Specific terms and definitions Pulmonary embolism (PE) is a clinical and pathophysiological syndrome of obstruction of the pulmonary artery by endogenous or exogenous emboli causing pulmonary circulatory disorders, including pulmonary thromboembolism, fat embolism syndrome, amniotic fluid embolism, air embolism, tumor embolism, etc. Pulmonary thromboembolism (PTE) is a disease caused by obstruction of the pulmonary artery or its branches by a thrombus from the venous system or the right heart. Pulmonary infarction (PI) is the most common type of pulmonary embolism, and is usually referred to as PE. pulmonary infarction (PI) is defined as a pulmonary embolism followed by necrosis if the lung tissue in the area of its innervation is blocked or interrupted by blood flow. Massive pulmonary embolism (MPE) is defined as pulmonary embolism of 2 or more lobes, or less than 2 lobes with a fall in blood pressure (circulating systolic blood pressure <90 mm Hg, or a fall of more than 40 mm Hg/5 minutes). Submassive pulmonary embolism (submassive pulmonary embolism) is a pulmonary embolism resulting in right ventricular hypoperfusion. Deep venous thrombosis (DVT) is the main source of thrombus that causes PTE. DVT occurs in the lower extremities or deep pelvic veins and is dislodged and circulated into the pulmonary artery and its branches, and PTE is often a comorbidity of DVT. Venous thromboembolism (VTE) is collectively referred to as VTE because PTE and DVT are interrelated in pathogenesis and are different clinical manifestations of two different stages in the course of the same disease. Economy class syndrome (ECS) refers to a prolonged air DVT and/or PTE, also known as cabin thrombosis, occurs as a result of prolonged air travel, sitting in a confined and restricted space, slowing venous return and stagnation of blood flow in both lower extremities. Prolonged travel by car (train, bus, carriage, etc.) can also cause DVT and/or PTE, so the broad definition of ECS is also called traveler's thrombosis. Epidemiology The incidence of venous thrombosis in the general population is 1-3/1000, mainly in the lower extremity DVT and pulmonary embolism, but in a few patients it can occur in the upper extremity DVT, retina, sinusoids, hepatic veins or mesenteric veins. In addition to the high mortality rate after the first occurrence of lower extremity DVT, it can also lead to the persistence of severe chronic complications in surviving patients: venous valve insufficiency and chronic pulmonary hypertension, which can occur in up to 20% of cases. Recent studies indicate that approximately millions of patients are diagnosed with pulmonary embolism and deep vein thrombosis each year worldwide. The number of cases of fatal and non-fatal symptomatic VTE in the United States exceeds 900,000 per year, with approximately 296,400 deaths and the remaining non-fatal VTE including 376,400 DVT and 237,100 PTE; of the fatal cases, approximately 60% are missed and only 7% are diagnosed and treated promptly and correctly.3 There is a lack of accurate epidemiologic information on pulmonary embolism in this country. The risk factors Risk factors The risk factors for VTE include embolic predisposition and acquired risk factors. In addition to factor V leiden, which causes embolism (see Table 1), ADRB2 and LPL gene polymorphisms have been found to be independently associated with VTE.4 The higher mortality rate of VTE in African Americans compared with whites also suggests that genetic factors are important risk factors. It was also found that the mortality rate of pulmonary embolism increased with age; there was no significant gender difference in the incidence of pulmonary embolism5; in addition, the incidence of VTE in obese patients was 2 to 3 times higher than that in the normal population; and the incidence of VTE in tumor patients was 5 times higher than that in the non-tumor population, suggesting that acquired risk factors play an important role in the pathogenesis of VTE. Once pulmonary thromboembolism occurs, the pulmonary artery lumen is obstructed and blood flow is reduced or interrupted, which can lead to different degrees of hemodynamic and respiratory function changes. In mild cases, there are no symptoms, but in severe cases, it can lead to a sudden increase in pulmonary vascular resistance, elevated pulmonary artery pressure, decreased cardiac output, and in severe cases, syncope or even death due to insufficient blood supply to coronary arteries and cerebral arteries. 1, hemodynamic changes: pulmonary thromboembolism can lead to increased pulmonary circulatory resistance and elevated pulmonary artery pressure. When the pulmonary vascular bed area is reduced by 25%-30%, the average pressure of pulmonary artery is mildly increased; when the pulmonary vascular bed area is reduced by 30%-40%, the average pressure of pulmonary artery can be more than 30 mm Hg, and the average pressure of right ventricle can be increased; when the pulmonary vascular bed area is reduced by 40%-50%, the average pressure of pulmonary artery can be 40 mm Hg, the filling pressure of right ventricle is increased, and the cardiac index is decreased; when the pulmonary vascular bed area is reduced by 50%-70%, persistent pulmonary hypertension can occur; when the pulmonary vascular bed area is reduced by 50%-70 persistent pulmonary hypertension; pulmonary vascular bed area reduction >85% can lead to sudden death.6 2. Right heart insufficiency: the extent of pulmonary vascular bed obstruction and the underlying cardiopulmonary function status are the most important factors for the occurrence of right heart insufficiency. Increased secretion of 5-serotonin and other vasoconstrictors, hypoxia and reflex pulmonary artery constriction will lead to further increase in pulmonary vascular resistance and pulmonary artery pressure, and eventually right heart insufficiency.7 Right ventricular overload can lead to elevated serum markers such as brain natriuretic peptide, N-terminal brain natriuretic peptide precursors and troponin, which indicate a poor prognosis for the patient. 3. Inter-ventricular interactions: A rapid increase in pulmonary artery pressure leads to a sudden increase in right ventricular afterload, causing right ventricular dilatation, increased ventricular wall tension and dysfunction. Right ventricular dilation will cause leftward shift of the ventricular septum, resulting in reduced left ventricular end-diastolic volume and reduced filling, and consequently reduced cardiac output, decreased blood pressure in the body circulation, reduced coronary artery blood supply and myocardial ischemia. Large pulmonary embolism causes increased right ventricular wall tension leading to decreased right coronary artery blood supply and increased oxygen consumption in the right ventricular myocardium, which can lead to myocardial ischemia, myocardial infarction, cardiogenic shock and even death. 4, respiratory function: Pulmonary embolism can also lead to increased airway resistance, relative alveolar hypoventilation, enlarged alveolar null lumen and intrapulmonary shunt and other respiratory function changes, causing pathophysiological changes such as hypoxemia and hypoCO2emia. Clinical manifestations 1. Symptoms: More than 80% of the patients with pulmonary embolism have no symptoms and are easily ignored clinically. The symptoms of symptomatic patients also lack specificity, mainly depending on the size and number of emboli, the location of embolism and the presence of underlying diseases of the heart and lungs.7,8 Smaller emboli may not have any clinical symptoms. Larger emboli can cause dyspnea, cyanosis, syncope, and sudden death. Sometimes syncope may be the only or first symptom of APTE. When pulmonary embolism causes pulmonary infarction, the clinical symptoms of “pulmonary infarction triad” may appear, which are: (1) chest pain, such as pleuritic chest pain or angina-like pain; (2) hemoptysis; (3) dyspnea. In case of combined infection, cough, sputum and high fever may be present. Due to hypoxemia and right heart insufficiency, hypoxic manifestations such as irritability, dizziness, chest tightness, palpitations, etc. may occur. Because of the lack of clinical specificity of the above symptoms, it brings some difficulties to the diagnosis, and should be differentiated from angina pectoris, stroke and pneumonia. 2. Signs: mainly respiratory and circulatory system signs, especially increased respiratory rate (more than 20 times/minute), accelerated heart rate (more than 90 times/minute), decreased blood pressure and cyanosis.8 Jugular vein filling or abnormal pulsation suggests increased right heart load; lower limb venous examination reveals that the circumference of one thigh or calf increases more than 1 cm compared with the opposite side, or lower limb varicose veins, pulmonary thromboembolism should be highly suspected. Other respiratory system signs include pulmonary auscultation of wet bow, large umbilical cord for raccoon black edge, hyperacusis or splitting of 2 heart sounds, and systolic murmur can be heard in the tricuspid region, and signs of right heart failure such as liver enlargement, hepatic and jugular venous reflux sign and lower limb edema can be seen when the acute right heart load is aggravated by APTE. 3, clinical syndromes of pulmonary embolism Acute pulmonary embolism can be divided into three types of syndromes, which help to estimate the prognosis and guide the development of treatment plan (see Table 3). Among them, large pulmonary embolism is prone to cardiogenic shock and multi-organ failure. Renal insufficiency, hepatic insufficiency and mental stress are common clinical manifestations and are emergencies requiring urgent management. 1.Arterial blood gas analysis: It is a screening index for the diagnosis of APTE. It should be based on the measurement of the patient in the prone position at the time of consultation, without oxygen, and the first arterial blood gas analysis, characterized by hypoxemia, hypocarbia, increased alveolar arterial partial pressure of oxygen difference [P(A-a)O2] and respiratory alkalosis. Because arterial partial pressure of oxygen decreases with age, the normal expected value of partial pressure of oxygen should be calculated according to the formula PaO2 (mm Hg) = 106 C 0.14 × age (years). It is worth noting that the detection index of blood gas analysis is not specific. According to statistics, about 20% of patients diagnosed with APTE have normal blood gas analysis results. 2. Plasma D-dimer: It is a soluble degradation product produced by cross-linked fibrin under the action of fibrinolytic system. In thromboembolism, its blood concentration increases due to thrombofibrinolysis. The sensitivity of plasma D-dimer for the diagnosis of APTE is 92%-100%, but its specificity is low, only 40%-43%, and D-dimer can be increased during surgery, trauma and acute myocardial infarction. The main value of plasma D-dimer determination is to exclude APTE.9 Patients with low-suspicion APTE are preferred to have plasma D-dimer quantitatively determined by ELISA, and APTE can be excluded if it is less than 500 μg/L; patients with high-suspicion APTE have little significance because APTE cannot be excluded in these patients regardless of the plasma D-dimer test results, and they all require pulmonary arteriography and other means. Pulmonary arteriography and other means are required for evaluation. In addition, D-dimer is also a biochemical marker to help us determine whether DVT recurrence has occurred and the efficacy of thrombolytic therapy. 3.Electrocardiogram: It is not specific for the diagnosis of APTE. Early ECG often shows ST-segment depression and T-wave inversion in chest leads V1~V4 and limb leads II, III and aVF. Some cases may show SⅠQⅢTⅢ (i.e. deepening of S-wave in lead I, Q/q wave and T-wave inversion in lead III), which is caused by acute pulmonary artery blockage, pulmonary hypertension, increased right heart load and right heart dilation. Attention should be paid to differentiate it from non-ST-segment elevation acute coronary syndrome and observe the dynamic changes of ECG. 4. Echocardiography: It has important value in suggesting the diagnosis, prognosis assessment and excluding other cardiovascular disorders.10 Echocardiography can provide direct and indirect signs of APTE. The direct sign can visualize proximal pulmonary artery or right heart cavity thrombus, but the positive rate is low, and the diagnosis can be made definitively if the patient’s clinical presentation is also consistent with PTE. Indirect signs are mostly manifestations of right heart overload, such as decreased local motion of the right ventricular wall, enlargement of the right ventricle and/or right atrium, increased velocity of tricuspid regurgitation and abnormal leftward motion of the septum, and widening of the pulmonary artery trunk. 5.Pulmonary artery embolism: If pulmonary artery embolism causes pulmonary hypertension or pulmonary infarction, X-ray plain film may show signs of pulmonary ischemia such as sparse and slender pulmonary texture, prominent or aneurysmal expansion of pulmonary artery segment, widening or truncation of right lower pulmonary artery trunk, and enlargement of right ventricle. Localized infiltrative shadows in the lung field; wedge-shaped shadows with the tip pointing to the hilum; disciform atelectasis; elevated diaphragm on the affected side; small amount of pleural effusion; thickened pleural adhesions, etc. may also appear. 6.CT pulmonary arteriogram: CT has the characteristics of non-invasive, fast scanning speed, clear image, and more economical, which can visually determine the site and scope of pulmonary artery embolism, the degree and shape of pulmonary artery embolism. Indirect signs include wedge-shaped strips of high density in the lung field or disciform atelectasis, dilated central pulmonary artery and reduced or absent distal vascular distribution.11 CT pulmonary angiography is an important noninvasive technique for the diagnosis of PTE, with a sensitivity of 90% and specificity of 78% to 100%. Its limitation lies mainly in the poor sensitivity to subsegmental and distal pulmonary artery thrombi. Attention should be paid to differentiate the CT manifestations of pulmonary artery tumors in situ from pulmonary thromboembolism. In clinical applications, CT pulmonary angiography should be judged in conjunction with the patient’s clinical likelihood score. In low-risk patients, a normal CT result can exclude PTE; in patients with a high-risk clinical score, a negative CT pulmonary angiography result does not exclude a single subsegmental pulmonary embolism. If CT shows segmental or above segmental thrombus, it can confirm the diagnosis of PTE, but for suspected subsegmental or more distant thrombus, further combination with lower extremity venous ultrasound, pulmonary ventilation and perfusion scan or pulmonary arteriography is required to clarify the diagnosis. 7.Radionuclide pulmonary ventilation and perfusion scan: The typical sign is a perfusion defect in the lung segment distribution that does not match the ventilation image. Its sensitivity is 92% and specificity is 87% for the diagnosis of pulmonary embolism, and it is not affected by the diameter of the pulmonary artery, especially in the diagnosis of sub-segmental pulmonary artery thromboembolism has special significance. However, any factors causing impaired pulmonary blood flow or ventilation such as pulmonary inflammation, pulmonary tumor, chronic obstructive pulmonary disease, etc. can cause local ventilation and blood flow disorders, so this test alone may cause misdiagnosis, and some patients with underlying cardiopulmonary disease and elderly patients also limit its clinical application due to intolerance and other factors. This test can be performed simultaneously with venous imaging of both lower extremities, and combined with chest X-ray plain film and CT pulmonary arteriography, it can greatly improve the specificity and sensitivity of diagnosis.12 8. Magnetic resonance pulmonary arteriography (MRPA): MRPA scan is completed under a single breath-hold (within 20 seconds), which can ensure higher signal intensity in the pulmonary arteries and directly show the emboli in the pulmonary arteries and the hypoperfusion zone caused by PTE. This method has high sensitivity and specificity for the diagnosis of intrapulmonary artery thrombus above the pulmonary segment and is suitable for people with iodine contrast allergy.13 However, most experts and literature currently do not recommend this method for routine diagnosis of pulmonary embolism. 9.Pulmonary arteriography: It is the “gold standard” for the diagnosis of pulmonary embolism, with a sensitivity of 98% and a specificity of 95%-98%. The direct signs of PTE include contrast filling defect in the pulmonary artery, with or without orbital sign of blood flow blockage; the indirect signs include slow flow of pulmonary artery contrast, local hypoperfusion, delayed venous return, and when the diagnosis is difficult to be confirmed by other examinations, such as the presence of iodine contrast. If there is no contraindication, contrast examination should be performed decisively when other examinations are difficult to confirm the diagnosis.14 Contrast often gives a more intuitive clinical impression to better guide the treatment. 10.Deep vein examination of lower extremity: pulmonary thromboembolism and deep vein thrombosis are different clinical manifestations of venous thromboembolism, 90% of PTE patients have emboli from DVT of lower extremity, and 70% of PTE patients have combined DVT.15 Because of the close relationship between PTE and DVT, and the easy operation of lower extremity venous ultrasound, the value of lower extremity venous ultrasound in the diagnosis of PTE should attract the attention of clinicians. The value of lower extremity venous ultrasound in the diagnosis of PTE should be emphasized by clinicians, and patients suspected of PTE should be tested for DVT formation in the lower extremities. In addition to conventional lower extremity venous ultrasound, compression venous ultrasonography (CUS) is recommended for the diagnosis of lower extremity venous thrombosis through techniques such as probe compression observation, and the inability of the vein to be compressed or the absence of blood flow signal in the venous lumen is a specific sign of DVT. The sensitivity of CUS for the diagnosis of proximal thrombosis was 90% and the specificity was 95%.16 Acute pulmonary embolism diagnostic process The Dutch study used a clinical diagnostic evaluation scale to stratify patients with clinically suspected pulmonary embolism, which is convenient and accurate.17 Only 5% of patients in the low-suspicion group were finally diagnosed with pulmonary embolism. Acute pulmonary embolism diagnosis process Acute pulmonary embolism treatment Acute pulmonary embolism requires a treatment plan that is tailored to the severity of the disease, so risk stratification must be performed quickly and accurately to provide an important basis for the development of appropriate treatment strategies. Risk stratification is based on clinical manifestations, signs of right ventricular insufficiency, and cardiac serum markers (brain natriuretic peptide, N-terminal brain natriuretic peptide precursors, and troponin).