1. Clinical incidence
Approximately 5% of adult patients with congenital heart disease develop pulmonary hypertension, of which 25-50% develop Eisenmenger syndrome.9 There are fewer statistics available on the incidence of late onset pulmonary hypertension after surgical repair. Earlier data showed that the incidence of postoperative pulmonary hypertension was 31% between 1980 and 1984, and the incidence of PAH decreased to 6.8% after routine treatment with NO inhalation. A Dutch national registry study suggested a 3% incidence of pulmonary hypertension in patients who had undergone surgical correction. The incidence of pulmonary hypertension with surgical treatment of congenital heart disease was approximately 2%, with a rate of 0.75% for pulmonary hypertensive crisis. Patients who develop pulmonary hypertensive crisis have a mortality rate of up to 20%, and pulmonary vascular disease is a major factor in the prolonged hospital stay and prolonged mechanical ventilation in patients undergoing surgery for congenital heart disease.5
2. Clinical types
Little is known clinically about late onset pulmonary hypertension after congenital heart disease, which is distinguished from reactive postoperative pulmonary hypertension (RPH) by the continued development or persistence of pulmonary hypertension despite successful passage through the early postoperative phase (>6 months).
(1) Post-complete correction: Pulmonary hypertension after surgical correction of congenital heart disease, which can occur immediately, months or years after surgery, with no residual leakage or sequelae associated with the surgical procedure.
(2) After incomplete correction: including functional single ventricle after performing BCPS and TCPC.
3. Pathophysiological characteristics
The patient’s underlying pathology is of the pulmonary hemopoietic congenital heart disease type, in which the pressure and flow of the pulmonary circulation and the lower oxygen saturation are decisive factors in determining the degree of structural changes in the pulmonary vasculature. In these children, the pulmonary vascular resistance decreases rapidly from a high level soon after birth, and the high pulmonary blood flow can lead to primary pulmonary edema, which increases respiratory work, causing shortness of breath and different degrees of respiratory failure. Even if adequate diuretic therapy is given, the above conditions can cause recurrent chest infections, feeding difficulties, and growth arrest.
Irreversible pulmonary vasculopathy is often a limiting factor in performing radical cardiac surgery, and a slight increase in pulmonary vascular resistance often makes it difficult for children with single ventricle to undergo Fontan surgery. As the pulmonary vascular lesion progresses, any reduction in resistance of the body circulation may reverse the direction of shunting, leading to acute cyanosis and rapid hemodynamic deterioration. If the abnormal shunt pathway has been surgically blocked, increased pulmonary vascular resistance will lead to right heart failure, and left heart failure will follow because of the obvious dependence between the right and left ventricles in infants.
4.Pathological characteristics
Patients with congenital heart disease often have abnormalities in the development of the pulmonary circulation. In many cases, such as congenital heart disease with left-to-right shunting, pulmonary venous obstruction type of congenital heart disease, mitral stenosis, arterial catheter-dependent circulation and complete transposition of the great arteries, the middle smooth muscle of the intrapulmonary micro-arteries in the child is not metamorphosed at birth, but instead continues to proliferate so that these micro-arteries are very susceptible to contraction.
5.Related pathogenic factors
The functional and structural condition of the pulmonary vascular bed in patients with congenital heart disease is a key factor in determining the patient’s symptoms and prognosis. Late onset of postoperative pulmonary hypertension may be related to late timing of surgery, miscalculation of surgical possibilities, and irreversible structural remodeling due to the long-term effects of increased right ventricular afterload.
Children are prone to sudden or persistent increases in pulmonary vascular resistance in the immediate postoperative period after surgical repair. Due to the increased responsiveness of the pulmonary vascular bed as a result of surgical repair of congenital heart disease, stimuli can lead to pulmonary vasospasm, inducing increased pulmonary circulatory resistance and sudden increases in pulmonary artery pressure, resulting in acute right heart failure, tricuspid regurgitation, hypotension of the body circulation, myocardial ischemia, and increased airway resistance. These conditions can occur even with mild irritation, and this fatal period is known as the “pulmonary hypertensive crisis”, which has a tendency to persist.
Risk factors associated with surgery: hypoxia, acidosis, stimulation of sympathetic nerves and surgical strain can lead to increased pulmonary vascular resistance; hyperventilation and atelectasis can also increase pulmonary vascular resistance; postoperative positive end-pressure ventilation (PEEP) increases pulmonary vascular resistance, but moderate PEEP can reverse pulmonary edema and atelectasis and reduce pulmonary vascular resistance; appropriate hyperventilation raises blood Ph values to 7.5, which usually reduces infant PVR.
Anesthesia-related risk factors: Although individual responses vary, some anesthetic agents can also affect pulmonary circulatory resistance. Ketamine was earlier reported to increase pulmonary vascular resistance, but in the pediatric population it does not increase pulmonary vascular resistance as long as normal ventilation is maintained [vii].
Factors associated with extracorporeal circulation: extracorporeal circulation can cause pulmonary vascular endothelial dysfunction, increase pulmonary circulatory resistance, and exacerbate preexisting pulmonary hypertension.
Factors related to interventional treatment: improper catheter manipulation leads to pulmonary vascular injury; contrast agents can damage pulmonary vascular endothelial cells due to higher osmotic pressure than plasma, or higher viscosity, aggravating pulmonary hypertension based on pre-existing disease.
6. Preoperative risk assessment of cardiac correction
How to accurately identify high-risk patients who may develop persistent pulmonary hypertension after surgery is a concern for clinicians. Currently, clinicians decide whether a patient is suitable for surgery based on different criteria, without a comprehensive consensus or recommendation, let alone a definitive guideline [viii]. The type and size of the defect, hemodynamic indices, the presence of other combined cardiac abnormalities, and the repair of the defect (unrepaired, palliation, complete repair) are common predictors of postoperative pulmonary hypertension.
(1) Electrocardiogram: It can show right ventricular hypertrophy and rightward deviation of the electrical axis, which cannot yet be used to determine the severity of pulmonary hypertension because of its low sensitivity and specificity. Supraventricular arrhythmias, especially atrial flutter and atrial fibrillation, are seen in severe cases and suggest a worsening clinical situation [ix].
(2) Chest radiograph: it can be used to exclude the presence of primary lung disease, pleural disease, and the presence of left heart insufficiency, but abnormal signs on the chest radiograph do not correlate with the severity of pulmonary hypertension.
(3) Chest CT: It can be used to exclude the presence of severe emphysema and interstitial lung disease; enhanced scan can be used to understand the presence of pulmonary vascular embolism.
(4) Pulmonary function tests and arterial blood gas analysis: to determine spirometry, pulmonary ventilation and pulmonary diffusion (diffusion of carbon monoxide), except for the presence of respiratory or interstitial lung disease. If obstructive sleep apnea is clinically suspected, nocturnal sleep apnea monitoring is feasible.
(5) Echocardiography: In the absence of pulmonary stenosis and right ventricular outflow tract stenosis, pulmonary artery systolic pressure can be estimated from tricuspid regurgitation velocity and mean pulmonary artery pressure from pulmonary artery systolic pressure [x]. Although there is a good correlation between regurgitant velocity through the tricuspid valve and differential tricuspid regurgitant pressure, on an individual basis, pulmonary artery pressure cannot yet be accurately determined using the Doppler method. Pulmonary artery pressure can be underestimated in patients with severe tricuspid regurgitation, and it is common for pulmonary artery pressure to be overestimated by 10 mm Hg. Other indices including pulmonary regurgitation velocity, right ventricular-pulmonary artery ejection acceleration time, right ventricular internal diameter, abnormal shape and function of the ventricular septum, right ventricular wall thickness, and main pulmonary artery dilatation are suggestive of pulmonary hypertension, but their sensitivity is questionable. Therefore, preoperative echocardiographic findings alone cannot be relied on to determine whether corrective cardiac surgery is feasible.
(6) Cardiac catheterization: Acute vasodilation test, whether using NO inhalation alone or mixed oxygen inhalation, is the gold standard for assessing the responsiveness of the pulmonary vascular bed.
(① For patients with biventricular circulation without vasodilation test, a pulmonary vascular resistance index <6 Woods U/m2 and a pulmonary circulation/body circulation resistance ratio <0.3 suggest a better long-term outcome of corrective surgery.
② If the baseline pulmonary vascular resistance index is 6C9 Woods U/m2 and the pulmonary circulation/body circulation resistance ratio is between 0.3 C 0.5, an acute pulmonary vasodilatation test (inhaled oxygen or NO) is recommended, and although there is no consensus, corrective surgery is feasible in patients who meet the following criteria.
20% reduction in pulmonary vascular resistance index;
Approximately 20% decrease in the pulmonary circulation/body circulation resistance ratio;
Acute vasodilatation test resulting in a decrease in pulmonary vascular resistance, ultimately <6 Woods U/m2;
Pulmonary/coronary resistance ratio < 0.3.
Problems in determining the feasibility of cardiac surgery based on cardiac catheterization findings.
Although cardiac catheterization provides a good evaluation of pulmonary vascular reactivity, its ability to accurately identify patients with CHD with increased pulmonary circulatory resistance who are suitable for corrective cardiac surgery is inconclusive, and cardiac centers have different views on the indications and contraindications for surgery in CHD combined with severe pulmonary hypertension.
The use of other medications in patients may affect the results of acute vasodilation tests.
The technique used during cardiac catheterization may affect the calculation of pulmonary vascular resistance.
The above-mentioned cardiac catheterization criteria do not apply to the determination of Fontan surgery in patients with single-ventricle precordial disease.
(7) Biomarkers: overexpression of Bcl-2 in vascular endothelial cells and endothelial cells in circulating blood are indicative of irreversible pulmonary hypertension.
(8) Hematology: Routine blood biochemistry, complete blood count, and thyroid function tests should be performed. Pre- and post-operative monitoring of BNP and ET-1 level changes is meaningful in determining the patient’s prognosis.
(9) Lung biopsy: Lung biopsy should be used for histopathological examination of pulmonary vessels, and the feasibility of cardiac repair surgery for precardiac disease should be assessed according to the results. Pulmonary histopathology of pulmonary hypertension associated with precardiac disease is mostly performed using simplified Heath-Edwards staging: grade O, normal; grade 1, myocardial pulmonary artery mid-layer hypertrophy; grade 2, intimal hyperplasia; grade 3, intimal concentric fibrosis or with extensive alveolar interstitial fibrosis; grade 4, pulmonary artery spherical dilatation or plexiform lesions.9 Clinicopathological data suggest that grade 1 and 2 lesions are reversible ; grade 4 are irreversible lesions; and grade 3 are critical lesions. Immunohistochemical studies of lung tissue revealed that PAH tends to be irreversible with increased type I collagen in pulmonary muscular arteries, while increased type IV collagen tends to be a reversible lesion. Studies have shown a correlation between apoptotic markers of macrophages in lung tissue and irreversible postoperative pulmonary arterial hypertension. Lung biopsies should continue to be used in clinical and basic research as they provide a better understanding of pathophysiological changes in the pulmonary vasculature and assess the efficacy of new drugs.
Indications for lung biopsy in patients with congenital heart disease.
(1) Pulmonary biopsy may be performed in patients with “critical” hemodynamic data, or severe PAH, or with bidirectional shunts, to help select indications for corrective cardiac surgery and to predict the long-term outcome of the procedure.
(2) Cardiac catheterization or clinical examination alone cannot accurately reflect the extent of pulmonary vascular lesions, and should be combined with pulmonary pathology for comprehensive analysis and judgment.
Problems with lung biopsy.
Pulmonary vascular disease is often considered reversible in patients without intimal thickening, but it may still progress to irreversible pulmonary hypertension after surgery; in addition, children under 2 years of age can be treated surgically despite severe pulmonary artery disease suggested by pulmonary histopathology.
Because lung biopsy is not representative of the whole lung lesion, it is considered to have reliability problems.
Lung biopsy itself carries certain risks, especially whether patients with pulmonary hypertension can tolerate open-heart surgery, and therefore there are ethical issues of clinical application.
7. Diagnosis
Patients with congenital heart disease with left-to-right shunts at the level of various ventricles and great arteries may have persistently elevated pulmonary vascular resistance even after radical surgery. Postoperative delayed pulmonary hypertension is defined as pulmonary hypertension that remains or reappears in such patients far after surgery (>6M).
All patients with postoperative delayed pulmonary hypertension should be evaluated with noninvasive tests, including pulse oxygen on oxygen as well as without oxygen, chest radiograph, electrocardiogram, echocardiogram, complete blood count, and MRI or CT ECG imaging.
To exclude other causes of postoperative pulmonary hypertension, the following tests are required: pulmonary function test, chest CT lung window. At least one cardiac catheterization as well as an acute pulmonary vasodilatation test.
Assess patient cardiopulmonary function using a 6-minute walk test or similar non-maximal cardiopulmonary exercise function test.