Pregnancy complicated by pulmonary embolism

　　1. Source of emboli
　　(1) Thrombus: the most common pulmonary embolism is thrombus, and pulmonary embolism (PE) caused by thrombus is also called pulmonary thromboembolism. 70% to 95% is due to deep vein thrombosis (DVT) lagging behind and entering the pulmonary artery and its branches through the blood circulation. The primary site is mainly the deep veins of the lower extremities, with literature reports reaching 90% to 95%, such as the femoral, deep femoral, and external iliac veins. The incidence of DVT is very high in patients with cerebrovascular accidents and acute myocardial infarction during chest, abdominal, and hip surgery. Within 24 to 48 hours after surgery, thrombosis can form in the popliteal veins of the lower legs, but most of them can disappear after activity. About 5% to 20% of the thrombi in this area can extend to high-level deep veins, and 3% to 10% can cause PTE within 4 to 20 days after surgery. Axillary and subclavicular veins also often form thrombi, but only 1% of the thrombi come from this place. Pelvic vein thrombosis is an important source of PTE in women, often occurring in gynecological surgery, pelvic diseases, etc. A very small number of thrombi come from the right ventricle or right atrium. In addition, it should also be noted that although superficial vein thrombophlebitis of the lower extremities cannot directly produce PTE, 20% of them are closely related to DVT.
　　(2) Other emboli: such as fat emboli, air emboli, amniotic fluid, bone marrow, parasites, placental trophoblast, metastatic cancer, bacterial emboli, cardiac vegetations, etc., can all cause PE.
　　2. Conditions for venous thrombosis formation
　　(1) Stagnant blood flow: the most important condition, making it difficult for activated coagulation factors to be inhibited by anticoagulants in the circulation, which is conducive to the formation of fibrin and promotes thrombosis. Common in the elderly, long-term bedridden patients, varicose veins of the lower extremities, obesity, shock, congestive heart failure, and pregnant women. According to the case data of Peking Union Medical College Hospital, 40% of PE have various types of heart disease, among which rheumatic heart disease is the most common.
　　(2) Venous vascular wall injury: such as surgery, tumor, burn, diabetes, etc., because after tissue damage, it is easy to produce endogenous and exogenous active thrombin that can easily cause damage to the vascular wall.
　　(3) High coagulability: seen in tumors, true polycythemia, severe hemolytic anemia, postoperative splenectomy with platelet lysis, homocystinuria (homocystinuria), oral contraceptives, etc. Foreign literature reports that pancreatic cancer has the highest incidence of DVT, therefore DVT may become a sign of malignant tumors. Laboratory examination reports show that patients with recurrent DVT have abnormalities in the coagulation mechanism, such as increased platelet adhesion and reduced lifespan, increased factors V and VII, deficiency of anticoagulant factor III, abnormal coagulation factor I, reduced plasminogen activator in the endothelial cells of the venous wall, increased inhibitors of plasminogen and plasmin, etc.
　　Diseases and pathological conditions that can produce the above conditions孕育着血栓形成的危险，and become the source of thrombus formation.

　　Due to the interruption of blood supply to the alveoli after pulmonary embolism, it can cause respiratory distress and induce ARDS (Acute Respiratory Distress Syndrome). It is a severe disease that threatens women's lives and must be diagnosed and treated in a timely manner.

　　According to the size of the embolus and the degree of blockage of the pulmonary artery, its clinical manifestations include:

　　1. There are no specific clinical manifestations, mainly sudden onset, a series of symptoms of brain hypoxia:

　　(1) Onset is sudden, patients suddenly develop sudden fainting of unknown cause, pale complexion, cold sweat, weakness. Among those with sudden shortness of breath, 82% have chest pain, 49% have cough, 20% have syncope, and 7% have hemoptysis.

　　(2) Brain hypoxia symptoms: patients are extremely anxious and restless, fearful, apathetic, fatigue, nausea, convulsions, and coma.

　　(3) Acute pain: chest pain, shoulder pain, neck pain, pain in the anterior chest and upper abdomen.

　　2. Large artery embolism can cause symptoms of acute right heart failure, even sudden death:

　　(1) The main signs of the cardiovascular system are tachycardia, even diastolic gallop rhythm, pulmonary artery second sound intensification, aortic valve and pulmonary artery valve splitting, shock, cyanosis, increased central venous pressure, jugular venous distension, and liver enlargement.

　　(2) The main signs in the lungs are tachypnea, moist rales, pleural friction sounds, wheezing, and signs of pulmonary consolidation.

　　(3) Electrocardiogram shows right axis deviation, inverted T waves, and right bundle branch block.

　　(4) Blood gas analysis shows low PaO2 and PaCO2.

　　(5) X-ray chest film shows hyperemia of lung atelectasis or pulmonary infarction, which usually appears within 12 to 36 hours.

　　1. Early screening:

　　Generally, through careful clinical examination, early detection of deep vein thrombosis in the lower limbs can prevent the occurrence of pulmonary embolism in 80% of patients. The following measures can be taken to prevent the formation of venous thrombosis:

　　(1) Cesarean section or difficult labor should be operated gently and carefully to minimize tissue damage, especially to avoid injury to blood vessels and induce thrombosis. It is necessary to correct dehydration and maintain water and electrolyte balance in the process of childbirth to prevent increased blood coagulability.

　　(2) After childbirth and surgery, encourage patients to turn over and flex their lower limbs as much as possible, and guide patients to get out of bed early to promote blood return and enhance blood circulation.

　　(3) Prophylactic anticoagulation therapy should be applied when necessary.

　　2. Drug anticoagulation to prevent thrombosis

　　(1) Low-dose heparin has a definite effect in preventing the occurrence of postoperative DVT.

　　(2) Oral anticoagulants: Acenocoumarol (new anticoagulant tablet, sinfrom) and warfarin (benzylidine coumarin, warfarin) are commonly used for patients with a history of DVT and severe varicose veins for prophylactic anticoagulation.

　　(3) Antiplatelet agents: Dipyridamole, 100mg orally daily, can inhibit platelet aggregation and adhesion. Non-steroidal anti-inflammatory drugs, such as low-dose aspirin (0.3 to 1.2g orally daily) and indomethacin, can inhibit thrombin A2, reducing the formation of venous thrombosis.

　　The items include:
　　1. Routine blood tests and biochemical tests:When there is pulmonary infarction, blood leukocyte count and erythrocyte sedimentation rate can increase.

　　2. Soluble fibrin complex (SFC), fibrin degradation products (FDP), and D-dimer SFC:It suggests recent thrombin generation, FDP indicates plasmin activity, and the positive rate in PTE is 55% to 75%. When both are positive, it is conducive to the diagnosis of PTE.

　　3. Arterial blood gas analysis and pulmonary function:

　　(1) When breathing air, about 85% of PTE patients show PaO2 below 10.7 kPa (80 mmHg), which can indicate the degree of embolism.

　　(2) The measurement of the difference between alveolar oxygen partial pressure and arterial oxygen partial pressure (PA-aDO2) is more meaningful than PaO2, because after embolism, patients often have hyperventilation, resulting in a decrease in PaCO2 and an increase in alveolar oxygen partial pressure (PaO2), so PA-aDO2 should be significantly increased.

　　(3) The ratio of dead space air/volume of tidal volume (VD/VT) increases during embolism. When patients have no restrictive or obstructive ventilation impairment, a ratio greater than 40% suggests the possibility of PTE, and a ratio less than 40% without clinical embolic symptoms can exclude PTE.

　　4. Electrocardiogram examination:The main manifestations are acute right ventricular dilation and pulmonary hypertension, showing a significant right deviation of the electrocardiographic axis, extreme counterclockwise rotation, right bundle branch block, and typical SⅠQⅢTⅢ waveform (deep S wave in lead I, significant Q wave in lead III, and inverted T wave), sometimes with pulmonary-type P wave or myocardial ischemia due to pulmonary-coronary reflex, such as abnormal elevation or depression of the ST segment, which often appear within 5 to 24 hours after onset, most of which recover within a few days or 2 to 3 weeks, and only 26% of patients have the above electrocardiographic changes. Most patients have normal electrocardiograms or only non-specific changes, so normal electrocardiograms cannot exclude the disease. In addition, electrocardiogram examination is also used as a means of distinguishing from acute myocardial infarction.

　　5. Chest X-ray findings:Due to the diverse pathological changes of pulmonary embolism, the X-ray manifestations are also varied. Patients suspected of having pulmonary embolism should undergo continuous chest X-ray examination, with more than 90% of patients showing certain abnormal changes, and pulmonary embolism cannot be ruled out even if normal.

　　6. Pulmonary perfusion imaging and pulmonary ventilation/perfusion imaging:It is currently a highly recommended PE diagnostic method. The typical finding of pulmonary perfusion scan in PE patients is the presence of perfusion defects in the distribution of pulmonary segments, and the pulmonary ventilation scan shows that inhaled radioactive gas is distributed throughout the lungs with air. Recently, a multicenter study was conducted in a group of patients suspected of having acute PE in the United States, with random sampling to estimate the sensitivity and specificity of PE diagnosis, known as the prospective study of PE diagnosis (PIOPED). Compared with pulmonary angiography (CPA), the sensitivity of the diagnosis was found to be 92% and the specificity 87%, but 4% to 5% of patients with normal diagnosis still had subclinical PE. Therefore, it can be used as a standard screening examination for suspected PE, but pulmonary angiography is still required for those highly suspected but not yet confirmed by clinical examination.

　　7. Spiral CT:Spiral CT is a new method for diagnosing PE, with direct signs such as crescent-shaped, annular filling defects, complete obstruction, and track sign, and indirect signs include main pulmonary artery and left and right pulmonary artery dilatation, etc. According to reports, the positive rate of PE diagnosis at the segmental level and above is 96%, but it is prone to false positives in diagnosing PE below the segmental level.

　　8. Pulmonary Angiography (CPA):Selective pulmonary angiography is currently the most accurate method for diagnosing PE, with a positive rate of 85% to 90%. It can determine the location and extent of the blockage. If supplemented with local magnification and oblique film shooting, even the embolism in the blood vessels with a diameter of 0.5mm can be displayed. Within 72 hours after the occurrence of embolism, CPA has extremely high sensitivity and specificity in diagnosing PE, and it is generally not easy to miss, with very few false positives, error rate of 6%, and sometimes it is difficult to detect due to small emboli, so it can produce perfusion imaging positivity. However, pulmonary angiography is negative, as the basis for diagnosing pulmonary embolism, the X-ray signs of pulmonary angiography must show filling defects or vessel interruption within the pulmonary artery lumen, other signs with suggestive significance include localized lung lobe, reduced vascular texture of lung segment, slow blood flow and reduced blood volume, etc.

　　9. Digital Subtraction Angiography (DSA):This method can significantly reduce the concentration, dosage and side effects of contrast agents, with basically no complications and deaths, and the coincidence rate with imaging is 83.5%. This method is suitable for highly suspicious imaging or those estimated to have embolism located in the main branches of the pulmonary artery, especially for patients with chronic obstructive pulmonary disease and those who cannot accept pulmonary angiography. Its X-ray signs are similar to angiography.

　　10. Magnetic Resonance Angiography (MRA):When compared with traditional CPA, it is found that its sensitivity is 75%, specificity is 95%, although lower than traditional CPA, MRA avoids ionizing radiation, avoids iodine contrast agents that may cause nephrotoxicity, and is relatively safe to operate, so it is still a worthy method for further research on PE diagnosis, but it is too expensive.

　　11. Echocardiography:Including routine transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE), etc., in recent years, their role in the diagnosis of pulmonary embolism has gradually received attention. TTE can show pulmonary artery trunk and its branches embolism, indirect signs include right ventricular enlargement, abnormal ventricular wall motion, tricuspid regurgitation, pulmonary hypertension, etc.

　　12. D-dimer (D-dimer):When thrombosis occurs, the concentration of D-dimer increases, which is a promising method of examination. Taking D-dimer > 500μg/L as the diagnostic standard, its sensitivity is only 35.2%, so this method cannot be used to diagnose thrombotic diseases, but can only exclude such diseases.

　　When suspected of pulmonary embolism, chest X-ray, electrocardiogram, blood gas analysis and other examinations are required, but diagnosis relies on pulmonary perfusion scanning or pulmonary angiography.

　　Dietary principles for patients with pregnancy complicated with pulmonary embolism:

　　Diet should be light, eat less high-fat, high-cholesterol, high-sugar, and刺激性 food, and eat more coarse grains, rough fiber vegetables and fruits.

　　Special recommendation for lowering blood pressure and blood lipids: black fungus, mushrooms, scallion, onion, garlic sprouts, celery, seaweed, kelp, corn, dairy products, hawthorn, tomatoes, pineapples, lemons, apples, etc.

　　One-day nutritional meal menu, for reference:

　　Breakfast: 1 cup of goji and oat milk, 1 boiled egg, 1 steamed bun;

　　Lunch: 200 grams of rice, bitter melon with spareribs, green beans with eggplant, cabbage with bean curd, tomato seaweed and shrimp skin soup;

　　Dinner: 1 bowl of fish slice congee, 1 soft cake (2 spoons of flour, 1 spoon of bean powder, 1 spoon of buckwheat powder), stir-fried celery and carrot with meat, cucumber and fungus.

　　1. General treatment:

　　(1) Patients should maintain absolute bed rest and high-concentration oxygen inhalation.

　　(2) Placing a central venous pressure catheter, measuring central venous pressure, controlling the volume and speed of fluid administration, and administering medication through this route.

　　(3) Analgesia: Morphine 5 to 10 mg can be used subcutaneously when there is severe chest pain, but it should be avoided in shock patients.

　　(4) Antishock: To reduce the excitability of the vagus nerve and prevent reflex spasm of the pulmonary vessels and coronary arteries, atropine 0.5 to 1 mg can be injected intravenously, or isoprenaline, phentolamine (phenoxybenzamine) can be used. Dopamine 200 mg added to 500 ml of glucose solution is commonly used for antishock, with an initial infusion rate of 2.5 μg/(kg·min), and the infusion rate is adjusted thereafter to maintain systolic blood pressure at 12.0 kPa (90 mmHg) [10 to 25 μg/(kg·min)]. Dextran can be used as the primary fluid expander and also has anticoagulant, promotes thrombus dissolution, and reduces platelet activity.

　　(5) Antispasmodic: Aminophylline drugs can be used.

　　2. Drug treatment:

　　Anticoagulant therapy Heparin (heparin) is the first-line anticoagulant drug during pregnancy. The molecular weight is 4,000 to 40,000. Heparin does not cross the placenta, does not enter breast milk, and is safe for the fetus and newborns who are breastfed, and does not increase the risk of miscarriage, preterm birth, or perinatal mortality.

　　(1) Heparin administration: ① Continuous intravenous infusion: Suitable for massive pulmonary embolism, the first application of a high dose of heparin (10,000 to 20,000 U) is infused intravenously to inhibit platelet adhesion to the thrombus. Standard therapy begins 2 to 4 hours later, with 1,000 U infused every hour, controlled by an infusion pump. The total daily dose is 25,000 U. ② Intermittent intravenous injection: Heparin is administered once every 4 hours (5,000 U heparin) or every 6 hours (7,500 U heparin) intravenously. The total daily dose is 36,000 U. ③ Intermittent subcutaneous injection: Heparin is injected subcutaneously once every 4 hours (5,000 U), 8 hours (10,000 U), or 12 hours (20,000 U). It is necessary to avoid intramuscular injection to prevent the occurrence of hematoma.

　　Heparin is generally used continuously for 9 to 10 days. When the embolic risk factors disappear, the patient can be moved, and there is no occurrence of PTE symptoms, at this time, oral anticoagulants can be used in combination. Once the oral anticoagulants take effect, heparin can be discontinued.

　　Heparin calcium (low molecular weight heparin, LMWH) is a new type of anticoagulant, which has been reported in recent literature to also be used for the treatment of pulmonary embolism (PE). Simonneau et al. randomly divided 612 symptomatic acute PE patients who had not received thrombolytic therapy into intravenous unfractionated heparin and subcutaneous LMWH groups. After 8 days, the risks of death, recurrence of embolism, and major bleeding in the two groups were 2.9% and 3.0%, respectively, and 7.1% and 5.9% after 90 days, indicating that LMWH has a better efficacy, but there was no statistical difference. LMWH can be administered subcutaneously, without the need for laboratory monitoring, making it more convenient to use.

　　Complications of heparin: mainly bleeding, which is commonly found at the site of skin catheter insertion, followed by gastrointestinal tract, retroperitoneal space, or intracranial. Abnormal coagulation, uremia, alcoholic hepatitis, diastolic blood pressure above 14.7 kPa (110 mmHg), or severe pulmonary hypertension are prone to bleeding. Therefore, when using heparin for treatment, it is necessary to monitor the PT and clotting time to keep them at 1.5 to 2 times the normal value. In case of bleeding, heparin should be discontinued immediately, and protamine sulfate in an equivalent amount should be used to counteract heparin. Heparin treatment can be resumed with a small dose after bleeding stops.

　　Contraindications of heparin: history of intracranial hemorrhage within 2 months, liver and kidney dysfunction, bleeding disorders, active peptic ulcer, major surgery performed within 10 days (especially intracranial and ophthalmic surgery) and subacute bacterial endocarditis.

　　Pregnant women due to hypercoagulable state, large doses of heparin are required, and medication should be discontinued during labor and delivery, especially for those who are scheduled for cesarean section. If medication is still being taken 48 to 72 hours before surgery, the risk of bleeding is high. After delivery, if there is no large incision and the uterine contraction is good, heparin can be used for anticoagulation a few hours after delivery, and it is safer to use it again 1 to 2 days later. Generally, warfarin or doublediphenyl is used 4 to 6 weeks after delivery.

　　(2) Vitamin K antagonists: commonly used oral anticoagulants that can inhibit coagulation factors dependent on vitamin K. The most commonly used in China is sodium warfarin (New Anticoagulant) tablets, which act quickly and reach their peak effect within 36 to 48 hours after oral administration. The initial dose is 2 to 4 mg, and the maintenance dose is 1 to 2 mg per day. Doublediphenyl and diphenyl ethyl (New Doublediphenyl) can also be used, with the initial dose of 200 mg, followed by 100 mg the next day, and then 25 to 75 mg per day for maintenance. The initial dose of warfarin is 15 to 20 mg, followed by 5 to 10 mg the next day, with a maintenance dose of 2.5 to 5 mg per day. The maintenance dose of all oral anticoagulants is adjusted according to the prothrombin activity, keeping it between 20% and 30%. Doublediphenyl, diphenyl ethyl (New Doublediphenyl), and warfarin require a certain period of time to exert therapeutic effects, therefore, heparin should be combined for several days until the effect of oral anticoagulants is achieved, and then heparin can be discontinued. Generally, oral anticoagulants need to be continued for 3 months. Whether to continue taking them thereafter depends on the presence of embolic risk factors and the risk of continuing anticoagulation therapy.

　　Warfarin can cause 'idiopathic embryopathy' when used between 6 to 11 weeks of pregnancy, including: underdeveloped nasal bone, underdeveloped epiphyses, central nervous system abnormalities, hemorrhage and malformation in the fetus and newborn. The use of this drug at any time during pregnancy can cause neonatal hemorrhage, and it is only given postpartum. The use of dicoumarol during pregnancy can also cause fetal hemorrhage and should not be used.

　　3. Fibrinolytic agents:

　　Fibrinolytic agents, also known as thrombolytic therapy. The use of thrombolytic therapy for pulmonary embolism has been a major advancement in recent years, which can dissolve thrombi in the pulmonary artery, improve blood perfusion in the lung tissue, reduce pulmonary circulation resistance and pulmonary artery pressure, and improve right heart function; dissolve thrombi in the deep venous system can also reduce the source of emboli, reduce the recurrence of pulmonary embolism, improve quality of life and long-term prognosis, and has therefore become the preferred method of treatment at present. Fibrinolytic agents are generally used within 5 days after embolism, with good effects, and are more suitable for acute massive pulmonary embolism. At this time, it can be used with heparin, or heparin can be used after the course of treatment. Commonly used drugs include streptokinase (SK), urokinase (UK), and tissue-type plasminogen activator (tPA).

　　(1) The loading dose of urokinase is 4400 U/kg, administered intravenously for 10 minutes, followed by a continuous intravenous infusion of 2200 U/(kg·h) for 12 hours; alternatively, a 2-hour thrombolysis regimen can be considered: 20,000 U/kg administered continuously for 2 hours.

　　(2) The loading dose of streptokinase is 250,000 U, administered intravenously for 30 minutes, followed by a continuous intravenous infusion of 100,000 U/h for 24 hours. Streptokinase has antigenicity, so a muscle injection of phenylhydrazine or dexamethasone is required before administration to prevent allergic reactions.

　　(3) Alteplase (rt-PA): 50 to 100 mg should be administered intravenously continuously for 2 hours. Do not use heparin concurrently when using urokinase or streptokinase for thrombolysis. There are no special requirements for stopping heparin when using alteplase (rt-PA) for thrombolysis.

　　Meneveau and others in France administered 1.5 million U of SK intravenously to 43 patients with acute massive pulmonary embolism within 2 hours, followed by a continuous intravenous infusion of heparin at 1000 U/h to maintain the activated partial thromboplastin time (APTT) at 2 to 3 times the normal control value. After 5 days, oral anticoagulants were given for 6 months, showing significant efficacy. This regimen can be routinely used for the treatment of acute massive pulmonary embolism.

　　UK is obtained from the urine purification of normal people, without antigenicity, and is widely used in China. It is generally recommended to administer 20,000 U/kg intravenously for about 2 hours, followed by heparin, then oral warfarin to maintain PT at 1.5 to 2.5 times the normal control value, for at least 4 to 6 months.

　　Alteplase (rt-PA) is a second-generation selective thrombolytic drug, with a recommended dosage of 50 to 100 mg, which should be administered intravenously over approximately 2 hours. Jezek found in a comparative study that alteplase (rt-PA) improves hemodynamic disorders and right heart function faster than SK or UK within 2 hours, which is more important for some critically ill patients. Its drawback is that it is expensive and currently difficult to be widely used.

　　After thrombolytic therapy, the prothrombin time (PT) or activated partial thromboplastin time (APTT) should be measured every 24 hours. When the level is less than twice the normal value, it should be restarted with standardized heparin therapy. After thrombolytic therapy, it is necessary to dynamically observe the clinical conditions and related auxiliary examination results, and evaluate the efficacy of thrombolytic therapy.

　　In recent years, some scholars have also conducted research on the efficacy of continuing anticoagulation after thrombolytic therapy. Konstantinides et al. selected 719 patients with massive pulmonary embolism without severe hemodynamic disorders, divided them into two groups, one group received thrombolytic therapy within 24 hours after diagnosis, followed by heparin anticoagulation, and the other group received simple heparin anticoagulation. The results showed that the mortality rate in the thrombolytic group from the 1st to the 30th day of treatment was 4.7%, significantly lower than that in the non-thrombolytic group (11.1%). The recurrence rate of embolism in the thrombolytic group and the non-thrombolytic group was 7.7% and 18.7%, respectively, suggesting that continuing anticoagulation after thrombolytic therapy is superior to simple anticoagulation.

　　Absolute contraindications to thrombolytic therapy include active gastrointestinal bleeding, intracranial hemorrhage within 2 months, craniocervical surgery, etc. Relative contraindications include major surgery within 10 days, childbirth, recent severe gastrointestinal bleeding, liver and kidney dysfunction, severe trauma, hypertension grade III, and bleeding disorders, etc.

　　4. Surgical treatment:

　　(1) Pulmonary embolism resection: The reported mortality rate is as high as 65% to 70%. However, this operation can still save the lives of some patients, and it is necessary to strictly control the indications: ① Pulmonary angiography shows that 50% or more of the pulmonary vessels are blocked, and the embolism is located in the main pulmonary artery or left and right pulmonary arteries; ② Anticoagulation and/or thrombolytic therapy has failed or has contraindications; ③ After treatment, the patient is still in severe hypoxemia, shock, renal, or brain injury.

　　(2) Cava occlusion: The main purpose is to prevent the recurrence of embolism, which may threaten the pulmonary vascular bed. Methods include surgical clips, umbrella devices, wire mesh method, folding surgery, etc. After cava occlusion, the diameter of collateral circulation vessels may increase, and emboli can pass through collateral circulation into the pulmonary artery. Thrombosis may also occur locally in the occlusion equipment, so anticoagulation therapy must be continued after surgery.