Idiopathic pulmonary artery hypertension (IPAH), previously referred to as primary pulmonary hypertension (PPH), is a relatively recently described entity with an unclear etiology.
IPAH is a serious syndrome, with significant morbidity and mortality. It can be associated with progressive elevation of pulmonary artery pressure and can lead to right ventricular failure. By definition, the cause is unexplained; this implies that associated causes of pulmonary hypertension have been ruled out.
The definition of pediatric IPAH, therefore, is the same as that of IPAH in adults: a mean pulmonary artery pressure greater than 25 mm Hg at rest with normal pulmonary capillary wedge pressure, in the absence of associated causes of pulmonary hypertension.
Some authors believe that including exercise hemodynamic abnormalities in the definition is important, especially in the pediatric population; therefore, a mean pulmonary artery pressure of greater than 30 mm Hg with exercise is also considered to be an abnormal response and is consistent with the definition of idiopathic pulmonary artery hypertension.
Because many of the symptoms of idiopathic pulmonary artery hypertension (IPAH) are nonspecific and the disorder is relatively rare, the diagnosis may be somewhat difficult to make (see Diagnosis).
The diagnostic assessment includes a variety of blood studies, coagulation studies, tests for collagen-vascular disease, and imaging studies, as well as a variety of other tests and procedures (see Workup).
The usual regimen for patients with IPAH includes warfarin (Coumadin), digoxin, and vasodilators, such as nifedipine, intravenous prostacyclin, or both. For those children who truly do not respond to long-term therapy and who are symptomatic, lung transplantation should be considered (see Treatment and Management).
Pulmonary hypertension (PH) in children is defined as a resting mean pulmonary artery pressure (PAP) of more than 25 mm Hg beyond the first few months of life.
At the time of initial PH diagnosis, a comprehensive history and physical examination, combined with diagnostic testing for assessment of PH pathogenesis/classification and formal assessment of cardiac function, should be performed before the initiation of therapy at an experienced center.
Imaging to diagnose pulmonary thromboembolic disease, peripheral pulmonary artery stenosis, pulmonary vein stenosis, pulmonary veno-occlusive disease (PVOD), and parenchymal lung disease should be performed at the time of diagnosis.
After a comprehensive initial evaluation, serial echocardiograms should be performed. More frequent echocardiograms are recommended in the setting of changes in therapy or clinical condition.
Cardiac catheterization is recommended before initiation of PAH-targeted therapy. Exceptions may include critically ill patients requiring immediate initiation of empirical therapy.
Cardiac catheterization should include acute vasoreactivity testing (AVT) unless there is a specific contraindication.
The minimal hemodynamic change that defines a positive response to AVT for children should be considered as a ≥20% decrease in PAP and pulmonary vascular resistance (PVR)/systemic vascular resistance (SVR) without a decrease in cardiac output.
Repeat cardiac catheterization is recommended within 3-12 mo after initiation of therapy to evaluate response or with clinical worsening.
Brain natriuretic peptide (BNP) or N-terminal (NT) proBNP should be measured at diagnosis and during follow-up.
The 6-minute walk distance (6MWD) test should be used to follow exercise tolerance in pediatric PH patients of appropriate age.
A sleep study should be part of the diagnostic evaluation of patients with PH at risk for sleep-disordered breathing.
A sleep study is indicated in the evaluation of patients with poor responsiveness to PAH-targeted therapies
Inhaled nitric oxide (iNO) is indicated to reduce the need for extracorporeal membrane oxygenation (ECMO) support in term and near-term infants with persistent PH of the newborn (PPHN) or hypoxemic respiratory failure who have an oxygenation index that exceeds 25.
Lung recruitment strategies can improve the efficacy of iNO therapy and should be performed in patients with PPHN associated with parenchymal lung disease.
ECMO support is indicated for term and near-term neonates with severe PH or hypoxemia that is refractory to iNO and optimization of respiratory and cardiac function.
In children with significant structural heart disease (ie, atrial septal defect [ASD], ventricular septal defect [VSD], and patent ductus arteriosus [PDA]) who have not undergone early repair (as generally defined as by 1-2 yr of age, depending on the lesion and overall clinical status), the following are recommended: cardiac catheterization should be considered to measure PVR index (PVRI) and to determine operability; repair should be considered if PVRI is <6 Wood units (WU)·m 2 or PVR/SVR is <0.3 at baseline.
Administration of opiates, sedatives, and muscle relaxers is recommended for reducing postoperative stress response and the risk for or severity of PH crises.
The exact pathogenesis and pathophysiology of idiopathic pulmonary artery hypertension (IPAH) are unclear. Pulmonary vasoconstriction appears to be the most widely accepted mechanism. Studies suggest that exposure to certain stimuli may initiate the characteristic vascular lesions in persons who are predisposed to the disorder. Triggers of pulmonary vasoconstriction in susceptible individuals include the following:
Other studies also invoke an imbalance of vasoactive mediators that favoring those causing vasoconstriction. Thromboxane, arachidonate metabolites, and prostacyclin, as well as other endothelial factors, have been invoked.
In addition, coagulation abnormalities may occur. This possibility is supported by the finding of microthrombi in the pulmonary vascular bed, which are noted at the time of lung biopsy, autopsy, or in explanted lungs at the time of lung transplantation. Whether this is a primary or secondary finding is unknown.
Much experimental work is being conducted in the area of endothelial metabolism of vasoactive substances. The hope is that this will lead to a better understanding of the control of the pulmonary circulation and to improved and more specific therapies for IPAH.
The frequency of IPAH in children is not known (nor is the frequency in adults known). Conceivably, more patients have the disease than previously suspected. As more knowledge of IPAH is currently available, the disease may be more easily recognized.
The incidence of familial IPAH has been thought to be 5-10%. The disorder appears to be autosomal dominant with incomplete penetrance.
The male-to-female ratio in adults is reported to be 1:1.7. In children, the ratio varies, with some studies showing an equal distribution between females and males in younger children, whereas other studies have shown a female preponderance of 1.5:1.
Before the age of vasodilator therapy, most children died within 1-2 years of diagnosis, whereas adults had a median survival of 2-3 years. Survival has improved, although morbidity and mortality remain significant. In 2009, the United Kingdom Pulmonary Hypertension Service for Children reported survival rates of 85.6% at 1 year, 79.9% at 3 years, and 71.9% at 5 years. 
Morbidity and mortality rates vary and depend on the age, the degree of pulmonary hypertension, and the response to vasodilator therapy. Death may occur as a result of both acute and chronic right heart failure and its associated arrhythmias. Additionally, patients can be affected by the complications associated with low cardiac output.
Children who respond to short-term vasodilator drug testing have a 5-year survival rate of 90%, whereas children who do not initially respond have a 5-year survival rate of 33%. However, follow-up studies suggest that this latter number may be much higher. Studies of newer medications, as well as combination medications, have found a much improved longer-term prognosis, even for the acute nonresponder group, with some studies suggesting as high as an 80% 5-year survival rate.
Finally, the morbidity associated with chronic vasodilator therapy and frequent intravenous line infections in patients on long-term continuous intravenous prostacyclin as well as long-term anticoagulation are well known.
Patients must be educated with regard to central line care, signs and symptoms of line infection, and signs and symptoms of deteriorating condition.
In addition, patients on continuous intravenous prostacyclin develop tachyphylaxis and require interval dose increases. Families must learn the proper operation of the intravenous pump and all the nuances of mixing and infusing the drug.
Provide counseling in the methods of birth control for female patients of reproductive age who have moderate-to-severe pulmonary hypertension. Labor and delivery is life threatening in patients with significant pulmonary hypertension; therefore, pregnancy should be avoided.
The guidelines on pediatric pulmonary hypertension by the American Heart Association and American Thoracic Society state that genetic testing with counseling can be useful for children with idiopathic PAH or in families with heritable PAH to define the pathogenesis, to determine family members at risk, and for family planning. 
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