Pulmonary arterial hypertension (PAH) is the most common type of pulmonary hypertension. patients with PAH have elevated mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR), leading to right heart failure and ultimately death. the prognosis for PAH is poor, with a median survival of only 2.8 years for untreated adults and an even worse prognosis for children. PAH is a rare disease, with a prevalence of 6.6 to 26 per 1,000,000 adults and 20 per 1,000,000 children. PAH is a rare disease with a prevalence of 6.6-26/1,000,000 adults and 20/1,000,000 children.
The pathophysiological mechanism of PAH is not clear, but the decrease in the level of diastolic antiproliferative substances and the increase in the level of constrictive proliferative substances due to endothelial dysfunction are important factors in the formation of PAH.
In the past decades, it has been found that the regulation of pulmonary artery pressure is mainly through three classical pathways: prostacyclin, nitric oxide pathway, and endothelin 1 pathway. Accordingly, three major classical drugs have been studied for the treatment of PAH: prostacyclin analogs, phosphodiesterase inhibitor-5 (PDE-5 inhibitor), and endothelin receptor antagonists (ERAs).
PAH drugs can improve survival in adult patients. Paediatric PAH differs from adult PAH in many ways; 50% of pediatric PAH patients have congenital heart disease, whereas connective tissue disease, portal hypertension, and drug-induced PAH are less common in children. Childhood patients with IPAH most often present clinically with syncope, while adult patients most often present with heart failure. However, due to the lack of credible research data on PAH in children, there are still no guidelines for the management of PAH in children.
General treatment
General treatment includes: anticoagulation, oxygen therapy, influenza or streptococcus pneumoniae vaccination
Calcium channel blockers
Studies have shown that calcium channel blockers (CCB) can improve survival in a minority (7%) of adult IPAH patients. Patients with a positive acute vascular response test on cardiac catheterization are effective for CCB drug therapy. It is generally accepted that pediatric IPAH patients have a higher response to CCB than adult patients. However, this study reported a wide range of fluctuations in the data (8% to 56%). The criteria for drug response status in adults were developed by Professor Sitbon et al.
For children, the criteria were developed by Prof. Barst et al. However, if the same criteria are applied to adults and children, both age groups will show a similar proportion of responders. Since responders may show no response to CCBs after a period of time and require further treatment, responders need to be evaluated frequently for hemodynamics as well as clinical effectiveness. Given the side effects of CCBs, they are not recommended for use in children under 1 year of age.
Prostacyclins
Prostacyclin has physiological effects of vasodilatory, antiproliferative, and anticoagulant effects. prostacyclin levels are decreased in patients with PAH. Prostacyclin analogs are the first generation of PAH medications. Side effects of this class of drugs include flushing, jaw pain, diarrhea, nausea, and headache. All of these side effects are associated with systemic vasodilation caused by the drugs.
Side effects due to the route of administration are also common and include: intravenous catheter infection when given intravenously; injection site pain when given subcutaneously; and bronchospasm, chest pain, and cough when given by the inhalation route.
Epoprostenol
Benefits: (1) Improved clinical symptoms, hemodynamic status, and survival in adult and pediatric PAH patients. (2) It can be used in patients of all ages, including infants and young children.
Disadvantages: (1) Short half-life and unstable at room temperature. (2) There is a risk of intracatheter thrombosis when administered through a central venous line and, more seriously, of intravenous catheter infection. Patients with congenital heart disease and those with right-to-left shunts can develop systemic embolic complications as a result. (3) Abrupt discontinuation of the drug can lead to a fatal rebound in pulmonary artery pressure.
Trilonil
Advantages: (1) Longer half-life and more stable chemical structure at room temperature. (2) Can be administered by subcutaneous, oral, and inhalation routes. The subcutaneous, intravenous, and inhalation routes of administration improve exercise tolerance, clinical status, and hemodynamic status (TRIUMPHtrial) in adult patients. The intravenous and subcutaneous routes of administration improved survival. Oral tretinoin monotherapy for 12 weeks improves exercise tolerance in adult patients with PAH. However, studies have also demonstrated no significant improvement in exercise tolerance after 16 weeks of oral trilonil treatment in addition to PDE-5 inhibitors and/or ERA analogs.
Disadvantages: pain and infection at the injection site, and subcutaneous injections should not be used in children.
There are few data on the use of Trandolonil in children. Two small studies have demonstrated that the addition of treponil (subcutaneous injection or inhalation) to the original treatment improved clinical and hemodynamic status with no significant side effects.
Beprostacycline
Beprostacyclin was the first prostacyclin-based drug to improve clinical symptoms and hemodynamic status in adult patients. However, the efficacy of this drug has diminished over the course of long-term follow-up (ALPHABETtrial).
Iloprost
Iloprost is a commonly used inhaled analog of prostacyclin. It requires at least one year after initiation of the drug to be effective (AIRandSTEPtrials). Studies have shown that this drug also improves clinical symptoms in pediatric patients. When patients who are not on the intravenous route become sicker, switching to or adding intravenous medication may improve clinical symptoms in only a small percentage of patients.
Endothelin receptor antagonists
Endothelin-1 levels are elevated in the blood of patients with PAH. There are two receptors for endothelin-1 in the body: the endothelin A receptor and the endothelin B receptor. Both receptors promote vasoconstriction, promote inflammatory responses, and are pro-proliferative. Endothelin B receptors are also present in the pulmonary artery endothelium and modulate vasoconstriction and activate antiproliferative substances. eRA drugs selectively antagonize endothelin A receptors or block both receptors.
The main side effects of ERA drugs are increased liver enzymes, peripheral edema and decreased hemoglobin. These drugs can be administered orally, so there are no side effects due to the route of administration.
Bosentan
Bosentan is a class of dual receptor antagonist drugs. It improves 6-minute walk distance, WHO functional class and delays disease progression in adult patients. Some studies have shown similar effects in children as in adults.
Benefits: (1) Well tolerated and safe in pediatric patients, and available in pediatric formulations. (2) Children are less likely to have elevated liver enzymes than adults. Nevertheless, routine screening tests are needed to adjust the dosage or discontinue the drug in time to detect elevated liver enzymes.
Ambesentan
Ambesentan is a selective endothelin A receptor antagonist. The effect of this drug is comparable to that of bosentan.
Advantages: Ambesentan has a better safety profile than bosentan, it causes less liver damage, and there are fewer drug-drug interactions.
Disadvantages: In a retrospective study of 38 children with PAH, ambrisentan was shown to be effective in only a small proportion of children.
Macitentan
Macitentan is a class of dual receptor antagonist drugs.
Advantages: (1) Sustained binding of receptors and high tissue penetration. (2) In a population study of 742 patients aged >12 years, the drug was shown to be effective in reducing mortality compared to the placebo group (SERAPHINtrial). Clinical data and hemodynamic data improved after 6 months of drug use. (3) The safety profile is good, with few elevations of liver enzymes as well as peripheral edema. Disadvantages: There are no data on this drug for pediatric patients.
Phosphodiesterase inhibitor-5
NO regulates vasodilation and anti-cellular proliferation via guanylate cyclase. pDE-5 promotes degradation of guanylate cyclase. And PDE-5 inhibitors can inhibit this effect of PDE and promote the vasodilatory effect of NO. The most common side effects are headache, flushing and epistaxis. PDE-5 can be administered orally, so there are no side effects caused by the route of administration.
Sildenafil
Advantages: (1) Some studies have demonstrated that the efficacy of sildenafil persists after 3 years of use in adult patients. (2) Sildenafil is well tolerated.
Disadvantages: The use of sildenafil in children is controversial. the START-1 trial found improved hemodynamics in the moderate and high dose sildenafil groups. The STARTS-2 trial demonstrated a lower survival rate with high doses of sildenafil in children.
The US Food and Drug Administration (USFDA) does not recommend the use of sildenafil in children, while the European Medicines Agency (EMA) recommends the use of sildenafil in children but prohibits high doses. The U.S. Pediatric Pulmonary Hypertension Network believes that low-dose sildenafil is safe for use in children and agrees with the EMA, but the long-term effects of the drug on children should be further studied.
Tadalafil
Advantages: (1) The drug is well tolerated and has a high safety profile. (2) One study demonstrated improvement in exercise tolerance, hemodynamic status, and quality of life in adult PAH patients after 16 weeks of tadalafil use, with a delayed time to progression. The improvement in exercise tolerance persisted after 62 weeks of use.
Cons: Data on tadalafil use in pediatric patients are lacking.
In a retrospective single-center cohort study of 33 children, 29 of whom were switched from sildenafil to tadalafil, mPAP, PVR, and pulmonary/coronary vascular resistance ratios improved in these 29 children, while exercise tolerance, brain natriuretic peptide, and cardiac index did not improve significantly. Four other children were treated with tadalafil at the start of treatment, and all four children showed improvements in clinical symptoms and hemodynamic status.
Newer drugs
Risaguante
Risiguanat is a soluble guanylate cyclase agonist. In contrast to PDE-5 inhibitors, this drug acts upstream of the NO pathway and directly activates guanylate cyclase to increase cyclic guanylate levels. The drug can act synergistically with NO or independently of NO. Some trials have shown that exercise tolerance, clinical symptoms and hemodynamic status of adult PAH patients can be significantly improved after 12 weeks of dosing compared to pre-drug and placebo groups. However, there is a lack of data on this drug in children.
Selexipag
Selexipag is an orally selective prostacyclin receptor agonist. phase II trials have shown improvement in PVR in 43 adult PAH patients after 17 weeks of Selexipag in addition to their previous treatment, and the drug is well tolerated. phase III trials are ongoing. However, there is a lack of data from studies of this drug in children.
Imatinib
Imatinib is a tyrosine and enzyme inhibitor. The drug was originally developed to treat chronic granulocytic leukemia.
Imatinib inhibits vascular smooth muscle cell proliferation. The drug’s main effect is anti-proliferative.
Pros: There are studies that demonstrate imatinib’s effectiveness in severe PAH.
Disadvantages: Serious adverse events have been reported, including subdural hematomas. However, the drug lacks data from studies in children and the authorities withdrew their permission for imatinib to be used to treat PAH.
Studies have now been proposed to cause new pathways to modulate pulmonary artery pressure, and many novel drugs are targeting new pathways. These include Rho kinase inhibitors that target the Rho/Rho kinase signaling pathway and endothelial progenitor cells that can regenerate and repair already damaged pulmonary microvasculature.
Combination drugs
The rationale for combination drugs is that targeting two or three of the three classical pathways is more effective than targeting only one pathway. As the data from combination studies have become more available, the recommendation and evidence levels for combination use have increased. However, these study data are based on studies of adult patients.
ERA + PDE-5 inhibitors
The use of ERA and PDE-5 inhibitors in adult PAH patients has been shown to be effective in improving exercise tolerance, functional status, and hemodynamic status better than either drug alone. The addition of macitentan to PDE-5 inhibitor therapy may improve adverse disease regression. The combination of drugs was better tolerated. Additional studies have shown better efficacy and safety with the addition of resiguanide to treatment with ERA or pulmonary intravenous prostacyclin analogs.
ERA/PDE-5 Inhibitors + Prostacyclin Analogs
The addition of sildenafil to long-term intravenous epoprostenol in adult patients improves clinical symptoms and hemodynamic status and may delay disease progression. The addition of inhaled tretinoin or inhaled iloprost to ineffective oral ERA and/or PDE-5 inhibitor therapy may be effective in improving functional status, exercise tolerance, and hemodynamic status.
Inhaled iloprost delays the time to disease progression, while inhaled tretinoin can be effective for up to 24 months. Subcutaneous trenbolone plus bosentan has also been shown to have a better therapeutic effect.
Many studies have demonstrated better outcomes in adult patients with the addition of medication to monotherapy that is ineffective. Data from studies in children are lacking. A recent study of 275 children showed that survival rates were better with the combination than with monotherapy, independent of the type of PAH.
Another study of 24 children showed that the addition of sildenafil to bosentan treatment was effective in improving WHO functional class and 6-minute walk distance, while children treated with bosentan alone had worse outcomes. Children treated with sildenafil had a higher survival rate than those treated with bosentan alone. Children with severe PAH improved clinical and hemodynamic status with the addition of inhaled or subcutaneous trenbolone.
Although the current study shows that the combination has been shown to be more effective in both adult and pediatric patient populations. However, when and how to combine drugs, and the rules for combining drugs in various types of PAH need to be further investigated.
Non-pharmacological treatment
Non-pharmacologic therapy is intended to maintain cardiac ejection volume and reduce right heart load. Non-pharmacologic therapy can be used as a treatment option for symptomatic relief or for lung transplant overload.
Atrial septal balloon stoma
Atrial septal balloon stoma (BAS) is usually used in patients with advanced IPAH or/and in patients with recurrent syncope. Syncope is a common symptom in the pediatric patient population, so BAS is more commonly used in the pediatric patient population.
Advantages: (1) Many small studies in pediatric patients and/or adult patients have shown that BAS can improve clinical and hemodynamic status. (2) BAS may improve survival by prolonging the excess time used to wait for lung transplantation.
Disadvantages: (1) It increases left ventricular preload and cardiac output, and decreases systemic arterial oxygen saturation. (2) It is an invasive procedure with attendant risks, especially in a high-grade population such as PAH patients.
In a population of patients with severely elevated atrial pressures, mortality is increased because of the potential for fatal hypoxia due to the large right-to-left shunt that can be generated. Therefore, it is recommended not to wait for hemodynamic changes such as right-to-left shunts to occur before considering BAS.
Pott shunt
A Pott shunt is an anastomosis that connects the pulmonary artery to the descending aorta, artificially causing a shunt of blood from the pulmonary vascular system to the systemic system. This technique is indicated for patients with pulmonary artery pressures that exceed the pressure of the body circulation and also for patients with severely elevated right ventricular pressures.
Advantages: Compared to BAS, this method’s can directly reduce the right ventricular load. (2) Postoperative hypoxia only occurs in the lower extremities.
Case reports of two children and a retrospective multicenter study of eight children with end-stage IPAH have shown that the Pott shunt technique improves functional status and exercise tolerance, reduces serum BNP levels, and has short- and long-term effects on the right ventricle. However, multicenter studies have also shown that the operation has a high postoperative mortality rate of 25%. More and larger studies of this procedure need to be performed.
Aortic narrowing
Aortic narrowing is an operation based on the ventricular-ventricular response. The theory is that right heart disease can alter left ventricular function and vice versa. A recent study of 23 rabbit models of chronic right ventricular pressure elevation showed that aortic narrowing improved ventricular function on both sides and prevented myocardial remodeling. However, there are no studies in humans, so the evaluation of this operation will continue to require extensive trials.
Lung (heart) transplantation
Lung (heart) transplantation has been the treatment of choice for the end stage of PAH. Since the heart can be restored to its original function and size, lung transplantation is most often used. In children, IPAH is the second most common indication for lung transplantation. Because of the greater risk associated with lung transplantation, lung transplantation is chosen when PAH is progressive and severe despite maximal drug therapy.
Several small studies have shown that lung transplantation improves WHO functional class, right ventricular function and survival, with a median survival of 45-70 months. The subjects of these studies included pediatric IPAH patients. Survival rates for paediatric PAH lung transplantation are equal to or higher than those for paediatric lung transplantation for cystic fibrosis. Whether and when a child undergoes lung transplantation is inconclusive at this time. These questions depend largely on expert judgment or the availability of donor lungs.
In conclusion, despite the limited research on pharmacologic therapy for pediatric PAH patients over the past 5 years, the limited data suggest that
(1) pharmacotherapy is equally effective in children.
(2) With the exception of sildenafil, which is controversial in children, all drugs are well tolerated and safe in children.
(3) Combination drug therapy targeting different physiologic pathways is more effective than monotherapy, also in pediatric patients.
(4) Novel drugs acting on new pathophysiologic pathways can improve the quality of survival and survival of pediatric PAH patients.
(5) Non-pharmacologic treatment options are available for pediatric patients, and it is believed that non-pharmacologic treatment will have a place in pediatric PAH treatment guidelines.
Treatment options
The development of a drug regimen for optimal treatment is as important as the development of new drugs. The questions of how to choose drugs, when to start drug therapy, when to start combination drug therapy, and how to choose combination drugs need to be addressed.
The treatment of PAH in adults is guided by a well-defined treatment plan. The goal of the physician is to achieve a predetermined clinical remission status, not just remission of a worsening clinical status. If the treatment goal is still not achieved after 3-6 months, adjustments to the treatment regimen need to be considered.
The goal of treatment for PAH is to improve quality of life and increase survival. Therefore treatment goals should be representative of improved quality of life, such as symptom remission and increased exercise tolerance. The treatment goal should also have a clinical estimate of the decreased probability of adverse outcomes (death, lung transplantation).
Thus variables used as treatment targets either directly reflect quality of life or meet the criteria that (1) they are closely related to disease regression (2) treatment can influence their values (2) changes in values due to treatment can reflect changes in disease regression.
Current treatment goals for adult patients were presented at the 2013 World Symposium on Pulmonary Hypertension (WSPH).The optimal prognostic criteria for PAH include: WHO functional class I-II, normal or near normal right ventricular size and function on echocardiography and cardiac magnetic resonance, right atrial pressure <8 mmHg and cardiac index >2.5~3 l/min/m2 on cardiac catheterization WSPH should be able to walk >380~440m in 6 minutes, peak oxygen consumption >15ml/min/kg in cardiopulmonary exercise test, and normal plasma N-BNP or BNP level.
Based on these expert recommendations, the WSPH Children’s Working Group has proposed a treatment protocol for children with IPAH. In this code, experts present risk predictions based on treatment goals. (Table 1)
Table 1.Treatment goals for children with pulmonary arterial hypertension used to guide treatment
Low risk
Treatment goals
High risk
None
Clinical evidence of right ventricular insufficiency
Yes
None
Exacerbation of clinical symptoms
Yes
No
Syncope
Yes
Growth and development
Stagnant growth
I, II
WHO functional classification
III, IV
Mildly elevated
Serum NT-proBNP/BNP levels
Severe elevation with increasing levels
Echocardiography
Severe right ventricular enlargement/insufficiency
Pericardial effusion
CI>3.0l/min/m2
mPAP/mSAP<0.75
Acute vascular response
Hemodynamics
CI<2.5l/min/m2
mPAP/mSAP>0.75
mRAP>10mmHg
PVRi>20WU/m2
>450m
6MWD-+
≤350m or decreasing
+ Although 6-minute walking distance is not a therapeutic goal, improving walking distance to normal standards or maintaining normal distance is clinically relevant in children with PAH, as improving exercise tolerance improves survival.
6MWD: 6-minute walking distance; BNP: brain natriuretic peptide; CI: cardiac index; mPAP/mSAP: mean pulmonary/somatic circulation vascular pressure ratio; mRAP: mean right atrial pressure; NT-proBNP: amino-terminal brain natriuretic peptide precursor; PVRi: pulmonary vascular resistance index; RV: right ventricle.
Clinical symptoms
Clinical symptoms of PAH in children include dyspnea, decreased exercise tolerance, syncope, fatigue and chest pain occurring at rest or/and during exercise, all of which can seriously affect quality of life. Reducing these symptoms is effective in improving quality of life and can be a therapeutic goal in the treatment of PAH in children. Although there are no studies addressing the relationship between syncope and survival in children, the presence of syncope after initiation of treatment is a sign of disease progression and, according to expert recommendations, requires escalation of treatment regimens.
Age-standardized scores for height and weight
Developmental arrest can occur in children with PAH. Studies have shown that low age-standardized scores for height and weight are associated with low survival rates. However, in the other two studies, this association was not present. In addition, initiation of medication does not lead to a return to normal growth, so age-standardized scores for height and weight cannot be used as a treatment goal.
WHO functional classification
The WHO functional class is a non-invasive test that subjectively assesses the clinical status of patients. It can be used as a therapeutic target for adult patients. It is difficult to assess in the infant and child patient population. The WHO functional class is a parameter that reflects clinical status in the pediatric patient population. The goal of PAH treatment in children is to achieve or maintain WHO functional class I-II.
The 6-minute walk test
The 6-minute walk test is frequently used to assess clinical status in the adult PAH patient population. However, a recent Meta-analysis has shown that improvement in the 6-minute walk test does not improve final disease regression. There are many limitations to performing the 6-minute walk test in children: infants do not walk; young children can be distracted during the test; and developmental delays may affect the study results. However, it is safe and reliable for children 7 years of age and older.
However, many children younger than 7 years of age need to be diagnosed. The available studies are not uniform in their conclusions about the significance of the test in the pediatric PAH patient population, so more research is needed. However, as in adults, children can improve the results of the 6-minute walk test with treatment. Because improved exercise tolerance can affect survival, the 6-minute walk test may be a treatment target for children with PAH.
Cardiorespiratory fitness test
In the adult patient population, the cardiopulmonary function test (CPET) is a predictor of survival. There are no studies on the relationship between treatment and it. The feasibility of CPET in the early childhood population is limited. A study of 40 children demonstrated that peak oxygen consumption was related to mPAP and PVR. CPET can also be used as a complement to the 6-minute walk test. There are no studies on the relationship between CPET and survival in pediatric patients. Therefore, the value of CPET in a targeted treatment strategy remains unclear.
NT-proBNP and BNP
NT-proBNP and BNP are biomarkers associated with right ventricular function and can be used to predict the prognosis of PAH. Studies have shown that serum (NT-pro)BNP is strongly associated with survival in both adult and pediatric patient populations. Recently, it has been shown that in the adult population, treatment reduces serum NT-proBNP levels and is associated with improved survival, so NT-proBNP may be a therapeutic target.
In pediatric patients, treatment-induced changes in serum (NT-pro)BNP levels have been associated with changes in WHO functional class, 6-minute walk distance test, and hemodynamic status. Although no studies have been performed to demonstrate whether treatment-induced changes in (NT-pro)BNP levels are associated with changes in survival, the pediatric working group of the WSPH continues to use normal levels of (NT-pro)BNP as a treatment target and as a routine observation at follow-up.
Echocardiography and cardiac magnetic resonance
Echocardiography and cardiac magnetic resonance are noninvasive tests for right ventricular function. Pre-treatment echocardiographic and cardiac magnetic resonance findings are associated with survival in both adult and pediatric patient populations. The WSPH Pediatric Working Group recommends upgrading treatment strategies when severe progressive right ventricular insufficiency or pericardial effusion is detected.
Hemodynamic Parameters
Hemodynamic parameters are objective indicators that can be observed at any age. In adult patient populations, hemodynamic status can predict survival. Recent studies have demonstrated that treatment-induced cardiac index and mixed oxygen saturation correlate with changes in survival and can be used as treatment targets.
In the pediatric population, right ventricular pressure, pulmonary vascular resistance index, cardiac index, and pulmonary/coronary vascular pressure ratio are all correlated with survival. Treatment can improve hemodynamic status. Invasive cardiac catheterization in children usually requires sedation or anesthesia, which poses some risk. The WSPH Pediatric Task Force identified hemodynamic variables as potential treatment targets.
Some medical centers may repeat cardiac catheterization during follow-up. However, the principle must be followed that these medical centers must be teams with sufficient experience and expertise in treatment to minimize the risk of testing.
Treatment regimens need to be adjusted gradually until they are the most appropriate, and not escalated when the disease has already deteriorated. Due to the lack of studies on treatment targets for PAH in children, the WSPH Children’s Working Group recommends several indicators as treatment targets, including: clinical symptoms, WHO functional class, (NT-pro)BNP, right ventricular imaging, and hemodynamic parameters. Of course, the rationality of these variables as therapeutic targets needs further corroboration.
Expert commentary
Despite the increasing number of drugs being developed for PAH, the prognosis of PAH in children remains poor. More rational treatment guidelines for children are urgently needed.
However, controlled studies in children are constrained by a number of difficulties: (1) difficulties in obtaining a sufficient number of cases because of the rarity of the disease. (2) The current standards for the use of some commonly used PAH drugs state that they are not recommended for children, which makes study design difficult. (3) There is a lack of validated indicators for children. For example, regulatory agencies do not accept invasive hemodynamic study parameters as indicators.
Is the treatment of children with IPAH the same as that of children with PAH combined with congenital heart disease (PAH-CHD)? Most studies have concluded that children with IPAH require a specific PAH treatment regimen. However, a growing body of data suggests that, with the exception of the CCB class of drugs, PAH drugs have similar efficacy and prognosis for both groups of disease. Although the prognosis of PAH-CHD has long been considered superior to that of IPAH, recent data suggest that both have a similar poor prognosis.
Based on the most recent studies, the authors concluded that children with IPAH and children with PAH-CHD can be treated with the same regimen. However, there are practical issues that need to be addressed for the individual child, such as the need for central venous placement in children with right-to-left shunts.
5-year outlook
In the next 5 years, there will be an increasing number of treatment options for PAH. Drugs targeting new pathways will be developed, and efficacy will be evaluated in controlled clinical studies. The effect of drugs in pediatric patient populations will need to be demonstrated in well-designed, controlled studies. Non-pharmacologic treatments need to be emphasized in addition to pharmacologic treatments. In particular, the role of Pott shunts for short- and long-term prognosis needs to be further investigated.
In the next few years, data on PAH in children will come from new or redesigned registry studies. These registry studies can be used to evaluate and identify new treatment targets. Guidelines for PAH in children will be established. New treatments that can reverse right ventricular insufficiency are expected to be discovered.
Key Points
(1) Arterial pulmonary hypertension (PAH) is a severely progressive and rare disease with a poor prognosis. With the discovery of PAH drugs and the development of evidence-based well-founded guidelines. Adult PAH survival rates have improved significantly.
(2) Adult PAH is significantly different from pediatric PAH in terms of pathophysiology, underlying factors, clinical presentation and ultimate prognosis. Therefore, the treatment regimen for adult PAH cannot be simply replicated for children.
(3) Data from a small number of validated clinical studies suggest that PAH drugs are equally effective when used in children. Survival rates in children with PAH have improved, but remain unobjective.
(4) Adult PAH treatment requires the achievement of clinical goals set in advance to guide clinical treatment protocols, and this approach can be applied to children. However, effective treatment goals for PAH in children are currently lacking.
(5) The Children’s Working Group of the 5th World Congress on Pulmonary Hypertension recommended a number of indicators that can be used as treatment targets for PAH in children, including: clinical symptoms, WHO functional class, brain natriuretic peptide/amino-terminal brain natriuretic peptide precursors, right ventricular imaging, and invasive hemodynamic testing.
(6) Further studies need to be initiated to establish and evaluate these potential treatment criteria, which are important for refining and treating PAH therapy and changing the poor prognosis of PAH in children.