Surgical ligation of patent ductus arteriosus in pre-term infants: a narrative review

Introduction

Background

The ductus arteriosus, originally described by Galen (along with the foramen ovale) in the second century CE, is a very important embryonic channel and an integral feature of foetal circulation (1). Though it is bilateral to start with, during 37 to 40 days of gestation, the right-sided duct atrophies and the left-sided duct persists (2). It facilitates blood flow from the pulmonary trunk to the aorta owing to the high pulmonary resistance in the in-utero period and it acts as a key segment of the placental circuit. Persistence of this embryonic channel in post-natal life is termed the patent ductus arteriosus (PDA) and is more common in premature infants.

Rationale and knowledge gap

PDA manifests in various clinical presentations from a stand-alone lesion in full-term babies; associated with other congenital cardiac anomalies as in the most severe forms of PDA-dependent systemic or pulmonary circulation in which PDA patency is critical for survival; and a haemodynamically significant PDA (hsPDA) in preterm babies. In the last group, PDA could profoundly alter blood flow dynamics and has the potential to cause haemodynamic instability leading to morbidity and mortality (3). Based on the understanding of the pathophysiology and natural history of PDA, treatment strategies for preterm patients include (I) prophylactic therapy with cyclooxygenase inhibitors (COX-i); (II) watchful waiting/pharmacotherapy with diuretics; (III) pharmacologic closure with COX-i agents; and (IV) physical closure by surgery or a device. The target population of ‘preterm’ patients varies significantly in birth weight (BW), gestational age (GA), maturity, comorbidities as well as the haemodynamic consequences introduced by the PDA. Hence, a review of available literature shows that there are multiple therapeutic strategies and there is no single, unified approach or algorithm on how best these patients should be treated. Furthermore, multiple reports compare the results of surgical ligation to pharmacological modalities on a one-to-one basis, despite different patient characteristics, conditions and timing of the respective interventions.

Objective

Surgical ligation, often being the last line of management for a haemodynamically significant PDA is mostly done on much sicker and nutritionally depleted infants. So, a head-to-head comparison of the various modalities may not offer clarity due to the presence of confounding factors. We aim to discuss the timing and results of this therapeutic modality. This narrative review was also undertaken to provide a balanced view on the current management of PDA in premature infants and to present an optimal decision-making algorithm based on the literature and the authors’ experience. We present this article in accordance with the Narrative Review reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-24-6/rc).

Methods

We searched PubMed, Cochrane and Embase databases using key search words including patent ductus arteriosus, PDA, ductus arteriosus, preterm, neonate, newborn, premature and surgical ligation. All peer reviewed articles including original articles, meta-analysis and systematic reviews that were in the English language were analyzed. Studies that described therapy for the PDA in preterm infants were selected. Some of these articles had citations that were deemed relevant for our study which did not appear on the original search. These were analysed as well. Compilation of these articles yielded a volume of literature relevant to the understanding of therapeutic options available along with their pros and cons which was used to construct this narrative review (Table 1).

Discussion

Spontaneous closure of PDA eventually occurs in 40% of premature infants in whom it is more common owing to the immaturity of the smooth muscles and immaturity of the oxygen sensing mechanisms (4). Therapies to close the duct in these infants expose them to the iatrogenic adverse effects of closure. Despite differing views, the common understanding is that medical or surgical closure of a PDA does not necessarily reduce the morbidity and mortality risk (4). A multi-centre, randomized, non-inferiority trial of early treatment versus expectant management of PDA in preterm infants (the BeNeDuctus trial)—undertaken in the Netherlands, Belgium and Denmark—concluded that the expectant management for PDA in extremely premature infants was non-inferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks’ post-menstrual age (5).

PDA—an innocent bystander or a driver of adversity?

Though it is physiologically possible, literature does not support a cause-effect relationship for some morbidities like necrotizing enterocolitis (NEC) and chronic lung disease (CLD) which are commonly associated with PDA, since other concomitant risk factors like prematurity may play a role (6,7). Also, some authors suggest that medical/surgical treatment may not prevent complications e.g., pulmonary haemorrhage, NEC, broncho-pulmonary dysplasia (BPD) or intracranial bleeds (7,8). Most studies consider the PDA to be an entity based on anatomy rather than its physiological consequence. PDA may actually represent a ‘continuum’ from an innocent bystander to an agent driving serious clinical consequences. It may be a challenge to identify subjects with severe ‘ductal disease’ who need to be treated from the ones that could be managed conservatively (9). The risks of intervention outweigh the benefits in the latter group. McNamara and Hellman have published a staging system based on echocardiographic and clinical severity of cardiovascular, respiratory, excretory and gastrointestinal (GI) systems which may be useful in assessing a PDA in preterm infants to identify ‘haemodynamically-significant’ PDA (9).

Haemodynamically significant PDA (hsPDA)

Definition of a haemodynamically significant PDA is based on echocardiography which is considered as the gold standard and also by the presence of clinical criteria (4,9,10) and it includes:

• Ductal diameter >1.5 mm (GA <26 weeks) or >2.0 mm (GA <30 weeks);
• Left atrium to aortic root diameter ratio of at least 1.4;
• LV output >300 mL/kg/min;
• Retrograde flow in descending thoracic aorta;
• Need for invasive or non-invasive respiratory support and frequent desaturations;
• Abdominal signs including distension, increased gastric residual volume or other pre-NEC signs;
• Renal failure, NEC or impaired near infra-red spectroscopy (NIRS) variables;
• Anterior cerebral artery resistance index >0.9 based on cerebral ultrasonography;
• Natriuretic peptides like brain natriuretic peptide (BNP) and n-terminal prohormone of BNP (NTpBNP) have showed a strong predictive ability to predict hsPDA in preterm infants (11,12).

Natural closure of the DA in relation to GA and BW

GA and BW closely correlate with PDA prevalence and impact. Most PDAs close by day 4 of life in preterm neonates of GA >29 weeks. In neonates with GA <28 weeks, 70% of PDAs fail to close and in GA <24–25 weeks: 80% (13). Clyman et al. also reported a marked difference in the normal involution of the ductus arteriosus based on GA at birth (14). With a GA >30 weeks, 90% of PDAs closed on day 4 and 98% at discharge in contrast to GA <24 weeks, where only 8% of PDAs closed on day 4 and 13% by day 7. The authors also noted a similar correlation with BW and PDA closure. When the BW was between 1,000–1,500 g: 35% of PDAs closed on day 4, 67% on day 7 and 94% of PDAs were closed at discharge. But in subjects with BW <1,000 g, they observed a spontaneous closure rate of 21% by day 4 and 34% on day 7 (14). A retrospective cohort analysis (103 neonates between 24–27 weeks of GA) by Rolland et al., however, reported a spontaneous PDA closure rate of 73% in all preterm infants without any specific treatment for the PDA (15). This concept, which proposes that most PDAs would ultimately close, serves as the basis of the conservative approach which has gained ground in many neonatal intensive care units (NICU) around the world.

Pathophysiology of a PDA

Prolonged PDA patency increases the pulmonary circulation leading to capillary endothelial injury which initiates the inflammatory cascade that results in pulmonary oedema and development of CLD—ultimately requiring increasing ventilator support (16). This could associate with haemorrhagic pulmonary oedema (pulmonary haemorrhage), left-sided cardiac dysfunction and pulmonary venous hypertension (17). Left-sided chambers dilate and pulmonary arterial pressures rises. This causes shear stress injury, endothelial cell dysfunction and results in pulmonary hypertension (PHT) (18). The risk of significant pulmonary haemorrhage in neonates who weigh <1,000 g is about 18.75% (19).

Decreased diastolic systemic blood pressure has serious consequences in end-organ perfusion. hsPDA causing diastolic flow reversal in systemic vessels, e.g., renal, superior mesenteric and middle cerebral arteries has been well documented with the use of ultrasound interrogations. This ‘ductal steal’ phenomenon has been proposed as the cause for NEC, acute kidney injury (AKI), intra-ventricular haemorrhage (IVH), leukomalacia of the brain, and CLD (20). An experiment on premature baboons showed arrested alveolarization and altered pulmonary mechanics when they were subjected to an open ductus for 2 weeks (21). Similar mechanisms could play a role in causing microcirculatory damage in human lungs leading to CLD (22). In the early days of neonatal life, a physiologically less compliant left ventricle (LV) is unable to compensate for systemic hypoperfusion related to hsPDA. As LV compliance gradually increases, improving output and deranged autoregulation could lead to end-organ reperfusion injury (22). This rationale encourages earlier intervention. Clinically, hsPDA presents with oxygenation difficulty, frequent apnoea, increased ventilatory requirements, feeding difficulties, systemic hypotension and metabolic acidosis.

Management principles

Review of available literature demonstrates four main approaches of medical PDA management as elucidated by Hamrick et al. (4):

• Targeted early prophylaxis of PDA. An important study in this context is the systematic review by Ohlsson et al. (23) to compare the role of prophylactic Ibuprofen to placebo/no intervention or Indomethacin in the prevention of PDA in premature infants. It showed prophylactic Ibuprofen reduced the incidence of PDA and the need for other therapeutic modalities. However, prophylactic Ibuprofen increased the risk of renal and GI side effects. It was noted this modality may expose many infants unnecessarily to Ibuprofen since many of the PDAs in this cohort may be expected to close without therapy. In a study by Cooke et al., prophylactic administration of indomethacin was noted to reduce the incidence of PDA by >50% and surgical ligation rates by 50%. Severe grade III and IV intraventricular haemorrhage and serious pulmonary haemorrhage rates were also reduced by 35% and—according to this study—there was no apparent adverse effect on long-term neurosensory outcomes (24). However, others argue that such favourable results may be attributable to indomethacin which was administered to an unselected group of preterms, irrespective of the ductal size and other parameters (25).
• Early targeted treatment of PDA for infants with GA of <28 weeks, and a moderate or large hsPDA needing more than minimal respiratory support (e.g., >2 L nasal cannula flow, >0.25 FiO₂ treatment). Fluid restriction and diuretic therapy is recommended. In the absence of significant respiratory requirements or small PDA, a conservative approach may be justified.
• Treatment of symptomatic infants with hsPDA with ibuprofen. Treatment of hsPDA in symptomatic very low birth weight infants (VLBWI) >6 days of age is considered, if they require more than minimal respiratory support and in the presence of additional risk factors such as an FiO₂ requirement >0.25 or ventilator dependency. However, positive effects on long-term outcomes with this strategy have not been confirmed.
• Late and rescue treatment of symptomatic infants with PDA: pharmacologic therapy in this group of infants is attempted with paracetamol, although the success rate is low (16). Indication for surgical or catheter-based closure in-hospital or following discharge from the neonatal intensive care unit would depend on individual institutional expertise and experience.

COX inhibitors use in PDA

The success rate of indomethacin therapy is 79% when the BW is <1,750 g (26). However, the failure rate is 40–50% if the BW <800 g (27). A significant reduction in the need for surgical ligation has been noted in the early selective treatment group involving high-risk VLBW infants with a BW of <800 g or with a GA of <27 weeks (28). It has been well proven that COX-i works less efficiently with subsequent courses and hence most institutions limit it to two courses. Furthermore, indomethacin could increase the incidence of NEC and bowel perforation in extremely low birth weight infants (ELBWI) (29). According to the PDA/INDO study, which analysed 252 premature infants with symptomatic PDA, treated with intravenous indomethacin, the incidence of bowel perforation was 30% (29). NEC occurred in 35% after indomethacin therapy (30). Oral Ibuprofen has been shown to have a high PDA closure rate (84%), low risk of grade 3 or 4 IVH; however, Ibuprofen was noted to increase the risk of oliguria. There was no effect on reducing mortality, BPD, IVH nor retinopathy of prematurity (ROP) (31).

NEC is a serious complication of indomethacin therapy. A rationale for gut perforation may be diminished splanchnic perfusion due to the PDA’s steal-effect, further aggravated by indomethacin leading to mucosal hypoxia (30). Mucosal hypoxia based on impaired splanchnic perfusion leads to mucosal ulceration; bacterial invasion occurs (32). Immaturity of the lungs, liver, kidney and especially the immune system make VLBW infants susceptible to sepsis. A sparse and flimsy omentum in premature infants contributes to bowel perforation and high mortality (33). GI complications have not been prevented by parenteral administration (32). Contraindications to COX-i therapy include GI bleeding, IVH > grade I, poor urine output, high serum creatinine, high blood urea, disseminated intravascular coagulation and thrombocytopenia.

Mandatory treatment versus non-intervention

A study from South Korea, compared mandatory treatment vs. non-intervention (34). They concluded that in a non-intervention approach, although closure of an hsPDA was more delayed, judicious use of diuretics and fluid restriction was not associated with increased mortality or morbidity such as IVH or NEC. The incidence of BPD was also noted to be lower when compared to mandatory treatment. However, larger and randomized control trials would be needed to irrefutably conclude on these observations. Lemmers et al. (35) demonstrated that long-standing hsPDA exposed the cerebral tissues to lower saturations and led to cerebral volume reduction at corrected term-age. So, long-term effect of the non-intervention strategy requires further elucidation. Furthermore, repeated administration of COX-i prevents intimal thickening in the PDA and may actually prevent ductal closure (36,37).

COX inhibitors versus surgical ligation—confounded?

Some studies have revealed that there was no significant difference in the survival rate between premature infants who underwent COX-i treatment when compared to surgical ligation (38). But majority of the patients who had surgical treatment had initial COX-i therapy and had spent a substantial amount of time on mechanical ventilation before being considered for surgical ligation (38). Prolonged exposure to hsPDA increases the duration of pulmonary hyperaemia and GI perfusion which leads to a poor pulmonary condition and poor nutritional status (4). Mellander et al. noted that failure of pharmacologic treatment in neonates prolonged ventilator duration after surgical ligation of PDA (39). Failure to adjust for confounding factors such as IVH, duration and intensity of mechanical ventilation, NEC, sepsis, introduces residual bias in observational studies (39). Confounding yet interrelated factors in both non-surgical and surgical groups, cloud the true merits of surgical ligation, per se.

The Brazilian Neonatal Research Network (BNRN) conducted an interesting multi-centre study analysing the outcomes of PDA treatment strategies on newborns with a BW of <1,000 g and GA <33 weeks (40). Group 1 (G1, n=187) had a conservative approach, Group 2 (G2, n=205) had pharmacological treatment and, Group 3 (G3, n=102)—with/out of previous therapy—underwent surgical ligation. The mortality rate in G1 was noted to be 51.3% whereas the mortality rate in G3 was only 14.7%. The highest prevalence of BPD (70.6%) and ROP was observed in G3. NEC, IVH (grade 3 or 4) were identified as risk factors for the outcome of death. Composite outcome of death/BPD was the best with pharmacological treatment (G2). Again, results could have been confounded by the fact that surgical ligation seldom was the primary mode of therapy but rather the last option among the three, which meant that G3 infants were exposed to the consequences of PDA, mechanical ventilation and nutritional deficiency and side effects of other, e.g., pharmacological modalities of therapy.

A study from the United States, analysed 429,900 neonatal admissions, using data from the National Inpatient Sample (NIS) and Kids Information database of the Healthcare Cost and Utilization Project from 1998 to 2015 (41). All infants with GA 24–32 weeks and BW <1,500 g were included. PDA was present in 149,473 (34.8%). PDA ligations were noted to be more likely in those with smaller GA and BW <1,000 g. Though the mortality rate was lower in the ligation group, incidence of NEC and pulmonary haemorrhage was higher. The authors comment that it is difficult to discern whether the association of NEC and pulmonary haemorrhage were directly related to surgical ligation or due to the other co-existing factors and comorbidities. Studies may fail to adjust for confounders and could be subject to inadvertent bias (42). A decline in surgical ligation rates was noted from 2004.

Growth and development post-surgical ligation

A British study from the National Health Services, UK, attempted to compare the growth outcomes of infants after PDA treated conservatively, medically or surgically (43). Growth outcomes were analysed at 36 weeks of age. Surgical management of PDA was noted to be associated with a greater degree of growth delay among premature infants with PDA. The authors concluded that mechanisms by which surgical ligation was associated with poorer growth outcomes were not fully understood; and it may be possible that ‘surgical ligation’ itself was a surrogate of implicating factors, e.g., lower GA, BW, co-morbidity, exposure and consequences of other management strategies.

Indications for surgical therapy

Surgical ligation should be considered in high-risk infants with hsPDA of a diameter >2 mm, that remains open in spite of two courses of COX-i therapy and requires mechanical ventilation by day 28 of life (20). PDA ligation may not be recommended in extubated patients to continuous positive airway pressure (CPAP)/nasal intermittent mandatory ventilation (NIMV); they can be followed up with serial echocardiograms. Infants with contraindications to COX-i including IVH, thrombocytopenia, renal failure or NEC are considered for surgical ligation when PDA is significant and other features, e.g., ventilator dependence, pulmonary oedema, systemic hypotension requiring at least a single inotrope, hourly episodes of desaturation and/or metabolic acidosis are present (41). Some authors recommend surgical ligation as the first line of management in contrast to COX inhibitors in preterm neonates weighing <800 g (27). Absolute contraindication to surgical ligation is severe PHT with right-to-left shunt, whereas, bidirectional flow, life-threatening sepsis and septic shock may be relative contraindications—in the latter cases, PDA ligation by improving haemodynamics could, indeed, be the only chance for survival (44).

Timing of surgical ligation

Some studies have shown, surgical ligation of hsPDA is associated with an increased incidence of CLD, ROP and NDI (36,45). Other investigators, however, contradict this observation as described below.

A study from South Korea (46), aimed to look at the outcomes following early surgical ligation (<10 days of life) in preterm neonates with hsPDA. After adjustments for confounding factors, the early ligation group was noted to have lower incidence of IVH > grade 3, culture-proven sepsis, NEC > grade 3 and time on mechanical ventilation >4 weeks. The late ligation group had significantly higher risk of prevalence of all these parameters.

Best timing of surgical ligation is still controversial, as prevailing policy leaves surgery as the last resort. Some reports have shown that early ligation (<2–3 weeks of life) has a reduced incidence of BPD and NEC, improved enteral feed tolerance and resulted in quicker return to full oral feeding. Early surgical intervention significantly improves the nutritional status and weight of these infants (47,48).

Two studies from the Hospital for Sick Children, Toronto, by McNamara and colleagues, have shown that ‘timely’ surgical ligation offered clear benefits to preterm infants by significantly decreasing mortality and without an increase of CLD, ROP and/or neuro-developmental impairment (NDI) (49,50).

Risks associated with surgical ligation

Surgical ligation represents an immediate and definitive solution to stop hsPDA’s left-to-right shunt. Early and late postoperative co-morbidities e.g., bleeding, chylothorax, left recurrent laryngeal nerve (LRN) injury, development of coarctation, sepsis, phrenic nerve injury, pneumothorax, hypothermia, lobar collapse and thoracic scoliosis are rare (51). Without risk adjustment (surgical candidates tend to be more premature, weigh less, are typically exposed longer to the ill effects of a hsPDA, as well as to mechanical ventilation and are usually nutritionally deficient) comparisons would be biased. Surgical ligation may not be available in all NICUs and transporting these very sick infants further increase the risk (36). Several observational studies have demonstrated association of CLD, ROP and NDI with surgical ligation, so clarification of any causative relationship warrants risk stratification (42,49,52-54).

Post-ligation physiology entails significant haemodynamic changes: LV afterload increases, whereas, its preload decreases acutely after surgical ligation. They cause a drop in cardiac output (55). The scenario of systemic hypotension, metabolic acidosis and respiratory failure is termed the post-ligation syndrome (56,57). Echocardiogram reveals decreased left ventricular end diastolic diameter (LVEDD) and left atrium to aortic ratio (LA/Ao ratio); it surrogates for LV preload/afterload conditions the LV is exposed to. Infants who undergo ligation at an earlier age are at a greater risk of haemodynamic instability since the immature myocardium is very sensitive to loading conditions (58,59) which may be attributed to the neonatally different myofibrillar architecture, immaturity of receptor development and/or regulation (60).

LRN injury resulting in left vocal cord paresis or palsy (LVCP) is a serious concern with surgical PDA ligation. The LRN loops around the PDA and injury to this delicate but important structure either by stretch/contact injury (including diathermy) is a well-recognised complication of PDA ligation. The reported incidence of LVCP varies considerably between different authors which may be due to different vocal cord assessment protocols post-surgery. The pooled incidence of LVCP was noted to be 32% (0–67% in individual studies) when only children examined with laryngoscopy were included (61-63). Low GA, low BW and low weight at surgery are known risk factors (64). A large PDA, however, can compress the LRN and cause LVCP by itself. Endotracheal intubation and prolonged ventilation in this group of VLBWI/ELBWI may be other etiological factors. Idiopathic or neurological causes of LVCP have been reported in neonates (65). Preoperative laryngoscopy was not performed in all but one study in the pooled series. Without preoperative laryngoscopy, surgery could be falsely implicated for this condition.

Early symptoms of LVCP include stridor, hoarseness, weak cry and feeding difficulties (62). Symptoms may not always be present or may be weak and sometimes might go unnoticed unless actively looked for. The recommended diagnostic method to look for LVCP is flexible nasolaryngoscopy (66). A national cohort study from Norway, studied lung function and exercise capacity of young adults who were born extremely premature and had neonatal PDA ligation (67). The mean age at examination was 19.4 years in 48 of the eligible 63 individuals. Fifty three percent of the study subjects had LVCP. They self-reported voice symptoms and laryngeal obstruction during exercise. Forced expiratory volume in one second (FEV₁) Z-score was reduced in the LVCP group as compared to controls. The authors concluded that these individuals born extremely premature and having had a difficult start in life, in spite of LVCP, achieved an exercise capacity only modestly decreased to peers born as full-term infants.

Though NDI has been associated with surgical ligation of PDA, these studies do not identify what specific surgery-related cause forms the pathophysiologic basis of NDI. A Japanese group looked at this aspect by enrolling 71 ELBWI (68). Parameters including the development quotient (DQ, surrogate for NDI) were collected and compared among three groups: (I) spontaneous closure group (G1, n=11); (II) patients who received COX therapy (G2, n=37); and (III) infants who underwent surgical ligation (G3, n=23). At the age of 36 months, there was no significant difference in the DQ among the three groups. A statistically significant DQ difference was only noted when the parameters were adjusted for prematurity, GA, BW, APGAR score at 1 minute and laser coagulation for ROP. There was no association with hsPDA. The authors concluded that the policy of surgically ligating hsPDAs early after failure of COX-i therapy may be safer to prevent NDI.

It is common practice and safe to perform PDA ligation in the neonatal intensive care unit (NICU) (69). Thermo-regulation of these tiny and fragile infants with haemodynamic compromise is poor and they also need multiple monitoring lines and equipment which makes their transport to the operating room cumbersome and unsafe. There are several other procedures that are being done in the NICU bedside including gastrostomy, tracheostomy, repair of trachea-oesophageal fistula, laparotomies, repair of abdominal wall defects and several urinary tract interventions (70). Open communication and teamwork among surgeons, anaesthesiologist, neonatologists, along with OR, NICU nurses and radiographers is the key to success. Open NICU incubators are suitable as they allow appropriate lighting, workspace and are accessible to monitoring equipment. Dislocation of the endotracheal tube during positioning of the patient or dislodgement of monitoring lines should be avoided at all costs. In a well-equipped NICU bedside PDA ligation could be carried out safely and expeditiously.

Anterior mini-thoracotomy for PDA ligation

Surgical ligation of PDA is usually performed through a left posterior or posterior-lateral thoracotomy, entering through the left 3^rd or 4^th intercostal space. It necessitates retraction of the left lung to approach the ductus. Congested or hypertensive lungs may not tolerate retraction for longer durations. Alternate approaches like left anterior mini-thoracotomy using a 2–3 cm incision entering the thorax through the left 2^nd intercostal space and clipping the ductus intra-pericardially has been described (71). The authors report an easy access to the ductus, minimal lung retraction, better cosmetics and shorter surgical times. A study from France compared anterior mini-thoracotomy for PDA ligation and transcatheter closure of the ductus in very preterm infants from 2010 to 2020 (72). Using a 1:1 propensity matched analysis 22 patients were included in each arm. Mean time to extubation, mean age at hospital discharge and incidence of mortalities and complications were noted to be similar.

Transcatheter closure of hsPDA in premature infants

Catheter based device closure of hsPDAs in premature infants has been gaining ground in many institutions. The long and tortuous anatomy of the DA in the ELBW infant (73) compromises the effectiveness of devices approved for use in infants and children >5 kg (74). The recently approved Amplatzer Piccolo occluder for use in infants and children >700 g seems to be promising. The success rate was quoted as 95.5% (191/200) in all patients and 99% (99/100) in patients <2 kg (75). It often requires the patient to be shifted to the catheterisation lab and is performed through the femoral vein since the femoral artery access is fraught with risk in these small infants. Coarctation of the aorta, device embolization, left pulmonary artery stenosis, tricuspid valve injury and residual shunt have been reported after this procedure (76). Rare complications include IVC laceration, cardiac perforation, pericardial effusion needing drainage and mortality/morbidity arising out of these complications (77). Post ligation syndrome has also been observed in ELBW infants post device closure, albeit in smaller numbers (78). Long-term outcomes in terms of BPD, death and impact on NDI have not been reported and remain to be seen. This mode of therapy appears promising and could become an established mainstream mode of treatment.

Our optimal management strategy

An optimal care provision is imperative for preterm infants in whom treatment options are varied and may be contentious at times. Based on pathophysiology and accepted therapeutic principles in the scientific literature (78,79), the following decision making algorithm is very useful, which is followed in our department (Figure 1, Table 2).

• Prophylactic indomethacin (a risk factor for IVH in ELBWs) is advocated for preterm with extremely low GA babies (<23 weeks without corticosteroid pretreatment), as it has been shown to significantly reduce IVH, symptomatic PDA and a need for surgical ligation (80).
• Early pharmacotherapy (within 7 days of life) has a limited role in extremely preterm infants (<26 weeks) with hsPDA. Randomized controlled trials (RCTs) have looked at the benefits of indomethacin vs. ibuprofen vs. acetaminophen (81). The safety of high-dose ibuprofen in extremely preterm neonates is less than optimal and it has to be used with caution. Periventricular leukomalacia has been reported in infants receiving more than two courses of Indomethacin and a third course has not been shown to be consistently beneficial either. We currently advocate early pharmacotherapy only in premature Infants with hsPDA who develop significant pulmonary haemorrhage.
• In premature infants with a higher GA and hsPDA, conservative therapy with fluid restriction and frusemide is appropriate; however, aggressive fluid restriction may potentially reduce systemic perfusion. Positive end expiratory pressure (PEEP) is another essential tool in the conservative therapy armamentarium. We tend to avoid frusemide if possible, opting for fluid restriction and stop frusemide at least 24 hours prior to the first dose of non-steroidal anti-inflammatory drug (NSAID).
• In premature infants with hsPDA, demonstrated on echocardiography and who are clinically symptomatic, our first line of therapy is to treat them with intravenous ibuprofen. If there are contraindications to ibuprofen (renal dysfunction, GI perforation, NEC, sepsis, severe hyperbilirubinemia, active bleeding, severe thrombocytopenia, hypersensitivity) intravenous paracetamol would be the option, as shown in the algorithm.
• Surgical ligation has a well-defined role and is indicated in infants who have not benefited from or who have contraindications to pharmacotherapeutic agents and still continue to have a symptomatic hsPDA.

Figure 1 Optimal PDA treatment strategy. PDA, patent ductus arteriosus; GA, gestational age; hsPDA, haemodynamically significant patent ductus arteriosus; PEEP, positive end expiratory pressure.

Strengths and limitations

This narrative review aiming to provide a balanced view combines the management principles of PDA in preterm infants by studying literature from multiple specialities including neonatology, paediatric cardiology and congenital cardiac surgery. However, most studies are retrospective and/or observational. Furthermore, given the heterogenicity of the included studies some key aspects could have been underplayed or overestimated. A comprehensive RCT with risk stratification seems essential to analyse individual therapeutic modalities to offer standardised high-quality care for this cohort of vulnerable patients.

Conclusions

We summarize the salient points on the current trends in the management of hsPDA in preterm infants:

• There is a strong correlation between smaller GA/lower BW and the prevalence of hsPDA/complications.
• PDA in preterm infants needs to be considered as a ‘spectrum’ rather than an isolated pathophysiological entity. A careful and complete understanding of each infant’s individual clinical situation is essential before appropriate therapy can be initiated.
• Many studies show that almost 40% of PDAs in preterm infants would ultimately close. Subjecting all preterm infants to therapy is not recommended; conservative management with judicious fluid restriction and diuretics with ventilation strategies may be effective.
• Studies are divided on the use of prophylactic interventions in ELBWI. The BeNeDuctus trial showed expectant management to be non-inferior to early Ibuprofen in this cohort of infants.
• With the advent of COX-i therapy, the need for surgical ligation has decreased significantly. COX inhibitors tend to become less effective with subsequent courses and persisting with more than two courses is not recommended.
• A number of studies noted higher incidence of mortality, NEC, CLD and NDI after surgical ligation; however, most of these studies may have a residual bias since surgical ligation was only applied as the last option of therapy. Infants undergoing surgical ligation are typically older (after other therapeutic trials), had been on prolonged mechanical ventilation and are nutritionally depleted. Direct comparison among the different modalities of therapy and their results is not justified.
• Timely therapeutic decisions on both COX-i and surgical ligation (within 2 weeks of the second failed COX-i attempts) may prevent complications in these vulnerable patients.
• Incidence of LVCP after PDA ligation is significant; however, it may be falsely high. Inclusion of preoperative laryngoscopy and a proactive survey for LVCP postoperatively would help identify the true incidence and the course of recovery. This complication should not be viewed as prohibitive to surgical ligation.
• Though identified to have a clear association with PDA, neurodevelopmental impairment and CLD are two conditions whose exact pathogenesis and association with therapeutic modalities has not been clearly described. Further studies are warranted to provide a clear understanding of these conditions.
• Catheter based interventions to close PDAs is a viable option especially after the approval of the Amplatzer-Piccolo device in infants >700 g and is gaining ground in many centres around the world so much so that it has taken over surgical ligation as the primary mode of Invasive closure in these centres (82,83).

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-24-6/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-24-6/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-24-6/coif). L.K. serves as an unpaid editorial board member of Pediatric Medicine from July 2024 to December 2025. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring the questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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