Guidelines for the diagnosis and treatment of pulmonary embolism
Terminology and Definition.
Pulmonary embolism (PE) is a general term for a group of diseases or clinical syndromes in which obstruction of the pulmonary arterial system by various emboli is the cause of their pathogenesis, including pulmonary thromboembolism, fat embolism syndrome, amniotic fluid embolism and air embolism. Pulmonary thromboembolism (PTE) is a disease caused by obstruction of the pulmonary artery or its branches by blood clots from the venous system or the right heart, with pulmonary circulation and respiratory dysfunction as its main clinical and pathophysiological features. This is called pulmonary infarction (PI). PTE is often a complication of DVT, and PTE and DVT belong together as venous thromboembolism (VTE), which is a second category of VTE.
Clinical signs.
1. Symptoms: The clinical symptoms of PTE are diverse, and different cases often have different combinations of symptoms, but all lack specificity. The severity of symptoms varies greatly from case to case, ranging from asymptomatic to hemodynamically unstable, or even sudden death. Based on the descriptive studies of PTE symptoms at home and abroad, the following clinical symptoms and signs and their rates of occurrence are listed: (1) Dyspnea and shortness of breath (80%-90%), which are the most common symptoms, especially after activity. (2) Chest pain, including pleuritic chest pain (40%-70%) or angina-like pain (4%-12%). (3), syncope (11%-20%), which can be the only or first symptom of PTE. (4), irritability, panic and even near-death feeling (55%). (5), hemoptysis (11%-30%), often small amount of hemoptysis, large hemoptysis is rare. (6), cough (20% to 37%). (7), palpitations (10%-18%). It should be noted that less than 30% of patients have the so-called “pulmonary infarction triad” (dyspnea, chest pain and hemoptysis).
2, signs: (1), shortness of breath (70%), respiratory rate > 20 times / min, is the most common sign. (2) Tachycardia (30%-40%). (3), blood pressure changes, in severe cases, blood pressure may drop or even shock. (4), Cyanosis (11%-16%). (5), fever (43%), mostly low fever, a few patients may have moderate or higher fever (7%). (6), Jugular vein filling or pulsation (12%). (7), Croup (5%) and/or fine wet rales (18% to 51%) may be heard in the lungs, and vascular murmurs may occasionally be heard. (8) The corresponding signs of pleural effusion (24%-30%). (9), hyperactive or split second sound in the pulmonary valve area (23%), P2 > A2, systolic murmur in the tricuspid valve area.
3, signs and symptoms of deep vein thrombosis: pay attention to the symptoms and signs related to PTE and consider the diagnosis of PTE while paying attention to the presence of DVT, especially DVT of lower limbs. DVT of lower limbs mainly manifests as swelling of affected limbs, thickening of circumference, pain or pressure, dilatation of superficial veins, skin pigmentation, easy fatigue or increase of swelling of affected limbs after walking. About half or more of the patients with lower extremity DVT have no conscious clinical symptoms and obvious signs.
4.Arterial blood gas analysis: It often shows hypoxemia, hypocarbia, and increased alveolar-arterial partial pressure difference of oxygen [P(A-a)O2]. The results can be normal in some patients.
5. Electrocardiogram: Most cases exhibit nonspecific ECG abnormalities. Other ECG changes include complete or incomplete right bundle branch block, pulmonary P waves, rightward deviation of the electrical axis, and clockwise transposition. Most of the ECG changes start immediately after the onset of the disease and then change dynamically as the disease evolves. The observation of dynamic changes in ECG is more significant than static abnormalities to suggest PTE.
6. Chest X-ray: Most of them have abnormal performance, but lack of specificity. It may show regional pulmonary vascular texture thinning, sparseness or disappearance, increased translucency in the lung field; local infiltrative shadow in the lung field; wedge-shaped shadow with the tip pointing to the lung door; pulmonary atelectasis or incomplete expansion; widening or truncation of the right lower pulmonary artery trunk; bulging of the pulmonary artery segment and enlargement of the right ventricle; elevation of the diaphragm on the affected side; small to medium amount of pleural effusion sign. The diagnosis of PTE cannot be confirmed or excluded by X-ray chest film alone, but it plays an important role in providing clues to suspected PTE and excluding other diseases.
7.Echocardiography: It has important value in suggesting the diagnosis and excluding other cardiovascular disorders. In severe cases of PTE, echocardiography can reveal reduced local motion of the right ventricular wall; enlargement of the right ventricle and/or right atrium; leftward shift of the septum and abnormal motion; dilatation of the proximal pulmonary artery; increased velocity of tricuspid regurgitation; and dilated inferior vena cava that does not atrophy during inspiration. These signs are indicative of pulmonary hypertension, right ventricular hyperload, and pulmonary origin heart disease and suggest or are highly suspicious of PTE, but are not yet definitive diagnostic criteria for PTE. Echocardiography is the basis for classifying submassive PTE. The thickness of the right ventricular wall should be noted at the same time as the examination; if thickened, it is suggestive of chronic pulmonary heart disease and is important to clarify the presence of a chronic embolic process in the case. If a thrombus is found in the right atrium or right ventricle, along with a clinical presentation of the patient consistent with PTE, a diagnosis can be made. Ultrasonography may occasionally confirm the diagnosis by finding a thrombus in the proximal pulmonary artery.
8, plasma D-dimer (D-dimer) D-dimer is a soluble degradation product produced by cross-linked fibrin under the action of fibrinolytic system, which is a specific marker of fibrinolytic process. The sensitivity of D-dimer for the diagnosis of PTE is 92% to 100%, but its specificity is low, only about 40% to 43%. Surgery, tumor, inflammation, infection, tissue necrosis and other conditions can cause D-dimer to increase. In clinical applications, D-dimer has a greater diagnostic value for the exclusion of acute PTE, if its content is lower than 500 μg / L, can basically exclude acute PTE. enzyme-linked immunosorbent assay (ELISA) is a more reliable detection method, recommended.
9. Nuclear lung ventilation/perfusion scan is an important diagnostic method for PTE. The typical sign is a lung perfusion deficit distributed in lung segments and mismatched with ventilation imaging. However, because many diseases can affect both pulmonary ventilation and blood flow, the results of ventilation/perfusion scans are complex and need to be interpreted in close clinical context. The results can be divided into three categories: (1) highly probable: the sign is a local perfusion defect in at least one or more lobes with good ventilation or no abnormality in the radiograph; (2) normal or near normal; (3) non-diagnostic abnormal: the sign is between highly probable and normal.
10, spiral CT and electron beam CT imaging: able to detect emboli in the pulmonary artery above the segment, is one of the means of confirming the diagnosis of PTE. direct signs of PTE are low-density filling defects in the pulmonary artery, partially or completely surrounded by opaque blood flow (orbital sign), or a complete filling defect with no distal vessels (sensitivity 53%-89%, specificity 78%-100%) The diagnostic value of CT for subsegmental PTE is limited, but CT scans can also show other thoracic disorders, both pulmonary and extra-pulmonary. CT scans are faster and can largely avoid artifacts due to the effects of heartbeat and respiration.
Magnetic resonance imaging (MRI) has higher sensitivity and specificity for the diagnosis of emboli in the pulmonary arteries above the segment, avoids the disadvantages of iodine contrast injection, is more acceptable to patients than pulmonary angiography, and is suitable for patients with iodine contrast allergy. MRI has the potential ability to identify old and new thrombi, which may provide a basis for determining the thrombolytic program in the future.
12. Pulmonary arteriography is a reference method for the diagnosis of PTE. The direct signs of PTE include intravascular contrast filling defect and blockage of blood flow with or without orbital signs; indirect signs include slow flow of pulmonary artery contrast, local hypoperfusion, and delayed venous reflux. Pulmonary arteriography is an invasive test with a 0.1% and 1.5% chance of fatal or serious complications, respectively, and its indications should be strictly controlled. If other non-invasive tests can confirm the diagnosis of PTE, and if only medical treatment is proposed clinically, it is not necessary to perform this test.
13, auxiliary examination of deep vein thrombosis ultrasound technology: through direct observation of thrombus, probe compression observation or squeezing distal limb test and Doppler flow detection, more than 95% of the thrombus in the proximal lower limb veins can be detected. The inability of the vein to be compressed or the absence of a blood flow signal in the venous lumen are specific signs and diagnostic bases for DVT. The positive rate is lower for peroneal veins and asymptomatic lower extremity DVT.
MRI: The sensitivity and specificity for the diagnosis of symptomatic acute DVT can be 90% to 100%, and some studies suggest that MRI can be used to detect asymptomatic DVT of the lower extremities. MRI has advantages in detecting pelvic and upper extremity DVT, but is less sensitive than venography for peroneal vein thrombosis.
Limb impedance volumetry (IPG): can indirectly indicate venous thrombosis. It has high sensitivity and specificity for symptomatic proximal DVT and low sensitivity for asymptomatic lower extremity venous thrombosis.
Radionuclide venography: a non-invasive DVT detection method, often combined with lung perfusion scan. It is also indicated for those who are allergic to contrast agents.
Venography: It is the “gold standard” for the diagnosis of DVT, showing the site, extent and degree of venous occlusion and the status of collateral circulation and venous function, and its diagnostic sensitivity and specificity are close to 100%.
Treatment
1. Treatment of acute PTE.
General treatment Patients with highly suspicious or confirmed PTE should be closely monitored and changes in respiration, heart rate, blood pressure, venous pressure, electrocardiogram and blood gas should be monitored, and patients with large PTE can be admitted to intensive care treatment unit (ICU). In order to prevent the embolus from dislodging again, absolute bed rest is required to keep the stool unobstructed and avoid exertion; patients with anxiety and panic symptoms should be comforted and appropriate sedatives can be used; analgesics can be given for chest pain; symptomatic treatment can be given for symptoms such as fever and cough.
Respiratory and circulatory support therapy For patients with hypoxemia, oxygen is administered via nasal cannula or face mask. When combined with severe respiratory failure, non-invasive mechanical ventilation via nasal or face mask, or mechanical ventilation via tracheal intubation can be used. Tracheotomy should be avoided to avoid massive local bleeding during anticoagulation or thrombolysis. Care should be taken to minimize the adverse circulatory effects of positive pressure ventilation in the application of mechanical ventilation.
In cases of right heart insufficiency with decreased cardiac output but still normal blood pressure, dobutamine and dobutamine, which have certain pulmonary vasodilator and positive inotropic effects, can be given; if blood pressure decreases, the dose can be increased or other vasopressors such as methotrexate and epinephrine can be used. Fluid loading therapy should be approached with caution, as excessive fluid loading may increase right ventricular dilatation and consequently affect cardiac output, and is generally limited to 500 ml.
Thrombolytic therapy Thrombolytic therapy can rapidly dissolve some or all of the thrombus, restore pulmonary tissue reperfusion, reduce pulmonary artery resistance, lower pulmonary artery pressure, improve right ventricular function, and reduce the death and recurrence rates of patients with severe PTE. Thrombolysis is mainly indicated in cases of massive PTE, i.e., cases with shock and/or hypotension due to embolism; in cases of submassive PTE, i.e., with normal blood pressure but echocardiographic evidence of right ventricular hypokinesis or clinical manifestations of right ventricular insufficiency, thrombolysis can be performed if there are no contraindications; in cases with normal blood pressure and right ventricular motion, thrombolysis is not recommended. Thrombolytic therapy is highly individualized. The time window for thrombolysis is generally set at 14 days or less, but given the possible dynamic formation of thrombus, the time window for thrombolysis is not strictly defined. Thrombolysis should be performed as carefully as possible under the premise of a confirmed diagnosis of PTE. It is advisable to start thrombolysis as early as possible in cases with indications for thrombolysis.
The main complication of thrombolytic therapy is bleeding. The risk and consequences of bleeding should be fully evaluated before drug administration, and blood should be matched and prepared for transfusion if necessary. Peripheral intravenous cannulae should be left in place before thrombolysis to facilitate blood sampling and monitoring during thrombolysis and to avoid repeated punctures of blood vessels. Absolute contraindications to thrombolytic therapy include active internal bleeding and recent spontaneous intracranial hemorrhage. Relative contraindications include major surgery within 2 weeks, delivery, organ biopsy or vascular puncture at a site that cannot be stopped by compression, ischemic stroke within 2 months, gastrointestinal bleeding within 10 days, severe trauma within 15 days, neurosurgical or ophthalmic surgery within 1 month, severe hypertension (systolic > 180 mmHg, diastolic > 110 mmHg) that is difficult to control, recent cardiopulmonary resuscitation , platelet count < 100,000/mm3, pregnancy, bacterial endocarditis, severe hepatic or renal insufficiency, diabetic hemorrhagic retinopathy, bleeding disorders, etc. For large PTE, the above absolute contraindications should also be considered as relative contraindications because of the great threat to life.
The commonly used thrombolytic drugs are urokinase (UK), streptokinase (SK) and recombinant tissue-type fibrinogen activator (rtPA). All three have similar thrombolytic effects and can be used clinically according to the conditions. rtPA may have a faster lysis effect on the thrombus. The doses of thrombolytic drugs that are fully applicable to the national population have not yet been determined. The following protocols and doses are mainly based on the recommended protocols in Europe and America for reference use.
(1) Urokinase loading dose of 4400 IU/kg for 10 minutes, followed by 2200 IU/kg/h for 12 hours; 2-hour thrombolysis protocol can be considered: 20,000 IU/kg for 2 hours.
(2) Streptokinase loading dose of 250,000 IU, 30 minutes of sedation, followed by 100,000 IU/h for 24 hours. Streptokinase is antigenic, so it is necessary to inject benadryl or dexamethasone intramuscularly before administration to prevent allergic reactions.
(3), rtPA 50 to l00mg continuous IV for 2 hours. Do not use heparin during thrombolysis with urokinase and streptokinase. There is no special requirement to discontinue heparin when thrombolysis is performed with rtPA.
After thrombolytic therapy, prothrombin time (PT) or activated partial thromboplastin time (APTT) should be measured every 24 hours, and standard heparin therapy should be restarted when the level is less than twice the normal value. After thrombolysis, dynamic observation of clinical and relevant ancillary tests should be noted to assess the efficacy of thrombolysis.
Anticoagulation therapy is the basic treatment for PTE and DVT, which can effectively prevent the re-formation and recurrence of thrombus, and at the same time, the body’s own fibrinolytic mechanism dissolves the formed thrombus. At present, the main anticoagulant drugs used in clinical practice are common heparin (hereafter referred to as heparin), low molecular weight heparin and warfarin. It is generally believed that the anticoagulant effect of antiplatelet drugs can not yet meet the anticoagulation requirements of PTE or DVT. Effective anticoagulation with heparin or low-molecular-weight heparin can be arranged when PTE is clinically suspected.
Before applying heparin/low-molecular-weight heparin, basal APTT, PT and blood count (including platelet count and hemoglobin) should be measured, and the presence of contraindications to anticoagulation, such as active bleeding, coagulation dysfunction, thrombocytopenia, and uncontrolled severe hypertension, should be noted. For confirmed PTE cases, most contraindications are relative.
Recommended use of heparin (for reference): 2000-5000 IU or 80 IU/kg followed by a continuous drip of 18 IU/kg/h. Measure APTT every 4-6 hours during the first 24 hours after starting treatment, adjust the dose according to APTT, and make APTT reach and maintain 1,5-2,5 times the normal value as soon as possible. After reaching a stable therapeutic level, the APTT will be measured once a day in the morning, and heparin anticoagulation will be used to achieve an effective level. Inadequate anticoagulation will seriously affect the efficacy and may lead to a significant increase in the recurrence rate of thrombosis.
Heparin can also be administered by subcutaneous injection. Generally, a loading dose of 2000-5000 IU is administered by sedation, followed by subcutaneous injection at a dose of 250 IU/kg once every 12 hours. The dose is adjusted to achieve a therapeutic APTT at 6 to 8 hours after injection. A commonly used monitoring indicator prior to heparin therapy is the APTT, which is a general coagulation status test and does not always reliably reflect plasma heparin levels or antithrombotic activity. This needs to be taken into account. If the plasma heparin level is available, maintaining it at 0.2-0.4 IU/ml (fisetin sulfate assay) or 0.3-0.6 IU/m l (amidolytic assay) may be a better way to adjust heparin therapy. The APTT values corresponding to the above therapeutic levels of plasma heparin can also be determined in advance in the laboratory of each unit as a basis for adjusting the heparin dose.
Because of the possibility of heparin-induced thrombocytopenia (HIT), the platelet count must be rechecked on the 3rd to 5th day of heparin administration. HIT rarely occurs after 2 weeks of heparin therapy. Heparin should be discontinued if there is a rapid or sustained decrease in platelets of 30% or more, or if the platelet count is < 100,000/mm3. Platelets usually start to recover gradually within 10 days after discontinuation of heparin. It is important to note that HIT may be associated with progression or recurrence of PTE and DVT. When the risk of recurrence of thrombosis is high and heparin must be discontinued, placement of an inferior vena cava filter may be considered, but caution should be exercised for combined vena cava thrombosis at the filter.
Recommended use of low molecular weight heparin (LMWH): administered subcutaneously once or twice daily according to body weight (anti-Xa IU/kg or mg/kg. The dose varies between LMWHs, as described below). In most cases, weight-based dosing is effective and does not require APTT monitoring or dose adjustment, but in overweight individuals or pregnant women, it is advisable to monitor plasma anti-Xa factor activity and adjust the dose accordingly.
Specific uses of various low molecular weight heparins.
Dapsigargin sodium: 200 anti-Xa IU/kg subcutaneously, once daily. The single dose should not exceed 1,80,000 IU.
Enoxaparin sodium: l mg/kg subcutaneously q12h, or 1,5 mg/kg subcutaneously once daily, single total dose not exceeding 180 mg.
Nadroparin calcium: 86 anti-Xa IU/kg subcutaneously q12h for 10 days, or 171 anti-Xa IU/kg subcutaneously once a day. Total single dose not to exceed 17,100 IU.
Tinzaparin sodium: 175 anti-Xa IU/kg subcutaneously once a day.
Different manufacturers’ preparations need to refer to their product instructions for use.
Low-molecular-weight heparin can also be used for the out-of-hospital treatment of PTE and DVT due to the lack of monitoring and the low incidence of bleeding. In addition to routine monitoring of APTT, monitoring of platelet counts during the first 5 to 7 days of low molecular weight heparin is not required. When the course of treatment is longer than 7 days, platelet counts need to be checked every 2-3 days.
Low-molecular-weight heparin is cleared by the kidneys and should be used with caution in cases of renal insufficiency, especially in cases where creatinine clearance is less than 30 ml/min. If used, the dose should be reduced and plasma anti-factor Xa activity should be monitored. It is recommended that heparin or low-molecular-weight heparin be administered for at least 5 days until clinical stabilization. For large PTE or iliofemoral vein thrombosis, heparin should be used for approximately 10 days or longer.
Recombinant hirudin and other small molecule thrombosis inhibitors: Recombinant hirudin is a more effective anticoagulant than heparin. In cases of PTE and HIT with combined thrombocytopenia, recombinant hirudin and other small molecule thrombosis inhibitors may be used for anticoagulation. Generally, recombinant hirudin is given first until the platelet count rises to 100,000/mm3 and then warfarin is administered.
Warfarin: Add the oral anticoagulant warfarin at an initial dose of 3,0-50 mg/d within the first 1-3 days after the start of heparin and/or low-molecular-weight heparin, and because warfarin requires several days to exert its full effect, it should be applied overlapping with heparin for at least 4-5 days, when the international normalized ratio (INR) measured on 2 consecutive days reaches 2,5 (2,0-3,0), or When the PT is prolonged to 1,5 to 2,5 times, heparin and/or low molecular weight heparin can be discontinued and oral warfarin therapy alone can be administered. The dose of warfarin should be adjusted according to INR or PT. INR should be measured daily until therapeutic levels are reached, monitored 2 to 3 times per week for the next 2 weeks, and then once per week or less depending on the stability of INR. For long-term therapy, the INR should be measured and the warfarin dose adjusted approximately every 4 weeks.
The duration of anticoagulation therapy varies from person to person. The usual course of oral warfarin is at least 3 to 6 months. In some cases, risk factors can be eliminated in the short term, such as taking estrogen or temporary braking, and a course of 3 months may be sufficient; in first cases with unknown source of emboli, anticoagulation needs to be given for at least 6 months; in recurrent VTE, combined pulmonary heart disease, or those with long-standing risk factors, such as cancer patients, anticardiolipid antibody syndrome, antithrombin III deficiency, and prone to embolism, the duration of anticoagulation therapy should be more extended up to 12 months or more, or even lifelong anticoagulation.
Warfarin is contraindicated during the first 3 months and the last 6 weeks of pregnancy and can be treated with heparin or low molecular weight heparin. Warfarin may be given to postpartum and lactating women. Women of childbearing age taking warfarin need to be careful with contraception.
The main complication of warfarin is bleeding. an INR higher than 3,0 does not usually help to improve the efficacy, but the chance of bleeding is increased. Warfarin-induced bleeding can be antagonized with vitamin K. Warfarin has the potential to cause angio-purpura, leading to skin necrosis, mostly in the first weeks of treatment.
Pulmonary artery thrombectomy is indicated for emergencies where aggressive conservative therapy has failed and requires a medical facility with the availability and experience to perform the procedure. Patients should meet the following criteria: (1) Large PTE with sub-total occlusion of the main or major branches of the pulmonary artery, not combined with fixed pulmonary hypertension (diagnosis confirmed by angiography if possible). (2) Those who have contraindications to thrombolysis. (3) Those who have failed thrombolysis and other aggressive medical treatment.
Transvenous catheter fragmentation and aspiration of thrombus: catheter fragmentation and aspiration of large thrombus in the pulmonary artery or balloon angioplasty, along with local low-dose thrombolysis. Indications include large PTE in the main pulmonary artery or major branches with the following conditions: contraindication to thrombolysis and anticoagulation, failure of thrombolysis or aggressive medical therapy, and lack of surgical conditions.
Venous filter: A filter can be installed in the inferior vena cava to prevent re-dislodgement of a large thrombus in the deep veins of the lower extremities to obstruct the pulmonary artery. This is indicated in cases of proximal venous thrombosis in the lower extremity where anticoagulation is contraindicated or bleeding complications are present; large PTE with recurrent PTE and hemodynamic changes despite adequate anticoagulation; large proximal thrombus before thrombolytic therapy; chronic recurrent PTE with pulmonary hypertension; and cases with pulmonary thrombectomy or pulmonary thromboendarterectomy. An upper vena cava filter can also be applied in cases of upper extremity DVT. After placement of the filter, if there is no contraindication, long-term oral warfarin anticoagulation is advisable, and regular review for thrombus formation on the filter.
(1), severe chronic embolic pulmonary hypertension 2, treatment of chronic embolic pulmonary hypertension: cases, if the obstruction site is in the proximal part of the surgically accessible pulmonary artery, pulmonary artery thromboendarterectomy can be considered.
(2), interventional treatment: balloon dilatation pulmonary arterioplasty. It has been reported, but the experience is still small.
(3), oral warfarin can prevent the re-formation of pulmonary artery thrombosis and inhibit the further development of pulmonary hypertension. Use: 3,0-5,0mg/d, adjust the dose according to the INR and keep the INR at 2,0-3,0.
(4).In the presence of recurrent lower limb deep vein thrombosis dislodgement, an inferior vena cava filter can be placed.
(5), Use vasodilators to reduce pulmonary artery pressure. Treat heart failure.
Prevention.
In cases where risk factors for DVT-PTE exist, it is appropriate to use appropriate prophylactic measures according to the clinical situation. The main methods used: mechanical prophylaxis, including compression stockings, intermittent sequential inflation pumps and inferior vena cava filters; pharmacological prophylaxis, including low-dose heparin subcutaneous injection, low-molecular-weight heparin and warfarin. Patients in key high-risk groups, including general surgery, obstetrics and gynecology, urology, orthopedics (artificial femoral head replacement, artificial knee replacement, hip fracture, etc.), neurosurgery, trauma, acute spinal cord injury, acute myocardial infarction, ischemic stroke, tumor, long-term bedridden, severe pulmonary disease (chronic obstructive pulmonary disease, interstitial lung disease, primary pulmonary hypertension, etc.), according to severity The risk of DVT-PTE should be assessed according to the severity of the disease, age, and whether other risk factors are compounded, and appropriate prevention programs should be developed. It is recommended that each hospital should develop a DVT-PTE prevention routine for the above cases and implement it in practice.