2.2. Endothelin Pathway

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that acts on two receptors: ET_A and ET_B. ET-1 is made by vascular endothelial cells. ET_A receptor promotes vasoconstriction while ET_B promotes vasodilation. This is the pathway targeted by endothelin receptor antagonists (ERA); in infants the most studied drug in this class is bosentan.

Bosentan is an ET-1 receptor antagonist and works at both ET_A and ET_B receptors. Bosentan is beneficial in adults with PH and there are limited studies in infants with some signal of benefit. In infants with PPHN a study by Kumar et al showed elevated levels of ET-1 in infants with PPHN compared to controls but this finding was not found in another study by McDonald et al who looked at ET-1 levels in infants with PPHN requiring ECMO.[34, 35] A study by de Laguisie in infants with CDH showed that ET receptors, and preferentially ET_A receptors, demonstrated over-expression and could contribute to PPHN in CDH.[36]

A 2016 Cochrane review examined 2 ERA studies for PPHN in infants. [37, 38, 39] In the first study by Mohamed et al., they compared bosentan alone vs placebo in 47 infants >= 34 weeks gestation. That study showed better oxygenation index and shorter duration of mechanical ventilation in the bosentan group. The second study by Steinhorn et al. compared inhaled nitric oxide plus bosentan vs inhaled nitric oxide plus placebo in 21 infants with PPHN who were >=34 weeks gestation. This study showed that bosentan was well tolerated by infants but there was no significant clinical improvement with treatment. The study was confounded by imbalance in markers of disease illness between groups (higher OI and use of vasoactives in the bosentan group). The pharmacokinetics from this study demonstrated that steady state was achieved by day 5 of treatment. Overall, the Cochrane review concluded that: “There is inadequate evidence to support the use of ERAs either as stand-alone therapy or as adjuvant to inhaled nitric oxide in PPHN. Adequately powered RCTs are needed.”[37]

Bosentan is metabolized by the liver and excreted via the biliary system. It induces the CYP3A4 enzyme which is clinically relevant especially because it will decrease the plasma concentration of sildenafil (which is cleared by hepatic metabolism). [40] It is only available in oral form. The infant dose of bosentan is typically 2–4 mg/kg/day divided twice a day.[41] It requires monitoring via the REMS program due to adverse reactions related to transaminitis and liver injury as well as teratogenicity. Per the company guidelines, bosentan should not be initiated or continued if the alanine transaminases and aspartate aminotransferases are three times the upper limit of normal or greater OR the total bilirubin is two times the upper limit of normal or greater. Patients require continued surveillance of their liver enzymes (and methods of contraception if childbearing age) while on the medication.[42]

Ambrisentan and macitentan are other endothelin receptor antagonists approved for adults with pulmonary hypertension, however there is limited data in children and specifically, infants. Ambrisentan is an oral, once-daily, ET_A-selective ERA. In adults it was associated with better exercise tolerance as measured by 6-minute walk test. It also has shown less risk of hepatotoxicity obviating the need for laboratory monitoring as well as less drug-drug interactions compared to bosentan (most notably bosentan interacts with sildenafil and warfarin, which was not seen in studies of ambrisentan). [43] Macitentan is an oral, once-daily, ET-1 receptor antagonist and works at both ET_A and ET_B receptors (similar to bosentan). Like ambrisentan, macitentan has less concern for hepatotoxicity and drug-drug interactions.[44] There is currently a multi-center study investigating macitentan in infants and children with pulmonary arterial hypertension (NCT02932410).

2.3. Prostacyclin Pathway

Prostacyclin medications are another class of pulmonary vasodilator therapy that work via the arachidonic acid-prostacyclin pathway and lead to activation of adenylate cyclase and production of cyclic AMP in vascular smooth muscle cells, specifically the pulmonary artery smooth muscle in PH. Prostaglandin I2 (PGI2) analogs are the main prostacyclins used clinically in PH therapy. Three main analogs of PGI2 are available and each has specific routes of administration: epoprostenol, iloprost, and treprostinil.

Epoprostenol is given commonly as an IV continuous infusion. It was the first prostacyclin analog approved for PH therapy in the 1990s. It has a short half-life of 6 minutes which can make it a challenging medication to manage as an outpatient. It also can reduce systemic blood pressure prohibitively, which can limit achieving ideal dosage and effect. A study of 36 patients demonstrated response in 15 patients when added to inhaled nitric oxide. In the responder group, the average improvement in oxygenation index was 11 within 4 hours.[45] Systemic hypotension can be avoided by using the inhaled version of epoprostenol. Typical dosage of inhaled epoprostenol is 50 ng/kg/min.[46]

Iloprost is another prostacyclin analog that can be used to treat PH via intravenous route or inhaled. In a study of infants with PPHN it has been shown to improve PaO2 and oxygenation index in a subset of responders (n=12).[47] Another study by Kahveci et al also showed clinical improvement (lower systolic pulmonary artery pressure and lower oxygenation index) in infants with PPHN treated with inhaled iloprost in comparison to oral sildenafil.[48] The dose in this study for infants was 1–2.5 mcg/kg/dose with an interval of 2–4 hr between doses for all patients. For reference, the recommended dose for older pediatric patients is 2.5 or 5 μg of inhaled iloprost. It is recommended to start with the lower dose and then increase the dose for the second inhalation, if tolerated. Iloprost should not be taken less than 6 times per day and up to 9 times are allowed. Max dosing is 45 mcg per day.[6, 7, 49]

Treprostinil is a prostacyclin analog that was developed to be more stable than epoprostenol, with a longer half-life of 3 hours in adults. It can be delivered by oral, subcutaneous, or intravenous route. There is limited literature in infants and children but that limited data seems to support that treprostinil may be safe in infants and children.[50, 51] In a study of 5 pediatric patients started on subcutaneous treprostinil for PH, the initial dose was 1.25 ng/kg/min with an up-titration of 1.25 ng/kg/min every 12–48 hours to a target dose of 20 ng/kg/min and then titrated up weekly to a range of 20–50 ng/kg/min. This medication should be used cautiously in patients with hepatic dysfunction and may require dose reduction or discontinuation. Hypotension has also been reported.[51]

Prostaglandin E1 (PGE1) also known as alprostadil is commonly used medication as a continuous IV infusion to keep the patent ductus arteriosus open in neonates with critical congenital heart disease as a palliation to promote either systemic or pulmonary blood flow. Similar to other prostacyclins, it acts by increasing cyclic AMP. It also has been theorized to be of benefit for neonates with severe PH consisting of supra-systemic pulmonary artery pressures by keeping the PDA open to allow for a right to left pop-off shunt to reduce the pressure load of the right ventricle. This concept is supported by a 2 small studies in CDH infants [52, 53] and a brief report of 51 infants with PPHN without congenital heart disease. In the PPHN study, PGE1 therapy was associated with shorter LOS but no difference in hospital mortality.[54] In summary, PGE1 can be considered for neonates with severe PH, particularly patients with CDH or PPHN.

In general, this group of medications has a common side effect profile that should be considered. Hypotension can be seen especially in IV formulations. Rebound pulmonary hypertension can occur with abrupt discontinuation of the medication. Flushing, syncope, and hypotension can also occur and may require dose reduction or discontinuation of the medication. These medications may also inhibit platelet aggregation and lead to bleeding complications. Significant jaw pain can develop in patients and limit tolerance to treatment. With inhalation forms of prostacyclin analogs, bronchospasm may occur.[7, 41]

2.4. Other Pharmacotherapies for Pulmonary Hypertension

Other common medications have been considered for treatment of PH including steroids, oxygen, calcium channel blockers, and diuretics. Clinical data regarding steroid use in infants with pulmonary hypertension is limited to case reports and case series.[55, 56] There is limited animal data that supports a possible role for glucocorticoids in PPHN via inhibition of phosphodiesterase-5, but clinical data is lacking.[57, 58] Oxygen therapy and the treatment of hypoxia promotes pulmonary vasodilation in preterm and term infants. However, this needs to be balanced with the risks of hyperoxia in preterm infants such as retinopathy of prematurity.[59] Optimal oxygen saturations are unclear but targeting 90–97% oxygen saturations appear to be a reasonable goal.[60] Although a common treatment in adults for pulmonary hypertension, calcium channel blockers have limited data in infants. One study of 9 infants with PH-BPD showed no improvement in PAP or PVR/SVR with treatment of a CCB.[61] Diuretics (including loops, thiazides, and K-sparing diuretics) can be used for symptomatic relief and decongestion experienced from RV or LV dysfunction in patients with PH. Interestingly, one study of PH in BPD demonstrated that 25% of infants with PH-BPD had evidence of LV diastolic dysfunction at cardiac catheterization.[7, 61] Use of diuretics requires careful management is required because over-diuresis can reduce the preload to the right ventricle and lead to impaired cardiac output.[7]

Pharmacotherapy for WHO Group 2 PH which is PH secondary to left-sided heart disease (post-capillary PH) includes a variety of medications to treat the underlying disease process. This group includes diseases such as left ventricular diastolic dysfunction, pulmonary vein stenosis, mitral stenosis/regurgitation, and assorted cardiomyopathies. Often these patients are placed on heart failure medications beyond the scope of this review but typically can consist of IV vasoactive support, beta-blockade, angiotensin converting enzyme inhibition, and diuretics including spironolactone. [62]

Newer PH drugs for adults have limited exposure to infants including selexipag, sotatercept, and riociguat. Selexipag is an oral prostacyclin receptor agonist. In adults it has demonstrated benefit but studies in infants and children are lacking.[63] Koo et al described a case of successful transition from IV Treprostinil to enteral selexipag in a 11-month-old infant but no actual studies have occurred.[64] Sotatercept is a protein that works on transforming growth factor beta and has been shown to improve 6 minute walk test in adults with PAH. Currently there is a trial in children (NCT 05587712) but no studies in infants have been performed. Riociguat was approved for use in adults with pulmonary hypertension in 2013 [65] specifically those patients with Group 1 PAH or Group 4 CTEPH. Riociguat is a soluble guanylate cyclase stimulator. This simulation of soluble guanylate cyclase acts to promote formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP) and promotes relaxation of the vascular smooth muscle cells. Riociguat also promotes nitric oxide binding to soluble guanylate cyclase to further simulate cGMP production and vasodilation. Thus, it has a nitric oxide independent and dependent mechanism of action. Limited studies have been performed in infants but recently a Phase 3 study of 24 children (age 6–17) was completed demonstrate a suitable dosing strategy for riociguat in children and adolescents with PH but did not assess efficacy. [66] A 2023 article reviewed a series of 10 infants treated with riociguat and demonstrated improvement of some clinical markers and echocardiographic markers of pulmonary hypertension, however 2 patients experienced a marked clinical change when transitioning from sildenafil to riociguat as these two medications cannot be administered together due to risk of hypotension.[67] Clinical trials are currently ongoing in children to assess riociguat (NCT 02562235).

3.2. Infants with Persistent Pulmonary Hypertension of the Newborn

At birth the normal transition of the pulmonary system is an immediate decrease in PVR leading to an increase in pulmonary blood flow to support the infants new need for respiration.[74] However, in infants with PPHN there is a failure of this normal transition leading to persistently elevated PVR and limited pulmonary blood flow causing hypoxemia and respiratory failure. Risk factors for PPHN include delivery via Caesarean, meconium aspiration syndrome, maternal smoking, and maternal use of medications including SSRI and NSAIDS.[75]

Inhaled nitric oxide is the most studied pulmonary vasodilators in this population. A recent Cochrane review showed that it is an effective therapy for term infants with hypoxemic respiratory failure including those with PPHN.[8] Sildenafil is also utilized as a treatment for PPHN and has some small studies that support its use as described in a recent 2017 Cochrane review article.[76] The authors found 5 trials comprising of 166 participants. The data suggests reduced mortality and improved oxygenation with sildenafil but the quality of evidence was rated as low and in need of a large scale study. Another recent randomized controlled trial (RCT) of IV sildenafil added to iNO compared to placebo in 59 infants demonstrated no improvement but that IV sildenafil was relatively safe with minimal significant adverse events.[21]

Multiple prostacyclin analogues have been studied in PPHN. A retrospective study of PGE1 in infants with PPHN demonstrated a benefit of shorter hospital length of stay but no benefit in mortality.[54] Iloprost was shown to be beneficial in patients with PPHN who were not responding to iNO in a small study of 22 patients.[47] IV treprostinil has limited data in PPHN: 2 case reports showed clinical improvement and tolerance of the medication. [77]

Studies of bosentan in PPHN have mostly been limited by small sample size. Generally, the studies have shown that bosentan is safe and tolerated in this population. Benefit is limited but there is some evidence that it can reduce PA pressures and improve oxygenation. Mortality benefit has not been established. [38, 78, 79, 80]

3.3. Infants with Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (CDH) is a condition due to improper formation of the diaphragm during fetal development. It can present with varying severity often related to the size of the defect. The defect in the diaphragm leads to abdominal contents to enter the thoracic cavity leading to a mass effect on the developing lungs. This causes abnormal lung development leading to pulmonary hypoplasia and pulmonary hypertension, which can be fatal. Studies show that an abnormal pulmonary vasculature develops with arterial remodeling, altered vascular response, and decreased vascular bed density [81, 82, 83]. Various PH therapies have been studied in the CDH population. Nitric oxide was studied in a multicenter study in 1997 in n=53 infants with CDH[84]. Patients were randomized to receive inhaled nitric oxide (treatment arm) or 100% oxygen (control arm). Treatment patients exhibited short-term improvements of oxygenation but no reduction in need for ECMO or death. Another study concluded that there may be a subset or CDH patients that respond to inhaled nitric oxide and that it can be beneficial in the extubated patient via nasal cannula [85]. Case reports of use of sildenafil in CDH patients show improvement in pulmonary artery pressures and oxygenation as well as echocardiographic indices of PH.[86, 87]

A case series in 6 infants with CDH and PH reviewed effects of milrinone and saw an improvement of echocardiographic indices of RV function, however rigorous data is limited.[88] There is an ongoing clinical trial evaluating milrinone in CDH patients for PH.[89] Bosentan has theoretical benefit in CDH patients with PH but no clinical trials have been done in CDH patients to show benefit.[90] Prostacyclins and prostaglandin E1 also have limited data but have been used to treat PH in CDH infants.[53, 91]

A related disease process to PH-CDH is PH secondary to lung hypoplasia. This can be seen in infants with premature rupture of membranes, kidney disorders, and omphaloceles. Research is limited on this topic. One large multicenter study showed no evidence of improved survival with inhaled nitric oxide in extremely premature infants and pulmonary hypoplasia; however, another case report demonstrated significant improvement with iNO.[92, 93] The mixed conclusions are likely a result of the heterogeneity of underlying causes of PH, leading to different patients having different responses to the limited array of PH therapies available.

This paper is supported by a mentoring award from the National Heart, Lung, and Blood Institute for M M Laughon (1K24HL143283).