Table 2

Pharmacotherapy for paediatric PH

Agent	Indication	Dosing	Expected benefit	Possible side effects	COR/LOE comments
Calcium channel blockers
Amlodipine	Only if reactive to vasodilator testing Do not use in patients with high right atrial pressure or low cardiac output	Starting dose: 0.1 mg/kg/dose (or 1–5 mg/ adult dose), twice daily orally, uptitrate Maintenance dose: 2.5–10 mg/dose twice daily orally Max. adult dose 20 mg/day orally	▸ Decrease in PVR	Bradycardia Decreased cardiac output Peripheral oedema Rash Gum hyperplasia Constipation	COR I LOE B Duration of benefit may be limited even with initial favourable response Efficacy in Eisenmenger syndrome is rare
Nifedipine	Only if reactive to vasodilator testing Do not use in patients with high right atrial pressure or low cardiac output	Starting dose 0.2–0.3 mg/kg/dose three times daily orally, uptitrate Maintenance dose: 1-2.5 mg/kg/dose twice daily orally Max. adult dose 120–240 mg/day orally in 3 divided doses May use extended release preparations (max. 180 mg/day orally)	▸ Decrease in PVR	Bradycardia Decreased cardiac output Peripheral oedema Rash Gum hyperplasia Constipation	COR I LOE B Duration of benefit may be limited even with initial favourable response Efficacy in Eisenmenger syndrome is rare
Diltiazem	Only if reactive to vasodilator testing Do not use in patients with high right atrial pressure or low cardiac output Use in neonates and infants is controversial	Starting dose 0.5–0.7 mg/kg/dose three times daily orally, uptitrate Maintenance dose: 1–1.7 mg/kg/dose three times daily orally Max. adult dose 240 mg—360 mg/day orally in 3 divided doses Use extended release preparations (max. 360 mg/day orally) only once an effective short-acting dose is tolerated	▸ Decrease in PVR	Bradycardia Decreased cardiac output Peripheral oedema Rash Gum hyperplasia Constipation	COR I LOE B Duration of benefit may be limited even with initial favourable response Efficacy in Eisenmenger syndrome is rare May cause bradycardia more than other CCB Suspension useful in younger children
Phosphodiesterase type 5 inhibitors
Sildenafil	Approved for adult PH Group 1 EMA approved for paediatric PH Group 1 (age>1 year) FDA warning (2012) and subsequent clarification (2014)	Oral: Starting dose: 0.3–0.5 mg/kg/dose three (eg, >1 year old) or four times (eg, <1 year old) daily orally Maintenance dose: 0.5–1 mg/kg/dose three (>1 year old) or four times (<1 year old) daily orally <8 kg (no RCT data) Starting dose 0.3–0.5 mg/kg/dose four times daily orally Maintenance dose: 1 mg/kg/dose four times daily orally. Maximum dose (controversial): 10 mg/dose orally three to four times daily (children) European dosing (EMA approved): 8–20 kg: 10 mg/dose three times daily orally (less in neonates/infants < 10 kg) ≥20 kg: 20 mg/dose three times daily orally Intravenous: 0.4 mg/kg bolus over 3 hours intravenous (optimal), then 1.6–2.4 mg/kg/d continous intravenous infusion; do not exceed 30 mg/d	Increase in CI Decrease in PVR May improve diastolic ventricular function in single and biventricular circulations based on preclinical studies Higher Sildenafil doses up to 7.2 mg/kg/d intravenous have been used in newborn infants with PPHN associated with congenital diaphragmatic hernia	Flushing Agitation Hypotension Vision and hearing loss are concerning findings in premature infants Priapism	COR I LOE B (COR III, LOE B for high dose) 1 paediatric RCT (STARTS-1/-2)39 40 A greater mortality was noted in the STARTS-2 extension study in treatment naïve children treated with high dose sildenafil monotherapy STARTS-1/-2 medium dosing regimen with best effect on VO₂ max was: 8–20 kg, >1year old: 10 mg/dose three times daily orally, 20.1–45 kg: 20 mg/dose three times daily orally >45 kg 40 mg/dose orally three times daily FDA warning (2012) and subsequent clarification (2014) of chronic use in children 1–17 years old concomitant use of CYP3A4 inhibitors decreases clearance of sildenafil co-administration of bosentan leads to decreased sildenafil concentrations and increased bosentan concentrations (clinical relevance is unclear though) Use in premature neonates not well studied
Tadalafil	▸ Approved for adult PH Group 1 by the EMA and the FDA in 2009	Starting adult dose: 20 mg/dose once daily orally Consider uptitration from 20 to 40 mg/dose once daily orally Max. adult dose: 40 mg/dose once a day orally Paediatric maintenance dose probably 1 mg/kg/day orally	Increase in CI Decrease in PVR	Side effects similar to sildenafil. Probably no significant effect on vision	COR I LOE B Once a day dosing Safety and efficacy data in children are limited
Guanylate Cyclase stimulators
Riociguat	▸ Approved by the EMA and the FDA for adult PH Group 1 in 2014: (IPAH/HPAH only) and Group 4 PH (CTEPH) for monotherapy or combination therapy with ERA	Starting adult dose 1 mg three times daily orally, uptitration required Maintenance adult dose 1–2.5 mg (dose three times daily orally Maximum adult dose 2.5 mg/dose three times daily No published data on paediatric dosing in 2015	Increase in CI Decrease in PVR	Systemic arterial hypotension Headache, dizziness, dyspepsia Do not use together with PDE5-inhibitors (sildenafil, tadalafil)	COR IIb LOE C Safety and efficacy data in children not available in 2015. COR I, LOE A for adult PH groups 1 and 4
ERA
Bosentan (dual ET_A and ET_B receptor antagonist)	Approved by the EMA and the FDA for adult PH Group 1 Approved by the FDA and the EMA for use in children >1 years old For patients over 12 years old, benefit also shown for functional class II	Starting dose: 0.3–1 mg/kg/dose twice daily, uptitration <10 kg: max. 2 mg/kg/dose twice daily orally 10–20 kg: max. 2 mg/kg/dose twice daily orally (32 mg tablets) 20–40 kg: 62.5 mg/dose twice daily orally > 40 kg: 125 mg/dose twice daily orally	Increase in CI Decrease in PVR	Abdominal pain, vomiting, extremity pain, fatigue, flushing, headache, oedema, nasal congestion, anaemia. Not recommended in patients with moderate or severe hepatic impairment Monthly LFTs required Incidence of AST/ALT elevation is less in children (3.5%) compared with adults Fluid retention Teratogenicity and male infertility are risks	COR IIa, LOE C. For Eisenmenger: COR I, LOE B Data have been published on efficacy in Eisenmenger PH Caution in concomitant use of CYP3A4 inducers and inhibitors
Macitentan (dual ET1_A and ET1_B receptor antagonist)	▸ Approved by the EMA and the FDA for adult PH Group 1 (IPAH/HPAH only)	Starting dose (adults): 5–10 mg once daily orally Maintenance adult dose 10 mg once daily orally No published data on paediatric dosing in 2015	Increase in CI Decrease in PVR	Class-specific side effects are similar to bosentan Headache, nasopharyngitis, anaemia Not recommended in patients with moderate or severe hepatic impairment Dependent oedema may limit usefulness Teratogenicity and male infertility are risks (decreases in sperm count have been observed)	COR IIb LOE C RCTs in adults (SERAPHIN)33 Safety and efficacy data in children not available in 2015 Caution in concomitant use of CYP3A4 inducers and inhibitors
Ambrisentan (selective ET1_A receptor antagonist)	Approved for adult PH Group 1 by the FDA and the EMA Use in paediatrics has not been extensively evaluated • In children >12 years old with intolerance to bosentan, there may be benefit	▸ Adult dosing starts with 5 mg daily up to 10 mg daily	Increase in CI Decrease in PVR	Class-specific side effects are similar to bosentan Incidence of serum aminotransferase elevation is low May decrease effectiveness of birth control Dependent oedema may limit usefulness Teratogenicity and male infertility are risks No drug–drug interactions between ambrisentan and sildenafil or tadalafil observed	COR IIa LOE C Safety and efficacy data in children are limited Caution in concomitant use of CYP3A4 inducers and inhibitors
Prostacyclin analogues (prostanoids)
Epoprostenol	▸ Approved by the EMA and the FDA for adult PH Group 1	Intravenous infusion Starting dose: 1–2 ng/kg/min intravenous without a known maximum Maintenance dose: 10–20—50–100 ng/kg/min intravenous In paediatric patients a stable dose is usually between 50 and 80 ng/kg/min intravenous at 1 year after start of treatment Doses > 150 ng/kg/min I intravenous have been used Dose increases are required High output failure at high doses can occur	Increase in CI Decrease in PVR Increased survival	Flushing, jaw, foot and bone pain, headaches and diarrhoea Systemic hypotension is possible The half-life is short (2–5 min) so PH crises occur rapidly if the infusion is stopped Ice pack cooling and remixing every 24 h needed Central line complications (infection, occlusion, extravasation) occur	COR I LOE B Standard therapy for severe PH (WHC FC class IV) A ‘temperature stable’ formulation is now available
Trepostinil	▸ Approved by the EMA the and FDA for adult PH Group 1	Intravenous or subcutaneous infusion Starting dose 1–2 ng/kg/min without a known maximum In paediatric patients, a stable dose is usually met between 50 and 80 ng/kg/min intravenous/subcutaneous at 1 year Tolerance occurs and dose increases are required initially Inhalation (nebuliser, inhaler) 1–9 patient activated breaths every 6 h	Increase in CI Decrease in PVR Improved or unchanged 1-year functional class Less severe side effects than epoprostenol	Flushing, jaw, foot and bone pain, headaches and diarrhoea are common side effects that reoccur after each dose increase The frequency and severity of side effects are less than with epoprostenol Elimination half-life is 4.5 h with distribution half-life of 40 min The drug is stable at room temperature so it does not require cooling Central line complications (infection, occlusion, extravasation) can occur Subcutaneous injection site pain and possible infection limits this route Inhaled drug can worsen reactive airway symptoms	For intravenous / subcutaneous: COR IIa, LOE C (intravenous), COR IIb, LOE C (subcutaneous) Safety and efficacy data in children are limited For intermittent inhalation: COR IIb LOE C The nebuliser requires patient activation and controlled inhalation limited by age and development
Iloprost	▸ Approved adult for PH Group 1	Intravenous infusion Paediatric dosing has not been determined Intravenous infusion Starting dose: 1 ng/kg/min intravenous, uptitrate Maintenance dose 5–10 ng/kg/min intravenously as tolerated. A maximum intravenous dose has not been described. Inhalation (nebuliser, inhaler) Nebuliser for children (< ca. 5 years) and small inhaling devices for older children Paediatric dosing has not been determined but 6–9 inhalations per day are required, each lasting 8–15 min Start with 2.5 μg/dose (1.25 μg in small children) and uptitrate to 5 μg/dose as tolerated Dose range: Ampules deliver 2.5–5 μg to the mouth piece	Improved CI Improved PVR	Intravenous infusion (rarely used): similar to epoprostenol and trepostinil for inhalation: jaw pain, wheezing; especially at the initiation of therapy a new chip for the adaptive aerosol delivery systems allows now to reduce the duration of inhalations from 10–15 down to 4–5 min	For intravenous infusion: COR IIb LOE C In paediatrics, the dosing frequency is not established For intermittent inhalation COR IIa LOE C In paediatrics, the dosing frequency and lack of compliance may limit its use Many experts recommend every 3 h inhalations during the day time for better compliance that can be recorded and monitored with a chip within the inhaler
Selexipag (oral use)	Prostacyclin IP receptor agonist Pending approval for adult PH group 1 (PAH) No paediatric data	Adult dosing: Starting dose: 200 μg orally twice daily. Dosing increase in 200 μg twice daily steps Max. dose 1.6 mg twice daily orally	Reduction of morbidity/mortality event. Improved CI Improved PVR	▸ To be determined (RCT and postmarketing surveillance pending)	COR IIb LOE C GRIPHON trial (1156 PAH patients)71 Significant risk reduction of morbidity/mortality events
MR antagonists
Spironolactone	Improves hepatic congestion and oedema Inhibits MR and may improve RV and LV diastolic dysfunction	Loop diuretics, thiazides and spironolactone are all dosed by weight and not differently than for other forms of heart failure	▸ Decreased signs of right heart failure	▸ Hyperkalaemia	COR IIa LOE C Better outcome of adult PAH patients in post hoc analysis with add-on spironolactone to ambrisentan (ARIES-1/-2) Better outcome in adult patients with LV failure with preserved ejection fraction (HFpEF; LV diastolic dysfunction). A similar benefit was noted for the oral MR antagonist eplerenone in HFpEF
Diuretics
Furosemide (loop diuretic)	▸ May improve hepatic congestion and oedema.	Loop diuretics, thiazides and spironolactone are all dosed by weight and not differently than for other forms of heart failure	Decreased signs of right heart failure May be overused in PAH	▸ Caution: moderate to excessive diuresis can reduce the preload of the failing RV and worsen clinical status	COR IIb LOE C
Hydrochlorothiazide (thiazide)	Improves hepatic congestion and oedema	Loop diuretics, thiazides and spironolactone are all dosed by weight and not differently than for other forms of heart failure	▸ Decreased signs of right heart failure	▸ Care is needed as over diuresis can reduce the preload of the failing RV	COR IIb LOE C
Inhalative therapies other than prostanoids
Oxygen	▸ Helpful for cyanotic patients with an element of CLD or intrapulmonary shunt	▸ 1–2 L/min by nasal prongs	▸ Improved sense of well-being	▸ Too high a flow rate can dry the nares and cause epistaxis or rhinitis	COR I LOE C Oxygen is not usually prescribed for children with PH unless the day time saturations are low (<92%) Polysomnography helpful in delineating the need for O₂ therapy at night Oxygen with sleep for sleep disordered breathing with SaO₂ decreasing to < 92% even if only transient Oxygen with exertion for patients with clinically significant desaturation with exertion
Nitric oxide (continuous inhalation)	PPHN Acute exacerbation of PAH, including PH crisis Acute PH in respiratory distress syndrome	0–5 ppm 20 ppm	▸ Selective fall in PVR	Methaemoglobin and NO₂ at higher doses Rebound PH on weaning off iNO (risk can be reduced by concomitant use of sildenafil)	COR IIa (PPHN),COR IIb (postop), LOE B Not approved by the EMA or the FDA for postoperative CHD
Anticoagulative and antiplatelet agents
Coumadin, warfarin, phenprocoumon (vitamin K antagonists)	No definitive studies in children Oral anticoagulation in patients with a history of thrombosis, hypercoagulation, central lines Some PH centres use coumadin or warfarin in paediatric IPAH or HPAH	Individual dosing depends on agent used, co-medication, patient history Goal INRs in the range of (1.5-) 2.0–2.5 are usually chosen for this indication. Higher INR may be needed for history of thrombosis or hypercoagulability	▸ Prevention thrombosis and thromboembolic events	The risk of anticoagulation in paediatrics must be balanced with the hypothetical benefits Teratogenic effects	For IPAH/HPAH: COR IIb LOE C For APAH: COR IIb LOE C ▸ Use of coumadin in children prior to walking well and in children may add risk
Acetylsalicylic acid (ASA; aspirin)	Alternative to oral anticoagulation (warfarin, coumadin) in paediatric IPAH/HPAH, especially in small/active children	Maintenance dose 2–4 mg/kg/dose once daily orally; max. 100 mg/dose Adult dose: 100 mg/dose once daily orally	Inhibition of platelet aggregation, thrombosis and thromboembolic events	Usual risks for ASA: bleeding, Reye syndrome, asthma Combination with clopidogrel or vitamin K antagonist carries moderate to high bleeding risk	COR IIb LOE C
Contraceptives	Pregnancy in women with moderate-to-severe PH bares a high risk of maternal and fetal death ,Endothelin receptor antagonists are teratogenic Bosentan use requires two separate methods of contraception	Non-oestrogen containing formulations are best Barrier methods may be effective	Prevention of pregnancy and associated morbidity/mortality		COR I LOE C

COR and LOE grading (higher than COR IIb and LOE C) is based on paediatric data only (or adult RCTs that included >10% children).
ALT, alanine aminotransferase; APAH, pulmonary arterial hypertension associated with disease; AST, aspartate aminotransferase; CCB, calcium channel blocker; CHD, congenital heart disease; COR, class of recommendation; CLD, chronic lung disease; EMA, European Medicines Agency; ERA, endothelin receptor antagonist; ET, endothelin; FDA, US Food and Drug Administration; HCT, haematocrit; HFpEF, patients with heart failure and preserved ejection fraction; HPAH, heritable pulmonary arterial hypertension; iNO, inhaled nitric oxide; INR, international normalised ratio; IPAH, idiopathic pulmonary arterial hypertension; LFT, liver function test; LOE, level of evidence; LV, left ventricle; MR, mineralcorticoid receptor; PDE5, phosphodiesterase type 5; PH, pulmonary hypertension; PPHN, persistent pulmonary hypertension of the newborn; PVR, pulmonary vascular resistance; RCT, randomised controlled trial; RV, right ventricular; STARTS, Sildenafil in Treatment-Naive Children, Aged 1–17 Years, with Pulmonary Arterial Hypertension.