Acute pulmonary embolism (PE) is a clinical and pathophysiological syndrome in which endogenous or exogenous emboli block the pulmonary arteries and cause obstruction of the pulmonary circulation. The incidence, mortality and misdiagnosis rates are quite high, and it is one of the important health care problems at home and abroad. Its important clinical significance is: ① high incidence – second only to coronary heart disease and hypertension among cardiovascular diseases; ② easy to miss and misdiagnosis – the vigilance of pulmonary embolism in China is not high, the correct diagnosis rate is low, and the miss rate is more than 80%; ③ high mortality rate without treatment – it can be as high as 20%-30%, and the mortality rate is the third cause of death, after tumor and myocardial infarction; ④ clear diagnosis and after active The mortality rate decreases significantly in those who are diagnosed and treated actively – it can be reduced to 2-8%.
Clinical manifestations of pulmonary embolism
Pulmonary embolism has a wide spectrum of clinical manifestations, from asymptomatic in mild cases to hypotension, shock and even sudden death in severe cases. The common clinical symptoms include dyspnea, chest pain, hemoptysis, syncope, etc. They may appear separately or together. Ninety-seven percent of PE patients with no previous cardiopulmonary disease have dyspnea, shortness of breath, syncope, or chest pain.
The rapid onset of simple dyspnea is often caused by PE near the center (not affecting the pleura); sometimes, dyspnea manifests itself as a progressive worsening over several weeks, so progressive dyspnea with no other explanation should be thought of as a possible PE; in patients with previous heart failure or pulmonary disease, worsening dyspnea may be the only symptom suggesting PE.
There are two types of chest pain: pleuritic chest pain and angina-like chest pain. Pleuritic chest pain is more intense, has a well-defined location, is associated with respiratory movements, and is a common clinical manifestation of pulmonary embolism. This pain is caused by the distal embolus irritating the pleura. Some patients present with angina-like chest pain in the form of retrosternal chest pain, the nature of which is unclear and may be related to right ventricular ischemia.
Syncope and shock are characteristic of patients with central PE combined with severe hemodynamic disturbances, and clinical signs of arterial hypotension in the body circulation, oliguria, extremity chills, and/or acute right heart failure.
Physical examination may reveal signs of pulmonary hypertension (P2 hyperactivity, systolic murmur in the pulmonary valve area, etc.), signs of increased right ventricular load (jugular venous filling, positive hepatic and jugular venous reflux sign), and in some patients, pleural effusion or solid lung manifestations.
Deep vein thrombosis in the lower extremities is the hallmark of PE, and the examination reveals asymmetric edema in both lower extremities, pressure pain in the deep vein area, superficial varicose veins, skin stiffness and hyperpigmentation.
According to the patient’s clinical manifestations and pathophysiological basis, PE can be divided into three types: large PE with embolization of two or more lung lobes, clinical shock or hypotension (systolic blood pressure <90 mmHg, or blood pressure drop >40 mmHg for more than 15 minutes), which can lead to sudden death and requires timely resuscitation; sub-large PE with right ventricular insufficiency and no hemodynamic disturbance; non-large PE without hemodynamic The prognosis is better for non-massive PE without hemodynamic disturbances and right heart insufficiency.
Chest X-ray usually shows abnormalities, such as reduced pulmonary blood at the embolization site, pleural exudate, discoid pulmonary atelectasis, and diaphragmatic elevation, etc. Typical wedge-shaped shadows are rare, but all these manifestations are nonspecific. Therefore, the main purpose of chest X-ray examination is to exclude other causes of dyspnea and chest pain, and normal X-ray examination cannot exclude PE.
The typical signs of arterial blood gas analysis are hypoxemia, hypocarbia (due to reflex hyperventilation) and increased partial pressure difference between alveolar and arterial oxygen. However, more than 20% of patients with confirmed PE have normal arterial partial pressure of oxygen and 15%-20% have normal alveolar-arterial partial pressure of oxygen. Therefore, abnormal blood gas analysis is suggestive of a diagnosis, but normal blood gas analysis does not exclude PE.
The common ECG changes of PE include: SⅠQⅢTⅢ waveform, T-wave inversion in V1 a V3 leads, right bundle branch block, right deviation of electrical axis, atrial arrhythmia, etc. However, these changes are usually associated with severe PE and can occur with right ventricular strain from various causes.
Ancillary tests
I. Radionuclide lung scan
Radionuclide lung scan has a sensitivity of 92%, a positive predictive value of 92%, a specificity of 87% and a negative predictive value of 88% for confirmation of PE. Therefore, about 25% of patients suspected of PE can negate the diagnosis due to normal lung perfusion and it may be safe without anticoagulation, about 25% of patients suspected of PE have highly probable lung scan findings and they may need to perform anticoagulation, and the rest need further diagnostic tests to confirm or exclude PE.
II. Spiral CT (sCT)
sCT angiography allows direct visualization of thrombus within the pulmonary arteries, as evidenced by a low-density filling defect within the vessel, partially or completely surrounded by impermeable blood, or a complete filling defect with no visualization of the distal vessels. indirect signs of PE include pleural-bottomed areas of hyperintensity, striated areas of hyperintensity or discoid pulmonary atelectasis, central or distal pulmonary artery dilatation, and pleural infiltrates of varying size. The value of these indirect signs is less clear.
Signs of chronic PE are eccentrically distributed calcified masses in the pulmonary arteries that are separated from the duct wall; lobar or segmental pulmonary artery truncation phenomenon, and lumen irregularities.
The sensitivity is 53-89% and the specificity is 78-100%. There are various reasons for the difference in specificity, including differences in study design, the investigator’s experience with SCT and the anatomy of the pulmonary vessels under study.
sCT allows for clearer detection of thrombi located in the main, lobar and segmental pulmonary arteries. For thrombi within subsegmental and more distal pulmonary arteries, the sensitivity of SCT is limited.
Echocardiography
Echocardiography is useful for identifying sudden onset of dyspnea, chest pain, circulatory failure and other clinical conditions that require consideration of the diagnosis of PE. It is especially valuable in excluding myocardial infarction, infective endocarditis, aortic coarctation, and pericardial tamponade.
Typical echocardiographic signs of PE with hemodynamic changes include right ventricular dilatation, reduced right ventricular motion, increased RV/LV ratio due to septal bulging to the left, proximal pulmonary artery dilatation, and increased tricuspid regurgitation velocity (3-3.5 m/s), and disturbances in right ventricular outflow tract flow velocity.
Recently, abnormal right ventricular local systolic wall motion has been considered as a specific sign for the diagnosis of acute PE. Unlike other causes of right ventricular systolic overload, the reduced ventricular wall motion due to acute PE does not affect the apical portion of the right ventricular free wall. This sign has a sensitivity of 77% and specificity of 94% in diagnosing acute PE in 85 patients.
The echocardiogram is unlikely to be normal in patients with PE with hemodynamic changes. In patients with more than 1/3 of the lung fields with perfusion defects on lung perfusion scans, reduced right ventricular free wall motion was present on echocardiography in 90%.
IV. Pulmonary angiography
Pulmonary angiography is an option in patients without definitive results on all non-invasive tests. Angiography can be used for therapeutic purposes in patients with contraindications to thrombolytic and heparin therapy. In addition hemodynamic measurements are part of the pulmonary angiography.
Immediate signs of PE include complete obstruction of the vessel (preferably with concave edges of the contrast column) or filling defects. It should be recognized, however, that the reliability of angiography decreases as the lumen diameter becomes smaller, i.e., it is difficult to make judgments below the subpulmonary segment level. Patient selection may also affect the diagnostic accuracy of pulmonary angiography.
Indirect signs of PE include slow contrast flow, local hypoperfusion, and slowed or delayed pulmonary venous blood flow. It should be recognized that these signs can draw attention to certain areas, but the lack of direct angiographic signs should not lead to a diagnosis of PE.
Pulmonary angiography has a sensitivity of 98% or less and a specificity between 95% and 98%. The specificity is slightly lower than the sensitivity because of other PE-like diseases, such as tumor-induced arterial obstruction.
V. Lower extremity deep vein examination
About 70% of the emboli of pulmonary embolism come from the deep veins of the lower extremities, so the examination of the deep veins of the lower extremities is very important for the diagnosis and prevention of pulmonary embolism. Since nearly half of the patients with lower limb venous disease have normal physical examination, they need to be clarified by other instruments. Radionuclide venography: 90% compliance rate with conventional venography. Vascular ultrasound Doppler: 88% to 93% accuracy. Limb impedance volumetric map: the compliance rate with venography is 70%-95%, the sensitivity of diagnosis is 65-86%, the specificity is 95%-97%, and the sensitivity of diagnosis of vein blockage in calf is lower.
VI. D-dimer
Plasma D-dimer is a cross-linked fibrin degradation product, which is detected by quantitative ELISA in acute PE or DVT, with a diagnostic sensitivity of >99%. in PE or DVT, D-dimer is more than 500 μg/L, and D-dimer <500 μg/L can exclude PE. On the other hand although D-dimer is very specific for fibrin, it is not specific for venous thromboembolism. Tumors, inflammation, infections, necrosis, postoperative, etc., D-dimer is mostly >500 μg/L, so D-dimer is poorly specific for PE. In addition, the specificity of D-dimer is also low for the elderly. Therefore, D-dimer testing cannot be used in these populations.
The traditional latex test and whole blood agglutination test have low sensitivity and positive predictive value and should be eliminated.
Treatment of pulmonary embolism
I. General treatment of pulmonary embolism
PE with hemodynamic instability should be admitted to the monitoring ward, and blood pressure, heart rate, respiration, electrocardiogram and blood gas analysis should be monitored. Patients should be absolutely bedridden to avoid thrombus dislodgement and re-embolization. Give analgesic drugs for severe chest pain.
Respiratory and circulatory support
Respiratory support: Hypoxia and hypocapnia are common in patients with pulmonary embolism. If PaO2<60-65mmHg and cardiac output is reduced, oxygen should be administered by face mask. If mechanical ventilation is required, care should be taken to avoid hemodynamic side effects. Positive intrathoracic pressure due to mechanical ventilation can reduce venous return and worsen right heart failure in patients with massive pulmonary embolism.
Circulatory support: Patients with acute massive pulmonary embolism are mostly associated with hemodynamic instability, mainly due to the reduced cross-sectional area of the pulmonary vascular bed and pre-existing cardiopulmonary disease. Right ventricular ischemia and left ventricular diastolic dysfunction in acute massive pulmonary embolism eventually lead to left ventricular failure. Many patients with massive pulmonary embolism die within hours of the onset of symptoms. Therefore, supportive therapy is important in patients with hemodynamic instability. For those with hypotension or shock, intravenous dobutamine, dobutamine, and alamine can be administered to maintain the systolic blood pressure of body circulation above 90 mmHg.
III. Thrombolytic therapy
1.Indications for thrombolytic therapy
If there is no absolute contraindication, all patients with massive pulmonary embolism should receive thrombolytic therapy. In patients with normal blood pressure, normal tissue perfusion and clinical and echocardiographic evidence of right ventricular insufficiency (submassive pulmonary embolism), thrombolysis can be performed if there are no contraindications. Patients with non-massive pulmonary embolism should not receive thrombolytic therapy.
2. Contraindications to PE thrombolytic therapy
Absolute contraindications
(1) Active internal bleeding.
(2) Recent spontaneous intracranial hemorrhage.
Relative contraindications
(1) History of major surgery, delivery, organ biopsy or vascular puncture that cannot be compressed (within 10 days).
(2) Ischemic stroke within 2 months.
(3) Gastrointestinal bleeding within 10 days.
(4) Serious trauma within 15 days.
(5) neurosurgical or ophthalmic surgery within 1 month
(6) Poorly controlled severe hypertension (systolic blood pressure >180 mmHg, diastolic blood pressure >110 mmHg).
(7) Recent cardiopulmonary resuscitation.
(8) Platelets <100,000/mm>.
(9) Pregnancy.
(10) infective endocarditis.
(11) Diabetic hemorrhagic retinopathy.
(12) Severe liver and kidney disease.
(13) Bleeding disorders.
The time window for thrombolytic therapy is 2 weeks after the onset of symptoms, and it may be effective if it is more than 2 weeks.
4.The commonly used thrombolytic regimen in China is
① Urokinase 20,000 IU/kg, 2 hours intravenous infusion; ②rt-PA 50-100mg 2 hours intravenous infusion.
5.Complications and side effects of thrombolysis
The main complication of thrombolytic therapy is bleeding. The most common is bleeding at the site of vascular puncture, and the incidence of severe intracranial bleeding is about 1%. During thrombolytic therapy, patients should be closely monitored for bleeding manifestations, such as vascular puncture sites, skin, gums, etc., and observed for visual and microscopic hematuria, and closely observed for new neurological symptoms and signs. If there is bleeding from the puncture site, compression can be applied to stop the bleeding. Severe hemorrhage should be terminated with thrombolysis and blood or plasma transfusion. The presence of intracranial hemorrhage should be treated as an emergency, with rapid contact with neurology or surgery to determine treatment
IV. Anticoagulation therapy
Anticoagulation therapy prevents the development and recurrence of pulmonary embolism and relies on its own fibrinolytic mechanism to dissolve the pre-existing thrombus. In 1-4 weeks of anticoagulation therapy, 25% of pulmonary artery clots are completely dissolved, and 50% after 4 months. Commonly used anticoagulant drugs are common heparin (UFH), low molecular heparin (LMWH) and warfarin.
Anticoagulation with UFH in acute pulmonary embolism must be administered at a dosage sufficient to prolong the partial prothrombin kinase activation time (aPTT) to 1.5-2.5 times the control value (plasma heparin levels equivalent to 0.3 to 0.6 anti-Xa factor activity). LMWH can be substituted for UFH in patients with pulmonary embolism in the absence of hypotension, shock, and right heart insufficiency, but not in large pulmonary emboli because these patients were not included in trials of LMWH for pulmonary embolism.
In patients with moderate or high clinical suspicion of pulmonary embolism, heparin should be administered intravenously immediately. A loading dose of 5,000-10,000 U is given intravenously followed by 800-1250 U/h or 15-20 U/kg/h of continuous sedative dosing. The rate of administration is adjusted according to body weight and the target aPTT is 1.5 to 2.5 times the control value. The dose adjustment method is shown in the attached table. There is variability in aPTT measured using different methods, so each laboratory should determine the range of aPTT depending on the method used. In some cases, aPTT does not reflect heparin dosage and anti-Factor Xa activity should be measured.
Contraindications to anticoagulation include thrombocytopenia, active bleeding, coagulation disorders, severe uncontrolled hypertension, and those with recent surgery. However, it is mostly a relative contraindication in patients with confirmed pulmonary embolism.
aPTT that is too prolonged is associated with bleeding. However, bleeding is uncommon with heparin application, unless interventional procedures are performed, local injury or hematological abnormalities are present, as is the case with LMWH.
Thrombocytopenia due to heparin is another side effect of heparin therapy. There are two types of this thrombocytopenia: those that appear early often occur 4-7 days after treatment, are reversible and have a benign course, and occur in about 1-2% of patients on plain heparin (lower than normal platelets or >50% drop in platelet count). It may be a direct effect of heparin on platelets without serious consequences. The second condition occurs mostly on days 5-15 of treatment, with an incidence of nearly 0.1-0.2%, and is immune-mediated by anti-platelet 4 factor-heparin complex antibody IgG; it is sometimes accompanied by arteriovenous thrombosis, leading to serious complications such as death or limb necrosis. Therefore, platelet counts should be monitored during heparin therapy, and caution must be exercised when platelets suddenly fall below 100,000/UL for no known reason or drop by more than 30%. Platelets gradually rise 10 days after stopping heparin, and platelet counts should be measured every two days during treatment.
LMWH is one of the options to replace UFH. The bioavailability of LMWH after subcutaneous injection is as high as 90% (compared to 40% for UFH), which is related to the weak affinity of its plasma proteins (including platelet 4 factor, fibronectin, glass-linked protein and vW factor). The anticoagulant effect of LMWH is well predicted and therefore does not require close monitoring of aPTT and repeated dose adjustments, and can be easily administered by subcutaneous injection. trials of UFH and LMWH in the treatment of non-massive pulmonary embolism have shown no differences in recurrence rates, bleeding and mortality in venous thromboembolism between the two classes of drugs. lMWH may reduce hospitalization days and improve patients’ quality of life.
If the pulmonary embolism occurs postoperatively, heparin should not be used within 12 to 24 hours after major surgery. If bleeding is still present at the surgical site, treatment should be further delayed. Heparin does not have to be given by static push and the dose should be moderately lower than the regular dose. The aPTT is measured 4 hours after starting treatment. if the patient is at high risk of bleeding, a venous filter should be placed.
Oral anticoagulants are started on the first or second day of heparin therapy. The starting dose is 2 to 3 mg of warfarin per day, and the dose is adjusted according to the INR. The loading dose does not achieve the target INR (2.0-3.0) faster than the maintenance dose, but is detrimental because the protein C and S have a shorter half-life than the other anticoagulants (II, VII, IX, X) and can cause a temporary hypercoagulable state. The INR should be monitored daily until it reaches therapeutic levels, twice a week for the first 2 weeks of treatment, and once a week or less thereafter depending on how well the INR has stabilized. For long-term treatment, monitoring should be done every 4 weeks. Effective treatment should result in an INR of 2.0 to 3.0. At an INR of 3 to 4.5, recurrent venous thromboembolism is not reduced and bleeding complications are increased fourfold.
The duration of anticoagulation depends on the type of clinical event and the coexisting risk factors. Patients with temporary or reversible risk factors (e.g., secondary to surgical or post-traumatic thrombosis) are treated with anticoagulation for 3-6 months. For idiopathic venous thromboembolism without predisposing risk factors after the first episode, anticoagulation for at least 6 months. For malignancy or recurrent venous thromboembolism anticoagulation should be administered indefinitely (>2 years).
The most common complication of oral anticoagulation is bleeding, the risk of which is related to the intensity of anticoagulation. There is sufficient evidence that bleeding is more common with an INR >3.0. Patients of advanced age are prone to bleeding. Bleeding often occurs early in treatment, especially in combination with tumors, gastrointestinal ulcers, and cerebral aneurysms. If clinically indicated, the drug may be discontinued and oral or injectable vitamin K antagonism may be administered. If the patient is bleeding severely, vitamin K and fresh plasma or prothrombin complex should be administered intravenously.
In patients who have to undergo surgery during oral anticoagulant therapy, the decision to discontinue anticoagulation or to adjust the anticoagulant dose is based on a balance between the risk of bleeding and the benefit of anticoagulation. Depending on the patient’s specific situation, the following strategies may be used: (1) discontinue warfarin for 3-5 days before surgery to return the INR to normal levels and restart anticoagulation after surgery; (2) reduce the dose of warfarin and maintain the INR at subtherapeutic levels during surgery; (3) discontinue warfarin and use heparin anticoagulation (LMWH is recommended) before and after surgery until warfarin therapy is restarted.
V. Transcatheter intervention
The thrombus can be broken or aspirated with a catheter, and local thrombolysis can also be performed in the pulmonary artery at the same time. It is suitable for those who have contraindications to thrombolysis and anticoagulation.
Sixth, surgical pulmonary artery embolization
Applicable to patients with large pulmonary embolism who have failed thrombolytic therapy or have contraindications to thrombolytic therapy. Before performing pulmonary artery embolization, pulmonary arteriography should be performed to confirm the site and scope of pulmonary artery blockage and ensure correct diagnosis. The risk of surgery in the acute phase is high, and the mortality rate is close to 40%.
VII. Inferior vena cava filter
Recurrent pulmonary embolism is closely associated with DVT of the lower extremities. Placement of a filter in the inferior vena cava by the percutaneous puncture route has the potential to prevent re-embolization. In patients at high risk of pulmonary embolism with contraindications to anticoagulation or recurrent embolism despite adequate anticoagulation, placement of an inferior vena cava filter may be beneficial