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Therapeutic strategy of patent ductus arteriosus in extremely preterm infants
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Pediatrics and Neonatology xxx (xxxx) xxx
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Review Article
Therapeutic strategy of patent ductus arteriosus in extremely preterm infants Bai-Horng Su a,b,*, Hsiang-Yu Lin a,b, Hsiao-Yu Chiu a, Ming-Luen Tsai a, Yin-Ting Chen a, I-Chun Lu a a b
Department of Neonatology, China Medical University Children’s Hospital, Taichung, Taiwan Department of Pediatrics, School of Medicine, China Medical University, Taichung, Taiwan
Received Apr 25, 2019; received in revised form Sep 15, 2019; accepted Oct 21, 2019
Available online - - -
Key Words early targeted treatment; extremely preterm infant; hemodynamically significant PDA (hs-PDA); intraventricular hemorrhage (IVH); patent ductus arteriosus (PDA)
The ductus arteriosus is likely to close without treatment in most infants born at gestational age (GA) > 28 weeks (73%), and those with birth weight > 1000 g (94%). However, the rates of spontaneous ductal closure among less mature or smaller infants with respiratory distress syndrome are not known. Extremely preterm infants born at GA < 28 weeks are associated with a high risk of severe intraventricular hemorrhage (IVH) or pulmonary hemorrhage, which usually occur within 72 h after birth and affect mortality and long-term neurological development. These serious hemorrhagic complications may be closely related to hemodynamic changes caused by a hemodynamically significant patent ductus arteriosus (hs-PDA). While prophylactic indomethacin has been shown to reduce the rates of PDA, PDA ligation, severe IVH and early pulmonary hemorrhage, the available evidence does not support its prophylactic use in preterm infants. Symptomatic or late treatment is associated with lower success rate, and increased complications of a hs-PDA. The issue of “to treat or not to treat a PDA” is controversial. Considering the relationship between the effectiveness and timing of pharmacological treatment, early targeted treatment may be an alternative approach for the early identification of a hs-PDA in specific high-risk patient population, especially infants <26 weeks GA who are at the highest risk of severe IVH or pulmonary hemorrhage. Serial echocardiographic studies can be used to select patients who are candidates for early targeted medical treatment of hs-PDA. Surgical ligation of PDA, and transcatheter closure if proven to be safe, can be used as back-up therapy for patients who fail medical treatment and continue to have cardiopulmonary compromise. Copyright ª 2019, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
* Corresponding author. Department of Neonatology, Children’s Hospital of China Medical University, 2, Yuh-Der Road, Taichung, 404, Taiwan. E-mail address: [email protected] (B.-H. Su). https://doi.org/10.1016/j.pedneo.2019.10.002 1875-9572/Copyright ª 2019, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002
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B.-H. Su et al
1. Introduction
3. Hemodynamically significant PDA
The ductus arteriosus remains patent at day 4 after birth in about 10% of preterm infants born at 30e37 weeks gestational age (GA), 80% of those born at 25e28 weeks, and 90% of those born at 24 weeks.1 At day 7 after birth, these rates decline to approximately 2%, 65%, and 87%, respectively (Table 1). Therefore, extremely preterm infants born at GA < 28 weeks are at the highest risk of developing a hemodynamically significant patent ductus arteriosus (hs-PDA) and the related complications. The ductus has been reported to close without treatment in 73% of infants born at GA > 28 weeks,2 and in 94% of those with a birth weight >1000 g.3 However, the rates of spontaneous ductal closure among extremely preterm infants with respiratory distress syndrome are not known. Extremely preterm infants born at GA < 28 weeks are associated with a high risk of intraventricular hemorrhage (IVH) and/or massive pulmonary hemorrhage, which usually occur within 72 h after birth and affects mortality and long-term neurological development. These serious hemorrhagic complications may be closely related to hemodynamic changes caused by a hsPDA.4 In this review, we discuss the optimal therapeutic strategy of PDA in extremely preterm infants.
2. To treat or not to treat a PDA in preterm infants There is still controversy about “to treat or not to treat a PDA” in preterm infants. The concern should be that whether the PDA is pathological or not pathological. If treatment to close a PDA makes no difference to the outcome, then the PDA may not be pathological. However, premature infants with persistent PDA may have more adverse outcomes including prolongation of assisted ventilation and higher rates of death, bronchopulmonary dysplasia (BPD), pulmonary hemorrhage, necrotizing enterocolitis (NEC), impaired renal function, IVH, periventricular leukomalacia, and cerebral palsy.5,6 The most relevant and clinically important question is how to change a hs-PDA into a PDA without compromising the infant’s circulation (either a decrease in size or fully closed) and the related complications.
Table 1
The rates of PDA in preterm infants after birth.
Gestational age, or Birth weight
Day 4 after birth (%)
Day 7 after birth (%)
At discharge (%)
30e37 weeks 27e28 weeks 25e26 weeks 24 weeks 1000e1500 g <1000 g
10 78 80 90 65 79
2 64 68 87 33 66
2 NA NA NA 6 NA
PDA, patent ductus arteriosus; NA, no available data.
3.1. Clinical manifestations The term “hs-PDA” is frequently used to differentiate consequential from inconsequential PDA. Physical findings in infants with hs-PDA may include heart murmur, persistent tachycardia (HR > 160/min), hyperactive precordial pulsation, prominent or bounding pulses, and either low systolic blood pressure or low diastolic blood pressure with a widened pulse pressure. However, these findings are nonspecific, and lack accuracy to diagnose a hs-PDA in early postnatal life.7,8 In many instances, the presence of a hsPDA is suspected on the basis of respiratory findings, such as cardiomegaly or pulmonary congestion on a chest X-ray, difficulty in weaning from a ventilator, or the need to increase ventilator settings or oxygen. Therefore, echocardiography has become essential in the evaluation of clinically significant ductal shunting.8,9
3.2. Echocardiographic parameters Various echocardiographic parameters have been suggested for guiding the treatment of PDA. Increased left atrium to aorta ratio (LA/Ao) 1.5 is a useful and simple tool. However, its use on day 1 of age is not recommended due to false negative results with large inter-atrial shunts.10 Color Doppler echocardiography can confirm ductal patency and be used to measure the ductal diameter. Carmo et al. used a ductal diameter >2.0 mm as an indicator for PDA treatment in the first 12 h of life, and concluded that this may avoid unnecessarily treating an infant who will have spontaneous closure.11 Su et al. identified four patterns of ductal flow based on the pulsed Doppler waveform, of which a growing or pulsatile pattern indicated a continuing risk of developing a hs-PDA.6,8,12 There is a strong correlation between ductal diameter and flow patterns. In infants with a pulmonary hypertension pattern, 82.4% had a ductal diameter >2.0 mm, and 98.1% of those with a closing pattern had a diameter <2.0 mm.11 The PDA in about 50% of those with a pulmonary hypertension pattern remained non-significant and changed to closing or closed patterns. According to the previous reports, when using a ductal diameter >2.0 mm as the indicator for treatment, 41.2% of the infants with a PDA with a pulmonary hypertension pattern may have been treated unnecessarily despite remaining non-significant and may finally have closed spontaneously.8,12,13 Therefore, simultaneously measuring ductal diameter and classifying the ductal flow pattern may further enhance the clinical predictive capacity of echocardiography. Although echocardiography has become essential in the evaluation and management of PDA, it is very important to perform serial echocardiographic assessments rather than depending only on a spot time measurement because of the dynamic transitional changes in PDA during early life in extremely preterm infants. Findings of reversed diastolic flow in the descending aorta or in cerebral or renal arteries also indicate hemodynamic compromise of the circulation caused by ductal shunting.14
Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002
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Treatment of PDA in extremely preterm infants
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3.3. Biomedical parameters
4. Therapeutic strategies for a PDA (Table 2)
Biomarkers such as serum concentrations of B-type natriuretic peptide (BNP), aminoterminal B-type natriuretic peptide (NT-proBNP),15,16 and cardiac troponin T (cTnT)17 may be used to identify a hs-PDA and determine the indication, timing, and treatment options. These biomarkers have been correlated with echocardiographic measures of shunt volume, and to decrease after ductal closure. In addition, they have been shown to be of particular benefit when combined with clinical evaluation if point of care echocardiography is not available.6,18
.
3.4. Near-infrared spectroscopy (NIRS) In preterm infants born at < 29 weeks, near-infrared spectroscopy (NIRS) monitoring of cerebral and renal saturation is a noninvasive method that can be used to suggest the presence of a hs-PDA as confirmed by echocardiography.19
Table 2
4.1. Prophylactic treatment A multicenter trial (Ment-trial) confirmed the beneficial effects of prophylactic indomethacin on the rates of PDA, PDA ligation, and severe IVH.20 Another multicenter trial (TIPP-trial) was performed to evaluate the long-term effects of prophylactic indomethacin on motor, sensory, and cognitive outcomes.21 The TIPP-trial confirmed the beneficial effects of prophylactic indomethacin on the rates of PDA, PDA ligation, severe IVH, and pulmonary hemorrhage. Previous studies have shown that prophylactic indomethacin can decrease the risk of severe IVH, and that severe IVH is strongly associated with neurodevelopmental abnormalities.22,23 Therefore, it seems reasonable to expect that the TIPP-trial would have found a difference in neurodevelopmental outcomes, however the results did not
Therapeutic strategies for a PDA in extremely preterm infants.
Therapeutic strategy
Comments
Prophylactic treatment
1. Prophylactic indomethacin may reduce the rates of PDA, PDA ligation, severe IVH, and pulmonary hemorrhage.20,21 2. No evidence of benefits on long-term neurodevelopmental outcome.21 (This may have been due to an anticipated effect size that was excessively large for the population studied).24 3. Routine prophylactic treatment will expose infants with a PDA that will never be hemodynamically significant to the potentially harmful side effects of treatment.1,18 4. Decreased use of prophylactic indomethacin has been associated with an increased incidence of surgical PDA ligation.24,32 5. Prophylactic indomethacin may reduce mortality rates in infants without intrauterine growth restriction and infants who do not require subsequent PDA treatment.30,31 6. Early prophylactic indomethacin may reduce BPD and BPD or death compared with delayed indomethacin treatment until at least 8 postnatal days.32 7. Early indomethacin exposure has not been found to have a negative effect on cognitive outcome in studies with 8 years of follow-up.27 8. Prophylactic ibuprofen did not show any superiority over prophylactic indomethacin.33 1. Early targeted treatment based on echocardiographic parameters may allow for the selection of high-risk extremely preterm infants prior to the duct becoming clinically significant.8,34 2. Treatment within 24 h of age may reduce severe IVH and pulmonary hemorrhage.4,34 3. Using echocardiographic PDA flow patterns (pulmonary hypertension, growing, pulsatile and closing pattern) can allow for the early prediction of hemodynamically significant PDA, and require a lower drugs dose to achieve an acceptable closure rates.6,8,12 4. Using a ductal diameter >2.0 mm as an indicator for PDA treatment in the first 12 h of life, may avoid the likelihood of unnecessarily treating an infant with subsequent closure.11 5. Simultaneously measuring ductal diameter and classifying the ductal flow pattern may further enhance the clinical predictive capacity of echocardiography.11e13 1. Using active treatment for symptomatic PDA allows for possible spontaneous closure and minimizing the risk of exposure to the hazards of treatment. 2. Late treatment has a lower closure rate.37 3. Late treatment increases complications of a hemodynamically significant PDA including pulmonary hemorrhage, severe IVH, chronic lung disease, potential disturbances of cerebral blood flow and cardiac failure.38,39
Early targeted treatment
Symptomatic treatment
BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PDA, patent ductus arteriosus.
Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002
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4 show a decrease in the rates of death or neurodevelopmental abnormalities. The negative conclusions of the TIPP-trial may have been due to an anticipated effect size that was excessively large for the population studied.24 These two multicenter randomized controlled trials have been associated with changes in the use of indomethacin prophylaxis. Following the Ment-trial, its use increased, and following the TIPP-trial its use decreased.24 The use of prophylactic indomethacin in the NICHD Registry was associated with a significant reduction in the rate of PDA in each of the gestational age groups (25 weeks, 26e27 weeks, and 28 weeks gestation), and a significant reduction in the rate of PDA ligations among infants born < 26 weeks GA.24 Similarly, the rate of PDA ligations, among infants born < 26 weeks GA fell significantly following the publication of Ment-trial, and rose again following publication of the TIPP-trial in parallel with changes in the use of indomethacin prophylaxis.24 Surgical ligation of a PDA is associated with many morbidities including thoracotomy, pneumothorax, chylothorax, infection, vocal cord paralysis, and profound hypotension.25 The cerebral vasoconstrictive effects of indomethacin are a frequent concern for neonatologists.26, However, neonatal indomethacin exposure was not shown to have a negative effect on cognitive outcomes in a follow-up study of children at 8 years of age.27 Both neuroimaging28 and long-term neurodevelopmental outcome data27,29 have been reassuring with regards to the lack of adverse effects and possible benefits of prophylactic indomethacin on neurodevelopmental outcome. Prophylactic indomethacin may be a reasonable choice in intensive care units where IVH and PDA are frequent problems. Jensen et al. analyzed 5 years of prospectively collected data from 35 hospitals in the Neonatal Research Network’s (NRN) registry. They found that among infants born at < 29 weeks or <1000 g birth weight, those treated with prophylactic indomethacin subsequently required less PDA treatment than nontreated infants (21% vs. 36%). In addition, subgroup analysis showed reduced mortality rates after prophylactic indomethacin in infants without intrauterine growth restriction and infants who did not require subsequent PDA treatment.30 These infants represent a large proportion of the patients treated in daily practice.31 In post-hoc analysis of the different rates of the use of prophylactic indomethacin, the authors showed a > 3-fold reduction in BPD in high-rate hospitals (>60% of eligible infants treated) compared with hospitals that never used prophylaxis. There was also a 2.8-fold lower rate of the composite outcome of death or BPD in hospitals with a high rate of prophylactic indomethacin compared to those that did not use prophylaxis.31 Liebowitz and Clyman performed a prospective controlled study of infants born at < 28 weeks GA. In their study, the early prophylactic indomethacin group had decreased rates of BPD and BPD or death compared with the conservative group in whom indomethacin treatment was delayed until at least 8 postnatal days. These effects were mediated by closure of the PDA.32 Prophylactic ibuprofen therapy at a dose of 10 mg/kg in the first 24 h of life followed by 5 mg/kg after 24 h and 48 h did not show any superiority over prophylactic indomethacin therapy. In addition, it was found to decrease the rate
B.-H. Su et al of PDA on day three, decreased the need for rescue treatment with indomethacin, and decreased the need for surgical ligation. However, its use negatively affected the renal function of preterm infants with no significant differences in mortality, IVH, or BPD.33
4.2. Early targeted treatment Early targeted treatment can be used to treat infants based on echocardiographic parameters prior to the duct becoming clinically significant in hopes that early closure will prevent detrimental impacts on other tissues.34 In centers with unrestrained access to echocardiography, this strategy may be an alternative approach to focus on highrisk patient populations with specific hemodynamic characteristics and to give treatment within 24 h of age to reduce pulmonary hemorrhage, severe IVH and subsequent symptomatic treatment without causing harm. Compared to prophylactic treatment, early targeted treatment may minimize the potential harmful side effects of treatment when administered to patients with a PDA that is not and never will be hemodynamically significant or patients in whom the ductus has a beneficial role in supporting either pulmonary or systemic blood flow (e.g. severe myocardial dysfunction and pulmonary hypertension).8,12,34,36 Su et al. used echocardiographic PDA flow patterns as a guide for early targeted treatment in extremely infants, and found that this approach could reduce the total doses of indomethacin while achieving an acceptable closure rate, and therefore a reduced rate of complications.12,35
4.3. Symptomatic treatment Whether and when to treat a PDA remains controversial.5,18 An expectant approach of treating the PDA at a later time and only when clinical signs indicate a hemodynamic significance, allows for possible spontaneous closure. This approach has the advantage of minimizing the risk of exposing preterm infants to the hazards of treatment but the disadvantage of late intervention such as lower success rate,37 and an increased risk of complications associated with a hs-PDA, including pulmonary hemorrhage, severe IVH, chronic lung disease, potential disturbances of cerebral blood flow and cardiac failure.38,39 Many of these complications occur early, in the first 24 h.4,39 A recent multicenter trial (PDA-TOLERATE Trial) conducted by Clyman et al. compared early routine pharmacologic treatment (ERT) of moderate-to-large PDA at the end of week 1 with a conservative approach that required prespecified respiratory and hemodynamic criteria before treatment could be given.40 They concluded that ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes (NEC, BPD, BPD or death, death, and duration of respiratory support), but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at 26 weeks of gestation. Nevertheless, the authors concluded that ERT (between 6 and 14 days of age; mean 8.1 2.1 days) did not reduce the primary outcome of PDA ligation or remaining open at discharge. In addition, their results showed that the ERT
Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002
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Treatment of PDA in extremely preterm infants group had a significantly lower rate of moderate-to-large PDA at 10 days after randomization (risk ratio [95% confidence interval]: 0.51 [0.40e0.66], P < 0.001) and a significantly lower rate of receiving rescue treatments (0.38 [0.24e0.60], P < 0.001) compared with the conservative treatment group. A possible explanation for these results is that pharmacologic treatment for PDA closure is known to be less effective in infants >10e14 days of age.37 A previous study by Liebowitz and Clyman,32 two principal authors of the PDA-TOLERATE Trial, found that the rates of moderate-to-large PDA on day 7 and duration of exposure to moderate-to-large PDA were significantly lower in the prophylactic indomethacin (PINDO) group than in the delayed conservative management group (no infant was treated with indomethacin until at least 8 postnatal days). They concluded that PINDO decreased BPD and BPD or death compared with delayed conservative management, and that these effects were mediated by PDA closure. The ERT in the TOLERATE Trial40 appeared to be comparable to the delayed conservative management in the PINDO study.32 The key factor in the discrepancy between the results of ERT and PINDO may have been the timing of pharmacological treatment, as the timing of ERT treatment was not as early as with prophylactic treatment (8.1 2.1 days vs. within 24 h after birth).20,21,32,40 While prophylactic indomethacin did reduce the rates of PDA, PDA ligation, severe IVH and early pulmonary hemorrhage, the available evidence does not support universal prophylactic treatment in preterm infants.31 Delayed symptomatic treatment carries the advantage of minimizing the risk of exposing preterm infants to the hazards of treatment but the disadvantages of late treatment such as lower success rate,37 and increased complications of a hs-PDA. The optimal timing of pharmacological treatment in early targeted treatment is within 24 h after birth, which is as early as with prophylactic treatment.34e36 The nature of target selected treatment may avoid unnecessary treatment as with early universal prophylactic treatment when administered to infants with a PDA that is not and never will be hemodynamically significant.8,12,34,36 Until there is new evidence to clarify the controversial issue of “to treat or not to treat a PDA”, and considering the relationship between the effectiveness and timing of pharmacological treatment,37 early targeted treatment may be an alternative approach for the early identification of a hs-PDA in certain high-risk patient populations, especially infants <26 weeks GA who are at the highest risk of severe IVH or pulmonary hemorrhage.
5. Therapeutic modalities (Table 3) .
5.1. Conservative management Fluid restriction has been widely recommended in the management of a PDA.41 A meta-analysis showed that fluid restriction significantly increased postnatal weight loss and significantly reduced the risks of PDA and NEC. In addition, there were trends toward an increased risk of dehydration and reduced risks of BPD, IVH, and death with fluid
5 restriction, however these trends were not statistically significant.42 There is currently not enough evidence to support the routine use of diuretics to prevent or treat congestive heart failure in infants with a hs-PDA. A systematic review of the combined use of furosemide with indomethacin showed a trend toward failure of ductal closure in furosemidetreated patients, and the authors concluded that this was because furosemide increases prostaglandin production and can potentially decrease the ductal response to indomethacin.43 Oxygen therapy has been shown to facilitate duct closure in preterm infants. In a retrospective study, infants treated with lower oxygen saturation target policy (83e89% versus 89e94%) had a higher risk of a hs-PDA.44
5.2. Pharmacological treatment 5.2.1. Indomethacin Indomethacin and ibuprofen are the most studied nonselective COX inhibitor for the prophylaxis and treatment of a PDA. The closure rate of PDA with indomethacin is dependent on the birth weight of the preterm infant. Gersony et al. reported a post-indomethacin closure rate of 80%e 86% in infants weighing 1000e1750 g and 54% in infants weighing <1000 g.45 The cumulative closure rate reached 90% with three courses, however the risk of periventricular leukomalacia increased.46 Prophylactic indomethacin for IVH beginning within 12 h of birth has been shown to reduce rates of IVH, IVH greater than grade II, and early severe pulmonary hemorrhage.21,47 In contrast to prophylactic use, treatment of a confirmed PDA with indomethacin has been associated with an increased risk of IVH.5 Adverse effects are common during indomethacin treatment including hyponatremia, oliguria, active bleeding, and impaired renal function, which are transient and seem to have no long-term sequelae. The simultaneous administration of indomethacin and steroids has been shown to increase the incidence of gastrointestinal perforations/NEC.1 5.2.2. Ibuprofen Ibuprofen has been shown to be effective in closing a PDA without reducing cerebral and mesenteric blood flow, and to have a smaller effect on renal perfusion than indomethacin.33 Intravenous ibuprofen has been shown to be as effective as indomethacin and to reduce the risks of NEC and transient renal insufficiency.35,48 A decreased risk of failure to close a PDA has been reported with oral ibuprofen compared with IV ibuprofen.48 There are currently no recommendations with regards to the use of a high dose vs. standard dose of ibuprofen, or early vs. expectant ibuprofen treatment.48 Prophylactic ibuprofen has been reported to decrease the rate of hs-PDA, but not the frequency of IVH.49 Pulmonary hypertension has been observed in some infants either after prophylactic use or after symptomatic treatment with ibuprofen.50 In vitro studies suggest that high doses of ibuprofen can displace bilirubin from albumin, thus, increasing free bilirubin levels and theoretically increasing the risk of
Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002
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kernicterus.51 A previous study reported an association between prophylactic ibuprofen and increased peak serum bilirubin levels and a longer duration of phototherapy.52 Another study reported significantly elevated total bilirubin levels in patients who received ibuprofen compared with indomethacin treatment for a hs-PDA.53 However, even with the increase in bilirubin, neither the number of days of phototherapy nor neurodevelopmental outcome at 2 years of age differed between the two groups.47,52,53 However, both of these reports were retrospective and a large randomized trial comparing ibuprofen, indomethacin, and a placebo would help to clarify this issue. Infants have been shown to advance to full enteral nutrition at a faster rate if they receive trophic enteral feedings (15 ml/kg/day) while receiving indomethacin or ibuprofen treatment for PDA, with no increases in the rates
Table 3
of infection, NEC, spontaneous intestinal perforation or other neonatal morbidities.54 5.2.3. Paracetamol (acetaminophen) Paracetamol appears to be a promising alternative to indomethacin and ibuprofen for the closure of a PDA with possibly fewer adverse effects, although some hepatic side effects with a transient increase in liver enzymes have been reported after intravenous paracetamol administration.55 There is currently insufficient evidence to recommend paracetamol as a standard treatment for PDA in preterm infants. Due to reports of a possible association between the prenatal use of paracetamol and the development of autism or autism spectrum disorders in childhood and language delay in girls, long-term follow-up must be to at least a postnatal age of 18e24 months.56
Therapeutic modalities for PDA in extremely preterm infants.
Therapeutic modality
Comments
Conservative management
1. Fluid restriction may significantly increase postnatal weight loss and reduce the risks of PDA and NEC.41,42 2. No evidence for the routine use of diuretics for the prevention or treatment of hemodynamically significant PDA. Combined use of furosemide with indomethacin showed a trend toward failure of ductal closure.43 3. Optimal saturation facilitates duct closure in preterm infants.44
Pharmacological treatment Indomethacin
Ibuprofen
Paracetamol
Surgical ligation
Catheterization closure
1. Intravenous indomethacin is used for prophylactic or symptomatic treatment for PDA closure. 2. Prophylactic indomethacin for IVH beginning within 24 h of birth may reduce IVH, early severe pulmonary hemorrhage and PDA ligation.20,21,47 3. Symptomatic treatment of confirmed PDA is associated with an increased risk of IVH.5 4. Adverse effects include hyponatremia, oliguria, active bleeding, and transient impaired renal function.45,46 5. Simultaneous administration of indomethacin and steroids has been shown to increase the incidence of gastrointestinal perforations/NEC.1 1. Intravenous ibuprofen is as effective as indomethacin in closing PDA and may reduce the risk of NEC and transient renal insufficiency.35,48 2. Oral ibuprofen appears to be as effective as intravenous ibuprofen.48 3. Prophylactic ibuprofen has been shown to decrease the incidence of significant PDA, but not the frequency of IVH.49 1. Paracetamol appears to be an alternative to indomethacin and ibuprofen for the closure of a PDA with possibly fewer adverse effects.55 2. Transient increase in liver enzymes may occur after intravenous paracetamol administration.55 3. There is insufficient evidence to recommend paracetamol as standard treatment for a PDA until long-term follow-up results are available.56 1. Postoperative cardiorespiratory instability often follows PDA ligation. The risk of this complication appears to decline substantially over the first 6 weeks after birth.57 2. Early surgical ligation is associated with a higher risk of developing BPD, retinopathy of prematurity, and neurodevelopmental impairment.58e60 3. Consider surgery only if medical treatment has failed or is contraindicated. Conservative management for PDA after failure of medical treatment, and considering surgery only when cardiopulmonary compromise develops has been associated with a lower rate of NEC and no increase in the rates of other adverse outcomes.61 1. The safety of catheterization closure should be assessed in randomized controlled trials to compare with standard surgical ligation.63 2. Transcatheter closure may be an alternative means for PDA ligation if proven to be safe.62
BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus.
Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002
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Treatment of PDA in extremely preterm infants
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5.3. Surgical ligation
Declaration of competing interest
Although surgical ligation is effective in achieving rapid and complete ductal closure, it is often followed by severe hemodynamic and respiratory collapse, requiring marked escalation in supportive intensive care.57 The risk of this complication appears to decline substantially over the first 6 weeks after birth. Long-term complications of surgical ligation include paresis of the left vocal cord or diaphragm, chylothorax, and scoliosis, and infants who undergo surgical ligation are more likely to develop BPD, retinopathy of prematurity, and neurodevelopmental impairment.25,58e60 A lower rate of surgical ligation in infants with PDA after failure of indomethacin prophylaxis has been associated with a lower rate of NEC and no increase in rates of other adverse outcomes.61
The authors have no conflicts of interest relevant to this article.
5.4. Catheterization closure There were previously only two options to actively close a PDA in preterm infants: medication or ligation. Because surgical ligation and medical therapy both have drawbacks, some pediatric cardiologists have considered interventional catheterization to be an alternative means of closing PDA in recent years.62 There is a risk of mortality associated with any form of treatment for a PDA, and therefore it is important that the safety of catheterization closure should be strictly tested in randomized controlled trials to compare with standard surgical ligation, as has been done for most transcatheter cardiac procedures, such as valve replacement, in adults.63,64
6. Conclusions Prophylactic treatment results in the overtreatment of infants who would normally have spontaneous closure of their ductus, and the available evidence does not support a routine universal prophylactic approach. Symptomatic treatment carries the disadvantages of late treatment such as a lower success rate, and increased complications of a hs-PDA. Further investigations are needed to determine which infants are most likely to benefit from treatment and the best strategy. Until there is new evidence to clarify the controversial issue of “to treat or not to treat a PDA”, and considering the relationship between the effectiveness and timing of pharmacological treatment, early targeted treatment may be an alternative approach for the early identification of a hs-PDA in specific high-risk patient populations, especially infants <26 weeks GA who are at the highest risk of severe IVH or pulmonary hemorrhage. These serious hemorrhagic complications are closely related to hemodynamic changes caused by a hs-PDA, usually occur within 72 h after birth, and affect mortality and long-term neurological development. Serial echocardiographic studies should be used to select patients who are candidates for early targeted medical treatment of a hs-PDA. Surgical ligation of PDA, and transcatheter closure if it can be proven to be safe, can be used as back-up therapy for patients who fail medical treatment and continue to have cardiopulmonary compromise.
References 1. Clyman RI, Couto J, Murphy GM. Patent ductus arteriosus: are current neonatal treatment options better or worse than no treatment at all? Semin Perinatol 2012;36:123e9. 2. Koch J, Hensley G, Roy L, Brown S, Ramaciotti C, Rosenfeld CR. Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics 2006;117:1113e21. 3. Nemerofsky SL, Parravicini E, Bateman D, Kleinman C, Polin RA, Lorenz JM. The ductus arteriosus rarely requires treatment in infants > 1000 grams. Am J Perinatol 2008;25: 661e6. 4. Su BH, Lin HY, Huang FK, Tsai ML, Huang YT. Circulatory management focusing on preventing intraventricular hemorrhage and pulmonary hemorrhage in preterm infants. Pediatr Neonatal 2016;57:453e62. 5. Benitz WE. Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis? J Perinatol 2010;30:241e52. 6. MacDonald MG, Seshia MMK, editors. Avery’s Neonatology. Pathophysiology & management of the newborn. 7th ed. NY.: Wolters Kluwer; 2016. p. 462e3. 7. Evans NJ, Iyer P. Change in blood pressure after treatment of patent ductus arteriosus with indomethacin. Arch Dis Child 1993;68:584e7. 8. Su BH, Watanabe T, Shimitzu M, Yanagisawa M. Echocardiographic assessment of patent ductus arteriosus shunt flow pattern in premature infants. Arch Dis Child Fetal Neonatal Ed 1997;77:F36e40. 9. Kluckow M, Evans N. Early echocardiographic prediction of symptomatic patent ductus arteriosus in preterm infants undergoing mechanical ventilation. J Pediatr 1995;127: 774e9. 10. Iyer P, Evans N. Re-evaluation of the left atrial to aortic root ratio as a marker of patent ductus arteriosus. Arch Dis Child Fetal Neonatal Ed 1994;70:F112e7. 11. Condo ` M, Evans N, Bellu ` R, Kluckow M. Echocardiographic assessment of ductal significance: retrospective comparison of two methods. Arch Dis Child Fetal Neonatal Ed 2012;97: F35e8. 12. Su BH, Peng CT, Tsai CH. Echocardiographic flow pattern of patent ductus arteriosus: a guide of indomethacin treatment in premature infants. Arch Dis Child Fetal Neonatal Ed 1999;81: F197e200. 13. Su BH, Chiu HY, Lin HY, Lin MH. Echocardiographic assessment of patent ductus arteriosus flow pattern in preterm infants. Arch Dis Child Fetal Neonatal Ed 2011. Published 23 May 2011. 14. McNamara PJ, Sehgal A. Towards rational management of the patent ductus arteriosus: the need for disease staging. Arch Dis Child Fetal Neonatal Ed 2007;92:F424e7. 15. Choi BM, Lee KH, Eun BL, Yoo KH, Hong YS, Son CS, et al. Utility of rapid B-type natriuretic peptide assay for diagnosis of symptomatic patent ductus arteriosus in preterm infants. Pediatrics 2005;115:e255e61. 16. Flynn PA, da Graca RL, Auld PA, Nesin M, Kleinman CS. The use of a bedside assay for plasma B-type natriuretic peptide as a biomarker in the management of patent ductus arteriosus in premature neonates. J Pediatr 2005;147: 38e42.
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8 17. El-Khuffash AF, Slevin M, McNamara PJ, Molloy EF. Troponin T, N-terminal pro natriuretic peptide and a patent ductus arteriosus scoring system predict death before discharge or neurodevelopmental outcome at 2 years in preterm infants. Arch Dis Child Fetal Neonatal Ed 2011;96:F133e7. 18. Benitz WE, Committee on fetus and newborn, American Academy of Pediatrics. Patent ductus arteriosus in preterm infants. Pediatrics 2016;137. https://doi.org/10.1542/peds.2015-3730. 19. Chock VY, Rose LA, Mante JV, Punn R. Near-infrared spectroscopy for detection of a significant patent ductus arteriosus. Pediatr Res 2016;80:675e80. 20. Ment LR, Oh W, Ehrenkranz RA, Philip AG, Vohr B, Allan W, et al. Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial. Pediatrics 1994;93:543e50. 21. Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med 2001;344: 1966e72. 22. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003;289: 1124e9. 23. Laptook AR, O’Shea TM, Shankaran S, Bhaskar B. Adverse neurodevelopmental outcomes among extremely low birth weight infants with a normal head ultrasound: prevalence and antecedents. Pediatrics 2005;115:673e80. 24. Clyman RI, Saha S, Jobe A, Oh W. Indomethacin prophylaxis for preterm infants: the impact of two multicentered randomized controlled trials on clinical practice. J Pediatr 2007;150: 46e50. e2. 25. Moin F, Kennedy KA, Moya FR. Risk factors predicting vasopressor use after patent ductus arteriosus ligation. Am J Perinatol 2003;20:313e20. 26. Edwards AD, Wyatt JS, Richardson C, Potter A, Cope M, Delpy DT, et al. Effects of indomethacin on cerebral haemodynamics in very preterm infants. Lancet 1990;335:1491e5. 27. Vohr BR, Allan WC, Westerveld M, Schneider KC, Katz KH, Makuch RW, et al. School-age outcomes of very low birth weight infants in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics 2003;111:e340e6. 28. Miller SP, Mayer EE, Clyman RI, Glidden DV, Hamrick SE, Barkovich AJ. Prolonged indomethacin exposure is associated with decreased white matter injury detected with magnetic resonance imaging in premature newborns at 24 to 28 weeks’ gestation at birth. Pediatrics 2006;117:1626e31. 29. Ment LR, Vohr BR, Makuch RW, Westerveld M, Katz KH, Schneider KC, et al. Prevention of intraventricular hemorrhage by indomethacin in male preterm infants. J Pediatr 2004;145: 832e4. 30. Jensen EA, Dysart KC, Gantz MG, Carper B, Higgins RD, Keszler M, et al. Association between use of prophylactic indomethacin and the risk for bronchopulmonary dysplasia in extremely preterm infants. J Pediatr 2017;186:34e40. e2. 31. Reese J, Shelton EL, Slaughter JC, McNamara PJ. Prophylactic indomethacin revisited. J Pediatr 2017;186:11e4. e1. 32. 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;187:119e26. e1. 33. Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2019;6:CD004213. 34. Ka ¨a ¨pa ¨ P, Lanning P, Koivisto M. Early closure of patent ductus arteriosus with indomethacin in preterm infants with
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9 60. Wickremasinghe AC, Rogers EE, Piecuch RE, Johnson BC, Golden S, Moon-Grady AJ, et al. Neurodevelopmental outcomes following two different treatment approaches (early ligation and selective ligation) for patent ductus arteriosus. J Pediatr 2012;161:1065e72. 61. Jhaveri N, Moon-Grady A, Clyman RI. Early surgical ligation versus a conservative approach for management of patent ductus arteriosus that fails to close after indomethacin treatment. J Pediatr 2010;157:381e7. e1. 62. Morville P, Douchin S, Bouvaist H, Dauphin C, et al. Transcatheter occlusion of the patent ductus arteriosus in premature infants weighing less than 1200 g. Arch Dis Child Fetal Neonatal Ed 2018;103:F198e201. 63. Bu’Lock F. Closing the patent duct: context and controversy. Arch Dis Child Fetal Neonatal Ed 2018;103:F194e5. 64. Vali P, Lakshminrusimha S, Pelech A, Underwood M, Ing F. Patent ductus arteriosus in preterm infants: is early transcatheter closure a paradigm shift? J Perinatol 2019. https://doi.org/10.1038/s41372-019-0506-7.
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Pediatrics and Neonatology xxx (xxxx) xxx
Available online at www.sciencedirect.com
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Review Article
Therapeutic strategy of patent ductus arteriosus in extremely preterm infants Bai-Horng Su a,b,*, Hsiang-Yu Lin a,b, Hsiao-Yu Chiu a, Ming-Luen Tsai a, Yin-Ting Chen a, I-Chun Lu a a b
Department of Neonatology, China Medical University Children’s Hospital, Taichung, Taiwan Department of Pediatrics, School of Medicine, China Medical University, Taichung, Taiwan
Received Apr 25, 2019; received in revised form Sep 15, 2019; accepted Oct 21, 2019
Available online - - -
Key Words early targeted treatment; extremely preterm infant; hemodynamically significant PDA (hs-PDA); intraventricular hemorrhage (IVH); patent ductus arteriosus (PDA)
The ductus arteriosus is likely to close without treatment in most infants born at gestational age (GA) > 28 weeks (73%), and those with birth weight > 1000 g (94%). However, the rates of spontaneous ductal closure among less mature or smaller infants with respiratory distress syndrome are not known. Extremely preterm infants born at GA < 28 weeks are associated with a high risk of severe intraventricular hemorrhage (IVH) or pulmonary hemorrhage, which usually occur within 72 h after birth and affect mortality and long-term neurological development. These serious hemorrhagic complications may be closely related to hemodynamic changes caused by a hemodynamically significant patent ductus arteriosus (hs-PDA). While prophylactic indomethacin has been shown to reduce the rates of PDA, PDA ligation, severe IVH and early pulmonary hemorrhage, the available evidence does not support its prophylactic use in preterm infants. Symptomatic or late treatment is associated with lower success rate, and increased complications of a hs-PDA. The issue of “to treat or not to treat a PDA” is controversial. Considering the relationship between the effectiveness and timing of pharmacological treatment, early targeted treatment may be an alternative approach for the early identification of a hs-PDA in specific high-risk patient population, especially infants <26 weeks GA who are at the highest risk of severe IVH or pulmonary hemorrhage. Serial echocardiographic studies can be used to select patients who are candidates for early targeted medical treatment of hs-PDA. Surgical ligation of PDA, and transcatheter closure if proven to be safe, can be used as back-up therapy for patients who fail medical treatment and continue to have cardiopulmonary compromise. Copyright ª 2019, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
* Corresponding author. Department of Neonatology, Children’s Hospital of China Medical University, 2, Yuh-Der Road, Taichung, 404, Taiwan. E-mail address: [email protected] (B.-H. Su). https://doi.org/10.1016/j.pedneo.2019.10.002 1875-9572/Copyright ª 2019, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002
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1. Introduction
3. Hemodynamically significant PDA
The ductus arteriosus remains patent at day 4 after birth in about 10% of preterm infants born at 30e37 weeks gestational age (GA), 80% of those born at 25e28 weeks, and 90% of those born at 24 weeks.1 At day 7 after birth, these rates decline to approximately 2%, 65%, and 87%, respectively (Table 1). Therefore, extremely preterm infants born at GA < 28 weeks are at the highest risk of developing a hemodynamically significant patent ductus arteriosus (hs-PDA) and the related complications. The ductus has been reported to close without treatment in 73% of infants born at GA > 28 weeks,2 and in 94% of those with a birth weight >1000 g.3 However, the rates of spontaneous ductal closure among extremely preterm infants with respiratory distress syndrome are not known. Extremely preterm infants born at GA < 28 weeks are associated with a high risk of intraventricular hemorrhage (IVH) and/or massive pulmonary hemorrhage, which usually occur within 72 h after birth and affects mortality and long-term neurological development. These serious hemorrhagic complications may be closely related to hemodynamic changes caused by a hsPDA.4 In this review, we discuss the optimal therapeutic strategy of PDA in extremely preterm infants.
2. To treat or not to treat a PDA in preterm infants There is still controversy about “to treat or not to treat a PDA” in preterm infants. The concern should be that whether the PDA is pathological or not pathological. If treatment to close a PDA makes no difference to the outcome, then the PDA may not be pathological. However, premature infants with persistent PDA may have more adverse outcomes including prolongation of assisted ventilation and higher rates of death, bronchopulmonary dysplasia (BPD), pulmonary hemorrhage, necrotizing enterocolitis (NEC), impaired renal function, IVH, periventricular leukomalacia, and cerebral palsy.5,6 The most relevant and clinically important question is how to change a hs-PDA into a PDA without compromising the infant’s circulation (either a decrease in size or fully closed) and the related complications.
Table 1
The rates of PDA in preterm infants after birth.
Gestational age, or Birth weight
Day 4 after birth (%)
Day 7 after birth (%)
At discharge (%)
30e37 weeks 27e28 weeks 25e26 weeks 24 weeks 1000e1500 g <1000 g
10 78 80 90 65 79
2 64 68 87 33 66
2 NA NA NA 6 NA
PDA, patent ductus arteriosus; NA, no available data.
3.1. Clinical manifestations The term “hs-PDA” is frequently used to differentiate consequential from inconsequential PDA. Physical findings in infants with hs-PDA may include heart murmur, persistent tachycardia (HR > 160/min), hyperactive precordial pulsation, prominent or bounding pulses, and either low systolic blood pressure or low diastolic blood pressure with a widened pulse pressure. However, these findings are nonspecific, and lack accuracy to diagnose a hs-PDA in early postnatal life.7,8 In many instances, the presence of a hsPDA is suspected on the basis of respiratory findings, such as cardiomegaly or pulmonary congestion on a chest X-ray, difficulty in weaning from a ventilator, or the need to increase ventilator settings or oxygen. Therefore, echocardiography has become essential in the evaluation of clinically significant ductal shunting.8,9
3.2. Echocardiographic parameters Various echocardiographic parameters have been suggested for guiding the treatment of PDA. Increased left atrium to aorta ratio (LA/Ao) 1.5 is a useful and simple tool. However, its use on day 1 of age is not recommended due to false negative results with large inter-atrial shunts.10 Color Doppler echocardiography can confirm ductal patency and be used to measure the ductal diameter. Carmo et al. used a ductal diameter >2.0 mm as an indicator for PDA treatment in the first 12 h of life, and concluded that this may avoid unnecessarily treating an infant who will have spontaneous closure.11 Su et al. identified four patterns of ductal flow based on the pulsed Doppler waveform, of which a growing or pulsatile pattern indicated a continuing risk of developing a hs-PDA.6,8,12 There is a strong correlation between ductal diameter and flow patterns. In infants with a pulmonary hypertension pattern, 82.4% had a ductal diameter >2.0 mm, and 98.1% of those with a closing pattern had a diameter <2.0 mm.11 The PDA in about 50% of those with a pulmonary hypertension pattern remained non-significant and changed to closing or closed patterns. According to the previous reports, when using a ductal diameter >2.0 mm as the indicator for treatment, 41.2% of the infants with a PDA with a pulmonary hypertension pattern may have been treated unnecessarily despite remaining non-significant and may finally have closed spontaneously.8,12,13 Therefore, simultaneously measuring ductal diameter and classifying the ductal flow pattern may further enhance the clinical predictive capacity of echocardiography. Although echocardiography has become essential in the evaluation and management of PDA, it is very important to perform serial echocardiographic assessments rather than depending only on a spot time measurement because of the dynamic transitional changes in PDA during early life in extremely preterm infants. Findings of reversed diastolic flow in the descending aorta or in cerebral or renal arteries also indicate hemodynamic compromise of the circulation caused by ductal shunting.14
Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002
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3.3. Biomedical parameters
4. Therapeutic strategies for a PDA (Table 2)
Biomarkers such as serum concentrations of B-type natriuretic peptide (BNP), aminoterminal B-type natriuretic peptide (NT-proBNP),15,16 and cardiac troponin T (cTnT)17 may be used to identify a hs-PDA and determine the indication, timing, and treatment options. These biomarkers have been correlated with echocardiographic measures of shunt volume, and to decrease after ductal closure. In addition, they have been shown to be of particular benefit when combined with clinical evaluation if point of care echocardiography is not available.6,18
.
3.4. Near-infrared spectroscopy (NIRS) In preterm infants born at < 29 weeks, near-infrared spectroscopy (NIRS) monitoring of cerebral and renal saturation is a noninvasive method that can be used to suggest the presence of a hs-PDA as confirmed by echocardiography.19
Table 2
4.1. Prophylactic treatment A multicenter trial (Ment-trial) confirmed the beneficial effects of prophylactic indomethacin on the rates of PDA, PDA ligation, and severe IVH.20 Another multicenter trial (TIPP-trial) was performed to evaluate the long-term effects of prophylactic indomethacin on motor, sensory, and cognitive outcomes.21 The TIPP-trial confirmed the beneficial effects of prophylactic indomethacin on the rates of PDA, PDA ligation, severe IVH, and pulmonary hemorrhage. Previous studies have shown that prophylactic indomethacin can decrease the risk of severe IVH, and that severe IVH is strongly associated with neurodevelopmental abnormalities.22,23 Therefore, it seems reasonable to expect that the TIPP-trial would have found a difference in neurodevelopmental outcomes, however the results did not
Therapeutic strategies for a PDA in extremely preterm infants.
Therapeutic strategy
Comments
Prophylactic treatment
1. Prophylactic indomethacin may reduce the rates of PDA, PDA ligation, severe IVH, and pulmonary hemorrhage.20,21 2. No evidence of benefits on long-term neurodevelopmental outcome.21 (This may have been due to an anticipated effect size that was excessively large for the population studied).24 3. Routine prophylactic treatment will expose infants with a PDA that will never be hemodynamically significant to the potentially harmful side effects of treatment.1,18 4. Decreased use of prophylactic indomethacin has been associated with an increased incidence of surgical PDA ligation.24,32 5. Prophylactic indomethacin may reduce mortality rates in infants without intrauterine growth restriction and infants who do not require subsequent PDA treatment.30,31 6. Early prophylactic indomethacin may reduce BPD and BPD or death compared with delayed indomethacin treatment until at least 8 postnatal days.32 7. Early indomethacin exposure has not been found to have a negative effect on cognitive outcome in studies with 8 years of follow-up.27 8. Prophylactic ibuprofen did not show any superiority over prophylactic indomethacin.33 1. Early targeted treatment based on echocardiographic parameters may allow for the selection of high-risk extremely preterm infants prior to the duct becoming clinically significant.8,34 2. Treatment within 24 h of age may reduce severe IVH and pulmonary hemorrhage.4,34 3. Using echocardiographic PDA flow patterns (pulmonary hypertension, growing, pulsatile and closing pattern) can allow for the early prediction of hemodynamically significant PDA, and require a lower drugs dose to achieve an acceptable closure rates.6,8,12 4. Using a ductal diameter >2.0 mm as an indicator for PDA treatment in the first 12 h of life, may avoid the likelihood of unnecessarily treating an infant with subsequent closure.11 5. Simultaneously measuring ductal diameter and classifying the ductal flow pattern may further enhance the clinical predictive capacity of echocardiography.11e13 1. Using active treatment for symptomatic PDA allows for possible spontaneous closure and minimizing the risk of exposure to the hazards of treatment. 2. Late treatment has a lower closure rate.37 3. Late treatment increases complications of a hemodynamically significant PDA including pulmonary hemorrhage, severe IVH, chronic lung disease, potential disturbances of cerebral blood flow and cardiac failure.38,39
Early targeted treatment
Symptomatic treatment
BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PDA, patent ductus arteriosus.
Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002
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4 show a decrease in the rates of death or neurodevelopmental abnormalities. The negative conclusions of the TIPP-trial may have been due to an anticipated effect size that was excessively large for the population studied.24 These two multicenter randomized controlled trials have been associated with changes in the use of indomethacin prophylaxis. Following the Ment-trial, its use increased, and following the TIPP-trial its use decreased.24 The use of prophylactic indomethacin in the NICHD Registry was associated with a significant reduction in the rate of PDA in each of the gestational age groups (25 weeks, 26e27 weeks, and 28 weeks gestation), and a significant reduction in the rate of PDA ligations among infants born < 26 weeks GA.24 Similarly, the rate of PDA ligations, among infants born < 26 weeks GA fell significantly following the publication of Ment-trial, and rose again following publication of the TIPP-trial in parallel with changes in the use of indomethacin prophylaxis.24 Surgical ligation of a PDA is associated with many morbidities including thoracotomy, pneumothorax, chylothorax, infection, vocal cord paralysis, and profound hypotension.25 The cerebral vasoconstrictive effects of indomethacin are a frequent concern for neonatologists.26, However, neonatal indomethacin exposure was not shown to have a negative effect on cognitive outcomes in a follow-up study of children at 8 years of age.27 Both neuroimaging28 and long-term neurodevelopmental outcome data27,29 have been reassuring with regards to the lack of adverse effects and possible benefits of prophylactic indomethacin on neurodevelopmental outcome. Prophylactic indomethacin may be a reasonable choice in intensive care units where IVH and PDA are frequent problems. Jensen et al. analyzed 5 years of prospectively collected data from 35 hospitals in the Neonatal Research Network’s (NRN) registry. They found that among infants born at < 29 weeks or <1000 g birth weight, those treated with prophylactic indomethacin subsequently required less PDA treatment than nontreated infants (21% vs. 36%). In addition, subgroup analysis showed reduced mortality rates after prophylactic indomethacin in infants without intrauterine growth restriction and infants who did not require subsequent PDA treatment.30 These infants represent a large proportion of the patients treated in daily practice.31 In post-hoc analysis of the different rates of the use of prophylactic indomethacin, the authors showed a > 3-fold reduction in BPD in high-rate hospitals (>60% of eligible infants treated) compared with hospitals that never used prophylaxis. There was also a 2.8-fold lower rate of the composite outcome of death or BPD in hospitals with a high rate of prophylactic indomethacin compared to those that did not use prophylaxis.31 Liebowitz and Clyman performed a prospective controlled study of infants born at < 28 weeks GA. In their study, the early prophylactic indomethacin group had decreased rates of BPD and BPD or death compared with the conservative group in whom indomethacin treatment was delayed until at least 8 postnatal days. These effects were mediated by closure of the PDA.32 Prophylactic ibuprofen therapy at a dose of 10 mg/kg in the first 24 h of life followed by 5 mg/kg after 24 h and 48 h did not show any superiority over prophylactic indomethacin therapy. In addition, it was found to decrease the rate
B.-H. Su et al of PDA on day three, decreased the need for rescue treatment with indomethacin, and decreased the need for surgical ligation. However, its use negatively affected the renal function of preterm infants with no significant differences in mortality, IVH, or BPD.33
4.2. Early targeted treatment Early targeted treatment can be used to treat infants based on echocardiographic parameters prior to the duct becoming clinically significant in hopes that early closure will prevent detrimental impacts on other tissues.34 In centers with unrestrained access to echocardiography, this strategy may be an alternative approach to focus on highrisk patient populations with specific hemodynamic characteristics and to give treatment within 24 h of age to reduce pulmonary hemorrhage, severe IVH and subsequent symptomatic treatment without causing harm. Compared to prophylactic treatment, early targeted treatment may minimize the potential harmful side effects of treatment when administered to patients with a PDA that is not and never will be hemodynamically significant or patients in whom the ductus has a beneficial role in supporting either pulmonary or systemic blood flow (e.g. severe myocardial dysfunction and pulmonary hypertension).8,12,34,36 Su et al. used echocardiographic PDA flow patterns as a guide for early targeted treatment in extremely infants, and found that this approach could reduce the total doses of indomethacin while achieving an acceptable closure rate, and therefore a reduced rate of complications.12,35
4.3. Symptomatic treatment Whether and when to treat a PDA remains controversial.5,18 An expectant approach of treating the PDA at a later time and only when clinical signs indicate a hemodynamic significance, allows for possible spontaneous closure. This approach has the advantage of minimizing the risk of exposing preterm infants to the hazards of treatment but the disadvantage of late intervention such as lower success rate,37 and an increased risk of complications associated with a hs-PDA, including pulmonary hemorrhage, severe IVH, chronic lung disease, potential disturbances of cerebral blood flow and cardiac failure.38,39 Many of these complications occur early, in the first 24 h.4,39 A recent multicenter trial (PDA-TOLERATE Trial) conducted by Clyman et al. compared early routine pharmacologic treatment (ERT) of moderate-to-large PDA at the end of week 1 with a conservative approach that required prespecified respiratory and hemodynamic criteria before treatment could be given.40 They concluded that ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes (NEC, BPD, BPD or death, death, and duration of respiratory support), but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at 26 weeks of gestation. Nevertheless, the authors concluded that ERT (between 6 and 14 days of age; mean 8.1 2.1 days) did not reduce the primary outcome of PDA ligation or remaining open at discharge. In addition, their results showed that the ERT
Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002
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Treatment of PDA in extremely preterm infants group had a significantly lower rate of moderate-to-large PDA at 10 days after randomization (risk ratio [95% confidence interval]: 0.51 [0.40e0.66], P < 0.001) and a significantly lower rate of receiving rescue treatments (0.38 [0.24e0.60], P < 0.001) compared with the conservative treatment group. A possible explanation for these results is that pharmacologic treatment for PDA closure is known to be less effective in infants >10e14 days of age.37 A previous study by Liebowitz and Clyman,32 two principal authors of the PDA-TOLERATE Trial, found that the rates of moderate-to-large PDA on day 7 and duration of exposure to moderate-to-large PDA were significantly lower in the prophylactic indomethacin (PINDO) group than in the delayed conservative management group (no infant was treated with indomethacin until at least 8 postnatal days). They concluded that PINDO decreased BPD and BPD or death compared with delayed conservative management, and that these effects were mediated by PDA closure. The ERT in the TOLERATE Trial40 appeared to be comparable to the delayed conservative management in the PINDO study.32 The key factor in the discrepancy between the results of ERT and PINDO may have been the timing of pharmacological treatment, as the timing of ERT treatment was not as early as with prophylactic treatment (8.1 2.1 days vs. within 24 h after birth).20,21,32,40 While prophylactic indomethacin did reduce the rates of PDA, PDA ligation, severe IVH and early pulmonary hemorrhage, the available evidence does not support universal prophylactic treatment in preterm infants.31 Delayed symptomatic treatment carries the advantage of minimizing the risk of exposing preterm infants to the hazards of treatment but the disadvantages of late treatment such as lower success rate,37 and increased complications of a hs-PDA. The optimal timing of pharmacological treatment in early targeted treatment is within 24 h after birth, which is as early as with prophylactic treatment.34e36 The nature of target selected treatment may avoid unnecessary treatment as with early universal prophylactic treatment when administered to infants with a PDA that is not and never will be hemodynamically significant.8,12,34,36 Until there is new evidence to clarify the controversial issue of “to treat or not to treat a PDA”, and considering the relationship between the effectiveness and timing of pharmacological treatment,37 early targeted treatment may be an alternative approach for the early identification of a hs-PDA in certain high-risk patient populations, especially infants <26 weeks GA who are at the highest risk of severe IVH or pulmonary hemorrhage.
5. Therapeutic modalities (Table 3) .
5.1. Conservative management Fluid restriction has been widely recommended in the management of a PDA.41 A meta-analysis showed that fluid restriction significantly increased postnatal weight loss and significantly reduced the risks of PDA and NEC. In addition, there were trends toward an increased risk of dehydration and reduced risks of BPD, IVH, and death with fluid
5 restriction, however these trends were not statistically significant.42 There is currently not enough evidence to support the routine use of diuretics to prevent or treat congestive heart failure in infants with a hs-PDA. A systematic review of the combined use of furosemide with indomethacin showed a trend toward failure of ductal closure in furosemidetreated patients, and the authors concluded that this was because furosemide increases prostaglandin production and can potentially decrease the ductal response to indomethacin.43 Oxygen therapy has been shown to facilitate duct closure in preterm infants. In a retrospective study, infants treated with lower oxygen saturation target policy (83e89% versus 89e94%) had a higher risk of a hs-PDA.44
5.2. Pharmacological treatment 5.2.1. Indomethacin Indomethacin and ibuprofen are the most studied nonselective COX inhibitor for the prophylaxis and treatment of a PDA. The closure rate of PDA with indomethacin is dependent on the birth weight of the preterm infant. Gersony et al. reported a post-indomethacin closure rate of 80%e 86% in infants weighing 1000e1750 g and 54% in infants weighing <1000 g.45 The cumulative closure rate reached 90% with three courses, however the risk of periventricular leukomalacia increased.46 Prophylactic indomethacin for IVH beginning within 12 h of birth has been shown to reduce rates of IVH, IVH greater than grade II, and early severe pulmonary hemorrhage.21,47 In contrast to prophylactic use, treatment of a confirmed PDA with indomethacin has been associated with an increased risk of IVH.5 Adverse effects are common during indomethacin treatment including hyponatremia, oliguria, active bleeding, and impaired renal function, which are transient and seem to have no long-term sequelae. The simultaneous administration of indomethacin and steroids has been shown to increase the incidence of gastrointestinal perforations/NEC.1 5.2.2. Ibuprofen Ibuprofen has been shown to be effective in closing a PDA without reducing cerebral and mesenteric blood flow, and to have a smaller effect on renal perfusion than indomethacin.33 Intravenous ibuprofen has been shown to be as effective as indomethacin and to reduce the risks of NEC and transient renal insufficiency.35,48 A decreased risk of failure to close a PDA has been reported with oral ibuprofen compared with IV ibuprofen.48 There are currently no recommendations with regards to the use of a high dose vs. standard dose of ibuprofen, or early vs. expectant ibuprofen treatment.48 Prophylactic ibuprofen has been reported to decrease the rate of hs-PDA, but not the frequency of IVH.49 Pulmonary hypertension has been observed in some infants either after prophylactic use or after symptomatic treatment with ibuprofen.50 In vitro studies suggest that high doses of ibuprofen can displace bilirubin from albumin, thus, increasing free bilirubin levels and theoretically increasing the risk of
Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002
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kernicterus.51 A previous study reported an association between prophylactic ibuprofen and increased peak serum bilirubin levels and a longer duration of phototherapy.52 Another study reported significantly elevated total bilirubin levels in patients who received ibuprofen compared with indomethacin treatment for a hs-PDA.53 However, even with the increase in bilirubin, neither the number of days of phototherapy nor neurodevelopmental outcome at 2 years of age differed between the two groups.47,52,53 However, both of these reports were retrospective and a large randomized trial comparing ibuprofen, indomethacin, and a placebo would help to clarify this issue. Infants have been shown to advance to full enteral nutrition at a faster rate if they receive trophic enteral feedings (15 ml/kg/day) while receiving indomethacin or ibuprofen treatment for PDA, with no increases in the rates
Table 3
of infection, NEC, spontaneous intestinal perforation or other neonatal morbidities.54 5.2.3. Paracetamol (acetaminophen) Paracetamol appears to be a promising alternative to indomethacin and ibuprofen for the closure of a PDA with possibly fewer adverse effects, although some hepatic side effects with a transient increase in liver enzymes have been reported after intravenous paracetamol administration.55 There is currently insufficient evidence to recommend paracetamol as a standard treatment for PDA in preterm infants. Due to reports of a possible association between the prenatal use of paracetamol and the development of autism or autism spectrum disorders in childhood and language delay in girls, long-term follow-up must be to at least a postnatal age of 18e24 months.56
Therapeutic modalities for PDA in extremely preterm infants.
Therapeutic modality
Comments
Conservative management
1. Fluid restriction may significantly increase postnatal weight loss and reduce the risks of PDA and NEC.41,42 2. No evidence for the routine use of diuretics for the prevention or treatment of hemodynamically significant PDA. Combined use of furosemide with indomethacin showed a trend toward failure of ductal closure.43 3. Optimal saturation facilitates duct closure in preterm infants.44
Pharmacological treatment Indomethacin
Ibuprofen
Paracetamol
Surgical ligation
Catheterization closure
1. Intravenous indomethacin is used for prophylactic or symptomatic treatment for PDA closure. 2. Prophylactic indomethacin for IVH beginning within 24 h of birth may reduce IVH, early severe pulmonary hemorrhage and PDA ligation.20,21,47 3. Symptomatic treatment of confirmed PDA is associated with an increased risk of IVH.5 4. Adverse effects include hyponatremia, oliguria, active bleeding, and transient impaired renal function.45,46 5. Simultaneous administration of indomethacin and steroids has been shown to increase the incidence of gastrointestinal perforations/NEC.1 1. Intravenous ibuprofen is as effective as indomethacin in closing PDA and may reduce the risk of NEC and transient renal insufficiency.35,48 2. Oral ibuprofen appears to be as effective as intravenous ibuprofen.48 3. Prophylactic ibuprofen has been shown to decrease the incidence of significant PDA, but not the frequency of IVH.49 1. Paracetamol appears to be an alternative to indomethacin and ibuprofen for the closure of a PDA with possibly fewer adverse effects.55 2. Transient increase in liver enzymes may occur after intravenous paracetamol administration.55 3. There is insufficient evidence to recommend paracetamol as standard treatment for a PDA until long-term follow-up results are available.56 1. Postoperative cardiorespiratory instability often follows PDA ligation. The risk of this complication appears to decline substantially over the first 6 weeks after birth.57 2. Early surgical ligation is associated with a higher risk of developing BPD, retinopathy of prematurity, and neurodevelopmental impairment.58e60 3. Consider surgery only if medical treatment has failed or is contraindicated. Conservative management for PDA after failure of medical treatment, and considering surgery only when cardiopulmonary compromise develops has been associated with a lower rate of NEC and no increase in the rates of other adverse outcomes.61 1. The safety of catheterization closure should be assessed in randomized controlled trials to compare with standard surgical ligation.63 2. Transcatheter closure may be an alternative means for PDA ligation if proven to be safe.62
BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; NEC, necrotizing enterocolitis; PDA, patent ductus arteriosus.
Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002
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Treatment of PDA in extremely preterm infants
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5.3. Surgical ligation
Declaration of competing interest
Although surgical ligation is effective in achieving rapid and complete ductal closure, it is often followed by severe hemodynamic and respiratory collapse, requiring marked escalation in supportive intensive care.57 The risk of this complication appears to decline substantially over the first 6 weeks after birth. Long-term complications of surgical ligation include paresis of the left vocal cord or diaphragm, chylothorax, and scoliosis, and infants who undergo surgical ligation are more likely to develop BPD, retinopathy of prematurity, and neurodevelopmental impairment.25,58e60 A lower rate of surgical ligation in infants with PDA after failure of indomethacin prophylaxis has been associated with a lower rate of NEC and no increase in rates of other adverse outcomes.61
The authors have no conflicts of interest relevant to this article.
5.4. Catheterization closure There were previously only two options to actively close a PDA in preterm infants: medication or ligation. Because surgical ligation and medical therapy both have drawbacks, some pediatric cardiologists have considered interventional catheterization to be an alternative means of closing PDA in recent years.62 There is a risk of mortality associated with any form of treatment for a PDA, and therefore it is important that the safety of catheterization closure should be strictly tested in randomized controlled trials to compare with standard surgical ligation, as has been done for most transcatheter cardiac procedures, such as valve replacement, in adults.63,64
6. Conclusions Prophylactic treatment results in the overtreatment of infants who would normally have spontaneous closure of their ductus, and the available evidence does not support a routine universal prophylactic approach. Symptomatic treatment carries the disadvantages of late treatment such as a lower success rate, and increased complications of a hs-PDA. Further investigations are needed to determine which infants are most likely to benefit from treatment and the best strategy. Until there is new evidence to clarify the controversial issue of “to treat or not to treat a PDA”, and considering the relationship between the effectiveness and timing of pharmacological treatment, early targeted treatment may be an alternative approach for the early identification of a hs-PDA in specific high-risk patient populations, especially infants <26 weeks GA who are at the highest risk of severe IVH or pulmonary hemorrhage. These serious hemorrhagic complications are closely related to hemodynamic changes caused by a hs-PDA, usually occur within 72 h after birth, and affect mortality and long-term neurological development. Serial echocardiographic studies should be used to select patients who are candidates for early targeted medical treatment of a hs-PDA. Surgical ligation of PDA, and transcatheter closure if it can be proven to be safe, can be used as back-up therapy for patients who fail medical treatment and continue to have cardiopulmonary compromise.
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Please cite this article as: Su B-H et al., Therapeutic strategy of patent ductus arteriosus in extremely preterm infants, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2019.10.002