The etiology of pulmonary hypertension is complex and varied, and the prognosis varies according to the cause and/or outcome of treatment. Idiopathic Pulmonary Arterial Hypertension (IPAH) is rare, but has a very poor prognosis, with an average survival of about 3 years after definitive diagnosis in untreated patients. Pediatric pulmonary hypertension has similarities with adults, but has some different features and differences from adults in terms of etiology, diagnosis and treatment. 1. Definition and classification First of all, we need to understand that Pulmonary Hypertension (PH) and Pulmonary Arterial Hypertension (PAH) are two different concepts. Pulmonary hypertension is currently recognized as a systolic pulmonary artery pressure of 30 mmHg at rest or a mean pulmonary artery pressure >25 mmHg (>30 mmHg with activity) and a pulmonary capillary wedge pressure (PCWP) <15 mmhg, as measured by a right heart catheter. This criterion applies to both children and adults; in addition, there are empirical indices used in clinical practice, such as ultrasound Doppler tricuspid regurgitation velocity >2,5 m/s (approximately equivalent to a pulmonary artery systolic pressure of 40 mmHg), or pulmonary artery systolic pressure exceeding 1/2 the systolic pressure of the body circulation, which can also be considered as pulmonary hypertension. The clinical etiology of pulmonary hypertension was revised at the 2003 WTO meeting in Venice, and is divided into 5 major categories and 21 subcategories, including: (1) pulmonary hypertension; (2) pulmonary hypertension associated with left heart disease; (3) pulmonary hypertension associated with respiratory disease or hypoxia; (4) pulmonary hypertension with chronic thrombosis and/or thrombosis; and (5) mixed pulmonary hypertension. For details, please refer to the “Expert Consensus on the Diagnosis and Treatment of Pulmonary Hypertension of the Evidence-based Medicine Committee of the Chinese Medical Association”. Persistent pulmonary hypertension in newborns (PPHN) is also included, but has its own unique pathogenesis. 2. Signs and symptoms Since pulmonary hypertension mainly affects the right heart system, most of them have manifestations due to right heart insufficiency in addition to the signs and symptoms of pulmonary hypertension with concurrent diseases, most of them have complaints or symptoms of dyspnea, especially intensified after exercise, and sometimes even symptoms of exercise-induced syncope. In addition, there may be complaints of weakness or post-exercise chest pain. The clinical manifestations vary according to the etiology. Newborns may present with cyanosis, hepatomegaly, and a loud second heart sound on auscultation; older children may also present with pestle-like fingers (toes). In a few patients, cyanosis, hemoptysis, and even right heart failure such as foot edema are the first symptoms. 3.Diagnosis and evaluation of pulmonary hypertension The diagnosis and evaluation of pulmonary hypertension includes the following aspects (1) firstly, the suspected diagnosis of pulmonary hypertension is considered based on the symptoms, signs and related clinical manifestations of the child; (2) electrocardiogram, X-ray chest radiograph and cardiac ultrasound are performed in suspected cases to determine the presence of pulmonary hypertension; (3) the etiology of pulmonary hypertension is clarified: including the examination of hematological indicators ( Such as biochemical, microbiological, immunological, etc., mainly for the differential diagnosis of connective tissue diseases, immune system diseases, etc.) and lung structure and function evaluation (such as spirometry, lung CT, pulmonary angiography, etc.) and other related examinations (such as abdominal ultrasound to exclude portal system abnormalities, etc.); (4) assessment of pulmonary hypertension: exercise such as 6-minute walk test to evaluate the exercise tolerance of the child, WHO pulmonary artery (4) assessment of pulmonary hypertension: exercise such as 6-minute walk test to evaluate exercise tolerance, WHO pulmonary artery functional classification to assess the status of cardiac function, right heart catheterization to detect hemodynamics to help determine the severity and nature of pulmonary hypertension; acute vasodilator response test (WHO recommends adenosine, inhaled prostaglandin, and also toltrazurine in China) to evaluate the potential therapeutic effect of drugs. In our experience, chest X-ray, electrocardiogram, cardiac ultrasound, abdominal ultrasound, and chest CT are the basic tests for every child suspected of pulmonary hypertension, and right heart catheterization is the indispensable gold standard for the diagnosis of pulmonary hypertension. Chest X-ray can observe the phenomenon that the main pulmonary artery is dilated in severe pulmonary hypertension, while the number of small peripheral pulmonary vessels is reduced resulting in less peripheral pulmonary blood; because the X-ray display results are sometimes not very fine, it is easy to cause a missed diagnosis. Cardiac ultrasound is the most commonly used technique for the clinical diagnosis of pulmonary hypertension and can confirm the presence of pulmonary hypertension, as well as detect or exclude congenital or secondary causes of pulmonary hypertension such as ventricular septal defect, cardiomyopathy, pulmonary venous The 6-minute walk test (6MWT) is a standardized method for evaluating exercise tolerance and oxygen saturation in children with pulmonary hypertension and is simple to perform in most older children (3 years of age and older). Cardiac catheterization is the gold standard for the diagnosis of pulmonary hypertension, allowing direct and accurate measurement of pulmonary artery pressure and also indirect calculation of pulmonary vascular resistance (PVR) to help determine the reversibility of pulmonary hypertension; for congenital heart disease with combined left-to-right shunts, it can help determine whether pulmonary artery pressure is reversible after surgery or the prognosis of idiopathic pulmonary hypertension. 4. Genetic studies It has been recognized that there are genetic factors in children with IPAH and in family members. Approximately 8% of patients have a family history of pulmonary hypertension, and the associated causative genes are being or have been identified. The more certain ones are BMP IIR and receptor genes related to the TGF-β signaling pathway such as ALK-1, and BNPR-2 has also been shown to be associated with IPAH; all of them are related to the SMAD signaling system, and phosphorylation of SMAD is very important in the process of heart development. For secondary pulmonary hypertension, there is no additional evidence for the presence of genetic factors. 5. Treatment of pulmonary hypertension The WTO has graded the cardiac function of pulmonary hypertension in accordance with the NYHA cardiac function classification. Pulmonary hypertension cardiac function grade I is normal, and cardiac function grade II is the starting point for treatment. The principles of treatment are similar in both adults and children, and in addition to treatment of the known cause, most include a combination of therapies such as cardiotonic, diuretic, oxygen and anticoagulation, as well as treatments selected based on the results of the vasodilator response test. For positive vasodilator response (pulmonary artery pressure or PVR decreased by more than 20%, but only about 10% of patients are positive clinically), long-term oral calcium channel blockers (CCBs) can be administered and re-evaluated periodically; for negative vasodilator response, treatment can be graded according to cardiac function, and for class III cardiac function, prostacyclin (class) drugs or endothelin (ET) receptor antagonists such as Bosentan, and some of those who fail to take CCBs can also be referred to this category; those with cardiac function grade IV can be treated with a combination of prostacyclin (class) drugs and ET receptor antagonists, and also with phosphodiesterase inhibitors such as Sildenafil, and some of those whose cardiac function grade III treatment is ineffective can also be treated with this regimen. The final option for those with ineffective treatment in cardiac function class III or IV is surgery such as atrial septostomy, lung transplantation or combined heart-lung transplantation. At present, only Bosentan and inhaled Iloprost are officially approved for clinical treatment of pulmonary hypertension in China; some medical units are also using Sildenafil and have achieved some efficacy. Another worth mentioning is that some units commonly used vasodilator drug captopril, only some animal experiments have shown that it is effective in pulmonary hypertension, which is the lowest level basis in evidence-based medicine and should not be used as a routine; and because it dilates the body circulation more than the pulmonary circulation, it may aggravate right-to-left shunt in pulmonary hypertension in precordial disease. (1) Comprehensive treatment: diuretics can reduce the excessive volume load of right heart insufficiency; digoxin can increase cardiac output and is effective in pulmonary hypertension with right heart insufficiency and reduced cardiac output, but there is not much clinical experience yet. Hypoxemia may cause pulmonary vasoconstriction and aggravate pulmonary hypertension, so oxygen therapy may be given to those with arterial oxygen concentrations below 90%, especially those with nocturnal paroxysmal dyspnea, but it is still controversial whether oxygen therapy is appropriate for Eisenmenger syndrome. Anticoagulants are mainly used in children with IPAH, because of their microthrombotic mechanism, but they can also be used for right heart insufficiency or long-term intravenous drug therapy, such as Warfin and aspirin, whose risk/benefit ratio should be evaluated for long-term use. In addition, reasonable use of sedation can prevent the occurrence of pulmonary hypertension crisis. 2) Calcium channel blockers: Nifedipine has been used in the treatment of pulmonary hypertension for a long time and is still used to identify vasodilatory responsiveness, and effective ones can reduce PVR by about 20%. About 5-10% of pediatric or adult patients with idiopathic pulmonary hypertension do well with Nifedipine and do not need other drugs. However, some patients do well on Nifedipine for the first few years and then suddenly become ineffective and turn to the addition of other medications. Other used in the treatment of pulmonary hypertension are Diltiazem, Amlodipine, etc. 3) NO: NO has the characteristics that it can be inhaled directly into the airway and the dose can be easily controlled. Children with post-operative congenital heart disease may only need a very low dose of NO inhalation of 3~10ppm; likewise, NO inhalation is a very good choice for persistent pulmonary hypertension in newborns. The disadvantage is that it is not convenient for long-term treatment in the home. 4) Prostacyclin (class) drugs: PGI2 can act directly on pulmonary vascular smooth muscle cells to increase their cAMP levels, thus reducing PVR; it can also be used in patients with ineffective or tolerated NO, and in the process of withdrawing NO as an alternative treatment. PGI2 is available in various dosage forms, but there is currently more experience with intravenous PGI2, which is currently recognized as one of the better treatments. For patients with severe IPAH, it can be used as a therapeutic starting point drug and a gold standard for evaluating the effectiveness of other treatments available for comparison, but should be used in experienced medical units to avoid its serious side effects, while its drug properties are unstable at room temperature and short half-life limit its clinical application. triprostinil is available for subcutaneous injection and has a longer half-life for drug metabolism, a Berapost is an oral dosage form with good compliance in children, but is relatively less effective than the intravenous form of prostacyclin. The inhaled form of Iloprost is easier to administer and has less side effects, but the more frequent dosing times (once every 2 hours) and the difficulty of ensuring the dose administered also limit its use in pediatric patients. (5) Phosphodiesterase inhibitors: Sildenafil is a phosphodiesterase type V inhibitor that acts on the NO pathway. Many other drugs of the same type are in clinical validation, including Zaprinast and even type I phosphodiesterase inhibitors, but their current clinical experience is very limited. These drugs can increase endogenous NO production and can be applied for transfer out of the ICU unit or for the gradual withdrawal of high concentrations of inhaled NO replacement therapy. The disadvantages are that the duration of action is very short, cannot be used for long-term, monotherapy, and can cause side effects such as memory loss and blurred vision. 6) Endothelin (ET) receptor antagonists: Bosentan, a dual endothelin receptor antagonist (anti-Eta and Etb receptors), has been shown to have a positive therapeutic effect in children with idiopathic pulmonary arterial hypertension (IPAH) and appears to have some effect in adults with Eisenmenger syndrome, but its effect on congenital heart disease and pulmonary hypertension due to high pulmonary blood flow However, its effect on congenital heart disease and pulmonary hypertension due to high pulmonary blood flow remains to be evaluated, and there is a more pronounced side effect of liver damage with long-term use. In addition, some new endothelin receptor antagonists are being clinically validated, such as Sitaxsentan, a new Eta receptor antagonist. 7) Extracorporeal membrane lung (ECMO): Since NO inhalation has been widely used in the clinic, the use of ECMO for severe pulmonary hypertension has been rare; however, it can still be used in patients in whom other methods have failed, especially in patients with pulmonary hypertension exacerbated by respiratory disease or with severe congenital heart disease requiring emergency surgery. (8) Surgery: Atrial septal stoma (Atrial Septostomy) is performed to reduce the right heart load and increase the volume of blood in the circulation by creating a right-to-left shunt, and due to the high risk, it is only used in patients with critical pulmonary hypertension, end-stage pulmonary hypertension and palliative care pending lung transplantation. Lung transplantation or combined heart-lung transplantation is usually used as a last resort treatment, which is not suitable for every end-stage patient due to disadvantages such as insufficient donor sources, many complications and high risks. 6. Pulmonary hypertension in congenital heart disease 1) Left-to-right shunt congenital heart disease: The severity of pulmonary hypertension mostly depends on the size of the shunt flow and the type of heart defect. If a young child with ASD has severe pulmonary hypertension, he or she should be alerted to the presence of IPAH or pulmonary vein stenosis; in contrast, children with large ventricular septal defect (VSD) can develop organic lesions of the pulmonary vasculature before the age of 2 years, and most of those with large-vessel dislocation lose the opportunity for surgery at 9 months of age. The majority of children with combined large vessel dislocation are lost to surgery by 9 months of age. (2) Transposition of the great vessels: The rapid progression of pulmonary vascular disease in children with VSD combined with transposition of the great vessels can be attributed to high shunt and high pulmonary artery pressure. It is difficult to understand why some children with intact ventricular septum and low pulmonary artery pressure develop severe pulmonary vasculopathy even after timely corrective surgery; the mechanism for this is unclear. (3) Pulmonary venous hypertension: Some pulmonary hypertension is caused by increased pulmonary venous pressure. For example, mitral stenosis can cause severe pulmonary hypertension due to obstruction of pulmonary blood return, but it can be reversed with surgical correction; dilated cardiomyopathy can also lead to pulmonary hypertension due to increased left atrial pressure. A more difficult dilemma is pulmonary vein stenosis, which can be caused by abnormal pulmonary venous return itself or a post-surgical complication that can lead to critical pulmonary hypertension immediately after surgery. (4) Postoperative pulmonary hypertension: For pulmonary hypertension with congenital heart disease, early surgical treatment is the best way to reduce the morbidity and mortality of the child; with the modern level of intensive care and the application of postoperative nitric oxide (NO) and other pulmonary vasodilators, the incidence of postoperative pulmonary hypertension has been significantly reduced compared to 20 years ago, and good mechanical ventilation, oxygenation and adjuvant medication will help to keep the mean pulmonary artery pressure in the normal range; however, in some children with combined IPAH, surgery may accelerate the development of pulmonary vasculopathy. In addition to the above-mentioned drugs that have entered the clinical phase, drugs such as Rho-kinase inhibitors and matrix metalloproteinase inhibitors are currently being investigated, which hold great promise for the treatment and even reversal of pulmonary hypertension and its resulting pulmonary vascular lesions, and the average survival of patients with IPAH can be extended by However, it should also be noted that the drugs that are really suitable for the treatment of pulmonary arterial hypertension in children are still very limited and very expensive, so the continuous efforts of the majority of adult physicians, pediatricians (including cardiac, respiratory, neonatal, etc.) and researchers are needed.