Pediatric Pulmonary Hypertension

The definition of pulmonary hypertension changed in 2018 to an elevation of the mean pulmonary artery pressure to greater than 20 mm Hg in children older than 3 months at sea level. As of 2022, pulmonary arterial hypertension consists of a pulmonary vascular resistance index equal or greater than 3 Woods units per meter squared and pulmonary capillary wedge pressure less than 15 mm Hg. Pediatric pulmonary hypertension is a complex disease that requires regular multidisciplinary monitoring and care, and it is a condition that physically and emotionally affects pediatric patients.After completing this article, readers should be able to: Define pulmonary hypertension.Identify genetic disorders associated with pulmonary hypertension.Describe the medical and surgical therapies used for pediatric pulmonary hypertension management.Pediatric pulmonary hypertension (PH) is a complex disease with high morbidity and mortality related to progressive right ventricular (RV) dysfunction and ultimately failure if left untreated. (1) The annual incidence of pediatric PH varies from 4.8 to 8.1 per million children in the United States to 0.47 to 0.7 per million in European countries or 2 to 5 per million in Western countries, and it can occur either in isolation or in association with other diseases (ie, bronchopulmonary dysplasia, congenital diaphragmatic hernia, systemic rheumatoid diseases, hereditary hemorrhagic telangiectasia, or other forms of genetic pulmonary underdevelopment) or congenital heart defects. (1)(2)(3) PH can be broadly grouped into 2 categories: transient and progressive. Most patients have transient PH, referring to the PH that usually resolves during infancy, most frequently secondary to congenital heart disease (CHD) that is ultimately repaired or to perinatal persistent PH of the newborn (PPHN). (4) Progressive PH refers to the condition that continues throughout the patient’s life span and worsens in severity over time.The 6th World Symposium on Pulmonary Hypertension changed the definition of PH in 2018 to an elevation of the mean pulmonary artery pressure (mPAP) to greater than 20 mm Hg in children older than 3 months at sea level, whereas it was previously defined as an mPAP greater than 25 mm Hg (5) and defined pulmonary arterial hypertension (PAH) as pulmonary vascular resistance (PVR) index ≥ 3 WUm2 and pulmonary capillary wedge pressure (PCWP) less than 15 mm Hg. (5)PVR is the “resistance that the blood has to overcome to pass through the pulmonary vasculature.” (7) In the pediatric population, a term frequently used is the PVR index, which refers to the absolute PVR value adjusted to a patient’s body surface area, and the units are Wood units per square meter. (7)In patients undergoing hemodynamic cardiac catheterization, obtaining a direct measurement of left atrial pressure may not be feasible. During the patient’s cardiac catheterization, the balloon-tipped catheter is advanced into a branch pulmonary artery; once it is inflated, it provides a PCWP. When there is unobstructed transpulmonary blood flow, PCWP correlates with left atrial pressure. (8)Eisenmenger syndrome is defined as a severe irreversible elevation of the PVR causing bidirectional or pulmonary-to-systemic shunting due to unrepaired large congenital heart defects, most commonly either a ventricular septal defect or a patent ductus arteriosus. (9)Different ways to classify PH are based on hemodynamic findings, etiology, or diseases. The simplest way is based on the patient’s cardiac catheterization findings and entails precapillary, postcapillary, or mixed findings. (6)This classification is defined as mPAP greater than 20 mm Hg, PVRI ≥ 3 WUm2 and PCWP of 15 mm Hg or less. Precapillary includes abnormalities in the pulmonary arteries/arteriole system.This classification is defined as mPAP greater than 20 mm Hg, PCWP greater than 15 mm Hg but with a PVRI of 3 Woods units or less. Postcapillary comprises abnormalities related to the pulmonary venules, veins, or left-sided cardiac obstruction or dysfunction.This classification is defined as a combination of precapillary and postcapillary disease. Mixed is defined as mPAP greater than 20 mm Hg, PVRI ≥ 3 WUm2 units, and PCWP greater than 15 mm Hg. Many postcapillary conditions, as they evolve, progress to precapillary PH.The World Symposium on Pulmonary Hypertension classification, also known as the World Health Organization classification, divides PH into 5 large groups based on etiologies of the PH: group 1 (PAH), group 2 (due to left-sided heart disease), group 3 (due to lung parenchymal abnormalities), group 4 (secondary to chronic thrombotic/embolic disease), and group 5 (unclear or multifactorial causes) (Fig 1). (9)In 2011, to develop a more specific PH classification for pediatric patients, the Pulmonary Vascular Research Institute Task Force, (10) after meeting in Panama, presented the first pediatric PH classification, known as the Panama classification. This scheme is a more specific, in-depth classification divided into 10 distinct groups that incorporates both prenatal and postnatal factors associated with PH (Fig 2).An increasing number of genetic mutations are being recognized as causes of PH. The mutation in 80% of the familial cases of PAH is the bone morphogenesis protein receptor 2 gene (BMPR2), which is autosomal dominant with variable penetrance. (2) Other mutations include genes ACVRL1, ENG, TBX4, ALK1, SOX17, SMAD-9, KCNK3, CAV1, ATP13A3, AQP1, and GDF2. (1)(6)PAH is characterized by abnormal hypertrophy or proliferation of 1 or more of the 3 components of the blood vessels (endothelium, smooth muscle, and fibroblast) in the distal pulmonary vasculature, with infiltration of inflammatory cells, an extension of the muscle layer to the distal pulmonary capillaries, and decrease in the luminal size of the vessels, as well as the development of plexiform lesions in the vessel walls. (2) In postcapillary disease, the pulmonary venous system has abnormal remodeling due to either left-sided heart disease or pulmonary venous obstruction (ie, pulmonary vein stenosis or pulmonary veno-occlusive disease). Patients with disorders of thrombosis may have platelet activation that results in distortion or destruction of the pulmonary endothelium, which may also result in the development of PH. Trigger factors that cause this abnormal pulmonary vascular remodeling are not always identified; however, there are genetic and inflammatory conditions, as well as medications, known to be associated with these abnormalities. (11)Presenting symptoms of PH may vary throughout childhood, from cyanosis at birth in the case of PPHN to syncope, dyspnea, failure to thrive, decreased endurance, or feeding intolerance in an older child. (2) It is not uncommon for children to have nonspecific symptoms that result in a delay in diagnosis. However, once there are concerns that the patient may have PH, the child should be referred to a cardiologist or pulmonologist with expertise in PH as soon as possible.Physical examination may be significant for a loud second heart sound, an RV heave, a systolic murmur, and stigmata of right-sided heart failure, which includes hepatic congestion, peripheral edema, and signs of decreased cardiac output.Initial studies should include an electrocardiogram (to evaluate for signs of right-sided heart enlargement/strain), a chest radiograph (to rule out lung or cardiac abnormalities or dilation of pulmonary arteries), an echocardiogram (to evaluate for CHD or left-sided cardiac abnormalities, RV systolic function, pressure, dilation, and hypertrophy, the position of the interventricular septum, the directionality of shunts if present, and pulmonary systolic and diastolic velocities). Concerning echocardiographic signs of poor RV compensation include a decline in RV function, worsening RV dilation, and pericardial effusion. Other additional tests that could be performed include chest computed tomography (to rule out vascular or lung parenchymal abnormalities), pulmonary function testing (to assess for restrictive and obstructive lung abnormalities), a sleep study (to evaluate for obstructive or central apnea), and chest computed tomography with angiography or lung perfusion scan (to rule out chronic thromboembolic disease).Laboratory studies in patients with PH should include serum B-type natriuretic peptide or NT-pro–B-type natriuretic peptide, which are nonspecific cardiac biomarkers produced by the ventricular myocyte as a response to stretching (11); thyroid hormone because hypothyroidism is associated with PH; basic metabolic panel, to evaluate for elevated bicarbonate levels in patients with chronic hypercarbia or evidence of kidney injury; complete blood cell count, to evaluate for polycythemia in those with chronic hypoxemia or thrombocytopenia, a sign of severe PH; and liver function tests.The gold standard to diagnose PH is cardiac catheterization. This invasive modality measures the pulmonary artery pressure, PCWP, total cardiac output, and blood flow going through the lungs versus the systemic circulation (Qp:Qs ratio) in the case of intracardiac shunting, and it detects acute vasoreactivity. An acute vasoreactivity test (AVT) consists of repeating hemodynamics after a 10- to 15-minute exposure to oxygen and nitric oxide (20–40 ppm) or prostacyclins. (12) The test will be considered positive if there is a reduction of mPAP of at least 10 mm Hg, reaching an mPAP of 40 mm Hg or less, (6) or a decrease of at least 20% of mPAP without a decrease in cardiac output and without a change or decrease in the PVR index to systemic vascular resistance ratio. (12) The AVT has been used to assess heart transplant candidacy, the appropriateness of initiation of calcium channel blockers (CCBs), or the significance of left-to-right shunts. (13) Of note, anesthesia and invasive procedures carry a high-risk profile in the PH setting, and cardiac catheterization should ideally be performed only at centers with experience taking care of pediatric PH.Functional testing can include a 6-minute walk test, which quantifies the exercise capacity by measuring distance walked, heart rate range, and percutaneous arterial oxyhemoglobin saturation achieved throughout the 6 minutes and at 2 minutes after recovery. Cardiopulmonary exercise testing, in which a child exercises using a bicycle or a treadmill, allows the medical team to assess heart rhythm, maximum oxygen consumption, pulmonary function, anaerobic thresholds, and carbon dioxide elimination.Once a child is diagnosed as having PH, the child will need periodic testing to evaluate the overall progression and response to PH-targeted medical therapy. These evaluations should include interval cardiac catheterizations every 1 to 2 years, along with repeated echocardiograms, laboratory evaluations, and functional testing. Further testing may also include cardiac magnetic resonance imaging to objectively assess the RV. (11)An objective longitudinal evaluation of functional capacity and growth in subsequent follow-up visits is necessary to monitor evolving disease burden. The PVRI Task Force in 2011 published a functional capacity classification from class II thru IV based on the patient’s age (0–6 months, 0.5–1 year, 1–2 years, 2–5 years, and 5–16 years) to guide the clinician as the patient grows. (14)PPHN is caused by pulmonary artery relaxation failure as neonates transition from fetal to neonatal life, causing hypoxemia and strain on the RV. (15) Treatment includes mechanical ventilation with increased fractions of inspired oxygen and inhaled nitric oxide with vasopressor and inotropic support, or in more challenging cases, the use of PH-targeted therapy with sildenafil or inhaled prostacyclins. Some patients who fail these initial treatments may require the use of extracorporeal membrane oxygenation. (11)An acute PH crisis is a sudden elevation of the pulmonary pressures that cause hemodynamic instability and RV failure. Signs and symptoms of a PH crisis vary depending on the presence of shunts (atrial or ventricular septal defects or a patent ductus arteriosus). Shunts are considered a “pop-off” for pulmonary vascular circulation. If shunts are present, the patient’s initial symptoms are hypoxemia post-shunt, without an initial blood pressure drop, unless metabolic acidosis progresses. However, if no shunt is present, the elevation of pulmonary artery pressures causes a sudden and significant afterload increase in the RV, progressing to RV systolic failure. Symptoms include hypoxemia, hypotension, bradycardia, or cardiac arrest.Initial management of an acute PH crisis includes the administration of pulmonary vasodilators such as oxygen and inhaled nitric oxide, as well as increasing the patient’s sedation. Inotropes (epinephrine, norepinephrine) may be needed for RV systolic support, and vasoconstrictors (phenylephrine/vasopressin) to assist with elevation of the systemic vascular resistance, maintain cardiac output, and improve interventricular interactions. Other second-line agents for severe PH crises include inhaled prostacyclins (iloprost/epoprostenol). Unfortunately, some patients may progress to cardiac arrest or require extracorporeal membrane oxygenation support until the underlying cause of PH is defined/improved or during initiation or titration of PH-targeted therapy. Although giving intravenous fluids to assist with hypotension is common in other low cardiac output states, this approach should be used with significant caution or avoided in the case of an acute PH crisis because it may cause worsened RV dilation and failure.The long-term management of PH includes medications that work through 3 different pathways. Nitric oxide, phosphodiesterase 5 inhibitors (sildenafil and tadalafil), endothelin receptor antagonists (ERAs) (bosentan, ambrisentan, macitentan), and prostacyclins (treprostinil, iloprost, epoprostenol, or prostacyclin receptor agonists) are the mainstays of therapy. CCBs are also used in select patients. Of these treatments, sildenafil and bosentan are currently Food and Drug Administration (FDA)–approved for use in pediatric PAH; other therapies are used off-label, and both the use and dose are extrapolated from anecdotal pediatric and adult studies.In patients with PH, there is decreased availability of endothelial nitric oxide. (15) Inhaled nitric oxide and phosphodiesterase 5 inhibitors increase the concentration of cyclic guanosine phosphate in the pulmonary endothelium, causing pulmonary artery relaxation. These medications have also been shown to improve remodeling by alleviating smooth muscle proliferation in the pulmonary vasculature and reducing platelet aggregation to the endothelium. (15) Agents most commonly used in the pediatric population include inhaled nitric oxide or phosphodiesterase 5 inhibitors such as sildenafil (administered orally or intravenously) or tadalafil (oral). The most frequent adverse effect of these medications includes hypotension. Riociguat is a nitric oxide availability–independent soluble guanylate cyclase stimulator that increases cyclic guanosine phosphate levels in the pulmonary smooth muscle, causing relaxation.Patients with PH are known to have upregulation of endothelin-1 in the lungs. (16) Endothelin-1 stimulates endothelin receptor A (associated with increased vasoconstriction and proliferation of the smooth muscle) and endothelin receptor B (decreased proliferation and causes vasodilation). Bosentan and macitentan are nonselective ERAs. In contrast, ambrisentan is a selective ERA type A antagonist. All ERAs can be administered orally only. Of note, bosentan has known teratogenic effects and hepatic toxicity, requiring specific monitoring to be prescribed.Patients with PH have decreased prostacyclin synthase (17) in the pulmonary endothelium. Prostacyclin analogues increase the cyclic adenosine monophosphate levels at the smooth muscle level, causing pulmonary arterial vasodilation, and have antiproliferative and antithrombotic properties. (15) These agents can be given orally, intravenously, as an inhalant, or subcutaneously. Adverse effects of these medications include vasodilatory reactions (locally, or headaches, nausea), hypotension, and platelet dysfunction. More recently, an oral prostacyclin receptor agonist (selexipag) has been increasingly used in the pediatric population as an alternative to the more traditional prostacyclins. (18)CCBs can be used in patients with a positive AVT and who are older than 1 year. CCBs prevent the influx of calcium into the smooth muscle, causing pulmonary vasodilation. (15) However, CCBs are contraindicated in patients with RV systolic failure with World Health Organization functional class IV. (19) These medications include amlodipine, nifedipine, and diltiazem.Despite targeted PH therapy use in children, some patients still progress to RV systolic failure requiring further intervention, either in the form of a palliative pulmonary-to-systemic shunt or lung transplant. These therapies are invasive, with significant associated morbidity and mortality.When considering the creation of a shunt to bypass the lungs, it must be remembered that the maintenance of cardiac output will be at the expense of the patient becoming more hypoxemic. These shunts could be intracardiac (atrial or ventricular septal defect creation) or extracardiac (recanalization of a ductus arteriosus, or a surgical or catheter-based creation of a pulmonary-to-systemic or reverse Potts shunt). Reverse Potts shunt refers to a connection between the proximal descending thoracic aorta and the left pulmonary artery. These procedures are considered palliative strategies and will not prevent the patient’s PH progression.Depending on the cause, severity, and response to therapy of the PH, these patients may be considered appropriate lung transplant candidates. Early referral to lung transplant teams to establish relationships and start an evaluation is encouraged. Survival of patients with PAH after lung transplant has significantly improved in recent years, with almost 50% survival 12 years after transplant. (20)Approximately 28% of patients with Down syndrome develop PH, which increases to 45% in those with CHD. (21) PPHN has been reported in 1.2% to 9.7% of newborns with Down syndrome, in contrast to 0.1% in the general population. (21) The cause of PH in this population is multifactorial, including atypical vasoreactivity, CHD, aspiration, sleep disorders, and/or hypothyroidism. (4) Abnormal lung development characterized by decreased alveolarization, pulmonary hypoplasia, airway abnormalities and an arrest of pulmonary vascular angiogenesis contribute to the PH diagnosis in patients with Down syndrome. (4) PH in patients with Down syndrome can be diagnosed in life 1 or with a of by 10 years of (21) of PH diagnosed may but it may during life with CHD are at for PH. Patients with CHD are also known to have increased of which may be a to the elevated PVR long-term in patients with In patients with such as those with bidirectional or an mPAP of 20 mm Hg be considered significantly elevated and cause hemodynamic that in this population, pulmonary vascular disease is defined as a PVRI ≥ 3 WUm2 or a transpulmonary left atrial or greater than 6 mm Hg. can be a or In patients diagnosed in the neonatal with PH due to PPHN or bronchopulmonary due to PH may be a that resolves with and not require significant In contrast, in children diagnosed in life or having PH is a progressive condition that may be able to be with but will still ultimately to the and of PH mortality or survival Survival of children with for 10 years is However, patients with PH to pediatric cardiac have mortality with other medical is a condition associated with a high of morbidity and mortality and can not only the patient but also or as Patients with PH are at for and using and referral to a and/or there are concerns are In patients and with different PH support groups is encouraged. is in patients with PH due to the mortality of to (6) and may PH (6) If a patient is of PH-targeted therapies is such as of and due to is and of birth has been associated with bosentan with PH should including and because patients with PH have less to significant with patients without PH. (6)