Approach

The main goal of treatment in premature infants is to prevent morbidity and mortality secondary to haemodynamic instability and co-morbidities such as respiratory distress syndrome, intraventricular haemorrhage, and necrotising enterocolitis.[21][23]​​​​​[24]​ As a result, there are different treatment strategies for premature infants, full-term infants/children, and adults. Integrating family-centred care into the treatment plan for children with PDA is crucial, promoting parental involvement in care routines and developmental support to foster a neurodevelopmentally stimulating environment. Perioperative care for children undergoing surgical correction of PDA should focus on maintaining haemodynamic stability and adequate cerebral oxygenation, with anaesthesia protocols designed to minimise potential brain injury.[8]

Premature infants

A great deal of controversy remains over how, when, and if to treat patent ductus arteriosus (PDA) in premature infants.[49] Four main management approaches can be differentiated:[50]

  1. Early targeted prophylaxis (<24 hours)

  2. Targeted therapy of asymptomatic infants (<6 days after birth)

  3. Symptomatic treatment when the PDA becomes haemodynamically relevant (≥6 days after birth)

  4. Late symptomatic treatment after watchful waiting OR rescue treatment after previously failed treatment.

Treatment options include medical therapy, conservative management, surgical intervention, or percutaneous catheter device closure. The cyclooxygenase (COX) inhibitor indomethacin, given intravenously, has been the mainstay of medical treatment since pharmacotherapy for PDA was introduced to clinical practice.[50]​ COX inhibitors work by inhibiting prostaglandin synthesis. New formulations, however, such as oral and intravenous ibuprofen, and oral and intravenous paracetamol, have now increased the range of treatment options. Furthermore, use of COX inhibitors is declining in favour of watchful waiting (conservative management).[50]​ Surgical ligation or percutaneous catheter device closure may be considered if initial medical treatment fails.

Early targeted prophylaxis - indomethacin

Prophylactic indometacin involves treatment with indometacin at 0 days of life before a PDA becomes clinically evident. The first dose is usually started within the first 12 hours of life. It is usually reserved for very low birth weight infants (the cut-off varies between centres, but is normally <1300 g or <1000 g). Cochrane reviews have found that it decreases the rate of PDA, the need for surgical ligation for PDA, and the rate of intraventricular haemorrhage in this population.[48][51][52][53]​​​ [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] ​​​​ However, no difference has been reported in mortality rate, incidence of morbidities such as necrotising enterocolitis and bronchopulmonary dysplasia, or long-term neurosensory outcome.[51] [ Cochrane Clinical Answers logo ] ​[53]​ Infants being treated with indomethacin must have electrolytes, creatinine, urine output, and platelets monitored regularly during administration. Feeds are withheld. Complications can include necrotising enterocolitis, bleeding, or renal dysfunction.[54][55]

Medical treatment - ibuprofen or indomethacin

Medical treatment is first-line for preterm infants in whom ductus has become clinically evident or has been diagnosed by echo and should be initiated within the first few days of life.

  • Ibuprofen: while indometacin was previously the standard of care, ibuprofen is now largely considered the pharmacotherapy of choice due to its similar efficacy but significantly better safety profile.[56][57][58][59]​​ One Cochrane review comparing both oral and intravenous ibuprofen with indometacin found a decreased risk of necrotising enterocolitis and transient kidney injury in patients treated with ibuprofen, with similar effectiveness between interventions.[56] [ Cochrane Clinical Answers logo ] ​​ Both ibuprofen and indomethacin have been shown to reduce the risk of severe intraventricular haemorrhage, although indomethacin appears to be more effective, hence why it is used in preference to ibuprofen as a prophylactic treatment in very low birth weight babies.[53]​ Studies suggest that high-dose ibuprofen may increase the likelihood of PDA closure compared to standard-dose ibuprofen.[53][56][60][61]​​​​​ High-dose ibuprofen may therefore be considered the preferred dosage; however, significant caution should be exercised in preterm infants younger than 26 weeks due to a lack of data in this age group.[57] Studies have reported that oral ibuprofen is as effective as intravenous ibuprofen, with no significant difference in morbidity demonstrated.[56][62][63]​ More recently, an overview paper, which summarised the evidence from 16 Cochrane Reviews of randomised controlled trials, found that oral ibuprofen appears to be more effective in PDA closure than IV ibuprofen in preterm infants.[53]

  • Indomethacin: treatment with indometacin has shown to be successful in closing symptomatic PDAs compared with placebo.[27][64]​​ While some centres practice a prolonged course of indometacin (>4 and usually 7 doses), no significant difference has been shown in successful PDA closure, need for re-treatment, need for surgical ligation, or such outcomes as mortality and the incidence of co-morbidities such as chronic lung disease or necrotising enterocolitis with this longer regimen.[65] B-type natriuretic peptide (BNP)-guided treatment has been shown to reduce the number of primary indometacin doses in infants with PDA.[66] In one small study, subsequent indometacin doses were withheld if a 12-hour or 24-hour BNP level after the first dose was <100, with no difference in PDA persistence found between the groups.[66]

​If the first course of ibuprofen or indometacin is unsuccessful, a second course is usually given prior to consideration of procedural closure.[57]

Conservative management

Conservative management may be considered as an alternative to medical treatment in certain circumstances. The Canadian Paediatric Society makes a conditional recommendation for conservative management of symptomatic PDA in the first 1-2 weeks post-birth.[57] One systematic review and meta-analysis found no significant differences in morbidity or mortality in clinical trials assessing conservative management compared to pharmacological or surgical treatment in preterm infants.[67] One Cochrane review had similar findings, with early (<7 days old) or very early (<72 hours old) empiric treatment of PDA no more effective than conservative management in mortality or morbidity outcomes (including development of chronic lung disease, necrotising enterocolitis, severe intraventricular haemorrhage, or neurodevelopmental abnormalities).[68] One multi-centre randomised controlled trial found that expectant management for PDA in extremely premature infants was non-inferior to early ibuprofen treatment with respect to necrotising enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks’ post-menstrual age.[69]​ Conservative management in preterm infants may involve diuretic therapy, increasing positive airway pressures, and fluid restriction, although these approaches have not been systematically assessed in clinical trials.[57][59][70][71]​​​ Significant caution should be exercised if considering conservative management in high-risk preterm infants (e.g., those younger than 26 weeks).[57]

Surgical ligation

Surgical ligation is usually reserved as a second-line treatment when medical treatment has failed or is contra-indicated.[57][72]​​​ It can be performed on premature infants as small as 600 g. Surgical ligation of the duct generally has very high success rates, with low associated morbidity.[54][73]​​​​​ Complications are rare and include recanalisation of the duct, pneumothorax, effusion, haemorrhage, and wound infection.[74]​ While one study did show a relatively high late mortality in preterm infants, this was felt to be related to the high risk inherent in this population, rather than to the surgery itself.[75] There has been some inquiry into the favourability of surgical ligation as first-line management in this population.[76][77]​​​ However, there are currently limited data to allow for adequate comparison of the two treatment approaches.[76] [ Cochrane Clinical Answers logo ] ​​​ One review suggested that there may be little benefit to prophylactic surgical ligation compared with no therapy or medical therapy, with no significant decrease in mortality or bronchopulmonary dysplasia.[78] Another review refuted earlier postulations that primary surgical ligation may decrease the incidence of necrotising enterocolitis.[79] Videothorascopic surgical ligation is being used with increasing frequency in selected cases with good results.[80]

Percutaneous catheter device closure

Transcatheter closure of PDA in preterm and extremely low birth weight infants is becoming more feasible and less complicated with the advent of smaller devices and smaller delivery sheaths. In practice, this is becoming a more common second-line therapy for ductal closure than surgical ligation in most academic centres.[57][59]​ Catheter devices include coils, the Amplatzer duct occluder, the Rashkind umbrella device, and the Gianturco-Grifka occlusion device. Choice of device depends on ductal morphology and operator choice during the procedure.[81]​ Patients are given subacute bacterial endocarditis prophylaxis for 6 months after the procedure, or longer if turbulent flow persists around the device.[82]

Full-term infants and children

The goal of treatment in this group is to alleviate or prevent heart failure and to prevent increased pulmonary pressures with a significant shunt. With smaller shunts or silent PDAs, the goal of treatment is the prevention of endarteritis through routine closure. However, this remains controversial. Any infant or child who is symptomatic usually has closure as soon as possible.

Percutaneous catheter device closure

First-line treatment in this group of patients is catheter device closure if patients are of sufficient size, as it avoids surgery and can usually be done with just a day admission or overnight hospital stay. Safe device closure has been reported in patients as young as 6 months and as small as 5 kg.[83] Transcatheter closure is also usually reserved for small- or moderate-sized ducts, although with newer devices, larger ducts have been able to be treated with increasing efficacy.[84] If infants are asymptomatic, the procedure is often delayed until they are close to 1 year of age. In children >1 year, the procedure can be scheduled at the time of diagnosis, either electively or as needed, depending on their symptoms and left heart overload. The procedure has an extremely high success rate of >95% with no mortality and few complications.[85][86]​ Complications can include coil embolisation, persistent turbulent flow around the device and residual leak.[86][87]​ Complications are more likely to occur in smaller children.[87] There are several types of device that can be employed for catheter closure and choice of device usually depends on the morphology of the duct.[81]

Diuretics

Patients who present with symptoms outside of the neonatal period, may not be large enough to undergo percutaneous device closure at the time of presentation. Provided that the child is gaining weight adequately, diuretic therapy with furosemide may be used on a temporary basis to improve symptoms and allow the patient to reach a suitable size for percutaneous intervention.

Surgical ligation

Surgical ligation in full-term infants and children is usually reserved for ducts that are too large for closure with a transcatheter device, or for symptomatic infants whose physical size and anatomy are thought to be too small for transcatheter device closure. However, the exact size below which transcatheter device closure is felt to be unsuitable may vary with clinician and institution.[83][88]​ If the patient is symptomatic, surgical ligation is undertaken as soon as possible. If asymptomatic, ligation can be scheduled electively. Success is high with few complications that can include operative pneumothorax, haemorrhage, effusion, or long-term recanalisation.[73][75]​ With increased percutaneous device closure experience, smaller and younger children are being taken to the catheterisation laboratory, so referral for surgical ligation is decreasing in infants younger than 6 months, although this is dependent on institution.[83][88]

Adults

Percutaneous catheter device closure or surgical ligation

In certain adults with PDA, closure may be necessary if there is significant left-to-right shunt and/or pulmonary hypertension. Surgical or catheter-based closure is recommended, provided that pulmonary vascular resistance is not prohibitively high.[39][89][90]​ Currently, most advocate closure via a transcatheter device in adults with a small-to-moderate patent ductus; this method has been shown to be safe and effective in this population.[91][92]​ Concerns regarding ductal tissue friability in adults with larger PDAs have led some centres to pursue video-assisted thoracic surgery (VATS) ligation, with good results.[93]

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