Table 1.

Pediatric Therapeutic Options for Pulmonary Hypertension

Class	Agent	Indication	Maximal dose	Expected benefit	Possible side effects	Comments
Ca channel blocker	Nifedipine	PH reactive to vasodilator testing by catheterization.	10 mg/kg/dose TID; it is appropriate to start at a lower dose. Extended release preparations should only be used once an effective short-acting dose has been tolerated.	Improved CI and, at times, long-lasting reduction in PVR	Relative bradycardia, decreased cardiac output, peripheral edema, rash. Possibly not indicated in infants, or patients with high filling pressures or CI < 2.1 L/min/m2	Duration of benefit may be limited even with initial favorable response; efficacy in Eisenmenger physiology is rare.
Phosphodiesterase type 5 inhibitor	Sildenafil	Approved in adults only with WHO Class 2, 3, or 4. We use in infants: Group 3 PH (associated with BPD/CLD) AND cyanotic spells, growth delay, or oxygen requirement. We use in children and adolescence with WHO Classes 2, 3, and 4 but only as add on therapy.	2 mg/kg/dose TID up to 20 mg/dose QID (40 mg/dose may have benefit, but is frequently not an insured benefit). (Starting dose in infants: 0.5 mg/kg/dose TID or QID)	Improved CI and, at times, long-lasting reduction in PVR. In infants a reduction in FiO2, NO dose and ventilator support constitutes a positive response. A reduction in the number and severity of “BPD spells” is possible. Hypothetically, there may be long-term benefit by improving alveolarization and neovascularization in BPD.	In general, the side effects are minimal: flushing and mild diarrhea are most common. Hypotension in infants is almost universally associated with a systemic infection and is not a common side effect. Vision and hearing loss are ubiquitous findings in premature infants and unlikely side effects of sildenafil.	PH is the norm in BPD, the difficult question is whether it should be treated; we treat if there is a sign or symptom that measurably can improve. We routinely evaluate hearing at the beginning of treatment and yearly. Data on vision loss in children is lacking; however, in adults a crowded “cup-to-disk ratio” is the only noted risk factor, so we document a normal ratio early in therapy.
Phosphodiesterase type 5 inhibitor	Tadalafil	Approved in adults with WHO Classes 2, 3, and 4. Extensive evaluation in children has not been reported.	Pediatric dosing is unknown; adult dose: 40 mg/dose once a day, so the equivalent sildenafil dose could be 60 mg/day.	Improved CI and, at times, long-lasting reduction in PVR	It is expected that in pediatrics the side effects will be similar to sildenafil.	The major reason to use tadalafil over sildenafil is the longer half-life.
Endothelin receptor antagonists	Bosentan (a nonselective ETa and ETb antagonist)	Approved for adults WHO Classes 3 and 4. For over 12 years of age, a benefit also shown for Class 2.	<10 kg: 5 mg/kg/day 10–20 kg: 31.25 mg BID 20–40 kg: 62.5 mg BID >40 kg: 125 mg BID	Improved CI, PAP, and PVR with improved or unchanged functional class at >1 year	Hepatotoxicity possible but unlikely if monthly aminotransferase levels are normal. Incidence of elevation is less in children (3.5%) compared with adults; but may be higher in infants exposed to long-term TPN. Dependent edema may limit usefulness. Teratogenicity and perhaps male infertility are important issues, both for the patient and for the caregiver if cutting the pill is required.	We have seen prolonged elevation in aminotransferase levels only in infants who have had prolonged TPN. There is debate on whether bosentan should be a first-line option for advanced PH because there are some data that prostacyclins are more effective. Data have been published on efficacy in advanced Eisenmenger’s PH.
Endothelin receptor antagonists	Ambrisantan (a highly selective ETa antagonist)	Approved in adults WHO Class 2 and higher. Use in pediatrics has not been extensively evaluated. However, in patients >12 years old with intolerance to bosentan, there may be benefit.	Adult dosing starts with 5 mg daily up to 10 mg daily.	Improved CI, PAP, and PVR with improved or unchanged functional class at >1 year	It seems that the side effects are class specific and therefore similar to bosentan. However, some patients will not have side effects to ambrisantan after experiencing them with bosentan. Dependent edema may limit usefulness.
Prostacyclin	Epoprostenol	Approved for adults with WHO Classes 3 and 4. Well studied in pediatrics at all age ranges.	Intravenous infusion: 2 ng/kg/min starting dose without a known maximum. In pediatric patients a stable dose is usually met between 50 and 80 ng/kg/min at around 1 year of therapy. Tolerance occurs and dose increases are required initially every 1–2 weeks.	Improved CI, PAP, and PVR with improved or unchanged functional class at >1 year	Flushing, jaw, foot and bone pain, headaches, and diarrhea are common side effects that reoccur after each dose increase. Systemic hypotension is possible as the drug is initiated or with inadvertent bolus dosing. Since a central line is required, line complications are possible. The half-life is short (2–5 min) so pulmonary hypertensive crises can occur rapidly if the infusion is stopped. The drug is not stable at room temperature so it is usually cooled with ice packs and remixed every 24 h.	This is the mainstay of PH therapy in WHO Class 4 patients of any age. Efficacy as determined by increased survival has been well-documented in pediatrics. Although the side effects are often fleeting, they do limit the rapidity with which an effective dose can be obtained and do decrease quality of life. It is believed that epoprostenol
Prostacyclin	Treprostilil	Approved for adults with WHO Class 2, 3, or 4. Data exist from all pediatrics age ranges.	Intravenous or subcutaneous infusion: 2 ng/kg/min starting dose without a known maximum. In pediatric patients a stable dose is usually met between 50 and 80 ng/kg/min at around 1 year of therapy. Tolerance occurs and dose increases are required initially every 1–2 weeks. Inhaled: 1–3 patient activated breaths every 6 h.	Improved CI, PAP, and PVR with improved or unchanged functional class at >1 year	Flushing, jaw, foot and bone pain, headaches, and diarrhea are common side effects that reoccur after each dose increase; however, the frequency and severity are less than with epoprostenol. Systemic hypotension is rare as the drug is initiated or with inadvertent bolus dosing. Since a central line is required, line complications are possible. The half-life is long (4.5 h) so pulmonary hypertensive crises do not occur rapidly if the infusion is stopped. The drug is stable at room temperature so it does not require icing and can be remixed every 48–72 h. Subcutaneous injection site pain clearly limits the usefulness of this route and only a highly motivated youngster will tolerate the discomfort. Inhaled drug can also worsen reactive airway symptoms and this side effect must be closely monitored.	Although side effects are clearly less with treprostilil compared with epoprostenol, there have not been comparative efficacy studies. It can be said that it is the rare patient who has deteriorated when switched from epoprostenol to treprostilil, and when it does occur aggressive up-titration of the dose is often—but not always—sufficient to return the patient to clinical stability.
Prostacyclin	Iloprost	Approved for adults with WHO Class 2, 3, or 4. Data in older pediatric patients exist.	Pediatric dosing has not been determined but 6–9 inhalations a day are required, each lasting 10–15 min.	Improved CI, PAP, and PVR with improved or unchanged functional class at >1 year	Flushing, jaw, foot and bone pain, headaches, and diarrhea are common side effects that reoccur after each dose increase. Systemic hypotension is. The half-life is relatively short so pulmonary hypertensive crises do occur if the drug is stopped. Furthermore, there are swings in the hemodynamics even at 9 times a day so less frequent dosing is associated with less that optimal control. Inhaled drug can also worsen reactive airway symptoms and this side effect must be closely monitored.	It is probable that iloprost is a good add-on drug for WHO Class 4 patients with minimal activity tolerance. In pediatrics, the additional burden of care has limited the usefulness of this formulation; however, when line infections have become difficult to control or clear, this drug has very beneficial possibilities.
Treatment for right ventricular failure	Digoxin	Possibly effective in improving RV function.	Usual age and weight dosing schedule	Improved RV function, decreased TR, and improved diuresis	Bradycardia is dose-limiting and may limit effectiveness in PH	Although widely used, there is a movement away from digoxin for heart failure, because of a lack of true efficacy and an increase in arrhythmic deaths. Other inotropic agents, as in i.v. dopamine, are acutely more effective and indicated for acute deterioration.
Treatment for right ventricular failure	Diuretics	Clearly effective in improving hepatic congestion and edema.	Loop diuretics, thiazides, and spirolactone are all dosed by weight and dosing is not different than for other forms of heart failure.	Improved sense of well-being and improved quality of life	Care is needed, as over diuresis of PH patients can reduce the preload for the failing RV. This is crucial, since it is not possible to decrease the afterload or for that matter increase the inotropic state.
Treatment for right ventricular failure	Oxygen	Helpful for cyanotic patients with an element of CLD or intrapulmonary shunt and can improve early morning headaches and activity levels. Crucial for PH patients while at altitude or flying.	1–2 L/min by nasal prongs	Improved sense of well-being and improved quality of life	Too high a flow rate can dry the nares and cause epistaxis or rhinitis. Most children are not compliant with night time O2 and most parents have difficulty keeping the infants from getting tangled at night.	Oxygen is not usually prescribed for children with PH unless the day time saturations are low (<92%). Sleep studies are indicated if there is any suggestion that polysomnography would delineate a need for O2 therapy.
Treatment for right ventricular failure	Coumadin	One of the first therapies for PH to show an improvement in survival; however, the efficacy of anticoagulation in pediatric PH has been indicated in patients with a history of thrombosis, hypercoagulation, and in patients with central lines and intracardiac shunt lesions.	INRs in the range of 1.8–2.2 are usual for this indication.	In addition to the obvious risk of thromboembolic complications, anticoagulation may positively affect the progression of idiopathic PH.	The risk of anticoagulation in pediatrics must be balanced with the hypothetical benefits. Clear plans for monitoring the INR, adjusting the dose and treating traumatic injury are necessary. Teratogenic effects can not be forgotten.	We do not use coumadin in children until they have learned to walk well, and have not used it in children who insist on playing sports unless there is a clear indication other than just having PH.
Treatment for right ventricular failure	Contraceptives	No female patient with PH can reliably survive a pregnancy. In addition, endothelin receptor antagonists are teratogenic.	Non-estrogen containing formulations are used.