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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 4  |  Page : 209-215

Worse outcomes of early targeted ibuprofen treatment compared to expectant management of patent ductus arteriosus in extremely premature infants


1 Division of Neonatology, Department of Obstetrics and Gynecology, Charles University, First Faculty of Medicine and General University Hospital in Prague, Czech Republic
2 Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University, First Faculty of Medicine and General University Hospital in Prague, Czech Republic

Date of Submission07-Jun-2021
Date of Acceptance29-Jun-2021
Date of Web Publication24-Sep-2021

Correspondence Address:
Jana Termerova
Department of Obstretics and Gynecology, Division of Neonatology, First Faculty of Medicine, Charles University and General Faculty Hospital in Prague, 18 Apolinarska Street, 128 00 Prague 2
Czech Republic
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.jcn_73_21

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  Abstract 


Aims: The aim of the study is to evaluate two different patent ductus arteriosus (PDA) management approaches and their impact on neonatal mortality and/or bronchopulmonary dysplasia (BPD) and 2-year outcomes. Subjects and Methods: For two consecutive periods, data on early mortality and morbidity were obtained retrospectively, while long-term morbidity data in children born before 28 weeks of gestation were collected prospectively. In the early targeted treatment period (TTP), ibuprofen was early indicated on patients with high clinical risk and PDA diameter of more than two millimeters in the first 3 days. In the expectant treatment period (EXP), the expectant approach was used. Results: A total of 201 eligible infants were screened. Of these, 99 were managed in the TTP and 102 in the EXP. From 99 infants in the TTP, 24 patients were treated early and 17 later. From 102 infants in the EXP, 17 infants with symptomatic PDA were treated. Severe BPD and/or death were more frequent in the TTP as compared to EXP (28 and 16 infants, respectively; P = 0.007; odds ratio = 2.12; confidence interval = 1.06–4.23; c = 0.216). Moreover, infants who underwent the expectant approach did not need further cardiological interventions after discharge. Conclusions: Early targeted treatment of large PDAs was associated with an increased risk of severe BPD and/or death. We must pay attention to the side effects of early ibuprofen treatment because these may outweigh the benefits of ductus closure, especially in the vulnerable population of extremely preterm infants.

Keywords: Bronchopulmonary dysplasia, echocardiography, extremely preterm infant, ibuprofen, patent ductus arteriosus


How to cite this article:
Termerova J, Kuběna AA, Paslerová R, Liška K. Worse outcomes of early targeted ibuprofen treatment compared to expectant management of patent ductus arteriosus in extremely premature infants. J Clin Neonatol 2021;10:209-15

How to cite this URL:
Termerova J, Kuběna AA, Paslerová R, Liška K. Worse outcomes of early targeted ibuprofen treatment compared to expectant management of patent ductus arteriosus in extremely premature infants. J Clin Neonatol [serial online] 2021 [cited 2021 Dec 2];10:209-15. Available from: https://www.jcnonweb.com/text.asp?2021/10/4/209/326616




  Introduction Top


Prolonged high pulmonary blood flow through an immature pulmonary vascular bed may increase the risk of chronic lung damage. However, there is no clear evidence that prophylactic or early closure of patent ductus arteriosus (PDA) reduces the incidence of bronchopulmonary dysplasia (BPD).[1],[2],[3] Reasons for possible bias in past studies may include early backup treatment and a generally high percentage of treatment in control groups, inconsistent definition of hemodynamically significant PDA (hsPDA),[4] high rate of spontaneous closure in the placebo arm, low rate of treatment-induced closure in treated arms, and treatment assignment not independent of baseline prognostic factors.[5] The risk appears to depend not on the presence of a PDA but on the magnitude of the PDA shunt and PDA exposure duration.[6] Moreover, the availability of precision ultrasound for infants <28 weeks of gestation was insufficient in older studies.[7]

Early cardiac ultrasound-targeted treatment is only indicated for patients with large shunts; thus, the number of infants who receive unnecessary treatment is reduced. This approach was used in the ductal echocardiographic targeting and early closure trial, which showed a reduction in pulmonary hemorrhage. However, the targeted indomethacin treatment had no effect on the primary outcome of death or abnormal cranial ultrasound and also had no effect on the incidence of BPD.[8] Furthermore, prophylactic indomethacin was not associated with either reduced or increased risk of BPD or death.[9] To our knowledge, only one double-blind, multicenter, randomized controlled trial of early echocardiography-targeted ibuprofen treatment has been published to date. Despite a proven reduction in the incidence of PDA, there was no reported difference in survival without cerebral palsy and respiratory outcome.[10] Owing to the good results of the conservative treatment,[11],[12] we changed our approach to PDA from early ultrasound-targeted treatment to expectant management.

Objectives

We aim to evaluate two different PDA management approaches: the early ultrasound-targeted and the expectant and their impact on neonatal mortality or BPD and 2-year outcomes. We hypothesized that there would be no difference in the incidence of BPD between these two time periods. To increase sensitivity, we used three levels of BPD to assess the impact on quality of life.


  Subjects and Methods Top


Patients

Our study was a single-center study conducted in a tertiary level neonatal intensive care unit. All viable infants born between 23 0/7 and 27 6/7 weeks of gestational age were included in the study. We retrospectively analyzed early mortality and morbidities in two time-series cohorts of two groups comprising neonates born between July 2011 and June 2015. In addition, follow-up data up to 2 years of corrected age were prospectively collected. Institutional ethical approval and parenteral consents were obtained for publication of data.

Echocardiography examination and patent ductus arteriosus management

All echocardiography studies were performed using the GE Vivid e Ultrasound Machine (GE Healthcare, Chicago, USA) with a 10 MHz transducer. Complete diagnostic echocardiography was performed to exclude patients with congenital heart disease.

In both periods, all infants were screened during the first 3 days of their lives for hsPDA. Our definition of hsPDA was based on the diameter of PDA of at least 2 mm and pulsatile flow pattern measured in the high left parasternal view, the site of maximal constriction with color images.

In the early targeted treatment period (TTP: 7/2011-6/2013, n = 99), infants with a left-to-right flow from hsPDA and high-risk factors (no antenatal steroids, difficult adaptation after delivery, or high ventilation support in the 1st days of life) were treated during the first 3 days of life with ibuprofen lysine (15 min intravenous infusion: 10 mg/kg, followed by 5 mg/kg after 24 and 48 h [Arfen injection, 400 mg/3 ml, Lisapharma, Erba, Italy]). During the expectant treatment period (EXP: 7/2013-6/2015, n = 102), infants with hsPDA were observed and not treated in the first 3 days of life. In both periods, the neonates were monitored for the development of severe clinical signs of hsPDA, which include pulmonary hemorrhage, severe respiratory failure requiring mechanical ventilation, cardiac decompensation, and renal insufficiency. Patients with these clinical signs and echocardiography-confirmed hsPDA were treated later, using an ibuprofen dosing scheme reflected on the postnatal age.[13]

Surgical ligation was performed in both periods only after the failure of pharmacological treatment in infants with high mechanical ventilation parameters (mean airway pressure >15 cm H2O, requiring high-frequency oscillatory ventilation) that could not be disconnected. We are not aware of any fundamental changes in our therapeutic approach to intensive care management of extremely premature infants between these two periods, including the use of postnatal steroids.

Study endpoints

The primary outcome of this study was the composite outcome of BPD and/or death before 36-week postmenstrual age (PMA). Since we used a high-flow nasal cannula (HFNC), we slightly modified the consensus definition (2002).[14],[15] Mild BPD was defined as the need for supplemental oxygen (O2) or the need for pressure support (including HFNC) for at least 28 days old. Moderate BPD was the treatment need of <30% O2 or HFNC with low oxygen therapy at 36-week PMA, which we changed to low-flow nasal cannula (LFNC) in children with HFNC and determined the need for O2 <30%. Furthermore, severe BPD requires O2 ≥30% and/or positive pressure support at 36-week PMA (every infant with nCPAP at 36-week PMA; HFNC was changed to LFNC and determined the need of O2 ≥30%). Our targeted SpO2 was 93%–96% at 36-week PMA.

Secondary outcomes included duration of invasive and noninvasive ventilation support and pulmonary hemorrhage (those with respiratory deterioration and massive bleeding). Additional outcomes are as follows: composite outcomes of death before 36-week PMA and prevalence of necrotizing enterocolitis, Bell Stages 2 and 3,[16] spontaneous intestinal perforation, intraventricular hemorrhage Grades 3 and 4, modified Papile nomenclature,[17] and retinopathy of prematurity requiring treatment. Moreover, we recorded the age at PDA closure and the number of necessary ligations.

In the follow-up examination at 2 years of age, major neurodevelopmental disability was determined provided at least one of the following conditions was present: cerebral palsy affecting independent locomotion (walking with support or inability to walk), cognitive delay (a Bayley II Mental Development Index score of <70, more than 2 standard deviation below the mean of 100),[18] visual impairment (light perception only or blindness), and hearing impairment (uncorrectable deafness or use of hearing aids). We also observed the duration of steroid inhalation therapy and cardiological follow-up, where there is a need for ligation, treatment by catheterization following discharge, or severe pulmonary hypertension requiring treatment.

Statistical analysis

Data were analyzed using Wolfram, Mathematica, version 11.3 (Wolfram Research of Champaign, Illinois). Statistical differences between the study periods were calculated using Chi-square tests (including Yates correction) for categorical variables and Mann–Whitney U-test for quantitative variables. The cumulative incidence of ductal patency rates and length of respiratory support were analyzed using Kaplan–Meier estimation. The differences between the two periods were analyzed using Cox proportional hazards regression. Statistical significance was set at P < 0.05. In addition, the corresponding effect size was calculated. According to Cohen's convention, the effect size was very small at d < 0.2, small at 0.2 ≤ d < 0.5, medium at 0.5 ≤ d < 0.8, and large at d ≥ 0.8.


  Results Top


We analyzed the medical records of 201 infants: 99 from the TTP and 102 from the EXP. [Table 1] shows no significant differences in baseline characteristics between the periods studied. Of the 99 infants from the TTP, 44 patients had hsPDA and 24 of those were treated early (during the first 3 days). Later, treatment in the TTP was administered to 17 infants based on their severe clinical symptoms (to 11 infants with hsPDA, but without clinical risk at the beginning of their life, and to six infants without hsPDA in the first 3 days). Seven other infants, who received early treatment, got a second-course treatment.
Table 1: Basic characteristics between the two consecutive periods

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Of the 102 infants from the EXP, 39 infants had hsPDA during the first 3 days. Upon observation of clinical signs of hsPDA, 17 infants were treated. [Figure 1] and [Figure 2] are graphical representations of the differences in treatment between the two groups.
Figure 1: Diagram showing the two-staged periods

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Figure 2: Comparison of the timing of treatment in the two periods

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There was a similar percentage of hsPDA incidence in the first 3 days of life in both periods (TTP 44, EXP 39). PDA closure in the 1st week of life was more frequent in the TTP than in the EXP (TTP 18, EXP 9), in which more children underwent closure of PDA after the 2nd month of life (TTP 10, EXP 15) with the Cox model: P =0.036. The number of children who underwent ligation was low in both periods (TTP 3, EXP 4). PDA at the time of discharge was more frequent in the EXP group compared to TTP group (TTP 13, EXP 22) [Figure 3].
Figure 3: Kaplan–Meier curves for the persistence of ductus arteriosus for the two periods: targeted treatment period (red line) and expectant treatment period (blue line); the table summarizes the closing of hemodynamically significant patent ductus arteriosus in the two periods

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Adverse outcomes

The total of 21 and 13 patients died in the TTP and EXP, respectively (P = 0.133; c = 0.112, small effect size). However, severe BPD and/or death were more frequent in the TTP than in the EXP (7 and 21 vs. 3 and 13, respectively) [P = 0.007; c = 0.216 medium effect size, [Table 2]. There were no significant differences in other early morbidities observed between the periods [Table 3]. Pulmonary hemorrhage occurred more frequently in the EXP than in the TTP (TTP 15, EXP 22); however, the difference was not statistically significant (P = 0.277, c = 0.082). We observed a mild tendency toward prolonged noninvasive respiratory support in the EXP. The mean duration of noninvasive respiratory support in the TTP was 61 days (until the 34 + 4/7 postnatal week), while that in the EXP was 68 days (until the 35 + 5/7 postnatal week). The time of noninvasive respiratory support, according to the Cox model, depends on a continuous variable which is the gestational week (P < 0.001), and on two binary variables, which are the two consecutive periods (P = 0.007). Every week of immaturity represented 1.72 times higher risk for long-term noninvasive respiratory support. Early treatment reduces the risk for noninvasive respiratory support 0.64 times (relative risk = 0.64, 95% confidence interval: 0.47–0.89).
Table 2: Degrees of bronchopulmonary dysplasia in the two periods

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Table 3: Short-term morbidities in both periods, where the bold font represents a statistically significant difference

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Long-term outcomes

Of the 201 children observed, 2-year follow-up results were available for 145 children (87%); however, 9 children from the TTP and 13 children from the EXP were lost. From the TTP, two children underwent PDA catheter closure, and three children were treated by ligation within 2 years following discharge from our clinic; two more children were observed for PDAs at 2 years of corrected age. From the EXP, only one child underwent ligation for PDA after discharge. An infant with severe pulmonary hypoplasia from the EXP died after discharge due to severe pulmonary hypertension secondary to severe pulmonary hypoplasia; another child from the EXP was surveyed for pulmonary hypertension. A partial anomalous pulmonary venous connection was detected in one child after release. We did not observe any differences between the two periods in terms of fundamental endpoints. Cerebral palsy (TTP 4, EXP 4), severe hearing disorders (TTP 0, EXP 2 [twins with a family history of the hearing disorder]), severe visual impairment (TTP 1, EXP 1), and severe psychological or mental developmental delay (TTP 7, EXP 8) were reported. The duration of therapy with inhaled corticosteroids did not differ between the two periods after discharge.


  Discussion Top


This study showed an association between early targeted ibuprofen treatment and the composite outcome of severe BPD and/or death. We observed more infants with severe forms of BPD and/or death in the TTP than in the EXP; on the contrary, lower mortality and more frequent but mild to moderate forms of BPD were reported in the EXP. This suggests that early ibuprofen exposure may have a negative impact on the composite outcome of BPD and/or death in extremely preterm children.

We hypothesize that early ibuprofen therapy can negatively affect immature renal function and cause pulmonary edema, resulting in more aggressive ventilation modes injuring preterm lungs. Although ibuprofen is less likely to induce oliguria than indomethacin,[2] the early treatment of the most vulnerable preterm infants can have serious side effects. In agreement with our assumption, the trial of indomethacin prophylaxis in preterm revealed decreased urine output and an increased need for supplemental oxygen at the beginning of life.[19] Similarly, Chen et al. reported a two-fold risk of BPD in infants exposed to oral ibuprofen during the 1st day of life.[20] Possible mechanisms by which ibuprofen could adversely affect immature lungs include the reduction in pulmonary prostacyclin levels,[21] the development of pulmonary hypertension,[22] and the negative effect on angiogenesis.[20]

In contrast to the present study, a retrospective cohort study by Jensen et al. in preterm infants found no association between prophylactic indomethacin and risks for BPD/death before 36-week PMA. In addition, a meta-analysis reported a slight reduction in the risk-adjusted odds of mortality associated with indomethacin prophylaxis.[23] Moreover, Chock et al. reported no association between treatment and BPD/death in a retrospective study, where 75% of infants were treated with indomethacin.[24]

The benefits of our study include the use of the entire three-level Jobe and Bancalari classification.[15] The mere definition of BPD as oxygen therapy after 36 weeks of PMA used in the previously mentioned studies may not sensitively predict the impact on quality of life. A large proportion of such infants has only mild or minimal problems with long-term respiratory health, while the diagnosis of severe BPD is more consistently associated with worse long-term respiratory outcomes.[25] The updated definition based on a workshop hosted by the National Institute of Child Health and Human Development (published 2018) takes into account the use of the HFNC and its association with long-term effects.[26]

This study does not question the possible negative impact of PDA on developing lungs but whether early ibuprofen treatment will favorably affect outcomes. The higher rate of moderate BPD and longer duration of noninvasive ventilation can be explained by the survival of more children in EXP and the known negative impact of long-term PDA. Infants who were exposed to moderate-to-large PDAs for 7-13 days had a double risk of BPD/death. The exposure time and the large PDAs (significance of the shunt) are important risk factors for developing BPD/death.[6]

Although there was no statistically significant difference, a higher incidence of pulmonary hemorrhage was observed in the EXP. This finding is consistent with previous studies[8],[10] and was not associated with a higher incidence of intraventricular hemorrhage. There were no reductions in the tendency for late symptomatic treatment despite more early PDA closures in the TTP. It is possible that we were not able to select infants that would benefit from early treatment. In addition, the PDA diameter and clinical risks as indicators of hemodynamic significance may not be sufficient. A study by El-Khuffash et al. offered more precise predictive factors, including diastolic functions of the left heart,[27] but this predictive approach has not yet been verified.

The main limitations of our study, besides its retrospective nature, were the limited sample size and arbitrary criteria for early PDA treatment defined only by the PDA diameter and clinical risks. This precluded us from adjusting for potential confounding variables. In the two consecutive periods, the better outcome of the early period may be influenced by the overall improvement in neonatal care over the years and not by the change in approach to PDA treatment. The results of ongoing multicenter randomized prospective trials, such as the Baby-OSCAR[28] and BeNeDuctus Trial,[29] will provide more reliable evidence of the link between early PDA treatment and BPD.


  Conclusions Top


This study demonstrated that early targeted treatment of hsPDA was associated with an increased risk of severe BPD and/or death. PDAs may indeed contribute to BPD development, but the harmful side effects of ibuprofen may outweigh its benefits in extremely premature children. Fluid adjustment should take into account the possible side effects of early pharmacological treatment in this population. Using a drug with fewer side effects, such as acetaminophen, may be a suitable alternative for extremely premature infants. Further goals include finding a better group of predictive factors that identify a subgroup of premature newborns that will benefit from PDA pharmacological treatment. In future trials, we must assess the risk-benefit analysis of treatments and well-categorized respiratory outcomes.

Acknowledgment

We acknowledge the support of Monika Costa and Dr. James I. Hagadorn, Hartford, Connecticut, for the proofreader and wider professional support. Thanks to Dr. Blanka Zlatohlavkova and Prof. Richard Plavka, Charles University, Prague, for their valuable comments and criticism of this work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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