Pulmonary Thromboembolism

Pulmonary Thromboembolism
Mohamed Kamel Sabry
Prof. ,Head of Dep.of Int.Med.& Immunology
Ain-Shams Univercity
ESSENTIALS OF DIAGNOSIS
. predisposition to venous thrombosis, usually of the lower extremities.
. Usually one of the following : dyspnea, chest pain, hemoptysis, syncope.
. Tachypnea and a widened alveolar arterial PO2 difference.
. Characteristic defects on ventilation-perfusion lung scan, spiral CT scan of the chest, or pulmonary angiogram.
General Considerations
Pulmonary thromboembolism, often referred to as pulmonary embolism, is a common, serious and potentially fatal complication of thrombus formation within the deep venous circulation. pulmonary thromboembolism is estimated to cause 50,000 deaths each year in the united states and is the third leading cause of death among hospitalized patients.
Many substances can embolize to the pulmonary circulation, including air (during neurosurgery, as a complication of central venous catheters), amniotic fluid (during active labor ), fat (as a complication of long bone fractures), foreign bodies (talc in intravenous drug users ), parasite eggs (schistosomiasis), septic emboli (as a complication of acute infectious endocarditis), and tumor cells (renal cell carcinoma ).
The most common embolus is thrombus, which may arise anywhere in the venous circulation or heart but most often originates in the deep veins of the major calf muscles . Thrombi confined to the calf rarely embolize to the pulmonary circulation . However, about 20% of calf vein Thrombi propagate proximally to the popliteal and ileofemoral veins, at which point they may break off and embolize to the pulmonary circulation . Fifty to 60 percent of patients with proximal deeb veins thrombosis (DVT) will develop pulmonary emboli; half of these embolic events will be asymptomatic. Nearly 70% of patients who present with asymptomatic pulmonary emboli will have lower extremity DVT when evaluated.
Pulmonary embolism and deeb venouse thrombosis are two manifestations of the same disease. The risk factors for pulmonary emboli are the risk factors for
thrombus formation within the venous circulation : venous stasis, injury to the vessel wall, and hypercoagulability. Venous stasis increases with immobility (bed rest-especially postoperative-obesity, stroke), hyperviscosity (polycythemia), and increased central venous pressures (low cardiac output states, pregnancy). Vessels may be damaged by prior episodes of thrombosis, orthopedic surgery, or trauma, Hypercoagulability can be caused by medications (oral contraceptives, hormonal replacement therapy)or disease (malignancy, extensive surgery) or may be
the result of inherited gene defects. The most common inherited cause in populations is resistance to activated protein C, also known as factor V Leiden. Other major risks for hypercoagulability include the following : dificiencies or dysfunction of protein C, protein S, and antithrombin III ; prothrombin gene mutation ; and the presence of antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibody).
Pulmonary thromboembolism has multiple physiologic effects. Physical obstruction of the vascular bed and vasoconstriction from neurohumoral reflexes both increase pulmonary vascular resistance. Massive thrombus may cause right ventricular failure. Vascular obstruction increases physiologic dead space (wasted ventilation) and leads to hypoxemia through right -to- left shunting, decreased cardiac output, and surfactant depletion causing atelectasis. Reflex bronchoconstriction promotes wheezing and increased work of breathing .
Clinical Findings
A . SYMPTOMS AND SIGNS
The clinical diagnosis of pulmonary thromboembolism is notoriously difficult for two reasons. First, the clinical findings depend on both the size of the embolus and the patient's preexisting cardiopulmonary status. Second common symptoms and signs of pulmonary emboli are not specific to this disorder.
Indeed, no single symptom or sign or combination of clinical findings is specific to pulmonary thromboembolism . Some findings are fairly sensitive: dyspnea and pain on inspiration occur in 75-85 % and 65-75 % of patients, respectively . Tachypnea is the only sign reliably found in more than half of patients A common clinical strategy is to use combinations of clinical findings to identify patients at low risk for pulmonary thromboembolism . For example, 97% of patients in the Prospective Investigation of
Pulmonary Embolism Diagnosis (PIOPED) study with angiographically proved pulmonary emboli had one or more of three findings : dyspnea,chest pain with breathing, or tachypnea.
B . LABORATORY FINDINGS
The ECG is abnormal in 70% of patients with pulmonary thromboembolism . However, the most common abnormalities are sinus tachycardia and nonspecific ST and T wave changes, each seen in approximately 40% of patients . Five percent or less of patients in the PIOPED study had P pulmonale, right ventricular hypertrophy, right axis deviation, and right bundle branch block.
Arterial blood gases usually reveal acute respiratory alkalosis due to hyperventilation. the arterial po2 and the alveolar- arterial oxygen difference (A-a DO2) are most often abnormal in patients with pulmonary thromboembolism compared with healthy, agematched controls .
Plasma levels of D-dimer, a degradation product of cross- linked fibrin, are elevated in the presence of thrombus. Using a D-dimer threshold between 300 and 500 ng/mL, the quantitative enzyme-linked immunosorbent assay (ELISA) has shown a sensitivity for venous thromboembolism of 97% and a specificity of 45% . Therefore, the absence of D-dimer using the ELISA assay provides strong evidence against venous thromboembolism .
C . IMAGING AND SPECIAL EXAMINATIONS :
1- Chest radiography The chest radiograph is necessary to exclude other common lung diseases and to permit interpretation of the ventilation - perfusion scan, but it does not establish the diagnosis by itself. The chest radiograph was normal in only 12% of patients with confirmed pulmonary thromboembolism in the PIOPED study .The most frequent findings were atelectasis, parenchymal infiltrates, and pleural
effusions. A prominent central pulmonary artery with local oligemia (Westermark's sign) or pleural based areas of increased opacity that represent intraparenchymal hemorrhage (Hampton's hump) are uncommon . Paradoxically, the chest radiograph may be most helpful when normal in the setting of hypoxemia.
2-Lung scanning A perfusion scan is performed by injecting radiolabeled microaggregated albumin into the venous system, allowing the particles to embolize to the pulmonary capillary bed. To perform a ventilation scan, the patient breathes a radioactive gas or aerosol while the distribution of radioactivity in the lungs is recorded.
3- CT - Spiral CT angiography requires administration of intravenous radiocontrast dye but is otherwise noninvasive . It is very sensitive for the detection of thrombus in the proximal pulmonary arteries but less so in the segmental and subsegmental arteries . Test results very widely by study and facility. Factors influencing results include patient size and cooperation, the quality of the scanner, the imaging protocol, and the experience of the radiologist
4- Venous thrombosis studies - Seventy percent of patients with pulmonary thromboembolism will have deep venous thrombosis on evaluation,and approximately half of patients with DVT will have pulmonary thromboembolism on angiography . Since the history and physical examination are neither sensitive nor specific for pulmonary thromboembolism and since the results of V/Q scanning are frequently equivocal, documentation of DVT in a patient with suspected pulmonary thromboembolism establishes the need for treatment and may preclude pulmonary angiography . Commonly available diagnostic techniques include venous ultrasonography, impedance
plethysmography, and contrast venography . In most centers, venous ultrasonography is the test of choice to detect proximal DVT .
Contrast venography remains the reference standard for the diagnosis of DVT . An intraluminal filling defect is diagnostic of venous thrombosis. However, venography has significant shortcomings and has been replced by venous ultrasound as the diagnostic procedure of choice.Difficulties include patient discomfort, expense, allergic reactions to radiocontrast media, contrast induced phlebitis, and technical Difficulties in cannulation of dorsal foot veins and in the interpretation of studies . There is a significant (2-4 %) risk of developing venous thrombosis from the procedure a risk that may be higher than the false negative rate of noninvasive studies . Venography is used principally in complex situations where there is discrepancy between clinical suspicion and noninvasive testing .
5-Pulmonary angiography Pulmonary angiography remains the reference standard for the diagnosis of pulmonary thromboembolism . An intraluminal filling defect in more than one projection establishes a definitive diagnosis. Secondary findings highly suggestive of pulmonary thromboembolism include abrupt arterial cutoff, asymmetry of blood flow especially segmental oligemia or a prolonged arterial phase with slow filling .
Pulmonary angiography is a safe but invasive procedure with well defined morbidity and mortality. Minor complications occur in approximately 5% of patients. Most are allergic contrast reactions, transient renal dysfunction, or related to percutaneous catheter insertion; cardiac perforation and arrhythmias are reported but rare.
6- MRI - MRI has sensitivity and specificity equivalent to contrast venography in the diagnosis of deep venous thrombosis . It has improved specificity when compared with venous ultrasound in the diagnosis of DVT, without loss of specificity . The test is noninvasive and avoids the use of potentially nephrotoxic radiocontrast dye. However, it remains expensive and not widely available. Artifacts introduced by respiratory and cardiac motion have limited the use of MRI in the diagnosis of pulmonary thromboembolism . New techniques have improved sensitivity and specificity to levels comparable with spiral CT, but MRI remains primarily a research tool for pulmonary thromboembolism .
Prevention
Venous thromboembolism is often clinically silent until it presents with significant morbidity or mortality. It is a prevalent disease, clearly associated with identifiable risk factors . For example, the incidence of proximal DVT, pulmonary thromboembolism, and fatal pulmonary thromboembolism in untreated patients undergoing hip fracture surgery is reported to be 10- 20% , 4- 10%, and 0.2- 5%, respectively . There is unambiguous evidence of the efficacy of prophylactic therapy in this and other clinical situations, yet it remains underused . Only about 50% of surgical deaths
from pulmonary thromboembolism had received any form of preventive therapy.
Options for therapy begin with mechanical such
as graduated compression stockings and intermittent pneumatic compression . The latter improves venous return and may increase endogenous fibrinolysis by stimulating the vascular endothelium . Standard pharmacologic therapy in medical patients is low dose unfractionated heparin, 500 units subcutaneously every 8-12 hours .Low molecular weight heparins are more expensive but have several advantages compared with unfractionated heparin : better bioavailability, once or twice daily dosing, and a lower incidence of heparin associated thrombocytopenia . In high risk surgical patients, low molecular weight heparins can be administered without the need for coagulation monitoring and dose adjustments, as would be the case with unfractionated heparin.
Treatment
A-ANTICOAGULATION
Anticoagulation is not definitive therapy but a form of secondary prevention . Heparin binds to and accelerates the ability of antithrombin Ⅲ to inactivate thrombin, factor Xa, and factor ⅠXa. It thus retards additional thrombus formation, allowing endogenous fibrinolytic mechanisms to lyse existing clot. The standard regimen of heparin followed by 6 months of oral warfarin results in an 80-90% reduction in the risk of both recurrent venous thrombosis and death from pulmonary thromboembolism .
Heparin has troublesome pharmacokinetics. Its clearance is dose - dependent; it is highly protein bound ; and a minimum or threshold level is necessary to achieve an antithrombotic effect . It is necessary to monitor the activated partial thromboplastin time (aPTT) and adjust dosing to maintain the (aPTT) 1.5-2.5 times control . In patients with a moderate to high clinical likelihood of pulmonary thromboembolism and no contraindications, full anticoagulation with heparin should begin with the diagnostic evaluation. Once the diagnosis of proximal DVT or pulmonary thromboembolism is established, it is critical to ensure adequate therapy. Failure to achieve therapeutic heparin levels within 24 hours is associated with a fivefold - increased risk of clot propagation.
Low molecular weight heparins are depolymerized Preparations of heparin With multiple advantages over unfractionated heparin . They exhibit less binding to cells and proteins and have superior bioavailability, a longer plasma half life, and more predictable dose response characteristics.They appear to carry an equivalent or lower risk of hemorrhage, and immune mediated thrombocytopenia is less common . LMW heparins appear to be at least as effective as unfractionated heparin in the treatment of venous thromboembolism . They are administered in dosages determined by body weight once or twice daily without the need for coagulation monitoring, and subcutaneous administration appears to be as effective as the intravenous route. This profile makes LMW heparins ideal for home- based therapy of venous
thromboembolism . Home - based therapy appears safe and efficacious in a small number of selected patients.
Anticoagulation therapy for venous thromboembolism is continued for a minimum of 3 months, so oral anticoagulant therapy with warfarin is usually initiated concurrently with heparin. Warfarin affects hepatic synthesis of vitamin K - dependent coagulant proteins . It usually requires 5-7 days to become therapeutic ; therefore, heparin is generally continued for 5 days . Warfarin is safe if begun concurrently with heparin, initially at a dose of 5-10 mg/d. The lower dose is preferred in older patients . Maintenance therapy usually requires 2-15 mg/d. Adequacy of therapy must be monitored by following the prothrombin time, most often adjusted for differences in reagents and reported as the international normalized ratio, or INR. The target INR is 2.5, with the acceptable range from 2.0 to 3.0 ; belw 2.0, there is an increased risk of thrombosis; above 4.0, there is an increased risk of hemorrhage.
Table 9 selected low molecular weight heparin anticoagulation regimens.
Modified and reproduced with permission, from Hyers TM et al:
Antithrombotic therapy for venous thromboembolic disease.
Chest 2001; 119(suppl) 176S.
Dose expressed in anti-Xa units; for enoxaparin, 1 mg = 100 anti-Xa units . All doses are to be administered subcutaneously.
The major complication of anticoagulation is hemorrhage . Risk factors for hemorrhage include the intensity of the anticoagulant effect; the duration of therapy; concomitant administration of drugs such as aspirin that interfere with platelet function; and patient characteristics, particularly increased age, previous gastrointestinal hemorrhage, and coexistent renal insufficiency .
B-THROBOLYTIC THERAPY
Streptokinase, urokinase, and recombinant tissue plasminogen activator (rt-PA; alteplase) increase plasmin levels and thereby directly lyse intravascular
thrombi. In patients with established pulmonary thromboembolism, thrombolytic therapy accelerates resolution of emboli within the first 24 hours compared with standard heparin therapy. This is a consistent finding using angiography, V/Q scanning, echocardiography, and direct measurement of pulmonary artery pressures . However at 1 week and 1 month after diagnosis these agents show no difference in outcome compared with heparin and warfarin.
Current evidence supports thrombolytic therapy for pulmonary thromboembolism in patients at high risk for death in whom the more raped resolution of thrombus may be lifesaving. Such patients are usually hemodynamically unstable despite heparin therapy.
Absolute contraindications to thrombolytic therapy include active internal bleeding and stroke within the past 6 weeks.
C-ADDITIONAL MEASURES
Interruption of the inferior vena cava may be indicated in patients with a major contraindication to anticoagulation who have or are at high risk for development of proximal deep vein thrombosis or pulmonary embolus . Placement of an inferior vena cava filter is also recommended for recurrent thromboembolism despite adequate anticoagulation, for chronic recurrent embolism with pulmonary hypertension, and with the concurrent performance of surgical pulmonary embolectomy or pulmonary thromboendarterectomy .
In rare critically ill patients for whom thrombolytic therapy is contraindicated or unsuccessful, mechanical or surgical extraction of thrombus may be indicated . Pulmonary embolectomy is an emergency procedure of last resort with a very high mortality rate . It is now preformed only in a few specialized centers . Several catheter devices to fragment and extract thrombus through a transvenous approach have been reported in small numbers of patients . Comparative outcomes with surgery, thrombolytic therapy, or heparin have not been studied .
Prognosis
Pulmonary thromboembolism is estimated to cause more than 50,000 deaths annually . In the majority of deaths, Pulmonary thromboembolism is not recognized antemortem or death occurs before specific treatment can be initiated .These statistics highlight the importance of preventive therapy in high risk patients. The outlook for patients with diagnosed and appropriately treated Pulmonary thromboembolism is generally good. Overall prognosis depends on the underlying disease rather than the Pulmonary thromboembolism itself . Death from recurrent thromboemboli is uncommon, occurring in less than 3% of cases. Perfusion defects resolve in most survivors. Approximately 1% of patients develop chronic thromboembolic pulmonary hypertension . Selected patients may benefit from pulmonary endarterectomy