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Diagnosis of venous thrombosis and pulmonary embolism
Diagnosis of Venous Thrombosis Pulmonary Embolism
and
Jack Hirsh, MD
Venous thrombosis and pulmonary embolism are closely related disorders. As many as 70 to 80% of patients with pulmonary embolism have associated proximal deep venous thrombosis. The clinical diagnosis alone of both venous thrombosis and pulmonary embolism is inaccur ate hecause of the insensitivity and nonspecificity of findiis, a problem that also occurs with a variety of other disorders. Invasive, objective tests are still the reference standard, hut they are not always easy to perform, they cannot he used for a conshkable number of very ill patlents, and they create some patient discomfort. There is an increasing trend toward using noninvaslve methods, either alone or in combination. These methods entail less risk, can be performed more quickly and conveniently, and are usually more cost-effective. Practical approaches to diagnosing venous tf~iomhosls and pulmonary embolism in the clinical setting are discussed. (Am J Cardid 1990;65:45C49C)
he common clinical manifestations of deep venous thrombosis are local pain, tenderness and swelling. The differential diagnosis includes the following conditions that may be confused with venous thrombosis: ruptured Baker’s cyst, cellulitis, muscle tear, muscle cramp, hematoma, external compression of the iliac vein, heart failure, varicose veins, leg immobilization, lymphedema, lipedema, self-induced edema and the postphlebitic syndrome. Before 1970, most physicians and hospitals in North America used clinical diagnosis exclusively to make management decisions in patients with suspected venous thrombosis. Data published about 1970 and subsequently have firmly established that the clinical diagnosis of venous thrombosis is inaccurate because clinical findings are both insensitive and nonspecific. Sensitivity is low because many potentially dangerous venous thrombi are nonccclusive and therefore clinically silent. Specificity is low because symptoms and signs of venous thrombosis can all be caused by nonthrombotic disorders. Patients with mild symptoms may have serious venous thrombosis; it is essential that these patients be treated. On the other hand, it is important not to treat patients unnecessarily or to overdiagnose venous thrombosis. In our experience, compatible with that of many others, 70% of patients investigated for clinically suspected venous thrombosis did not have the diagnosis confirmed by objective tests. These patients included many who were told, incorrectly, that they had so-called recurrent intractable thrombosis-a chronic, potentially fatal disease-engendering significant and totally unnecessary anxiety. The careful documentation of symptoms and signs in patients with clinically suspected deep-vein thrombosis, although not helpful in establishing a diagnosis of venous thrombosis in most patients, may nevertheless be valuable for identifying or excluding other disorders that readily lend themselves to clinical diagnosis. But whenever another diagnosis cannot clearly be established by clinical examination, objective tests are necessary to confirm or exclude the diagnosis of venous thrombosis.
T
INVASIVE DIAGNOSIS OF VENOUS THROMBOSIS
From the Hamilton Civic Hospitals Research Centre, and McMaster University, Hamilton, Ontario, Canada. Address for reprints: Jack Hirsh, MD, Hamilton Civic Hospitals Research Centre, Henderson General Division, 11 Concession Street, Hamilton, Ontario L8V 1C3, Canada.
Venography is accepted as the reference standard for diagnosing venous thrombosis. The aim of venography is to outline the deep venous system of the legs by injecting a radiopaque contrast medium into a dorsal foot vein. When good technique is used, ascending venography outlines the entire deep venous system of the lower legs, including the external and common iliac veins in most patients. However, common femoral and iliac venogra-
THE AMERICAN
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A SYMPOSlUM:
THROMBOSlS
AND ANTlTHROMBOTlC
THERAPY--DIRECTION
FOR THE ’90s
combination is as good as that of a negative result in a venogram. Pros Fibrinogen leg scanning detects more than 90% of Diagnostic standard for venous thrombosis acute calf vein thrombi, but detects only between 60 and Outlines entire deep venous system of lower extremities, 80% of proximal vein thrombi, depending on their locaincluding external and common iliac veins tion. Fibrinogen scanning is relatively insensitive in the Cons Invasive upper thigh, and insensitive to venous thrombi in the Requires expertise to administer and interpret pelvis. Fibrinogen scanning should never be used as the Inferior vena cava. internal iliac, and deep femoral vein only diagnostic test because it fails to detect many high not visualized proximal vein thrombi, and also because it may take hours or even days for enough fibrinogen to accumulate in the thrombus to make the test result positive. TABLE II Fibrinogen Leg Scanning Table II summarizes the advantages and disadvantages of fibrinogen scanning in the diagnosis of venous Pros thrombosis. Screens high-risk patients Noninvasive Impedance plethysmography: IPG is a noninvasive Complements IPG in diagnosis exclusion or confirmation method that detects volume changes in the leg when a Detects 90% of acute calf vein thrombi pneumatic thigh cuff is inflated and deflated, resulting Cons in changes in electrical resistance (impedance). These Requires hours or days before definitive result available Insensitive to proximal venous thrombi changes are reduced in patients with obstruction (e.g., Increases the expense thrombosis) of the popliteal or proximal veins. The accuIn,. - :-^^~^^^^^I^*,--^--^~,, racy of IPG is critically dependent on the degree of venous filling during cuff occlusion. Venous filling is improved by prolonging the period of cuff occlusion and by phy may be needed if the external and common iliac using repeated sequential testing. veins are not properly visualized by the ascending techThe IPG test is sensitive and specific for thrombosis of nique or if the inferior vena cava must be outlined. The the popliteal, femoral or iliac vein (proximal veins). Bemost reliable criterion for diagnosing thrombosis is the cause it detects only thrombi that produce obstruction to presence of an intraluminal filling defect that is con- venous outflow, it will not detect calf vein thrombi. It may stant in all x-ray films and is seen in a number of projec- also overlook small, nonocclusive proximal vein thrombi, tions. and may likewise be negative when proximal vein thromVenography is difficult to perform and requires con- bosis is associated with well-developed collaterals. Finalsiderable experience to execute and to interpret. Radiololy, the IPG test does not distinguish between thrombotic gists and clinicians must be sensitive to the pitfalls of this and nonthrombotic obstruction to venous flow. It may technique, and must either repeat venography when tests therefore lead to false-positive results if the patient is are inadequate or base their diagnoses on noninvasive positioned incorrectly or is inadequately relaxed, with tests. constriction of veins by contraction of leg muscles; if Table I summarizes the advantages and disadvan- compression is caused by an extravascular mass; or if tages of venography in the diagnosis of venous thrombovenous outflow is raised by central venous pressure. sis. It is of practical clinical importance to know the frequency with which an abnormal IPG result returns to NONINVASIVE DIAGNOSIS normal, because patients with proximal vein thrombosis OF VENOUS THROMBOSIS frequently have symptoms in the affected leg during or Noninvasive methods for the diagnosis of venous after long-term anticoagulant therapy. The IPG returns thrombosis include: 1251-fibrinogen scanning, impedance to normal by 3 weeks for approximately 30% of patients, plethysmography (IPG), Doppler ultrasonography and by 6 weeks for 50% of patients, at 3 months for 60% of B-mode ultrasonography. patients, at 6 months for 80% and at 12 months for 90%. Fibrinogen scanning: 12SI-fibrinogen leg scanning Because of these findings, we perform baseline IPG for all depends on incorporation of circulating radioiodine-lapatients with proximal vein thrombosis when anticoagubeled fibrinogen into the thrombus. The resulting radio- lant therapy is discontinued. active fibrin is then detected by measuring the increase of Table III summarizes the advantages and disadvanoverlying surface radioactivity with an isotope detector. tages of IPG in the diagnosis of venous thrombosis. Although very limited as a diagnostic test in patients with Doppler URrasonography: Doppler ultrasonograhy clinically suspected thrombosis, fibrinogen scanning can was introduced and developed at about the same time as be used to screen medically and surgically treated pa- IPG, and has similar advantages and limitations. In extients who are at high risk of developing venous thrombopert hands, Doppler ultrasonography is a sensitive methsis. It can also be used to complement IPG in confirming od for detecting proximal vein thrombosis, but it is less or excluding the diagnosis of clinically suspected thromsensitive for detecting calf vein thrombosis. This method bosis. It has been demonstrated that if both the 1251- involves directing a beam of ultrasound energy percutafibrinogen scan and the impedance plethysmogram yield neously at an underlying vein, where it is reflected from negative results, the negative predictive value of that blood cells. If the blood is stationary, no flow sound is TABLE I Venography
46C
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
heard. If the blood particles are moving, the beam is reflected at a changed frequency (the Doppler shift) that is proportional to the velocity of flow and produces an audible signal, or flow sound. This technique can be performed more conveniently and rapidly than IPG and is less expensive. It is almost as sensitive as IPG to symptomatic proximal vein thrombosis, and more sensitive to symptomatic calf vein thrombosis than IPG, detecting about 50% of such thrombosis. It can be used for patients who have their legs in plaster casts or who are in traction. Interpretation of results is subjective, however, and requires considerable skill and experience. Table IV summarizes the advantages and disadvantages of Doppler ultrasonography in the diagnosis of venous thrombosis. B-mode ultrasonography: B-mode ultrasonography, or duplex scanning, is a recently introduced, very promising diagnostic procedure that is being used with increasing frequency in the diagnosis of venous thrombosis. Bmode ultrasonography is performed using a high-resolution, real-time ultrasound scanner equipped with a ~-MHZ electronically focused linear-array transducer. The common femoral vein is localized in the groin with the patient in the supine position. Visualization of both the femoral artery and vein is necessary. If only the artery is seen, the patient performs a Valsalva maneuver in order to obtain visualization of the vein. The presence or absence of an intraluminal echogenic band and the percentage change in vein diameter during the Valsalva maneuver can also be assessed.The femoral vein is visualized in cross section and longitudinally. The popliteal vein is localized in the popliteal fossa with the patient in the prone position. The compressibility of the vein being examined is assessed by compressing the vein with the transducer probe and observing the effect on the monitor. The result is scored either as noncompressible, or if no residual lumen is observed, as fully compressible. Single-hand firm compression with the transducer probe is sufficient to evaluate noncompressibility. Hard copies can be obtained from the freeze-frame image of both stages of the procedure. Like IPG and Doppler ultrasonography, B-mode ultrasonography is highly sensitive and specific for proximal vein thrombosis, but of limited sensitivity in the detection of calf vein thrombosis. Other noninvasive tests: Less common techniques used to diagnose venous thrombosis (which have not been as thoroughly evaluated) include strain-gauge plethysmography and thermography. Blood tests that reflect intravascular fibrin formation and fibrin proteolysis are currently being evaluated. SERIAL IMPEDANCE
PLETHYSMOGRAPHY
A practical noninvasive approach to diagnosing clinically suspected venous thrombosis is based on serial IPG. It is likely that B-mode ultrasonograhy can be used in the same way. The use of serial IPG alone has been evaluated in a number of prospective studies and has been found to be effective. To date, the effectiveness and safety of
TABLE
III
impedance
Plethysmography
Pros Sensitive and specific for thombosis of popliteal. femoral or iliac proximal veins Useful for monitoring patients after anticoagulant therapy is discontinued Noninvasive Cons Does not detect calf vein or small proximal vein thrombi Does not distinguish between thrombotic and nonthrombotic obstruction False-positive results from incorrect patient position, contracted leg muscles, the presence of extravascular mass, or elevated central venous pressure
TABLE IV
Doppler
Ultrasonography
Pros Sensitive for proximal vein thrombosis Noninvasive, rapid, inexpensive Easily performed 50% sensitive to symptomatic calf vein thrombosis Cons Interpretation subjective and requires expertise
Doppler ultrasonography alone, and of B-mode ultrasonograhy, have not been formally evaluated. Repeated studies have demonstrated that untreated symptomatic calf vein thrombi only very rarely cause serious thromboembolic events if the thrombus does not extend from the calf. But the thrombus does extend in about 20 to 30% of patients with symptomatic calf vein thrombosis, usually within about 7 days of the thrombus onset. Repeated IPG is based on this confirmed observation that calf vein thrombi are clinically important only when they extend into the proximal veins, at which point detection with IPG becomes possible. By performing repeated IPG examinations of patients with clinically suspected venous thrombosis, it is possible to identify patients with extending calf vein thrombosis who can be appropriately treated. An algorithm (Fig. 1) for the noninvasive diagnosis of clinically suspected venous thrombosis is as follows: IPG (or B-mode ultrasonograhy) is performed when the patient is referred; if the IPG result is positive, and in the absence of clinical conditions that are known to produce false-positive results, the diagnosis of venous thrombosis is established, and the patient is treated accordingly. If the result of the initial test is negative, anticoagulant therapy is withheld and the test is repeated the following day, again on day 5, and on days 10 to 14. If the impedance plethysmogram or B-mode ultrasonogram yields positive results during this time, a diagnosis of venous thrombosis is made, and anticoagulant therapy is begun. A positive impedance plethysmogram result in the presence of conditions known to produce a false-positive result (e.g. congestive heart failure) should be confirmed by venography. If noninvasive tests are not available, a clinical suspicion of venous thrombosis should be objectively confirmed or excluded by performing ascending venography.
THE AMERICAN
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A SYMPOSIUM:
YRROMROSIS AND ANllTHROMROTlC
A Practical Diagnostic Venous Thrombosis
TRERAPY-DIRECTIOR
Algorithm:
Impedance Plethysmography (IPG) (or B-mode Ultrasonography) I 4 Positive
4 Negative Repeat
4 Negative
Remains Cllnlcslly Deep Thrombosis
4 IPG (cr E-Mode
4 Treatment
scan)
Becomes
4
Positive
4 Treatment
4 Slgnlflcent Venous Excluded
FlGURE1.Allalgdthmforthenoninvtive~ofdEnl-
cdysuspecWvenour~s,usinglerialimpedance WW=WV&Y or B-mode *m&y.
PULMONARY EMBOLISM Pulmonary embolism is a common complication of deep venous thrombosis of the legs. As many as 70 to 80% of patients with pulmonary embolism have leg vein thrombosis by venography at the time of clinical presentation. The clinical diagnosis of pulmonary embolism is as nonspecific as the clinical diagnosis of venous thrombosis, because all the symptoms and signs of pulmonary embolism can be caused by other cardiorespiratory disorders. More than half of all patients with clinically suspected pulmonary embolism do not have this diagnosis confirmed by objective testing. Arterial blood gas measurements are almost as nonspecific as clinical diagnosis and should not be used to make a diagnosis of pulmonary embolism. In addition, normal Pa02 (>80 mm Hg) does not exclude the possibility of an embolism. The radiologic findings associated with pulmonary embolism are also nonspecific and may show no abnormality. However, the chest x-ray may reveal other causes
A Practical
Diagnostic Chest
Algorithm:
x-ray,
ECG,
Physical
Pulmonary
FOR THE ’90s
of the patient’s condition (e.g., pneumothorax), and it is also required for interpretation of the lung-scan findings. An electrocardiogram may be useful in differentiating between pulmonary embolism and myocardial infarction, but the electrocardiogram is frequently normal or nonspecific. The time-honored findings of right-axis shift and the Sr, Qs, T3 pattern are uncommon and also nonspecific. Lung scanning is extremely useful-when the result is normal-to exclude a diagnosis of pulmonary embolism. When there is a large ventilation-perfusion mismatch, lung scanning can be used to diagnose pulmonary embolism. Other lung-scan findings do not have sufficiently high or low predictive power either to rule out or to rule in pulmonary embolism, and a diagnosis of pulmonary embolism requires pulmonary angiography to confirm it. Objective tests for venous thrombosis are also useful because, as mentioned earlier, most pulmonary emboli are associated with deep-vein thrombosis of the legs. Most pulmonary emboli are clinically silent. When manifested, their signs and symptoms include transient dyspnea and tachypnea, and the syndrome of pulmonary infarction or congestive atelectasis (also known as ischemit pneumonitis or incomplete infarction), which is associated with pleuritic chest pain, cough, hemoptysis, pleural effusion and pulmonary infiltrates on chest x-ray. Other clinical manifestations of pulmonary emboli can include right-sided cardiac failure associated with severe dyspnea and tachypnea; cardiovascular collapse with hypotension, syncope and coma; and various less common and less specific clinical features, including confusion and coma, pyrexia, wheezing, resistant heart failure and unexplained arrhythmia. The differential diagnosis of shortness of breath includes atelectasis, pneumothorax, pneumonia, acute bronchitis, acute bronchiolitis, and acute bronchial obstruction due to mucus plugging, bronchoconstriction or acute pulmonary edema. Pleuritic-type chest pain may be a prominent feature of musculoskeletal abnormalities of the chest wall, in-
Embolism
exam
+ Compatible PE t
Negative
t
with
Perfusion
PE
scan
+
Positive
excluded
FlGURE2.Ahgmmticdgoithmforthe Perfusion defect segmental or greater
Perfusion defect subsegmental/or indeterminate scan
Ventilation
Venography
t Mismatch (ventilation/ perfusion)
scan Match (ventilation/ perfusion)
+ Diagnostic
48c
THE AMERICAN
4 PE
JOURNAL
Further
t Posltlve
Negative
+ Begin treatment
4 Pulmonary angiography
tests
OF CARDIOLOGY
or IPG
VOLUME
65
-ofcpnicrly-pulno-
nmyembdlsm.ECG=~m;
eluding fractured ribs, myositis, muscle strain, and occasionally acute pericarditis. Hemoptysis associated with pulmonary embolism must be differentiated from hemoptysis caused by bronchitis, bronchogenic carcinoma, tuberculosis, mitral stenosis, bronchial adenoma and bronchiectasis. If acute right ventricular heart failure complicates pulmonary embolism, it is almost always associated with severe dyspnea and tachypnea. These features can also be due to acute pulmonary hypertension, which complicates left ventricular failure, acute infection in patients with severe chronic obstructive lung disease, and pulmonary emboli of nonthrombotic origin. Acute pulmonary hypertension can complicate mitral stenosis or acute left ventricular failure, which is most frequently caused by acute myocardial infarction. In patients with chronic obstructive lung disease, acute pulmonary hypertension, severe dyspnea and right-sided cardiac failure may develop when the course of their illness is complicated by acute chest infection. Finally, myocardial infarction complicated by cardiogenie shock, acute pericardial tamponade, acute massive blood loss and gram-negative septicemia may be confused with massive embolism. PULMONARY ANGIOGRAPHY Pulmonary angiography is the reference standard for establishing the presence or absence of pulmonary embolism. The diagnostic resolution of pulmonary angiography is improved, and the risk of the procedure is reduced by using selective angiography and magnification views. A well performed pulmonary angiogram that has negative results excludes a diagnosis of pulmonary embolism. Selective pulmonary angiography is a safe technique as long as patients do not have severe chronic hypertension or severe cardiac or respiratory decompensation. Approximately 20% of patients with clinically suspected pulmonary embolism and abnormal perfusion lung-scan findings cannot undergo pulmonary angiography because of the severity of their primary illness. Because of the limitations of pulmonary angiography, extensive efforts have been made to replace this invasive technique with less invasive diagnostic tests. NONINVASIVE DIAGNOSIS OF PULMONARY EMBOLISM Perfusion lung scans and ventilation lung scans are used in the noninvasive diagnosis of pulmonary embolism. To accomplish perfusion lung scanning, particles of human macroaggregated albumin labeled with i3’I are trapped in the pulmonary capillary bed, and their distribution, reflecting the distribution of lung blood flow, is recorded with an external photoscanner. Improvements in instrumentation, particularly the development of the gamma camera, as well as more effective radiopharmaceuticals, have led to wide acceptance of this technique for investigating pulmonary embolism. Although perfusion lung scanning can detect regions
of poor perfusion as small as 2 cm in diameter, an abnormal perfusion scan is nonspecific and cannot identify the cause of the perfusion defect. A number of studies have confirmed the poor specificity of perfusion lung scanning for diagnosing pulmonary embolism. In a recent prospective study of a consecutive series of 305 patients with suspected embolism and abnormal perfusion lung-scan findings, pulmonary embolism was demonstrated by angiography in only 95 of 183 patients (52%)’ Ventilation lung scanning uses either radioactive gases or radioactive aerosols that are inhaled and exhaled by the patient while a gamma camera records the distribution of radioactivity within the alveolar gas exchange units. Ventilation imaging was introduced on the assumption that ventilation is preserved in areas that have reduced perfusion because of pulmonary embolism (ventilation-perfusion mismatch), whereas ventilation is abnormal when perfusion defects occur as a consequence of primary ventilation abnormalities (ventilation-perfusion match). This assumption has recently been shown to be only partly correct. A DIAGNOSTIC ALGORITHM A diagnostic algorithm for the management of clinically suspected pulmonary embolism may be offered (Fig. 2). After the history and physical examination, electrocardiogram, and chest x-ray, all patients should undergo perfusion lung scanning. Finding negative results on a perfusion lung scan rules out clinically significant pulmonary embolism, and anticoagulant therapy is withheld. If the perfusion lung scan shows 1 or more segmental (or greater) perfusion defects, ventilation lung scanning should be performed because the probability of pulmonary embolism is markedly increased if a mismatch is found (positive predictive value, 86%). This provides an end point for begining anticoagulant therapy for most patients. A matched ventilation-perfusion defect does not rule out the possibility of pulmonary embolism, and further objective testing is required for these patients. Similarly, when patients have small perfusion defects (1 or more subsegmental defects), or when patients have indeterminate lung-scan findings (in which the perfusionscan defects correspond to a defect shown on the chest xray), the predictive values obtained from these ventilation-perfusion-scan patterns are neither sufficiently high or low to confirm or exclude pulmonary embolism. For these patients, venography or IPG could be performed as the initial step of the diagnostic workup. If objective testing confirms the presence of deep-vein thrombosis, anticoagulant therapy can begin without the need to perform pulmonary angiography. If results of venography are negative, however, pulmonary angiography is required to confirm the presence or absence of pulmonary embolism. REFERENCES 1. Hull RD, Hirsh J. Carter CJ, et al. Diagnostic value of ventilation-perfusion lung scanning in patients with suspected pulmonary embolism. Chest /985;88: 819-828.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
FEBRUARY
2.1990
49c
and
Jack Hirsh, MD
Venous thrombosis and pulmonary embolism are closely related disorders. As many as 70 to 80% of patients with pulmonary embolism have associated proximal deep venous thrombosis. The clinical diagnosis alone of both venous thrombosis and pulmonary embolism is inaccur ate hecause of the insensitivity and nonspecificity of findiis, a problem that also occurs with a variety of other disorders. Invasive, objective tests are still the reference standard, hut they are not always easy to perform, they cannot he used for a conshkable number of very ill patlents, and they create some patient discomfort. There is an increasing trend toward using noninvaslve methods, either alone or in combination. These methods entail less risk, can be performed more quickly and conveniently, and are usually more cost-effective. Practical approaches to diagnosing venous tf~iomhosls and pulmonary embolism in the clinical setting are discussed. (Am J Cardid 1990;65:45C49C)
he common clinical manifestations of deep venous thrombosis are local pain, tenderness and swelling. The differential diagnosis includes the following conditions that may be confused with venous thrombosis: ruptured Baker’s cyst, cellulitis, muscle tear, muscle cramp, hematoma, external compression of the iliac vein, heart failure, varicose veins, leg immobilization, lymphedema, lipedema, self-induced edema and the postphlebitic syndrome. Before 1970, most physicians and hospitals in North America used clinical diagnosis exclusively to make management decisions in patients with suspected venous thrombosis. Data published about 1970 and subsequently have firmly established that the clinical diagnosis of venous thrombosis is inaccurate because clinical findings are both insensitive and nonspecific. Sensitivity is low because many potentially dangerous venous thrombi are nonccclusive and therefore clinically silent. Specificity is low because symptoms and signs of venous thrombosis can all be caused by nonthrombotic disorders. Patients with mild symptoms may have serious venous thrombosis; it is essential that these patients be treated. On the other hand, it is important not to treat patients unnecessarily or to overdiagnose venous thrombosis. In our experience, compatible with that of many others, 70% of patients investigated for clinically suspected venous thrombosis did not have the diagnosis confirmed by objective tests. These patients included many who were told, incorrectly, that they had so-called recurrent intractable thrombosis-a chronic, potentially fatal disease-engendering significant and totally unnecessary anxiety. The careful documentation of symptoms and signs in patients with clinically suspected deep-vein thrombosis, although not helpful in establishing a diagnosis of venous thrombosis in most patients, may nevertheless be valuable for identifying or excluding other disorders that readily lend themselves to clinical diagnosis. But whenever another diagnosis cannot clearly be established by clinical examination, objective tests are necessary to confirm or exclude the diagnosis of venous thrombosis.
T
INVASIVE DIAGNOSIS OF VENOUS THROMBOSIS
From the Hamilton Civic Hospitals Research Centre, and McMaster University, Hamilton, Ontario, Canada. Address for reprints: Jack Hirsh, MD, Hamilton Civic Hospitals Research Centre, Henderson General Division, 11 Concession Street, Hamilton, Ontario L8V 1C3, Canada.
Venography is accepted as the reference standard for diagnosing venous thrombosis. The aim of venography is to outline the deep venous system of the legs by injecting a radiopaque contrast medium into a dorsal foot vein. When good technique is used, ascending venography outlines the entire deep venous system of the lower legs, including the external and common iliac veins in most patients. However, common femoral and iliac venogra-
THE AMERICAN
JOURNAL
OF CARDIOLOGY
FEBRUARY
2,199O
45c
A SYMPOSlUM:
THROMBOSlS
AND ANTlTHROMBOTlC
THERAPY--DIRECTION
FOR THE ’90s
combination is as good as that of a negative result in a venogram. Pros Fibrinogen leg scanning detects more than 90% of Diagnostic standard for venous thrombosis acute calf vein thrombi, but detects only between 60 and Outlines entire deep venous system of lower extremities, 80% of proximal vein thrombi, depending on their locaincluding external and common iliac veins tion. Fibrinogen scanning is relatively insensitive in the Cons Invasive upper thigh, and insensitive to venous thrombi in the Requires expertise to administer and interpret pelvis. Fibrinogen scanning should never be used as the Inferior vena cava. internal iliac, and deep femoral vein only diagnostic test because it fails to detect many high not visualized proximal vein thrombi, and also because it may take hours or even days for enough fibrinogen to accumulate in the thrombus to make the test result positive. TABLE II Fibrinogen Leg Scanning Table II summarizes the advantages and disadvantages of fibrinogen scanning in the diagnosis of venous Pros thrombosis. Screens high-risk patients Noninvasive Impedance plethysmography: IPG is a noninvasive Complements IPG in diagnosis exclusion or confirmation method that detects volume changes in the leg when a Detects 90% of acute calf vein thrombi pneumatic thigh cuff is inflated and deflated, resulting Cons in changes in electrical resistance (impedance). These Requires hours or days before definitive result available Insensitive to proximal venous thrombi changes are reduced in patients with obstruction (e.g., Increases the expense thrombosis) of the popliteal or proximal veins. The accuIn,. - :-^^~^^^^^I^*,--^--^~,, racy of IPG is critically dependent on the degree of venous filling during cuff occlusion. Venous filling is improved by prolonging the period of cuff occlusion and by phy may be needed if the external and common iliac using repeated sequential testing. veins are not properly visualized by the ascending techThe IPG test is sensitive and specific for thrombosis of nique or if the inferior vena cava must be outlined. The the popliteal, femoral or iliac vein (proximal veins). Bemost reliable criterion for diagnosing thrombosis is the cause it detects only thrombi that produce obstruction to presence of an intraluminal filling defect that is con- venous outflow, it will not detect calf vein thrombi. It may stant in all x-ray films and is seen in a number of projec- also overlook small, nonocclusive proximal vein thrombi, tions. and may likewise be negative when proximal vein thromVenography is difficult to perform and requires con- bosis is associated with well-developed collaterals. Finalsiderable experience to execute and to interpret. Radiololy, the IPG test does not distinguish between thrombotic gists and clinicians must be sensitive to the pitfalls of this and nonthrombotic obstruction to venous flow. It may technique, and must either repeat venography when tests therefore lead to false-positive results if the patient is are inadequate or base their diagnoses on noninvasive positioned incorrectly or is inadequately relaxed, with tests. constriction of veins by contraction of leg muscles; if Table I summarizes the advantages and disadvan- compression is caused by an extravascular mass; or if tages of venography in the diagnosis of venous thrombovenous outflow is raised by central venous pressure. sis. It is of practical clinical importance to know the frequency with which an abnormal IPG result returns to NONINVASIVE DIAGNOSIS normal, because patients with proximal vein thrombosis OF VENOUS THROMBOSIS frequently have symptoms in the affected leg during or Noninvasive methods for the diagnosis of venous after long-term anticoagulant therapy. The IPG returns thrombosis include: 1251-fibrinogen scanning, impedance to normal by 3 weeks for approximately 30% of patients, plethysmography (IPG), Doppler ultrasonography and by 6 weeks for 50% of patients, at 3 months for 60% of B-mode ultrasonography. patients, at 6 months for 80% and at 12 months for 90%. Fibrinogen scanning: 12SI-fibrinogen leg scanning Because of these findings, we perform baseline IPG for all depends on incorporation of circulating radioiodine-lapatients with proximal vein thrombosis when anticoagubeled fibrinogen into the thrombus. The resulting radio- lant therapy is discontinued. active fibrin is then detected by measuring the increase of Table III summarizes the advantages and disadvanoverlying surface radioactivity with an isotope detector. tages of IPG in the diagnosis of venous thrombosis. Although very limited as a diagnostic test in patients with Doppler URrasonography: Doppler ultrasonograhy clinically suspected thrombosis, fibrinogen scanning can was introduced and developed at about the same time as be used to screen medically and surgically treated pa- IPG, and has similar advantages and limitations. In extients who are at high risk of developing venous thrombopert hands, Doppler ultrasonography is a sensitive methsis. It can also be used to complement IPG in confirming od for detecting proximal vein thrombosis, but it is less or excluding the diagnosis of clinically suspected thromsensitive for detecting calf vein thrombosis. This method bosis. It has been demonstrated that if both the 1251- involves directing a beam of ultrasound energy percutafibrinogen scan and the impedance plethysmogram yield neously at an underlying vein, where it is reflected from negative results, the negative predictive value of that blood cells. If the blood is stationary, no flow sound is TABLE I Venography
46C
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
heard. If the blood particles are moving, the beam is reflected at a changed frequency (the Doppler shift) that is proportional to the velocity of flow and produces an audible signal, or flow sound. This technique can be performed more conveniently and rapidly than IPG and is less expensive. It is almost as sensitive as IPG to symptomatic proximal vein thrombosis, and more sensitive to symptomatic calf vein thrombosis than IPG, detecting about 50% of such thrombosis. It can be used for patients who have their legs in plaster casts or who are in traction. Interpretation of results is subjective, however, and requires considerable skill and experience. Table IV summarizes the advantages and disadvantages of Doppler ultrasonography in the diagnosis of venous thrombosis. B-mode ultrasonography: B-mode ultrasonography, or duplex scanning, is a recently introduced, very promising diagnostic procedure that is being used with increasing frequency in the diagnosis of venous thrombosis. Bmode ultrasonography is performed using a high-resolution, real-time ultrasound scanner equipped with a ~-MHZ electronically focused linear-array transducer. The common femoral vein is localized in the groin with the patient in the supine position. Visualization of both the femoral artery and vein is necessary. If only the artery is seen, the patient performs a Valsalva maneuver in order to obtain visualization of the vein. The presence or absence of an intraluminal echogenic band and the percentage change in vein diameter during the Valsalva maneuver can also be assessed.The femoral vein is visualized in cross section and longitudinally. The popliteal vein is localized in the popliteal fossa with the patient in the prone position. The compressibility of the vein being examined is assessed by compressing the vein with the transducer probe and observing the effect on the monitor. The result is scored either as noncompressible, or if no residual lumen is observed, as fully compressible. Single-hand firm compression with the transducer probe is sufficient to evaluate noncompressibility. Hard copies can be obtained from the freeze-frame image of both stages of the procedure. Like IPG and Doppler ultrasonography, B-mode ultrasonography is highly sensitive and specific for proximal vein thrombosis, but of limited sensitivity in the detection of calf vein thrombosis. Other noninvasive tests: Less common techniques used to diagnose venous thrombosis (which have not been as thoroughly evaluated) include strain-gauge plethysmography and thermography. Blood tests that reflect intravascular fibrin formation and fibrin proteolysis are currently being evaluated. SERIAL IMPEDANCE
PLETHYSMOGRAPHY
A practical noninvasive approach to diagnosing clinically suspected venous thrombosis is based on serial IPG. It is likely that B-mode ultrasonograhy can be used in the same way. The use of serial IPG alone has been evaluated in a number of prospective studies and has been found to be effective. To date, the effectiveness and safety of
TABLE
III
impedance
Plethysmography
Pros Sensitive and specific for thombosis of popliteal. femoral or iliac proximal veins Useful for monitoring patients after anticoagulant therapy is discontinued Noninvasive Cons Does not detect calf vein or small proximal vein thrombi Does not distinguish between thrombotic and nonthrombotic obstruction False-positive results from incorrect patient position, contracted leg muscles, the presence of extravascular mass, or elevated central venous pressure
TABLE IV
Doppler
Ultrasonography
Pros Sensitive for proximal vein thrombosis Noninvasive, rapid, inexpensive Easily performed 50% sensitive to symptomatic calf vein thrombosis Cons Interpretation subjective and requires expertise
Doppler ultrasonography alone, and of B-mode ultrasonograhy, have not been formally evaluated. Repeated studies have demonstrated that untreated symptomatic calf vein thrombi only very rarely cause serious thromboembolic events if the thrombus does not extend from the calf. But the thrombus does extend in about 20 to 30% of patients with symptomatic calf vein thrombosis, usually within about 7 days of the thrombus onset. Repeated IPG is based on this confirmed observation that calf vein thrombi are clinically important only when they extend into the proximal veins, at which point detection with IPG becomes possible. By performing repeated IPG examinations of patients with clinically suspected venous thrombosis, it is possible to identify patients with extending calf vein thrombosis who can be appropriately treated. An algorithm (Fig. 1) for the noninvasive diagnosis of clinically suspected venous thrombosis is as follows: IPG (or B-mode ultrasonograhy) is performed when the patient is referred; if the IPG result is positive, and in the absence of clinical conditions that are known to produce false-positive results, the diagnosis of venous thrombosis is established, and the patient is treated accordingly. If the result of the initial test is negative, anticoagulant therapy is withheld and the test is repeated the following day, again on day 5, and on days 10 to 14. If the impedance plethysmogram or B-mode ultrasonogram yields positive results during this time, a diagnosis of venous thrombosis is made, and anticoagulant therapy is begun. A positive impedance plethysmogram result in the presence of conditions known to produce a false-positive result (e.g. congestive heart failure) should be confirmed by venography. If noninvasive tests are not available, a clinical suspicion of venous thrombosis should be objectively confirmed or excluded by performing ascending venography.
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A SYMPOSIUM:
YRROMROSIS AND ANllTHROMROTlC
A Practical Diagnostic Venous Thrombosis
TRERAPY-DIRECTIOR
Algorithm:
Impedance Plethysmography (IPG) (or B-mode Ultrasonography) I 4 Positive
4 Negative Repeat
4 Negative
Remains Cllnlcslly Deep Thrombosis
4 IPG (cr E-Mode
4 Treatment
scan)
Becomes
4
Positive
4 Treatment
4 Slgnlflcent Venous Excluded
FlGURE1.Allalgdthmforthenoninvtive~ofdEnl-
cdysuspecWvenour~s,usinglerialimpedance WW=WV&Y or B-mode *m&y.
PULMONARY EMBOLISM Pulmonary embolism is a common complication of deep venous thrombosis of the legs. As many as 70 to 80% of patients with pulmonary embolism have leg vein thrombosis by venography at the time of clinical presentation. The clinical diagnosis of pulmonary embolism is as nonspecific as the clinical diagnosis of venous thrombosis, because all the symptoms and signs of pulmonary embolism can be caused by other cardiorespiratory disorders. More than half of all patients with clinically suspected pulmonary embolism do not have this diagnosis confirmed by objective testing. Arterial blood gas measurements are almost as nonspecific as clinical diagnosis and should not be used to make a diagnosis of pulmonary embolism. In addition, normal Pa02 (>80 mm Hg) does not exclude the possibility of an embolism. The radiologic findings associated with pulmonary embolism are also nonspecific and may show no abnormality. However, the chest x-ray may reveal other causes
A Practical
Diagnostic Chest
Algorithm:
x-ray,
ECG,
Physical
Pulmonary
FOR THE ’90s
of the patient’s condition (e.g., pneumothorax), and it is also required for interpretation of the lung-scan findings. An electrocardiogram may be useful in differentiating between pulmonary embolism and myocardial infarction, but the electrocardiogram is frequently normal or nonspecific. The time-honored findings of right-axis shift and the Sr, Qs, T3 pattern are uncommon and also nonspecific. Lung scanning is extremely useful-when the result is normal-to exclude a diagnosis of pulmonary embolism. When there is a large ventilation-perfusion mismatch, lung scanning can be used to diagnose pulmonary embolism. Other lung-scan findings do not have sufficiently high or low predictive power either to rule out or to rule in pulmonary embolism, and a diagnosis of pulmonary embolism requires pulmonary angiography to confirm it. Objective tests for venous thrombosis are also useful because, as mentioned earlier, most pulmonary emboli are associated with deep-vein thrombosis of the legs. Most pulmonary emboli are clinically silent. When manifested, their signs and symptoms include transient dyspnea and tachypnea, and the syndrome of pulmonary infarction or congestive atelectasis (also known as ischemit pneumonitis or incomplete infarction), which is associated with pleuritic chest pain, cough, hemoptysis, pleural effusion and pulmonary infiltrates on chest x-ray. Other clinical manifestations of pulmonary emboli can include right-sided cardiac failure associated with severe dyspnea and tachypnea; cardiovascular collapse with hypotension, syncope and coma; and various less common and less specific clinical features, including confusion and coma, pyrexia, wheezing, resistant heart failure and unexplained arrhythmia. The differential diagnosis of shortness of breath includes atelectasis, pneumothorax, pneumonia, acute bronchitis, acute bronchiolitis, and acute bronchial obstruction due to mucus plugging, bronchoconstriction or acute pulmonary edema. Pleuritic-type chest pain may be a prominent feature of musculoskeletal abnormalities of the chest wall, in-
Embolism
exam
+ Compatible PE t
Negative
t
with
Perfusion
PE
scan
+
Positive
excluded
FlGURE2.Ahgmmticdgoithmforthe Perfusion defect segmental or greater
Perfusion defect subsegmental/or indeterminate scan
Ventilation
Venography
t Mismatch (ventilation/ perfusion)
scan Match (ventilation/ perfusion)
+ Diagnostic
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THE AMERICAN
4 PE
JOURNAL
Further
t Posltlve
Negative
+ Begin treatment
4 Pulmonary angiography
tests
OF CARDIOLOGY
or IPG
VOLUME
65
-ofcpnicrly-pulno-
nmyembdlsm.ECG=~m;
eluding fractured ribs, myositis, muscle strain, and occasionally acute pericarditis. Hemoptysis associated with pulmonary embolism must be differentiated from hemoptysis caused by bronchitis, bronchogenic carcinoma, tuberculosis, mitral stenosis, bronchial adenoma and bronchiectasis. If acute right ventricular heart failure complicates pulmonary embolism, it is almost always associated with severe dyspnea and tachypnea. These features can also be due to acute pulmonary hypertension, which complicates left ventricular failure, acute infection in patients with severe chronic obstructive lung disease, and pulmonary emboli of nonthrombotic origin. Acute pulmonary hypertension can complicate mitral stenosis or acute left ventricular failure, which is most frequently caused by acute myocardial infarction. In patients with chronic obstructive lung disease, acute pulmonary hypertension, severe dyspnea and right-sided cardiac failure may develop when the course of their illness is complicated by acute chest infection. Finally, myocardial infarction complicated by cardiogenie shock, acute pericardial tamponade, acute massive blood loss and gram-negative septicemia may be confused with massive embolism. PULMONARY ANGIOGRAPHY Pulmonary angiography is the reference standard for establishing the presence or absence of pulmonary embolism. The diagnostic resolution of pulmonary angiography is improved, and the risk of the procedure is reduced by using selective angiography and magnification views. A well performed pulmonary angiogram that has negative results excludes a diagnosis of pulmonary embolism. Selective pulmonary angiography is a safe technique as long as patients do not have severe chronic hypertension or severe cardiac or respiratory decompensation. Approximately 20% of patients with clinically suspected pulmonary embolism and abnormal perfusion lung-scan findings cannot undergo pulmonary angiography because of the severity of their primary illness. Because of the limitations of pulmonary angiography, extensive efforts have been made to replace this invasive technique with less invasive diagnostic tests. NONINVASIVE DIAGNOSIS OF PULMONARY EMBOLISM Perfusion lung scans and ventilation lung scans are used in the noninvasive diagnosis of pulmonary embolism. To accomplish perfusion lung scanning, particles of human macroaggregated albumin labeled with i3’I are trapped in the pulmonary capillary bed, and their distribution, reflecting the distribution of lung blood flow, is recorded with an external photoscanner. Improvements in instrumentation, particularly the development of the gamma camera, as well as more effective radiopharmaceuticals, have led to wide acceptance of this technique for investigating pulmonary embolism. Although perfusion lung scanning can detect regions
of poor perfusion as small as 2 cm in diameter, an abnormal perfusion scan is nonspecific and cannot identify the cause of the perfusion defect. A number of studies have confirmed the poor specificity of perfusion lung scanning for diagnosing pulmonary embolism. In a recent prospective study of a consecutive series of 305 patients with suspected embolism and abnormal perfusion lung-scan findings, pulmonary embolism was demonstrated by angiography in only 95 of 183 patients (52%)’ Ventilation lung scanning uses either radioactive gases or radioactive aerosols that are inhaled and exhaled by the patient while a gamma camera records the distribution of radioactivity within the alveolar gas exchange units. Ventilation imaging was introduced on the assumption that ventilation is preserved in areas that have reduced perfusion because of pulmonary embolism (ventilation-perfusion mismatch), whereas ventilation is abnormal when perfusion defects occur as a consequence of primary ventilation abnormalities (ventilation-perfusion match). This assumption has recently been shown to be only partly correct. A DIAGNOSTIC ALGORITHM A diagnostic algorithm for the management of clinically suspected pulmonary embolism may be offered (Fig. 2). After the history and physical examination, electrocardiogram, and chest x-ray, all patients should undergo perfusion lung scanning. Finding negative results on a perfusion lung scan rules out clinically significant pulmonary embolism, and anticoagulant therapy is withheld. If the perfusion lung scan shows 1 or more segmental (or greater) perfusion defects, ventilation lung scanning should be performed because the probability of pulmonary embolism is markedly increased if a mismatch is found (positive predictive value, 86%). This provides an end point for begining anticoagulant therapy for most patients. A matched ventilation-perfusion defect does not rule out the possibility of pulmonary embolism, and further objective testing is required for these patients. Similarly, when patients have small perfusion defects (1 or more subsegmental defects), or when patients have indeterminate lung-scan findings (in which the perfusionscan defects correspond to a defect shown on the chest xray), the predictive values obtained from these ventilation-perfusion-scan patterns are neither sufficiently high or low to confirm or exclude pulmonary embolism. For these patients, venography or IPG could be performed as the initial step of the diagnostic workup. If objective testing confirms the presence of deep-vein thrombosis, anticoagulant therapy can begin without the need to perform pulmonary angiography. If results of venography are negative, however, pulmonary angiography is required to confirm the presence or absence of pulmonary embolism. REFERENCES 1. Hull RD, Hirsh J. Carter CJ, et al. Diagnostic value of ventilation-perfusion lung scanning in patients with suspected pulmonary embolism. Chest /985;88: 819-828.
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