Pulmonary Hypertension in Children
From The Child's Doctor, Spring 2012
- Nicolas Porta, MD
- Attending physician, Neonatology; Associate director, The Bridges Program - Pediatric Palliative and End-of-Life Care, Ann & Robert H. Lurie Children's Hospital of Chicago; Assistant professor, Pediatrics, Northwestern University Feinberg School of Medicine
- Disclosure: Dr. Porta has no industry relationships to disclose and does not refer to products that are still investigational or not labeled for the use in discussion.
Other Disclosure Information
At the conclusion of this activity, participants will be able to:
Describe clinical characteristics of children with pulmonary hypertension (PH)
Discuss approaches to the evaluation and diagnosis of children with PH
Discuss therapeutic options and outcomes of PH in children
Pulmonary hypertension (PH) results from abnormal constriction development or obstruction of pulmonary vessels. Severe cases may progress to right heart failure and even death. Many aspects of the evaluation, diagnosis and management of children with PH have been extrapolated from data collected from adult patients, but there are also many differences in the associated conditions, presentation and outcomes for children. In pediatrics, PH can complicate various pulmonary, cardiac or other conditions, diseases and exposures, but can also be idiopathic. When idiopathic, PH is usually progressive, while when associated with other conditions, the course and severity of PH typically parallels the underlying condition. While significant PH is uncommon, presenting symptoms are usually subtle and non-specific. Because of these factors, PH is often diagnosed late, when prognosis is less favorable. This article will describe clinically relevant physiologic and pathophysiologic aspects of PH, clinical characteristics of children with PH, general approaches to the diagnosis, evaluation and management of children with PH, and outcomes for these children.
Under normal circumstances, the pulmonary circulation must accommodate the entire cardiac output. The usually smaller right ventricle (RV) is able to maintain the work necessary to perfuse the lungs because of the relatively low pulmonary artery (PA) pressure that results from high capacitance of the pulmonary vasculature. In adults, PH is diagnosed when the measured mean pulmonary artery pressure is equal to or greater than 25 mmHg, with normal pulmonary capillary wedge pressure (<15 mmHg) and high pulmonary vascular resistance (PVR >3 Wood units/m2). In children, the normal systemic blood pressure (BP) is lower than in adults, so that after the first few weeks of life, a more practical pediatric definition for PH includes a PA pressure that is greater than 1/3 of the systemic systolic blood pressure (with normal wedge pressure and high PVR). The PA pressure can be estimated by echocardiography, but is more accurately determined by direct measurement during cardiac catheterization.
PH results from a combination of physiologic and anatomic abnormalities in the pulmonary circulation. Constriction or inadequate dilation of pulmonary vessels can increase their resistance leading to elevated PA pressure. Regulation of pulmonary vascular tone is mediated by many factors, including vasodilators nitric oxide (NO) and prostacyclin (PGI2), and vasoconstrictors endothelin (ET-1) and thromboxane (TXA2). An imbalance in the signaling of these factors with decreased vasodilators or increased vasoconstrictors can lead to increase in pulmonary vascular resistance and PH. Abnormalities in the development of the pulmonary vessels (configuration, distribution or number) or obstruction of their lumen through cellular hyperplasia can also lead to increase in the overall pulmonary vascular resistance. Whether through increased vascular tone or luminal obstruction or both, the result is PH, and the consequence is more work required by the RV to overcome this resistance. If this becomes severe or prolonged, the RV can become overwhelmed and ultimately fail, leading to death.
There are many possible causes of PH, with potential therapeutic implications. Over the years, classification schemes have been based on anatomical, diagnostic, or mechanistic criteria. Anatomic classification takes into account the fact that the increased resistance can occur across the pulmonary circulation. Thus PH can result from pre-capillary or post-capillary obstruction. Postcapillary causes of PH can originate in pulmonary veins or left heart structures. Early diagnostic classification separated PH into primary (idiopathic) or secondary (associated with other conditions). Mechanistic classification is based on the stimuli that lead to pulmonary vascular abnormalities that lead to increased resistance. These can be mechanical (increased vessel wall thickness, obstruction of vascular lumen), or functional (disruption of cellular signaling between vascular endothelial and smooth muscle cells). A comprehensive classification of PH that incorporates these various characteristics of PH can be a useful tool to direct research strategies, optimize therapeutic approaches, and predict patient outcomes.
Not surprisingly, classification schemes for PH have historically targeted adult patients. These schemes have been very useful in the investigation and advancement of treatment strategies, but the comorbidities associated with PH in pediatric patients are unique, and can have specific impact on the pulmonary vasculature. Recognition of fetal and developmental complications and contributions is essential in the care of children with PH. A diagnostic classification scheme specific to pediatric patients with pulmonary hypertension has been recently proposed (Table 1). An important goal of this classification scheme includes facilitating the collection of pediatric specific data for the presentation, specific interventions and trajectory of children with PH, expediting advances in the overall care and outcomes for these children. It is important to note that some children may fit into several categories. The best use of the classification scheme is to target the most specific group so that comparative data can best be generated. Conditions associated with PH are varied, and awareness of these conditions can help accelerate the identification of PH in children with non-specific symptoms.
Historical symptoms of PH are not specific, and usually other diagnoses are considered first. In children, symptoms are affected by age and associated conditions, and can include poor appetite, poor growth, fatigue, dyspnea (especially with exertion), palpitations, chest pain, dizziness and syncope, which may be exaggerated in children with underlying conditions. Children with potential right to left cardiac shunts can also present with cyanosis. Infants typically present with failure to thrive and respiratory distress. Older children are more likely to present with chest pain and dizziness. Rarely children will present with seizures. Many children will have been diagnosed with asthma, pneumonia and gastro-esophageal reflux before PH is entertained.
Physical signs of PH include visible and exaggerated jugular venous pulsations, loud second heart sound, right ventricular precordial heave, and sometimes a murmur associated with tricuspid valve regurgitation. In more severe cases, there can also be signs of heart failure, such as peripheral edema, hepatomegaly, and poor pulses.
The diagnosis of PH requires appropriate suspicion. Guided by history and physical exam, the most sensitive initial screening test is echocardiography. Findings consistent with PH seen by echocardiography include RV hypertrophy, RV dilation, distortion of the interventricular septum (either flattening toward or inversion into the left ventricle), dilation of the main pulmonary artery, decreased RV function, and increased tricuspid valve regurgitation (TR) jet velocity. When the echocardiogram suggests PH, right heart catheterization is necessary for accurate measurement of PA pressure and full evaluation of hemodynamics, which is essential to confirm the diagnosis, evaluate for complicating features, and guide therapy. If the general pediatrician suspects that the patient may have PH, serious consideration should be given to referral to a dedicated pediatric pulmonary hypertension program in a tertiary care center for complete evaluation and management.
Complete evaluation of children with PH is necessary to determine the underlying cause and guide optimal treatment. Appropriate tests will be directed by the age and presenting features of the patient, and include blood tests, imaging studies, electrocardiogram, pulmonary function testing, exercise stress testing, and cardiac catheterization (Table 2). While associated conditions may help direct and prioritize the extent of the evaluation for a specific child, when patients are otherwise healthy or when initial results are normal, a more thorough approach is essential.
Key information to be obtained during cardiac catheterization includes measured pressures throughout the right heart (right atrium, RV, PA), left sided filling pressures (either pulmonary capillary wedge pressure or left atrium pressure), estimation of cardiac output, and determination of intra-cardiac shunting and pulmonary to systemic flow ratio. These measurements should be taken under baseline conditions and after treatment with an acute vasodilator such as inhaled NO (if possible).
PH can be quantified by either functional class or hemodynamic measurements. The functional class is determined symptomatically, according to the World Health Organization modification of the New York Heart Association functional classification for congestive heart failure (Table 3).
Pediatric age range scales have recently been proposed that include assessment of development, growth and school attendance (Table 4).
When using hemodynamic measurements obtained by cardiac catheterization, PH can be classified into mild (PA pressure less than half of the systemic BP), moderate (PA pressure equal to or greater than half and up to ~85% of systemic BP), and severe (PA pressure greater than ~85% of systemic BP).
In most cases, PH is not curable, only manageable. When associated with lung disease in premature infants, lung growth and improvement in lung disease often leads to improvement and eventual resolution of PH. However, in infants with chronic lung disease who develop severe PH, mortality is very high (~75% by 18 months of age), and aggressive vasodilator therapy should be considered. Other forms of PH are likely to progress, so those children will need therapies in order to slow down the progression and improve their symptoms. A recent analysis of 211 children with severe PH showed that 5-year survival was ~75%.
Among the most important factors in determining the best treatment for any child with PH are the underlying conditions, the hemodynamic measurements and response to acute vasodilator treatment. Depending on the chronicity and trajectory, the optimal treatment for children with high PA pressure and preexisting cardiac shunting may be different than for children with idiopathic PH. Children with substantial response to acute vasodilator treatment during cardiac catheterization carry a more favorable prognostic outcome in general, and often can be successfully managed for extended periods of time with less aggressive therapies. In children with significant underlying pulmonary or collagen vascular diseases, optimal management of the underlying disease is critical to ensure the best possible outcome. Children with PH due to obstructive sleep apnea may require surgical correction (eg, tonsillectomy and/or adenoidectomy).
The clinical rationales for using the available medical therapies are driven by the ease of use, compliance and combinations of side effects. The biologic rationales for the various pulmonary vasodilator therapies are based on responses in experimental models of PH and in patients with PH. It is important to fully characterize the hemodynamic findings in order to most optimally target therapeutic interventions. For example, children with significant left sided cardiac disease and high left sided filling pressures can deteriorate when treated with pulmonary vasodilators.
Calcium channel blockers (CCB): By decreasing intracellular calcium in vascular smooth muscle cells, CCB can promote pulmonary vasodilation in patients who demonstrated substantial response to acute vasodilator challenge during cardiac catheterization. The long-term prognosis is very good for patients with robust response to acute vasodilator challenge and who are subsequently treated with CCB.
Inhaled nitric oxide: NO is a small gas molecule that can be given directly into the lungs by inhalation with immediate effects. It is normally produced in vascular endothelial cells and regulates blood vessel tone throughout the body. NO stimulates production of cyclic GMP in vascular smooth muscle cells, leading to vasodilation. When given by inhalation, it has diagnostic and prognostic value during cardiac catheterization and therapeutically in acute and unstable patients. NO has a very short half-life and must be given continuously; interruption can lead to acute worsening. Inhaled NO is not an option for long-term therapy, since it cannot be easily administered outside of the hospital setting.
Phosphodiesterase (PDE) inhibitors: The type 5 PDE (PDE5) breaks down cyclic GMP, making it inactive. Oral PDE5 inhibitors such as sildenafil and tadalafil lead to increased availability of cyclic GMP in the vascular smooth muscle cells, and thus promote vasodilation. Sildenafil has been used extensively and has been shown to improve functional outcome and survival in adults and children with PH. These medications are generally well tolerated, though side effects such as headache and abdominal discomfort may occur.
Endothelin receptor antagonists (ERAs): ET-1 acts through binding to specific receptors on vascular smooth muscle cells leading to vasoconstriction. Oral ERAs such as bosentan decrease the effects of ET-1 resulting in vasodilation. Bosentan has also been used extensively and improves functional outcomes and survival in children with PH. Of note, more that 10% of adults (possibly fewer children) taking bosentan develop elevation of serum liver enzymes. This necessitates monthly surveillance of liver enzymes, adding to the burden of this therapy. In most cases, normalization of liver enzymes occurs after stopping bosentan.
Prostacyclin (PGI2) and PGI2 analogues: PGI2 stimulates production of cyclic AMP in vascular smooth muscle cells, leading to vasodilation. When given intravenously by continuous infusion, PGI2 is the most effective available therapy for PH in terms of functional outcome and survival. Unfortunately, its half-life is very short and continuous therapy requires a central venous catheter (CVC) with associated risks (infection and thrombosis), and even brief interruptions can be life-threatening. Important side effects of PGI2 include systemic hypotension, headache, bone pain (especially jaw pain), and gastrointestinal discomfort. Despite these apparent shortcomings, PGI2 has been used extensively, and for prolonged periods of time. Commercially available pumps for ambulatory use allow many children to engage in nearly any activity they enjoy.
Synthetic PGI2 analogues with longer half-lives have been developed and can be given by inhalation, or systemically. When given by inhaled route, the risks associated with CVC are avoided and systemic side effects are decreased, but efficacy is also decreased and respiratory side effects can occur. Iloprost (given by inhalation 6-9 times/day) has been shown to improve symptoms and facilitate weaning off intravenous PGI2 in some children. An important side effect of inhaled iloprost is bronchoconstriction, which may be alleviated by adding bronchodilator therapy but may prevent its use. Treprostinil (given by inhalation 4 times/day), has also been shown to improve symptoms. Common side effects of inhaled treprostinil are sore throat and cough, though these may be less common in children. Treprostinil can also be given systemically (intravenously or subcutaneously), with side effects that are similar to those of PGI2. Systemic treprostinil requires continuous infusion, but interruptions of even a few hours can be tolerated. The subcutaneous route avoids the need for CVC, but in addition to general systemic side effects, local pain can be severe during the first few days of a new infusion site. The local pain with subcutaneous treprostinil appears to be better tolerated in children and especially in infants than in adults.
Other medical therapies: Children with underlying lung disease who have intermittent hypoventilation may benefit from supplemental oxygen (especially during sleep) as oxygen is a vasodilator. Some patients with normal saturation but severe PH and dyspnea may also benefit from supplemental oxygen. Anticoagulation with warfarin has been shown to improve survival in adults. Due to the risks of bleeding, caution is warranted, especially in young children. Unless there is a known thrombophilic condition, a modestly elevated target INR is appropriate (~1.5-2.5). Digoxin has been used in some cases, especially when myocardial dysfunction is seen. During acute exacerbations that require hospitalization, intravenous milrinone by continuous infusion may be helpful.
Other surgical therapies: In children with progressive heart failure and syncope despite aggressive medical management using multiple medications, atrial septostomy may temporarily alleviate the symptoms, though survival is probably not affected. In children with chronic end-stage PH, lung transplantation may represent a viable option. It is important to recognize that while PH is potentially cured, poor outcomes for lung transplantation and limited organ availability make this strategy less reassuring.
Ongoing research into the pathobiology of pulmonary hypertension suggests many new potential therapeutic approaches. The hyperplasia seen in the pulmonary blood vessels is reminiscent of neoplastic diseases, and suggests that antiproliferative strategies may yield not just stabilization of symptoms but even improvement and eventual resolution. While many of these approaches have been found to be very efficacious in animal models of PH, safely translating those findings to human patients will require further research.
For Further Reading
[1.] Barst RJ. Pulmonary hypertension: past, present and future. Ann Thorac Med 2008 Jan;3(1):1-4.
[2.] Berger RM, Beghetti M, Humpl T, et al. Clinical features of paediatric pulmonary hypertension: a registry study. Lancet 2012 Feb 11;379(9815):537-546. Epub 2012 Jan 11.
[3.] Cerro MJ, Abman S, Diaz G, et al. A consensus approach to the classification of pediatric pulmonary hypertensive vascular disease: report from the PVRI Pediatric Taskforce, Panama 2011. Pulm Circ 2011;1(2):286-298.
[4.] Haworth SG, Hislop AA. Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001-2006. Heart 2009 Feb;95(4):312-317. Epub 2008 Oct 24.
[5.] Hislop A. Developmental biology of the pulmonary circulation. Paediatr Respir Rev 2005 Mar;6(1):35-43.
[6.] Lammers AE, Adatia I, Cerro MJ, et al. Functional classification of pulmonary hypertension in children: report from the PVRI pediatric taskforce, Panama 2011. Pulm Circ 2011 Aug 2;1(2):280-285.
[7.] Porta NF, Steinhorn RH. Pulmonary vasodilator therapy in the NICU: inhaled nitric oxide, sildenafil, and other pulmonary vasodilating agents. Clin Perinatol 2012 Mar;39(1):149-164.
[8.] Rich S, Herskowitz A. Targeting pulmonary vascular disease to improve global health: pulmonary vascular disease: the global perspective. Chest 2010 Jun;137(6 Suppl):1S-5S.