants who had an echocardiographic confirmation of a moderate to large PDA and required respiratory support at the end of 1 week of life, early routine medical therapy (indomethacin, ibuprofen, or acetaminophen) and conservative management had comparable outcomes in terms of ligation or the presence of a PDA at discharge (32 vs. 39 percent). From 2004 to 2008, a Canadian Neonatal Network observational study of 3556 infants with PDA found that 2026 were treated with indomethacin alone (57%), 626 with surgical ligation and indomethacin (18%), 577 with conservative treatment (16%), and 327 with surgical ligation alone (9%) had a higher mortality and morbidity (i.e., BPD, Grade 3) for patients treated with surgical ligation, irrespective of previous indomethacin therapy. There were no differences in mortality or morbidity between the groups treated with indomethacin alone or with conservative measures.
Our study found that paracetamol was more frequently used to close PDA in our NICUs than ibuprofen or indomethacin. As far as we are aware, this alternative appears to be safe in comparison to either ibuprofen or indomethacin, provided that these preliminary findings can be confirmed in well-conducted randomized controlled trials. There is limited evidence that oral and intravenous preparations of acetaminophen, which inhibits prostaglandin synthase, successfully close PDA., However, the dose of acetaminophen administered was 60 mg/kg daily for 2–7 days, which is significantly higher than the recommended doses for pain and fever control in neonates. As a result, concerns about hepatotoxicity and the long-term effect on neurodevelopment remain. However, our study found no evidence of hepatotoxicity in PT infants receiving paracetamol. Ibuprofen was as effective as indomethacin at closing PDA in systematic reviews of randomized clinical trials and was associated with a lower risk of NEC and transient renal insufficiency. The risks of mortality, Grade 3 and Grade 4 IVH, pulmonary hemorrhage, intestinal hemorrhage, sepsis, and ROP were comparable between ibuprofen and indomethacin.,
The limitation of our study was retrospective in nature and did not include indomethacin or surgical ligation because we had only one patient received indomethacin and one patient who had a surgical ligation during the study period. We concluded that while there is no difference in mortality or morbidity between conservative and pharmacological treatment of hemodynamically significant PDA in PT <34 weeks, additional randomized controlled trials are needed to confirm our findings.
| Conclusion|| |
In PT 34 weeks, there was no difference in mortality or morbidity between conservative and pharmacological treatment of hemodynamically significant PDA.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Isayama T, Kusuda S, Reichman B, Lee SK, Lehtonen L, Norman M, et al
. Neonatal intensive care unit-level patent ductus arteriosus treatment rates and outcomes in infants born extremely preterm. J Pediatr 2020;220:34-9.e5.
Sellmer A, Bjerre JV, Schmidt MR, McNamara PJ, Hjortdal VE, Høst B, et al
. Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed 2013;98:F505-10.
Kluckow M, Evans N. Ductal shunting, high pulmonary blood flow, and pulmonary hemorrhage. J Pediatr 2000;137:68-72.
Todd DA, Jana A, John E. Chronic oxygen dependency in infants born at 24-32 weeks' gestation: The role of antenatal and neonatal factors. J Paediatr Child Health 1997;33:402-7.
Martin CG, Snider AR, Katz SM, Peabody JL, Brady JP. Abnormal cerebral blood flow patterns in preterm infants with a large patent ductus arteriosus. J Pediatr 1982;101:587-93.
Cassady G, Crouse DT, Kirklin JW, Strange MJ, Joiner CH, Godoy G, et al
. A randomized, controlled trial of very early prophylactic ligation of the ductus arteriosus in babies who weighed 1000 g or less at birth. N Engl J Med 1989;320:1511-6.
Liebowitz M, Koo J, Wickremasinghe A, Allen IE, Clyman RI. Effects of prophylactic indomethacin on vasopressor-dependent hypotension in extremely preterm infants. J Pediatr 2017;182:21-7.e2.
Letshwiti JB, Semberova J, Pichova K, Dempsey EM, Franklin OM, Miletin J. A conservative treatment of patent ductus arteriosus in very low birth weight infants. Early Hum Dev 2017;104:45-9.
Vanhaesebrouck S, Zonnenberg I, Vandervoort P, Bruneel E, Van Hoestenberghe MR, Theyskens C. Conservative treatment for patent ductus arteriosus in the preterm. Arch Dis Child Fetal Neonatal Ed 2007;92:F244-7.
Walsh MC, Kliegman RM. Necrotizing enterocolitis: Treatment based on staging criteria. Pediatr Clin North Am 1986;33:179-201.
Francis E, Singhi AK, Lakshmivenkateshaiah S, Kumar RK. Transcatheter occlusion of patent ductus arteriosus in pre-term infants. JACC Cardiovasc Interv 2010;3:550-5.
Bose CL, Laughon MM. Patent ductus arteriosus: Lack of evidence for common treatments. Arch Dis Child Fetal Neonatal Ed 2007;92:F498-502.
Hamrick SEG, Sallmon H, Rose AT, Porras D, Shelton EL, Reese J, et al
. Patent ductus arteriosus of the preterm infant. Pediatrics 2020;146:e20201209.
Backes CH, Giesinger RE, Rivera BK, Berman DP, Smith CV, Cua CL, et al
. Percutaneous closure of the patent ductus arteriosus in very low weight infants: Considerations following US food and drug administration approval of a novel device. J Pediatr 2019;213:218-21.
Sung SI, Chang YS, Chun JY, Yoon SA, Yoo HS, Ahn SY, et al
. Mandatory closure versus nonintervention for patent ductus arteriosus in very preterm infants. J Pediatr 2016;177:66-71.e1.
Slaughter JL, Reagan PB, Newman TB, Klebanoff MA. Comparative effectiveness of nonsteroidal anti-inflammatory drug treatment vs. no treatment for patent ductus arteriosus in preterm infants. JAMA Pediatr 2017;171:e164354.
Benitz WE; Committee on Fetus and Newborn; American Academy of Pediatrics. Patent ductus arteriosus in preterm infants. Pediatrics 2016;137. Epub 2015 Dec 15.
Liebowitz M, Clyman RI. Prophylactic indomethacin compared with delayed conservative management of the patent ductus arteriosus in extremely preterm infants: Effects on neonatal outcomes. J Pediatr 2017;187:119-26.e1.
Hills NK, Clyman R. Paracetamol (Acetaminophen) for patent ductus arteriosus: Where do we stand? J Pediatr 2020;222:18-21.
Clyman R, Wickremasinghe A, Jhaveri N, Hassinger DC, Attridge JT, Sanocka U, et al
. Enteral feeding during indomethacin and ibuprofen treatment of a patent ductus arteriosus. J Pediatr 2013;163:406-11.
Terrin G, Conte F, Oncel MY, Scipione A, McNamara PJ, Simons S, et al
. Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: A systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2016;101:F127-36.
Neumann R, Schulzke SM, Bührer C. Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: A systematic review and meta-analysis. Neonatology 2012;102:9-15.
Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev 2015;2:CD003481.
[Table 1], [Table 2]