In patients with congenital heart disease pulmonary hypertension, early surgery can prevent irreversible pulmonary vascular lesions. In patients with severe pulmonary hypertension, the nature of pulmonary hypertension should be evaluated before surgery to determine whether there is an indication for surgery. In the past 20 years, with the in-depth research on the pathogenesis of pulmonary hypertension, the treatment of pulmonary hypertension has gained great progress, and these treatments have also begun to be applied to the treatment of congenital heart disease combined with advanced pulmonary vascular lesions, the following is a brief introduction to the treatment of pulmonary hypertension.
I. General measures
1.Physical activity
It is not clear what effect physical activity has on the progression of pulmonary hypertension, but patients should be active in such a way that no symptoms, such as dyspnea, chest pain and syncope, appear.
2.Travel and altitude
Hypoxia can exacerbate pulmonary vasoconstriction in patients with pulmonary hypertension and should be avoided in high altitude zones. When traveling in commercial airplanes, similar to the state of 1500 to 2600 meters above sea level, patients with pulmonary hypertension are recommended to inhale oxygen while traveling.
3.Prevent infection
Patients with pulmonary hypertension are prone to complications of pulmonary infections and are poorly tolerated. According to statistics, pneumonia accounts for 7% of the total causes of death in pulmonary hypertension. Therefore, patients with pulmonary hypertension should actively prevent pulmonary infections, and once they appear, they should be diagnosed and treated as early as possible.
4.Pregnancy and contraception
Pregnancy and childbirth can worsen the condition of patients with pulmonary hypertension and even death, with the death rate of patients with Eisenmenger syndrome as high as 30 to 50%. The American Heart Association and the American College of Cardiology reached an expert consensus and agreed that for women of childbearing age with cyanotic congenital heart disease and Eisenmenger syndrome, appropriate contraceptive measures are necessary, and those who are already pregnant should terminate their pregnancies early, but no agreement has been reached on the specific contraceptive methods.
5.Hemoglobin level
Patients with pulmonary hypertension are highly sensitive to a decrease in hemoglobin levels and should be treated promptly even for mild anemia. On the contrary, in patients with Eisenmenger syndrome and other patients with right-to-left shunts, there is a compensatory increase in red blood cells and an increase in erythrocyte pressure product due to prolonged hypoxia. When the erythrocyte pressure product exceeds 65% and is accompanied by symptoms such as headache and inattention, bloodletting therapy can be considered to reduce blood viscosity and increase the ability of blood to release oxygen to tissues.
II. Drug therapy
1.Oral anticoagulant
Patients with severe pulmonary hypertension with preconditioning are prone to thromboembolic events, including pulmonary embolism and cerebral embolism, due to their preference for a sitting position, combined with venous insufficiency, enlarged right heart chambers and slow pulmonary blood flow. In patients with pulmonary hypertension with sudden death, fresh thrombus can sometimes be found in the pulmonary artery at autopsy. However, patients with preexisting pulmonary hypertension have a hypercoagulable state on the one hand and a bleeding tendency on the other, predisposing them to symptoms such as hemoptysis. It has been shown that adult patients with idiopathic pulmonary hypertension can benefit from long-term anticoagulation therapy, but the efficacy is uncertain in patients with Eisenmenger syndrome, and the advantages and disadvantages need to be weighed in its application.
2. Diuretics
Patients with pulmonary hypertension combined with right heart failure often experience fluid retention, resulting in increased central venous pressure, abdominal organ congestion, peripheral edema and, in severe cases, ascites. The use of diuretics can significantly reduce symptoms and improve the condition. Although the effectiveness of diuretics has not been verified by randomized controlled clinical trials, it has been widely accepted in clinical treatment. In patients with severe preexisting pulmonary hypertension, diuretics must sometimes be used with caution. For certain patients who rely on preload to maintain effective cardiac output, excessive diuresis should be avoided; in addition, in patients with severe hyperhemoglobinemia, diuretics can increase the risk of stroke and related complications and need to be used with caution.
3. digitalis drugs and dopamine
Decreased myocardial contractility is one of the important mechanisms of progressive right heart failure in patients with pulmonary hypertension, so certain positive inotropic drugs are sometimes used for treatment. The effectiveness of digitalis and other positive inotropic drugs is controversial, and some studies have shown that short-term application of digitalis can increase cardiac output in patients with pulmonary hypertension combined with right heart failure, but the effect of long-term application is unclear. In most cardiac centers, treatment with dobutamine for patients with end-stage pulmonary hypertension can lead to a certain degree of improvement in clinical symptoms and maintain them for a period of time.
4.Oxygenation
Although reports suggest that long-term low-flow oxygen inhalation can benefit some patients with pulmonary hypertension, there are no clinical randomized controlled trials to support this, and it is now generally accepted that oxygen therapy is recommended for patients with pulmonary hypertension with oxygen saturation below 91% (except in congenital heart disease). In congenital heart disease with a right-to-left shunt, even oxygen inhalation does not improve the patient’s hypoxemia. It is controversial whether long-term oxygen therapy is needed for patients with pulmonary hypertension in precardiac disease, and some trials have shown that patients with Eisenmenger syndrome do not benefit from long-term oxygenation.
5.Vasodilator drugs
1) Calcium channel blockers (CCB)
CCB is a traditional vasodilator and has been used for a long time in the treatment of pulmonary arterial hypertension. However, it is clear that only a small number of patients with pulmonary hypertension respond to CCB, in addition, CCB is not selective for pulmonary vasodilation, and it dilates the pulmonary vasculature as well as the vasculature of the body circulation, which may produce side effects such as hypotension; CCB may also produce negative inotropic effects and is not suitable for patients with decompensated cardiac insufficiency. CCB should be used only in patients with a positive acute vascular test. If CCB is applied blindly and empirically in patients with unresponsive pulmonary hypertension, it may cause a significant decrease in pressure in the body circulation but not in the pulmonary circulation, thus affecting coronary artery perfusion and leading to myocardial ischemia, which may eventually lead to rapid deterioration of the patient’s condition or even have lethal consequences. In patients with congenital heart disease combined with severe pulmonary vascular disease, the effectiveness of acute vascular testing and CCB is far less clear in patients with idiopathic pulmonary hypertension, with positive responses reported in only 7% of patients, but the Pulmonary Hypertension Working Group of the European Society of Cardiology still recommends acute vascular testing and cautious administration of CCB in this group of patients, with close observation of the effectiveness and safety of the drug.
2) Nitric oxide and its donor
The mechanism of action of NO is to relax vascular smooth muscle by activating guanylate cyclase (GC), which increases the level of guanosine cyclophosphate (cGMP) and further activates cGMP-dependent protein kinase.NO has a very short half-life and after entering the body NO has a very short half-life and is rapidly converted to nitrite and nitrate after entering the body, so NO inhalation selectively dilates the pulmonary vasculature without affecting the pressure of the body circulation. Animal experiments have confirmed that long-term NO inhalation can alleviate pulmonary vascular structure reconstruction due to hypoxia, but the effect on pulmonary vascular structure reconstruction due to high pulmonary blood flow is not clear.
NO inhalation is used in the clinical treatment of some critical pulmonary hypertension, including congenital heart disease combined with pulmonary hypertension. there is no uniform standard for the dose of NO inhalation, and it is generally believed that inhalation of small doses of NO (5-80 PPm) is safe and effective. although NO inhalation is an effective method for treating pulmonary hypertension in congenital heart disease, NO inhalation requires ventilator support, which is costly and the instrumentation is complicated. The operation of the instrument is complicated, and long-term continuous inhalation of NO can inhibit the production of endogenous NO and has certain toxic side effects, thus limiting its wide clinical application. In view of the above disadvantages, some scholars at home and abroad have adopted NO donor to replace NO inhalation, and have achieved certain efficacy.
3) Prostacyclin analogues
Prostacyclin is mainly produced by vascular endothelial cells, and the dysfunction of vascular endothelium in pulmonary arterial hypertension leads to a decrease in prostacyclin production. Prostacyclin can activate adenylate cyclase by binding to prostacyclin receptors on vascular smooth muscle, which increases intracellular cAMP concentration and inhibits Ca2+ inward flow, thus producing a diastolic effect. In addition to its potent vasodilatory effects, prostacyclin also produces antiproliferative and antifibrotic effects, antithrombotic effects, and anti-inflammatory effects. Patients with negative vascular response tests and those who fail to maintain a response to long-term treatment with CCB may also benefit from treatment with prostacyclin.
Prostacyclin analogs that have been clinically used in recent years have similar pharmacodynamics, although they have different pharmacokinetic profiles than prostacyclin. A variety of prostacyclin analogs have been developed, including intravenous Epoprostenol, subcutaneous Treprostinil, oral Beraprost, and inhaled Iloprost. The only drug currently available in China is Iloprost (Vantave from Schering, Germany), which selectively dilates the pulmonary vasculature and has less effect on blood pressure in the body circulation. Long-term application of this drug can reduce pulmonary artery pressure and pulmonary vascular resistance, increase exercise tolerance, and improve quality of life. The drug has a rapid onset of action, but a short half-life, the number of inhalations per day is 6 to 9 times, the recommended dose for children is 25ng/kg, min, adults should start with 2, 5µg per inhalation (the dose provided by the oral apparatus in the inhalation device), and can gradually increase the dose to 5, 0µg according to the needs and tolerance of different patients. need to emphasize that the application of the drug for nebulized inhalation The correct nebulization device needs to be selected and patients need to be specifically trained in the use of the nebulizer before receiving treatment to achieve optimal results. Adverse effects of Vantavir include frequent coughing, facial flushing and headache, and in a few patients, hypotension, but in general, the drug is well tolerated. Vantavir is indicated for patients with NYHA functional class III and IV pulmonary hypertension, but experience with its use in pediatric patients is limited.
4) Endothelin-1 receptor antagonists
ET-1 is a 21-peptide produced mainly by endothelial cells with strong vasoconstrictive and proproliferative effects. ET-1 exerts its biological effects by binding to two G protein-coupled receptors (ETA and ETB), with ETA distributed in smooth muscle cells and ETB distributed in both endothelial and smooth muscle cells. By activating ETA and ETB receptors in vascular smooth muscle cells, vasoconstriction and proliferation can be mediated; by activating ETB receptors in endothelial cells, the clearance of endothelin-1 and the release of NO and prostacyclin can be promoted. In patients with pulmonary hypertension, the endothelin system is activated and ET-1 levels in plasma and lung tissue are increased, which may be involved in the pathogenesis of pulmonary hypertension.
The relationship between endothelin and pulmonary hypertension provides a new target for the treatment of pulmonary hypertension. The most effective antagonists of the endothelin-1 system are selective ETA receptor antagonists and nonselective ETA and ETB receptor antagonists. The most effective antagonists of the endothelin-1 system are selective ETA receptor antagonists and non-selective ETA and ETB receptor antagonists, including sitaxsentan and ambrisentan, and the non-selective ETA and ETB receptor antagonists are bosentan, which are currently available in China. Long-term oral administration of bosentan can reduce pulmonary artery pressure and resistance, improve clinical symptoms and exercise tolerance in patients with pulmonary hypertension. The dose for adult patients is 62,5 mg twice daily for the first four weeks, followed by 125 mg twice daily. Dose-related increases in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and in some cases elevated bilirubin, may occur after bosentan administration, but recovery is usually spontaneous after dose reduction or discontinuation. Bosentan is potentially teratogenic and should not be used by pregnant women. Other side effects of bosentan include anemia, testicular atrophy, male infertility, fluid retention, and lower extremity edema. Bosentan is indicated for patients with NYHA functional class III and IV pulmonary hypertension. Indications for registration in China include NYHA functional class III and IV idiopathic pulmonary hypertension and pulmonary hypertension due to scleroderma. However, bosentan is also effective in pulmonary hypertension caused by congenital heart disease. Several studies have shown that bosentan can improve the clinical manifestations, exercise tolerance and hemodynamic status of patients with congenital pulmonary hypertension (mainly patients with Eisenmenger syndrome), and there is limited information on the application of bosentan in pediatric patients.
5) Type 5 phosphodiesterase inhibitors
Sildenafil is a selective type 5 phosphodiesterase inhibitor that inhibits the breakdown of cyclic guanosine monophosphate (cGMP), thereby enhancing NO-mediated vasodilation and antiproliferative effects. Studies have shown that sildenafil can reduce pulmonary artery pressure, improve cardiac function and increase exercise tolerance in patients with pulmonary hypertension, and it has been approved by the US FDA for the treatment of pulmonary hypertension under the trade name “REVATIO”. Although sildenafil has not been formally approved for the treatment of pulmonary hypertension in China, some cardiovascular centers are already using sildenafil for the treatment of pulmonary hypertension. The current dosage of sildenafil is recommended in accordance with foreign recommendations, i.e. 20 mg orally three times a day for adult patients and 0.5 mg/kg three times a day for pediatric patients. Side effects of sildenafil include nasal button, rhinitis, headache, diarrhea, dyspepsia, myalgia, flushing, fever, gastritis, etc. In rare cases, it may cause visual impairment. Sildenafil is indicated for patients with NYHA functional class II and III pulmonary hypertension.
6) Combined medication
The development of pulmonary hypertension is a multifactorial pathophysiological process, and the use of drugs with different mechanisms of action in combination for intervention therapy may be an attractive option. The combination of two drugs with different mechanisms of action can be applied simultaneously or sequentially, and their effectiveness and adverse effects need to be re-evaluated after the combination. Ongoing clinical trials of combinations include VISION (sildenafil + iloprost), TRIUMPH (bosentan + travoprost), STEP (bosentan + iloprost), COMPASS 2 (sildenafil + bosentan), PACES (iboprostenol + sildenafil), and BREATHE 2 (iboprostenol + bosentan). There are more “questions than answers” as to whether the combination provides additional benefit in patients with pulmonary hypertension.
(iii) Balloon atrial septal stoma
Several experimental studies and clinical observations suggest that the presence of an atrial septal defect may be beneficial in patients with severe pulmonary arterial hypertension. Although the presence of a right-to-left shunt at the atrial level may decrease the oxygen saturation of the body circulation, it may increase the blood flow of the body circulation, thus improving the perfusion and oxygen supply of the body circulation; in addition, the presence of a right-to-left shunt at the atrial level may reduce the pressure in the right atrium and right ventricle, thus reducing the signs and symptoms of right heart failure.
The efficacy of balloon atrial septal stoma in the treatment of pulmonary hypertension has not been fully confirmed, and it is currently used mainly in patients with pulmonary hypertension with recurrent syncope or intractable right heart failure who have failed to respond to drug therapy, thus preparing them for lung transplantation. Balloon atrial septal stoma is risky and should be performed in experienced cardiovascular centers. In addition, for patients with end-stage pulmonary hypertension, balloon atrial septal stoma is not recommended due to the high mortality rate of balloon atrial septal stoma.
(iv) Heart-lung transplantation
Combined heart-lung transplantation has been widely recognized as an effective treatment for end-stage cardiopulmonary disorders, but there is a shortage of heart-lung transplant donors and certain serious complications may occur after transplantation, including loss of graft lung function (PG D), post-transplantation endovascular proliferative disease (CAV), post-transplantation immune rejection, infection, etc. The success rate and long-term survival of heart-lung transplantation are not satisfactory at present .
The indications for cardiopulmonary transplantation in patients with pulmonary hypertension are: patients with advanced pulmonary hypertension with NYHA functional class III-IV and no improvement with current treatment. The natural history of patients with Eisenmenger’s syndrome is significantly different from that of patients with idiopathic pulmonary hypertension, with most patients surviving up to 20 years after diagnosis; therefore, heart-lung transplantation in patients with Eisenmenger’s syndrome can be delayed for many years.