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Pulmonary Embolism - a review by Cal Shipley, M.D.
PULMONARY EMBOLISM
PULMONARY EMBOLISM
The primary function of the human lung is to provide a means for the transfer of oxygen from the air in the bronchial tubes into the bloodstream, and, of equal importance, to allow for the transfer (ventilation) of carbon dioxide from our bloodstream to the bronchial tubes, and then to the atmosphere. This exchange of oxygen and carbon dioxide takes place in the lungs at the physical interface between the bronchial system and the pulmonary blood circulation (or pulmonary arteries).
CARDIOPULMONARY PHYSIOLOGY
The peripheral veins in the human body act as both a reservoir for blood and as conduits to return blood from the limbs and organs to the heart and lungs. Microscopic clots are continually forming in the veins, and then are rapidly dissolved by elements of the coagulation system. Under a variety of abnormal situations, these tiny clots may not dissolve, and instead, become much larger clots. Fragments of these clots can then break off and travel to the heart and lungs. A clot which lodges in the blood circulation (pulmonary arteries) of the lung is known as a pulmonary embolism (plural emboli). An embolism in the lung will cut off blood flow beyond the point where it is lodged. This stops the normal exchange of oxygen and carbon dioxide in the affected artery or arteries. This effect is directly related to the size and or number of clots which enter and lodge in the pulmonary arterial circulation of one or both lungs. A large clot or a large number of smaller clots that embolize may reduce oxygen and carbon dioxide exchange so severely as to lead to death. In addition, embolization may cause severe strain on the right ventricle of the heart. The purpose of the right ventricle is to circulate blood from the right side of the heart, to the lungs, and back to the left side of the heart. Significant obstruction in the pulmonary blood vessels (ie-emboli) may dramatically increase the pressure required for the right ventricle to function, and may lead to heart failure.
Although embolic clots may arise from virtually anywhere in the venous system, the majority form in the veins in the lower limbs, and in particular, in the veins of the calf. Approxiamtely 80% of clots starting in the calf will extend above the knee, but even those clots that remain confined to the calf may cause fatal embolization.
OTHER SOURCES OF EMBOLI
Although blood clots are by far the most common form of embolus, other substances may embolize to the pulmonary circulation, including fat (especially with fracutres of the long bones of the limbs, air (typically related to medical procedures) and amniotic fluid (in pregnant women). Emboli may also arise from such diverse sources as contaminants of intravenous (IV) drug preparations, mercury, barium, broken catheters, parasites, tumor, brain tissue, bullets, cardiac vegetations, marrow, and bile. For the purposes of this discussion, only blood-clot based embolization will be considered further.
RISK FACTORS FOR VENOUS CLOT FORMATION
Significant venous clots may be said to arise from one or more of three causes: 1) decreased blood flow or pooling (stasis) 2) injury to vein walls (endothelial injury) 3) an abnormally increased tendency to form clots (hypercoaguability). These risk factors are known as Virchow’s Triad.
Stasis
Immobility is the most common cause of venous stasis. The vein system in the lower limbs consists of 2 parts; a set of veins located near the surface of the limb (superficial) and a set of veins located toward the center of the limb (deep). There exists also a set of connector veins that join the superficial and deep systems. In a healthy state, venous blood flows from the superficial to the deep system via the connector veins, and from the deep system to the heart and lungs. A system of one way valves located in the connector and deep veins prevents reverse flow. Unlike the flow in arteries, the blood flow in veins is a low-pressure system. Effective movement of venous blood in the lower limb is especially dependent on the repeated contraction and relaxation of the limb muscles. The muscles act as a pumping system to assist the flow of blood upward. Individuals who are bedridden or who suffer from paralysis have impaired flow, with pooling of large amounts of blood in the limb. This pooled blood has a much increased tendency to clot.
Even active individuals may experience venous stasis in the lower limbs as a result of remaining stationary for prolonged periods (ie-overseas airlines flights) with subsequent clot formation and embolization.
Venous Insufficiency
Disease involving the venous valve system may occur as weakness from birth (congenital) or acquired in conditions such as obesity or pregnancy. Malfunctioning valves may lead to much reduced or even reverse blood flow within the venous system, as well as inflammation of the vein walls (venous insufficiency) with resultant blood stasis and clot formation.
Endothelial injury
Surgical procedures are responsible for the majority of clots arising from endothelial injury of the veins. In recent, the incidence of such problems has been dramatically reduced with the use of pre and post surgical blood thinners in higher risk procedures.The dramatic increase in the number of catheter-based procedures in recent years had led to a greater percentage of related venous clots and subsequent pulmonary emboli. Invasive catheter–based procedures both diagnostic (ie-angiogram) and therapeutic (ie-placement of transvenous pacemaker) may lead to endothelial injury, as may the insertion of central venous catheters that are left in place for extended periods of time.
Hypercoaguable states
An abnormally increased tendency to form clots may occur in a large variety of conditions. This leads to a greater risk of venous clot formation and subsequent pulmonary embolization, especially when stasis and/or endothelial injury are also present.Hypercoaguability may occur from blood-based disorders involving abnormally active components of coagulation, or a deficiency of naturally occurring anti-coagulants that maintain the normal balance between clot formation and dissolution. Individuals with non-O blood type have a 2 to 4 times greater risk of venous clot formation than those with O-type blood.Other conditions such as malignancy, AIDS, severe burns, pregnancy, chemotherapy, inflammatory bowel disease, auto-immune diseases such as lupus erythematosis, and the use of estrogen containing medications are all associated with an increased tendency to clot formation.
PULMONARY EMBOLISM – SIGNS AND SYMPTOMS
Despite the fact that pulmonary embolism (PTE) is not a rare occurrence, the presenting signs and symptoms are notoriously variable, and may be so subtle as to preclude consideration of serious disease by the examiner. The two cardinal symptoms that should prompt consideration of PTE are unexplained chest pain and shortness of breath. The classic triad of chest pain, shortness of breath (dyspnea) and blood-tinged cough (hemoptysis) are present in only 20% or proven cases. Misdiagnosis of the condition is therefore very common.
The difficulty of accurate diagnosis is further compounded when affected individuals present with non-typical presentations. Pulmonary embolism may present with abdominal pain, back pain, significant fever, productive cough, asthma-like symptoms, hiccups, rhythm disturbances of the heart, and a variety of other non-specific symptoms.
Further confusing the issue of diagnosis, the chest pain associated with pulmonary embolism may manifest itself in a wide range of locations and qualities. Common presentations include sudden onset of sharp pain aggravated by breathing, mild chest wall tenderness, abdominal or shoulder pain, or even a heavy central chest pressure indistinguishable from heart-based pain due to coronary artery disease (angina pectoris). Affected individuals may have tenderness when pressure is applied topically to the chest wall, mimicking less worrisome conditions of soft tissue inflammation.
SYMPTOMS IN PATIENTS WITH ANGIOGRAPHICALLY PROVEN PULMONARY EMBOLISM
DIAGNOSIS OF PULMONARY EMBOLISM
Diagnosis of pulmonary embolism is said to be made if a definitive test such as pulmonary angiogram or spiral computed tomography scan (CT) is positive. On the other hand, the diagnosis is considered disproven if either of these 2 tests are negative, or if a ventilation-perfusion scan (VQ) shows a low-probability of pulmonary embolism in a scenario where the signs and symptoms present make the diagnosis unlikely. The other side of this coin is that if an individual has signs and symptoms consistent with pulmonary embolism, a low-probability result on a VQ scan does not definitively rule out the diagnosis. Such individuals must have either an angiogram or CT scan to confirm the situation one way or the other.
Ventilation-Perfusion (V/Q) Scanning
The VQ scan is a relatively non-invasive, low risk technique for determining the likelihood of pulmonary embolism. The technique is based on comparisons of gas flow in the bronchial tree (ventilation) to blood flow in the pulmonary arterial system (perfusion). Radioactive markers are injected into the blood stream, and at the same time, a radio marker gas is inhaled. A scanner capable of detecting the concentration of both markers then takes a series of pictures as the markers are distributed through respiration (ventilation) and blood flow. The usefulness of the technique is based on the fact that shortly after an embolism has lodged in the pulmonary circulation, the scanner will detect an area of abnormally low blood perfusion, while ventilation in the corresponding airways remains normal. This finding is known as a ventilation-perfusion “mismatch”, and its presence increases greatly the likelihood of pulmonary embolism.
As time passes form the moment of initial embolization, the perfusion/ventilation mismatch may lessen due to a variety of confounding factors, such as decreased breating due to pain, lung lobe collapse, presence of inflammatory fluid, and spasm of the bronchial tubes. It is critical, therefore, that the VQ scan be done as promptly as possible after the initial onset of symptoms, while the sensitivity of the test is still high.
VQ scanning is at best an imprecise tool for diagnosing pulmonary embolism. Only 40% of individuals with a pulmonary embolism proven on angiography will have a "high probability" VQ scan. To further cloud the issue, many radiologists will provide interpretations such as "moderately high", "indeterminate", "intermediate", "low", "ultra-low", or "near-normal" probability. In fact, the usefulness of VQ scanning is highest if interpretation is limited to one of three possibilities: 1) high probability, 2) non-diagnostic, or 3) normal.
High Probability
85% of individuals with a “high-probability” scan interpretation will have a pulmonary embolism (specificity of 85%) whereas only 40% of individuals with pulmonary embolism proven on angiography will have a high-probability VQ result (sensitivity of 40%). This means that there is a 60% chance that a non-diagnostic or normal scan result will be falsely negative. As a rule of thumb, those individuals with pre-scan clinical findings suspicious for pulmonary embolism, and who also have a high-probability scan result, may be reliably said to have pulmonary embolism.
Non-diagnostic
A non-diagnostic scan interpretation has a sensitivity of pulmonary embolism detection of 42% and a specificity of just 20%, thus, it cannot be used to rule out the diagnosis of pulmonary embolism. Irrespective of the degree of pre-test clinical suspicion for pulmonary embolism, a non-diagnostic scan result is never an acceptable end-point for the workup.
Normal
Normal VQ patterns (no perfusion defects seen) have a specificity of 96%. Therefore, scans interpreted as normal will miss 4% of individuals who actually have a pulmonary embolism. However, if the pre-scan clinical suspicion is low, a normal scan result may reliably be used to rule out the diagnosis and conclude the workup.
Pulmonary Angiography
The detection of pulmonary emboli by injecting radio-opaque dye into the arterial system of the lung is still considered the gold standard for detection of pulmonary embolism. Arteried blocked by emboli show up on angiography as defects where no dye will flow. The technique does have its limitations. Lung tumors and other benign masses may falsely indicate the presence of pulmonary embolism, while smaller emboli in the periphery of the arterial system may not be detected. This technique is also the most “invasive” of studies performed to detect pulmonary embolism , requiring the placement of catheters into the circulatory system, with the risk of hemorrhage or additional clot formation, and the injection of dyes which may cause severe allergic reactions.
Overall, a skillfully administered and interpreted pulmonary angiogram has a detection specificity of virtually 100% when the test is positive, and a sensitivity of greater than 90% in ruling out the diagnosis when the test is negative. For the time being, angiography remains the test of last resort when other assessments fail to conclusively make the diagnosis.
Computed Tomography
The development of the Spiral (or helical) CT Scan has greatly improved the ability of CT scanning to detect pulmonary embolism. This technique permits far more rapid scanning of large areas of the lung after the injection of radio-markers than previously possible. In addition, the arterial anatomy may be specifically reconstructed in post-test images (CTA or CT Angiography). Many centers have stopped doing VQ scans and angiograms in favor of this technique, but to date, many analyses have shown Spiral CT to have a sensitivity of only 52% (ie- may miss the diagnosis 48% of the time) and a specificity of 81% (ie- may indicate the presence of pulmonary embolism falsely 19% of the time). Despite this current situation, as the technology of CT Angiography becomes more sophisticated, it will likely replace VQ scans and conventional dye-based angiograms as the gold standard in detection of pulmonary embolism.
Magnetic Resonance Imaging
Blood flowing in pulmonary vessels has little or no signal intensity on MRI scanning of the lungs. In addition, MRI images are not reliable for distinguishing between decreased blood flow due to pulmonary embolism and other diseases which affect arterial flow. MRI is therefore currently of limited use in the diagnosis of pulmonary embolism, though this is likely to change as the new technique of MRI Angiography is developed.
D-dimer — D-dimer is a degradation product of cross-linked fibrin. It can be detected in serum using a variety of different assays:
•Enzyme-linked immunosorbent assay (ELISA) (results in >8 hrs)
•Quantitative rapid ELISA (results in 30 min)
•Semi-quantitative rapid ELISA (results in 10 min)
•Qualitative rapid ELISA (results in 10 min)
•Quantitative latex agglutination assay (results in 10 to 15 min)
•Semi-quantitative latex agglutination assay (results in 5 min)
•Erythrocyte agglutination assay (SimpliRED) (results in 2 min)
For the quantitative assays, a level >500 ng/mL is usually considered abnormal.
D-dimer assays for the diagnosis of PE have been extensively studied. They are best characterized as having good sensitivity and negative predictive value, but poor specificity and positive predictive value.
Sensitivity — D-dimer levels are abnormal in approximately 95 percent of all patients with PE when measured by ELISA, quantitative rapid ELISA, or semi-quantitative rapid ELISA [31]. This falls to approximately 90 percent when measured by qualitative rapid ELISA or quantitative latex agglutination, 86 percent when measured by semi-quantitative latex agglutination, and 82 percent when measured by erythrocyte agglutination [31]. Among patients who have subsegmental PE, D-dimer levels are abnormal in only 50 percent when measured by quantitative latex agglutination.
Specificity — D-dimer levels are normal in only 40 to 68 percent of patients without PE, regardless of the assay used [31]. This is a consequence of abnormal D-dimer levels being common among hospitalized patients, especially those with malignancy or recent surgery (table 3). The specificity decreases even further in the setting of severe renal dysfunction (ie, GFR <60 mL/min) and/or increased patient age.
Negative predictive value — The ability of a normal or negative D-dimer assay to exclude acute PE depends on both the type of D-dimer assay and the clinical pretest probability that a patient has acute PE. Taken together, the evidence indicates that a D-dimer level <500 ng/mL by quantitative ELISA or semi-quantitative latex agglutination is sufficient to exclude PE in patients with a low or moderate pretest probability of PE. A negative D-dimer by erythrocyte agglutination is only sufficient to exclude PE in patients with a low pretest probability of PE.
Electrocardiogram (EKG) EKG is notoriously unreliable for the diagnosis of pulmonary embolism. The classic findings are related to strain on the right ventricle, and include a tall peaked P wave in lead II (P pulmonale), right axis deviation, right bundle branch block, atrial fibrillation, and the so-called S1-Q3-T3 pattern. While such findings may suggest pulmonary embolism, they have no predictive value. The most common findings on EKG are rapid hear rate and non-specific ST and T wave changes. Only 20% of individuals with proven pulmonary embolism will have the classic EKG findings, and 25% of affected individuals have no changes at all.
Chest x-ray
Chest radiographic findings are both nonspecific and insensitive for the diagnosis of pulmonary embolism. Most individuals with pulmonary embolism have a normla chest x-ray.
Pulse Oximetry
Pulse oximetry (measured as percent of possible oxygen saturation in the blood) has no value in the diagnostic evaluation of pulmonary embolism. Many individuals with a pulmonary embolus will have normal saturation readings, and low readings may be caused by a wide variety of conditions..
TREATMENT
Goals
The goals of treatment are to prevent death in the immediate period after diagnosis, prevent formation of more emboli, and reduce long-term complications.
HEPARIN - STRUCTURE AND ACTION
Anticoagulation
Anticoagulation of the blood has been the mainstay of therapy for pulmonary embolism for many years. Heparin is the most commonly used agent to achieve rapid anticoagulation after diagnosis. Heparin’s action does not dissolve blood clots, but rather, prevents extension of existing clots, and formation of new ones. This gives the body’s naturally occurring “clot busters” a chance to dissolve existing clots and restore blood flow in blocked arteries. The natural process of clot dissolution may take weeks to months to occur, and so it is critical that anticoagulation be continued for several months (usually at least 6 months) after hospital discharge. Outpatient anticoagulation is typically accomplished through the daily administration of an oral anticoagulant, warfarin (coumadin). Heparin treatment is generally continued for several days after the diagnosis of pulmonary embolism, at least until affected individuals are in stable condition, and oral warfarin treatment has begun.
HEPARIN IN PULMONARY EMBOLISM
Fibrinolysis
Fibrinolysis involves the intravenous administration of “clot busting” drugs, in an attempt to dissolve pulmonary emboli in the immediate period after diagnosis. Use of fibrinolytics may cause dangerous bleeding from the brain (intracranial hemorrhage). In view of this, fibrinolytics are generally used only in individuals who have a pulmonary embolism associated with low blood pressure, fainting (syncope), abnormally low blood oxygen levels, or have other evidence of significant cardio-vascular compromise. Studies have consistently demonstrated a marked benefit in reduced death rate and long- term recurrence in those receiving fibrinolytic agents, even in those without evidence of cardio-vascular compromise. By comparison, the increase in death due to intra-cranial bleeding from fibrinolytics is very small. The routine use of fibrinolytics in pulmonary embolism is, however, still controversial, particularly in those who have had an angiogram prior to treatment, where the risk of significant bleeding is tripled.
Embolectomy
The surgical removal of pulmonary emboli is termed embolectomy. This technique was used more frequently in the pre-fibrinolytic era for individuals with massive pulmonary embolism and significant cardio-vascular compromise. Today, embolectomy is reserved for circumstances in which fibrinolytic agents are contra-indicated (ie-history of previous hemorrhagic stroke), when there is not enough time to achieve adequate fibrinolysis, or when fibrinolysis has failed. The risk of death with embolectomy is high – from 25-40%.
General Treatment Measures
Supplemental oxygen, even when measured blood levels are normal, helps by causing expansion of pulmonary blood vessels. Intravenous fluid administration, as well as chemical agents (pressors) to increase blood pressure, can reduce shock in the immediate period after diagnosis of pulmonary embolism. Normalization of systemic blood pressure through such measures, however, should not be confused with restoration of normal heart-lung function, and should never delay the institution of anticoagulation and other more aggressive measures, as previously discussed.
all images and sounds copyright 2011 Trial Image Inc./ Cal Shipley, M.D.