1 pulmonary 0 thromboembolism -...

217 7

Pulmonary ThromboembolismHerbert L. Fred, Shahzad Hashim, and

Fady A. Joudah

ach year in the United States, an estimated 5 million people suffer an episode of venous thrombosis,1 650,000 experience a pulmonary embolic event,2 and as many

as 200,000 of them die.3 Although pulmonary thromboem-bolism (PTE)* occurs in all age groups, most victims are middle-aged or older.4 A concurrent illness usually is present, but PTE can strike seemingly healthy, active persons,5 including children6 and adolescents.7

Risk Factors

Numerous factors—acquired8 and inherited9–12—can predis-pose a person to venous thromboembolism. The acquired factors with strong predictive values are major trauma (espe-cially to the lower extremities and pelvis), major general surgery, hip or knee replacement, and paralytic spinal cord injury.8 Those with moderate predictive values include respi-ratory or congestive heart failure, immobility (from medical illness, surgical procedures, or prolonged sitting), previous venous thromboembolism, malignancy,13 antiphospholipid antibodies,14 central venous lines,15,16 oral contraceptive therapy,17,18 hormone replacement therapy,19 and chemother-apy.20 Those with weak predictive values are obesity, preg-nancy,21,22 use of antipsychotic drugs,23,24 increasing age, varicose veins in the legs, and myeloproliferative disorders.

Of the various inherited factors, mutations in the factor V gene (factor V Leiden) and the prothrombin (factor II) gene are the most common.10 Factor V Leiden is present in about

5% of healthy people of northern European ancestry9 but almost never affects black or Asian people.11 Most carriers of this defect are heterozygous with a relatively low risk for thrombosis.9,12 In the homozygous carriers, however, the risk is signifi cantly higher.25 Other inherited factors—all rare—include increased levels of clotting factors VIII, IX, and XI,9–11 hyperhomocysteinemia,26,27 dysfi brinogenemia, and defi cien-cies of antithrombin III, protein C, and protein S.

Two recently reported fi ndings are noteworthy. Rates of deep vein thrombosis and PTE in Asians/Pacifi c Islanders are markedly lower than in whites and African Americans.28 Explanations for this phenomenon remain speculative.29 Additionally, the use of tamoxifen as prophylaxis against breast cancer carries an increased risk of venous thrombo-embolism.30 The benefi ts of tamoxifen, however, far out-weigh this particular risk.31

Sources of Emboli

For several reasons, statistics vary as to the sites from which pulmonary emboli originate. The mere presence of thrombi in peripheral veins, right atrium, or right ventricle does not prove that these sites are the source of such emboli. Indeed, thrombi sometimes exist in these areas when no pulmonary emboli are evident. Moreover, once a clot becomes detached, its site of origin may appear normal when examined by imaging techniques or at autopsy.

These points aside, most pulmonary emboli arise from veins in the lower extremities32 or pelvis.33 Occasionally, the heart is the source34 (Fig. 104.1C), particularly in patients with septic pulmonary emboli from right-sided endocar-ditis.35 Other sites of origin at times are the inferior vena cava, veins in the upper extremities,36 prostatic venous plexus,37 renal veins,38 and veins of the cerebral sinuses and nasopharynx.6

104

Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2177Sources of Emboli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2177Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2178Radiographic Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . 2179Electrocardiographic Findings . . . . . . . . . . . . . . . . . . . . 2182

Miscellaneous Laboratory Findings . . . . . . . . . . . . . . . . 2183Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2183Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 2185Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2190Course and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 2192

E

* PTE as used here refers to acute or subacute pulmonary throm-boembolism with or without resultant infarction of the lung. The term does not include septic pulmonary embolism or chronic major-vessel pulmonary hypertension.

CAR104.indd 2177CAR104.indd 2177 12/1/2006 9:52:09 AM12/1/2006 9:52:09 AM

217 8 c h a p t e r 10 4

A

C

B

Clinical Features

Manifestations of PTE depend on the number and size of emboli, the presence or absence of infarction, the duration of the thromboembolic process, and the type and severity of associated disease(s). The clinical picture, therefore, varies considerably. Moreover, one cannot consistently judge the seriousness of PTE by the nature of its presentation. A large embolus, for example, may be clinically silent, whereas a small embolus may produce an alarming set of fi ndings. We believe that the best way to understand and remember the protean expressions of PTE is to divide them into two groups:

those occurring before and those appearing after pulmonary infarction develops.

Pulmonary Thromboembolism Without Infarction

Dyspnea without orthopnea is the most common and impor-tant symptom.4 It is often sudden in onset, progressing at times to gasping respirations. Frequently, however, the dyspnea is mild and fl eeting. Chest pain is rare; when present, it is typically dull and retrosternal and usually refl ects occlu-sion of major pulmonary arteries.39–41 Wheezing respirations, ordinarily transient and occasionally recurrent, can be a her-

FIGURE 104.1. A 47-year-old woman with unexplained shortness of breath had a referring diagnosis of Munchausen syndrome. (A) Chest radiograph shows mild cardiomegaly, prominent central pulmonary arteries, and distal oligemia bilaterally. (B) Pulmonary arteriogram demonstrates obstructed blood fl ow to both lungs, especially the lower lobes. (C) Autopsy view of a large thrombus in the right ventri-cle. Numerous old and new thromboemboli were present throughout the pulmonary arterial tree.


p u l mon a ry t h rom b oe m b ol i s m 217 9

alding feature.42 Neurologic abnormalities, such as syncope, convulsions, restlessness, anxiety, stupor, coma, and weak-ness or paralysis of limbs, predominate in about 5% of the cases and may be the fi rst, the most prominent, or the only manifestation.43 Unexplained apprehension and a sense of impending doom are common.44 Rarely, the patient experi-ences a sudden strong urge to defecate or may faint or die during defecation.45

Tachycardia44 and tachypnea46 are frequent and often disproportionately severe. Signs of venous thrombosis in the legs, such as pain, heat, discoloration, or enlargement, develop in less than half of the patients and may not become evident for days or even months after the onset of pulmonary symp-toms.47 Cyanosis may appear when embolism is massive or there is coexisting cardiopulmonary disease, shock, or both. Hypotension is relatively uncommon. Characteristically, it is of short duration, but if persistent, it indicates that the diagnosis is wrong or that embolism is massive. In some cases, sudden, profound, or prolonged shock is the only indi-cation of PTE. Acute cor pulmonale can result from massive PTE and may be accompanied by an accentuated pulmonic valve closure sound, right ventricular gallop rhythm, or increased jugular venous pressure.

One point merits special attention. Signs of PTE without infarction may regress spontaneously just as dramatically as they appear. In these cases, the patient seems well one minute and moribund the next, only to recover rapidly.

Pulmonary Thromboembolism with Infarction

Fewer than 10% of pulmonary thromboemboli lead to infarc-tion of the lung.48 Pleuritic pain emerges in only half of these patients and may be sudden or gradual in onset and mild or severe.49 Hemoptysis occurs in about one third of these patients.4 At fi rst, the expectorant is bright red; it then appears as dark clots, and fi nally as dark brown, semiliquid material. Fever of varying duration and pattern is common.50,51 Temperatures usually range between 100°F and 103°F but can reach 105°F in the absence of demonstrable infection (Fig. 104.2). Cough is uncommon and, when present, is inter-mittent and mild.52 Pleural friction rub, audible in only about one fourth of these patients,49 sometimes precedes radio-graphic evidence of pulmonary infarction. Rales and signs of pleural effusion are common, but classic signs of consolida-tion are rare. Jaundice can develop when the infarction is extensive or when congestive heart failure, hepatic disease, or both are present.53

Radiographic Findings

The radiographic patterns of PTE depend on the size, number, and distribution of the thromboemboli, the preex-isting anatomic and functional status of the heart and lungs, and the frequency with which chest radiographs are obtained. Before frank infarction develops, the chest radiograph typically shows no abnormality. This is true even when one suspects PTE and searches specifi cally for its signs. In some cases, however, one or both main pulmo-nary arteries become enlarged (Figs. 104.1A, 104.3A, and

104.4), with decreased peripheral vascular markings in the affected portions of lung (oligemia) and engorged vessels in the non affected areas (pleonemia) (Fig. 104.4). The hemidia-phragm on the involved side may be elevated consequent to atelectasis.

After infarction develops, the chest radiograph almost always shows some abnormality, typically within 24 hours (Fig. 104.5). Rarely, it takes up to 5 days for an abnormality to appear.54 Any segment of lung may be involved, but the lower lobes, especially the right, are the usual sites.55 Atel-ectasis and small pleural effusions are common, but large pleural effusions, some loculated,56 may also occur. Paren-chymal densities range in size from mere visibility to that of an opacifi ed lobe (Fig. 104.2). Their patterns are so diverse that no shape necessarily suggests or excludes pulmonary infarction. Traditional teaching that the typical radiographic appearance of a pulmonary infarct is that of a “wedge-shaped” shadow has served more to confuse than to facilitate the diagnosis of pulmonary infarction.

The radiographic fi ndings of pulmonary infarction can mimic those of many diseases, especially pulmonary infec-tion.51,56 Sometimes it simulates cancer57 (Fig. 104.6A,C), and, if cavitation occurs, the lesion can be mistaken for pulmo-nary abscess (Fig. 104.2). Infarction involving an upper lobe occasionally masquerades as pulmonary tuberculosis. Septic pulmonary embolism—an infectious process, not an obstruc-tive process—typically appears as small, patchy lesions

FIGURE 104.2. Chest radiograph of a 61-year-old man with chronic heart failure, hemoptysis, fever of 105°F, and a total leukocyte count of 40,000/mm3. Note the cardiomegaly, opacifi ed right lower lobe with an air–fl uid level (arrow), and enlarged right pulmonary artery. Autopsy the next day showed a large thromboembolus occluding the right pulmonary artery with extensive infarction and cavitation of the right lower lobe. There was no evidence of pulmonary infection.


218 0 c h a p t e r 10 4

FIGURE 104.3. A previously healthy 37–year-old man had a sudden syncopal episode followed by persistent dyspnea. Six hours later, he died. (A) Chest radiograph shows prominence of the central pulmo-nary arteries with abrupt tapering of the lower lobe branches and possible enlargement of the pulmonary outfl ow tract and right

atrium. (B) Electrocardiogram demonstrates sinus tachycardia, pro-longed QT interval, and anterior T-wave changes consistent with ischemia or acute right heart strain. Autopsy disclosed a saddle embolus at the bifurcation of the pulmonary arterial trunk extend-ing into and obstructing the right and left pulmonary arteries.

A

I

II

III

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

B

A BFIGURE 104.4. A 66-year-old woman had rapidly progressive short-ness of breath initially attributed to cardiac failure. (A) Chest radio-graph at the onset of symptoms shows slight prominence of the right hilar vessels. (B) Repeat study 1 month later demonstrates marked

enlargement of the central pulmonary arteries, oligemia of the right lung, and relative pleonemia of the left lung. At autopsy, large thromboemboli completely occluded the right pulmonary artery and severely obstructed the left pulmonary artery.


p u l mon a ry t h rom b oe m b ol i s m 2181

A B C

FIGURE 104.5. Serial chest radiographs of a 33-year-old woman who had severe right upper quadrant pain 3 weeks after undergoing a hysterectomy. The admitting diagnosis was acute cholecystitis.

On the second hospital day, pulmonary arteriography showed com-plete obstruction of the arteries supplying the right middle and lower lobes.

A B

C

FIGURE 104.6. A 68-year-old man had congestive heart failure, hemoptysis, and a right hilar mass thought to be bronchogenic car-cinoma. (A) Chest radiograph shows cardiomegaly, density in the right hilar region, and patchy infi ltrates in the right lower lobe. (B) Selective pulmonary arteriogram demonstrates complete obstruc-tion of the arteries to the middle and lower lobes. (C) Sagittal section of the right lung shows an organized thrombus extending 8 cm from the hilum, totally occluding the right middle and lower lobe arteries, and accounting for the hilar mass seen on the chest radiograph.


218 2 c h a p t e r 10 4

(frequently cavitary) scattered throughout the lungs, often mimicking metastases or tuberculosis.35

Chronic major vessel thromboembolic pulmonary hyper-tension usually results in clear lung fi elds. In some patients, however, the right atrium and right ventricle are dilated, with enlargement or asymmetry of the central pulmonary arteries.58

Electrocardiographic Findings

Electrocardiographic abnormalities are commonly absent and always nonspecifi c. Moreover, preexisting cardiac or pul-monary disease can modify or prevent the changes that might otherwise suggest PTE. When abnormalities do appear (Table 104.1), they are often fl eeting and may go undetected unless multiple tracings are made within a short time. The transient nature of these alterations is characteristic, however, and serves as an important clue to PTE. Sinus or supraventricular tachycardias, ST-segment and T-wave changes in the right precordial leads, and right bundle branch block are the most frequent electrocardiographic abnormali-ties (Figs. 104.3B, 104.7A, and 104.8A). But even when the embolism is acute and massive, the electrocardiogram may show no signs of right ventricular strain.59 In that regard, a Qr in lead V1 is closely related to right ventricular dysfunction.60

In patients who have obliterative pulmonary hyperten-sion from recurrent small pulmonary emboli61 or from chronic major vessel pulmonary thromboemboli,58 the elec-trocardiogram may be normal or may show right-axis deviation, P pulmonale, or a pattern of right ventricular hypertrophy and strain.

TABLE 104.1. Electrocardiographic fi ndings in pulmonary thromboembolism*

No change at allSinus tachycardiaS1–Q3 patternS1, S2, S3 patternAppearance of right-axis deviation and change to a vertical heart positionST-segment depression in leads II, III, aVF, and occasionally, in I and left precordial leadsFlat or inverted T waves in leads II, III, aVF, and occasionally, in I and left precordial leadsPeaked P waves in leads II, III, and aVFDevelopment of extreme clockwise rotation of the heartAppearance of right bundle branch block or right ventricular enlargement patternsInverted T waves with ST-segment deviations in the right precordial leadsQr in lead V1

Development of various types of transient supraventricular and, rarely, ventricular tachycardiasCombinations of these

* Not listed in order of frequency or importance.

I

II

III

V1A

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

B

LA

RA

T

S

C

ct angiogram--pulmonary artery

R

135

FIGURE 104.7. A 31-year-old diabetic woman with a painful, swollen right leg suddenly became dyspneic. A V/Q lung scan showed intermediate probability for pulmonary thromboembolism. Ultrasonography demonstrated clots in the right common femoral and popliteal veins. (A) Electrocardiogram shows accelerated nodal tachycardia with retrograde P waves, right bundle branch block, pathologic anteroseptal Q waves, and an S1-Q3-T3 pattern—fi ndings consistent with severe pulmonary hypertension. (B) Transesopha-geal echocardiogram, short-axis view (20 degrees), shows a large, lobulated opacity in the right atrium (RA) suggestive of a thrombus (T). LA, left atrium; S, atrial septum. (C) Contrast-enhanced spiral computed tomographic scan shows a large fi lling defect (arrows) in the bifurcation of the pulmonary arterial trunk. The patient died just as thrombolytic therapy was being initiated.



normal value (<500 µg/L), however, makes PTE,73–76 as well as deep vein thrombosis,77–80 most unlikely.

Blood levels of troponin and brain natriuretic peptide correlate closely with right ventricular function.81–83 In that light, normal values of these biomarkers suggest normal right ventricular function and predict good patient outcome.81,84,85 Elevated levels, however, signal right ventric-ular impairment for which echocardiographic evaluation should be considered.86,87

Diagnosis

Constant awareness of PTE is the key to early diagnosis. If one waits for hemoptysis, pleural friction rub, signs of venous disease in the legs, pulmonary parenchymal infi ltrates, or abnormal electrocardiographic patterns to develop, most cases will escape recognition. By contrast, the diagnosis should never be doubted or rejected simply because of high fever, leukocytosis, normal jugular venous pressure, normal arterial blood gas analysis, “atypical” pulmonary lesions, or failure to detect the source of emboli.

DEC 19 DEC 29

I V1

V2

V3

V4

V5

V6

II

III

aVR

aVL

aVF

I V1

V2

V3

V4

V5

V6

II

III

aVR

aVL

aVF

AFIGURE 104.8. (A) Electrocardiograms of a 55-year-old man who underwent surgical correction of sigmoid volvulus. Left: The preop-erative tracing was within normal limits. Right: On the ninth post-operative day, the patient abruptly became dyspneic, tachypneic, cyanotic, and hypotensive. A tracing made at that time showed a marked shift in the QRS electrical axis to the right. These clinical

and electrocardiographic changes prompted an erroneous diagnosis of massive pulmonary thromboembolism. Several hours later, the patient died. (B) Autopsy view of the patient’s intestines shows purulent peritonitis that resulted from disruption of the colon at the site of operative repair. There were no pulmonary thromboemboli.

B

Miscellaneous Laboratory Findings

Results of routine laboratory tests in patients with PTE are nonspecifi c. The total leukocyte count usually is normal or slightly elevated62; however, in the presence of massive, bland necrosis of pulmonary tissue, it may reach 40,000/mm3 (Fig. 104.2). The sputum, if examined soon after infarction devel-ops, commonly shows many erythrocytes but few leukocytes or organisms. Pleural fl uid, when present, is bloody in 50%49 to 65%63 of the cases and may be a transudate or an exudate.63

Arterial blood gas analysis often shows hypoxemia, hypo-carbia, respiratory alkalosis, and an increase in the P(A − a)O2 gradient.64–66 Yet up to a fourth of patients with documented PTE do not have hypoxemia while breathing room air,65–67 and an increase in the P(A − a)O2 gradient can occur in condi-tions other than PTE.66,67 Hence, a normal blood gas analysis does not exclude PTE,68 and abnormal results, in and of themselves, do not appreciably increase the likelihood of PTE.69

Plasma levels of D-dimer, a degradation product of cross-linked fi brin, are nearly always increased with PTE.70 But this increase can occur in a wide variety of settings.71–73 A


218 4 c h a p t e r 10 4

Findings that should alert the physician to the possibility of PTE are fever of unknown origin and fever that does not respond to antibiotic therapy (especially in patients who have congestive heart failure or in those who are postpartum or postsurgical); congestive heart failure that increases rapidly in severity or is unresponsive to the usual therapeutic mea-sures; dyspnea or wheezing of unknown cause; paroxysmal arrhythmias; unexplained sinus tachycardia; appearance of an “abscess” on chest radiograph; bloody pleural effusion; and sudden, profound, or prolonged shock.

If initial studies are inconclusive and the suspicion for PTE remains, additional testing is indicated. In this circum-stance, physicians traditionally have turned to the ventila-tion/perfusion (V/Q) lung scan.88–93 Perfusion scans image the distribution of intravenously injected macroaggregates of albumin labeled with technetium-99m (99mTc). Distribution of these macroaggregates in a segment of lung is proportional to the relative pulmonary blood fl ow to that segment.

Ventilation scans involve the inhalation and washout of a tracer, usually xenon-133 (133Xe) gas. This technique deter-mines regional pulmonary ventilation. Reduction of both ventilation and perfusion generally implies parenchymal or bronchial disease,94 whereas ventilation without perfusion points to pulmonary vascular obstruction.95

A normal lung scan is as reliable as a normal pulmonary arteriogram in ruling out PTE.90,96,97 Nevertheless, most scans are reported as showing high, intermediate, or low probability.89,91,92,94,95 These probabilities have distinct limita-tions. The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED),92 in comparing V/Q scanning with pul-monary arteriography, found that only 41% of patients with arteriographically proven PTE had a high-probability lung scan. Other studies have shown similar results.98,99 Further-more, from 15% to 30% of patients with low-probability scans do, in fact, have PTE.92,94,95,97,98 For these reasons, newer imaging techniques have gained popularity.100–107

Contrast-enhanced spiral computed tomography (CT angiography) images the pulmonary vessels directly. Throm-boemboli appear as fi lling defects within the opacifi ed arter-ies107,108 (Fig. 104.7C). This test has the advantages of being minimally invasive, of identifying disorders that can mas-querade as PTE,109–111 and of monitoring the resolution of es -tablished blood clots.112 In addition, it has the capacity to detect right ventricular enlargement, which, in and of itself, predicts poor patient outcome.113,114 Its accuracy for detecting throm -boemboli proximal to the subsegmental level approaches that of pulmonary arteriography.112,115–117 Nevertheless, CT angiog-raphy has certain limitations. It requires breath-holding, which poses diffi culty for the tachypneic patient.107,115,118 It also exposes the patient to high doses of radiation.119 And it does not reliably identify clots in the periphery of the lungs.108,118,120,121 Such peripheral clots may be important, however, because they could adversely affect the outcome, especially in patients with underlying cardiopulmonary disease.108,121 These clots could also lead to chronic thrombo-embolic pulmonary hypertension.121,122 Better information on the clinical signifi cance of these clots can be expected with the increasing availability of multislice spiral CT.108,121,123

Compression venous ultrasonography is the standard method for diagnosis of proximal deep vein thrombosis.124–129 A positive fi nding represents surrogate evidence of

PTE.93,95,104,130–133 This test, however, does not reliably detect calf vein thrombi, which pose the threat of proximal exten-sion with subsequent embolization. Therefore, a repeat study 1 to 2 weeks after clinical signs develop may prove worth-while in a small percentage of patients.127–129,134

Computed tomographic venography accurately identifi es venous thrombi in the abdomen, pelvis, thigh, and calf135; however, the radiation it delivers to the reproductive organs is a considerable drawback.136 The exact role of this procedure awaits further study.

Contrast venography is the gold standard for diagnosis of deep vein thrombosis.137–139 It is particularly useful when non-invasive studies are inconclusive,128,129 as in asymptomatic postoperative patients suspected of having proximal deep vein thrombosis and in patients thought to have calf vein throm-bosis or recurrent deep vein thrombosis.128,129,138,140

Pulmonary arteriography is the most reliable means of establishing the presence of pulmonary thromboemboli and determining their location and extent.92,95,99 Nowadays, however, use of this procedure is limited to situations in which the clinical suspicion of PTE persists despite normal results from noninvasive studies.104,132,133 The arteriographic fi ndings of PTE consist of completely obstructed pulmonary arteries (Figs. 104.1B, 104.6B, and 104.9), intraarterial fi lling defects (Fig. 104.9), decrease in volume of affected lung seg-ments (Fig. 104.9), and changes in arterial caliber proximal or distal to the embolus.141–143 By contrast, the arteriographic fi ndings of chronic pulmonary thromboembolism refl ect the structural changes resulting from partial resolution of the embolic material. These changes characteristically appear as intraarterial webs, pouch-like fi lling defects, or various intimal irregularities.144–146

Echocardiography is valuable in detecting right ventricu-lar dysfunction, a fi nding not always apparent clinically.147–149 This fi nding, however, correlates with increased mortal-

FIGURE 104.9. Pulmonary arteriogram obtained 24 hours after the onset of dyspnea and right pleuritic pain in a 71-year-old man. Note the large fi lling defect in the right upper lobe artery, collapse of the right middle and lower lobes, and multiple occlusive lesions in the lobar and segmental arteries of the left lung. Autopsy confi rmed the arteriographic fi ndings.



ity150,151 and should prompt immediate consideration of thrombolytic therapy.152,153 Moreover, assessing right ven-tricular function with this technique is an excellent means of monitoring therapeutic effi cacy.154–156 Echocardiography can also detect a patent foramen ovale, a condition that places patients with PTE at increased risk of dying.157 Addi-tionally, this test can identify diseases that masquerade as PTE, such as acute cardiac tamponade and dissecting hema-toma of the aorta.

The echocardiographic signs of PTE include dilated right atrium, dilated hypokinetic right ventricle, fl attening or paradoxical motion of the interventricular septum, and Doppler evidence of tricuspid or pulmonary regurgita-tion.155,156,158–160 Regional right ventricular dysfunction with normal motion of the apical wall is another strong indica-tion.161 In addition, the echocardiogram may show clots in the right atrium (Fig. 104.7B) or right ventricle162 and, occa-sionally, in the central pulmonary arteries.160,163

Gadolinium-enhanced magnetic resonance (MR) angiog-raphy images the pulmonary vessels directly but has a sen-sitivity lower than that of spiral CT angiography.107,164–167 It also takes a long time to perform. Nevertheless, this proce-dure is free of ionizing radiation and does not require iodin-ated contrast material.107,168 It is particularly useful, therefore, in documenting venous thrombosis in the pelvis and lower limbs of pregnant patients, orthopedic patients, and those with renal insuffi ciency or allergy to iodine.107,108,167,169,170

Percutaneous angioscopy171 and intravascular ultra-sound172–174 do not have an established role in the diagnosis of PTE. They are, however, useful in the preoperative evalu-ation of patients with chronic thromboembolic pulmonary hypertension.146,174

Differential Diagnosis

The manifestations of PTE are so protean that even experi-enced clinicians occasionally mistake the illness for some other disorder. In addition, many other disorders often mas-querade as PTE (Table 104.2). In this section, we show how confusion in diagnosis comes about, and, when possible, suggest simple means of resolving the issue. We also indicate when specialized diagnostic procedures are indispensable for proper management.

Parenchymatous Respiratory Disorders

Pneumonia

Both pulmonary infarction and bacterial pneumonia can cause dyspnea, tachypnea, cough, pleuritic pain, fever, hemoptysis, and leukocytosis. Moreover, both can cause similar abnormalities on chest radiograph.51 To minimize diagnostic error, physicians should consider both disorders whenever they make a tentative diagnosis of either, particu-larly when the process involves the lower lobes, especially the right. Accurate clinical differentiation of pulmonary infarction from bacterial pneumonia often takes several days and may be impossible without imaging of the pulmonary arteries. Therefore, as long as the diagnosis is uncertain, we favor treatment for both conditions.

TABLE 104.2. Differential diagnosis of pulmonary thromboembolism

Respiratory disordersParenchymatous Pneumonia Pyogenic abscess Neoplasm Granulomatous infection Amebiasis Obstructive pulmonary disease Atelectasis AsthmaPleural Viral Tuberculosis Neoplasm Systemic lupus erythematosusCongenital Agenesis of pulmonary arteryCardiovascular disorders Myocardial infarction Congestive heart failure Pericarditis Acute cardiac tamponade Dissecting hematoma of aorta Right-sided intracavitary cardiac lesionsNeurologic disorders Disturbances of consciousness Convulsive disorders Cerebrovascular diseasePsychiatric disorders Anxiety states Munchausen syndromeAbdominal disorders Acute cholecystitis Subdiaphragmatic abscess Ruptured viscus Pancreatitis Splenic infarctionInfectious disorders Bacteremia PeritonitisPulmonary-renal disorders Goodpasture’s syndrome Wegener’s granulomatosis UremiaHematologic disordersAcute blood loss Intraintestinal Intrathoracic Intraperitoneal; retroperitonealSickle cell diseaseDisseminated intravascular coagulationMetabolic disorders Pheochromocytoma Lactic acidosisParticulate matter disorders Fat Amniotic fl uid Tumor Air

Certain features are useful in distinguishing between these two illnesses. Patients with bacterial pneumonia fre-quently experience gradually increasing malaise followed by shaking chills and a cough productive of purulent sputum.


218 6 c h a p t e r 10 4

Physical signs of lung consolidation are common. By con-trast, patients with pulmonary infarction often become ill with dramatic suddenness, seldom have a troublesome cough, never experience true shaking chills (unless the emboli are septic), and almost never show physical signs of consolida-tion. Parenchymal infi ltrates that appear fi rst in one lung and then the other or “pneumonia” unresponsive to therapy suggests pulmonary infarction.

A pleural friction rub is of no value in differentiating these disorders unless it appears in the absence of parenchy-mal infi ltrates on chest radiograph. In such cases, if the patient is well hydrated, pneumonia is unlikely, and the prime considerations would be early pulmonary infarc-tion, fractured rib, viral pleuritis, and subdiaphragmatic infl ammation.

Sputum examination is particularly helpful in differen-tiating bacterial pneumonia from pulmonary infarction. In pneumonia, the sputum classically is purulent, is occasion-ally foul smelling, and may contain bright red fl ecks of blood. Gram stain typically shows many bacteria. Conversely, early in the course of pulmonary infarction, sputum (when present) usually is frankly bloody with few bacteria or infl ammatory cells. Blood cultures often yield the causative microorganism in patients with bacterial pneumonia but show no growth in patients with PTE.

The total leukocyte count may be normal or high in both PTE and bacterial pneumonia.

Pleural fl uid in PTE is often sanguineous and character-istically sterile. In bacterial pneumonia, however, it rarely is frankly bloody and often harbors the causative microorgan-ism. The specifi c gravity and protein concentration of the pleural fl uid are not distinctive for either disorder.

Imaging of the pulmonary arteries is the most specifi c means of differentiating bacterial pneumonia from pulmo-nary infarction. The pulmonary arteries in pneumonia—in contrast to PTE—show no fi lling defects or obstruction.51

Pyogenic Abscess, Neoplasm, Granulomatous Infection, and Amebiasis

These disorders, like PTE, can manifest fever, cough, dyspnea, hemoptysis, and pleuritic pain. In addition, like PTE, their radiographic features may include any combination of enlarged hilum, “mass lesion,” parenchymal infi ltrate, cavity (with or without an air–fl uid level),175,176 and pleural effusion. Correct diagnosis, therefore, often requires bronchoscopy, pulmonary-artery imaging, pleural biopsy, or thoracotomy.

Obstructive Pulmonary Disease

Obstructive pulmonary disease, as well as PTE, can cause wheezing, breathlessness, cough, hemoptysis, fever, and cya-nosis. In addition, the chest radiograph in either disorder may show prominence of one or both main pulmonary arteries, together with localized or diffuse zones of increased radiolu-cency in which the peripheral vascular markings are dimin-ished or absent. Moreover, both disorders may manifest electrocardiographic evidence of supraventricular arrhyth-mias, right-axis deviation, or a pattern suggesting right ven-tricular overload. In such instances, purulent sputum and hypercapnia suggest obstructive pulmonary disease, whereas hypocapnia favors PTE. Because perfusion defects occur in

both conditions, lung scanning has limited usefulness, and CT angiography101,102 may become necessary.

Atelectasis

Both atelectasis and PTE are common in bedridden and post-operative patients. Each can also cause dyspnea, tachypnea, and cyanosis, together with rales and decreased breath sounds over the involved areas of lung. Furthermore, these disorders may cause similar radiographic changes, such as segmental collapse. Marked radiographic improvement after tracheo-bronchial suction or bronchoscopy favors atelectasis alone.

Asthma

Common to PTE and bronchial asthma are recurrent attacks of wheezing, dyspnea, and anxiety, associated with either a normal-appearing chest radiograph or one that shows scat-tered pulmonary parenchymal infi ltrates. Cyanosis and signs of rapidly developing pulmonary hypertension may also occur in both conditions. A long-standing history of atopy, together with elevated blood eosinophil count, tenacious and occasionally purulent sputum, or prompt therapeutic response to bronchodilators, supports a diagnosis of bron-chial asthma. If, however, the patient is acutely ill, the diag-nosis is in doubt, and precise differentiation is mandatory, imaging of the pulmonary arteries may become necessary.

Pleural and Congenital Respiratory Disorders

Viral

Epidemic pleurodynia (also called epidemic myalgia, devil’s grip, and Bornholm’s, Daae’s, or Sylvest’s disease) is an acute enteroviral infection usually caused by group B coxsackie-viruses and generally occurring in epidemics. Like early pulmonary infarction, it produces paroxysms of severely discomforting intercostal muscle spasms, pleuritic pain, pleural friction rub, and a normal chest radiograph. Develop-ment of bloody sputum, pulmonary parenchymal infi ltrates, or both, signals PTE, whereas a cluster of cases of pleurisy with persistently normal chest radiographs points to epi-demic pleurodynia.

Tuberculosis and Neoplasm

These illnesses, like PTE, can present with pleuritic pain, pleural friction rub, and grossly bloody pleural effusion. Defi nitive diagnosis rests on bacteriologic and histologic examination of the pleura and associated effusion.

Systemic Lupus Erythematosus

Patients with systemic lupus erythematosus occasionally exhibit sudden breathlessness, tachypnea, hyperpnea, tachy-cardia, cyanosis, pleuritic pain, pleural friction rub, and pleural effusion, accompanied at times by pulmonary parenchymal infi ltrates and hemoptysis. In this circum-stance, there is no consistent clinical means of distinguish-ing between systemic lupus erythematosus per se and concomitant PTE. Therefore, we sometimes resort to imaging of the pulmonary arteries for guidance in managing these patients.



Agenesis of the Pulmonary Artery

Congenital absence of a main branch of the pulmonary artery (usually the left) can lead to recurrent hemoptysis and dyspnea simulating PTE. In almost all cases, however, fi nd-ings on conventional chest radiograph are suffi ciently char-acteristic to permit recognition of this syndrome.177 The fi ndings consist of decreased volume of the affected lung with ipsilateral shift of the heart and mediastinal structures, absence of normal hilar shadow on the involved side, and plethora of the contralateral lung. Exact diagnosis requires visualization of the pulmonary arteries.

Cardiovascular Disorders

Myocardial Infarction

Often PTE mimics myocardial infarction (MI), particularly in the fi rst few hours after the embolic episode and before distinct clinical or radiographic signs of pulmonary infarc-tion develop. To complicate matters, PTE occasionally is a sequel of MI,178 and MI occasionally results from the sys-temic hypotension and pulmonary hypertension brought about by PTE. Certain features, however, are helpful in dis-tinguishing between these two entities.

One good way of differentiating these disorders is to cor-relate the patient’s blood pressure with the electrocardio-gram. If hypotension develops concomitantly with or after the onset of chest pain, and the accompanying electrocardio-gram does not show defi nite or strongly suggestive evidence of acute MI, cardiac necrosis is most unlikely. In contrast, when PTE causes hypotension, the electrocardiogram typi-cally shows only sinus tachycardia and nonspecifi c T-wave changes or, sometimes, right-heart strain.

The duration of hypotension is another important diag-nostic clue. Hypotension from MI ordinarily persists and usually requires vasopressor therapy. By contrast, hypoten-sion from PTE ordinarily is transient and disappears within minutes to a few hours, often without the aid of vasopressors. If prolonged, hypotension indicates massive obstruction to pulmonary blood fl ow with consequent decrease in cardiac output.

Finally, two contrasting features of PTE and MI warrant emphasis. Patients with PTE characteristically have dyspnea out of proportion to the degree of pain, hypotension, cyano-sis, or radiographic changes. They may also appear moribund one minute and nearly well the next. Conversely, in patients with acute MI, dyspnea frequently is absent and, when present, usually refl ects the degree of associated pulmonary vascular congestion. And once patients with MI appear mori-bund, they rarely recover spontaneously or rapidly.

Congestive Heart Failure

Features common to both congestive heart failure and PTE are dyspnea, wheezing, apprehension, cyanosis, tachycardia, rales in the lung, hypotension, pleural effusion, bright red sputum, and elevated jugular venous pressure. To complicate the picture, congestive heart failure predisposes patients to PTE, and PTE sometimes precipitates and is responsible for the persistence of congestive heart failure.

Although clinical differentiation of these two disorders may be quite diffi cult, points favoring PTE are distinct clots of blood in the sputum, a normal heart size, and no pulmo-nary congestion on chest radiograph. Echocardiographic demonstration of contractile dysfunction predominantly of or limited to the left ventricle will usually establish a cardiac cause. Occasionally, imaging of the pulmonary arteries, direct measurement of pulmonary capillary pressure, or both may be necessary for exact diagnosis.

Pericarditis

When infarction of the lung develops contiguous with the pericardium, a pleuropericardial friction rub, electro-cardiographic signs of pericarditis, or both may appear. A pericardial-like rub may also become audible in the area overlying a main pulmonary artery distended by massive thromboemboli.39–41,179 In our experience, the pericarditis induced by PTE is not associated with demonstrable pericar-dial effusion.

Acute Cardiac Tamponade

When acute cardiac tamponade presents with abrupt onset of dyspnea, tachypnea, tachycardia, cyanosis, distended neck veins, hepatomegaly, hypotension, and occasionally chest pain, it closely simulates massive PTE. Pulsus paradoxus, inspiratory distention of neck veins (Kussmaul sign), and distant heart sounds may also occur in either disorder. Because small amounts of pericardial fl uid accumulated rapidly can lead to signifi cant hemodynamic alteration without signifi cant cardiomegaly, chest radiographs may not be useful in differentiating these two processes. Correct diag-nosis may require echocardiography, CT angiography, mag-netic resonance angiography, or cardiac catheterization.

Dissecting Hematoma of the Aorta

Chest pain (usually severe and occasionally pleuritic), dyspnea, tachypnea, hypotension, neurologic manifestations, and even hemoptysis are features of dissecting hematoma of the aorta that simulate PTE. Additional diffi culty in diagno-sis can develop if the hematoma ruptures into the pericardial sac, causing cardiac tamponade, or into the pleural space (usually the left), resulting in hemothorax. A hematocrit value of the pleural fl uid approaching that of the peripheral blood is evidence of a ruptured vessel and weighs heavily against pulmonary infarction. Widening of the aorta, medi-astinum, or both on chest radiograph is another sign of dis-secting hematoma. Precise diagnosis ordinarily requires echocardiography, CT angiography, magnetic resonance imaging, or a combination thereof.

Right-Sided Intracavitary Cardiac Lesions

When the ball-valve action of a right-sided cardiac thrombus or neoplasm impedes orderly fl ow of blood into the lungs, the patient may exhibit intermittent dyspnea, syncope, tachycar-dia, cyanosis, chest pain, arrhythmias, or various cardiac murmurs. Unlike the fi ndings in PTE, these signs and symp-toms may change as the patient’s position changes. If the lesion abuts the pulmonic valve, the pulmonic component of the second heart sound may be muffl ed. If the lesion becomes


218 8 c h a p t e r 10 4

calcifi ed, it may be evident on chest radiograph. Echocardiog-raphy, however, is the most sensitive and reliable means of detecting right-sided intracavitary masses.

Neurologic Disorders

Because the neurologic manifestations of PTE are usually abrupt in onset and are often transient and recurrent, they commonly masquerade as cerebrovascular disease.43 Con-versely, cerebrovascular diseases, such as hemorrhagic infarc-tion and subdural hematoma, may be associated with labored respirations, pulmonary parenchymal infi ltrates,180 and electrocardiographic changes.181 Therefore, distinguishing between these two conditions can be diffi cult. Findings sug-gestive of PTE are cardiorespiratory abnormalities or signs of phlebitis that appear in association with sudden, transient, or recurrent neurologic dysfunction. Another clue to PTE is syncope at rest. When this occurs, the patient usually is elderly, is bedridden, or has heart disease.

Psychiatric Disorders

It is easy to mistake PTE for a functional disorder when tachypnea, diaphoresis, apprehension, and feelings of suffo-cation are the major clinical features. Conversely, functional disorders can mimic PTE, particularly when spurious hemop-tysis is part of the clinical picture. We have seen this diag-nostic dilemma over a full spectrum, from fatal PTE masquerading as Munchausen syndrome* (Fig. 104.1) to true Munchausen syndrome prompting vena caval ligation for suspected PTE. Differentiation depends primarily on thor-ough probing of the patient’s complaints and credibility and use of tests appropriate for the given situation.

Abdominal Disorders

Pulmonary infarction of the lower lobes often presents with signs and symptoms typical of disease in the upper abdomen. Diagnostic confusion increases when the initial chest radio-graph is normal and imaging studies of the abdomen are negative. In such cases, serial chest radiographs will resolve the issue if PTE is the culprit (Fig. 104.5).

Infectious Disorders

Bacteremia

When bacteremia presents with breathlessness, hyperpnea, tachypnea, tachycardia, peripheral cyanosis, and hypoten-sion, the clinical picture mimics that of PTE. Hints of bac-teremia are high fever, shaking chills, warm dry skin, and an obvious source of infection. If the diagnosis remains unsettled and the chest radiograph shows no parenchymal disease, a normal lung scan excludes PTE.

Peritonitis

Postoperative peritonitis (Fig. 104.8B) can simulate PTE when it causes sudden circulatory collapse, rapid respira-tions, cyanosis, and pleural friction rub without causing the usual signs of peritoneal infl ammation. Moreover, concomi-tant electrocardiograms may show changes consistent with those of massive PTE (Fig. 104.8A). Clues to peritonitis in such cases are a progressive rise in the hematocrit value (indicating sequestration of fl uid in the peritoneal cavity), a low central venous pressure, or a purulent perito-neal aspirate.

Pulmonary-Renal Disorders

Goodpasture’s Syndrome

Recurrent dyspnea, hemoptysis, and transient pulmonary infi ltrates are features of Goodpasture’s syndrome that mimic PTE. Despite such similarities, clinical separation of these two entities ordinarily is easy. Patients with Goodpas-ture’s syndrome characteristically are young and previously healthy and have iron-defi ciency anemia along with iron-fi lled macrophages in their sputum. They may also exhibit proteinuria, hematuria, and cylindruria. During the acute stages of hemoptysis, their chest radiographs commonly show ill-defi ned, bilateral nodular densities, usually in a perihilar distribution sparing the apices and bases. Between bouts of hemoptysis, a fi nely granular, reticular pattern of increased interstitial markings may develop throughout the lungs.

Wegener’s Granulomatosis

Wegener’s granulomatosis, like PTE, may give rise to breath-lessness, pleuritic pain, hemoptysis, pleural friction rub, pleural effusion, and cavities in the lung. Ultimately, most of these patients show evidence of widespread, multi-system disease, especially nephritis. Defi nitive diagnosis requires histologic demonstration of granulomatous disease of the respiratory tract, necrotizing vasculitis, and focal glomerulitis.

Uremia

We and others183 have observed patients with advanced uremia who exhibit apprehension, tachypnea, hyperpnea, wheezing, pleuritic pain, pleural friction rub, progressive cyanosis, and, occasionally, hemoptysis and hypotension. When these manifestations develop abruptly and demise is rapid, the similarity to PTE is remarkable. Our experience indicates that differentiating these entities may not be pos-sible without an autopsy.

Hematologic Disorders

Acute Blood Loss

When internal blood loss is sudden and severe, it may present as syncope associated with air hunger, tachycardia, periph-eral cyanosis, and hypotension. These same features may also herald massive PTE. Because both disorders can be fatal

* A label applied to persons “who, in the absence of appropriate medical or surgical need, have made hospitalization a primary way of life.”182



if not treated promptly and appropriately, early correct diag-nosis is essential. In that regard, a low central venous pres-sure favors hypovolemia, whereas an elevated central venous pressure with an accentuated pulmonic valve closure sound points to massive PTE.

Sickle Cell Disease

Patients with sickle cell disease often experience acute chest pain, accompanied at times by fever, dyspnea, tachypnea, hypoxemia, pulmonary parenchymal infi ltrates, and small pleural effusions. This so-called acute chest syndrome184 pre-sumably results from pulmonary infection or in situ pulmo-nary microthromboses. Whatever the cause, the clinical picture closely mimics that of PTE.

Differentiating these two illnesses is important, particularly from the standpoint of therapy. In sicklers, anticoagulation is relatively ineffectual and inferior vena caval interruption potentially harmful. Moreover, pulmo-nary arteriography is generally contraindicated, because the hypertonic radiographic contrast material might precipitate further sickling and aggravate the condition. Thus, initial management of these patients should be conservative, con-sisting of pain control, hydration, supplemental oxygen, and, if necessary, empiric antibiotics and partial exchange transfusion.

Disseminated Intravascular Coagulation

Like PTE, disseminated intravascular coagulation can cause fulminant dyspnea, cyanosis, neurologic abnormalities, and hypotension. In addition, like PTE, it tends to occur in obstetric and postsurgical patients. It may even be the pre-senting manifestation of unrecognized PTE.185 Unlike PTE, however, disseminated intravascular coagulation commonly leads to purpuric skin lesions, proteinuria, hematuria, frag-mented erythrocytes on peripheral blood fi lm, thrombocyto-penia, and depletion of plasma coagulation factors.

Metabolic Disorders

Pheochromocytoma

This tumor can cause paroxysms of hypotension, tachy-cardia, tachypnea, sweating, peripheral cyanosis, cardiac murmur, fever, and leukocytosis. The patient may also seem well one minute, desperately ill the next, and then recover spontaneously and rapidly. So similar are these fi ndings to those of PTE that the true nature of the illness can be totally overlooked while lung scanning,186 pulmonary arteriography, right heart catheterization, and even ligation of the inferior vena cava are carried out.187 Clues to pheochromocytoma are hyperglycemia, signs of hypermetabolism, a history of hypo-tension, a pronounced sensitivity to the hypotensive effects of phenothiazines, or discovery of an abdominal mass.

Lactic Acidosis

Rarely, lactic acidosis leads to acute and increasingly severe signs of pulmonary hypertension simulating massive PTE. In one case, clinical evidence of PTE was so convincing that the surgeon did an emergency pulmonary arteriotomy but

found no pulmonary emboli.188 Any process responsible for decreased oxygenation of peripheral tissues coupled with low serum carbon dioxide content should alert the physician to the possibility of lactic acidosis. Demonstration of an extremely low arterial pH in association with excess blood lactate confi rms the diagnosis.

Particulate Matter Disorders

Fat Embolism

In a patient with recent fracture of the long bones, sudden development of respiratory disability, pulmonary parenchy-mal infi ltrates, central nervous system abnormalities, or combinations thereof, suggests fat embolism as well as PTE. The best clue to fat embolism in such cases is the appearance of a petechial rash over the anterior part of the shoulders, the anterosuperior portion of the chest, the base of the neck, the axillae and conjunctivae, or, occasionally, the abdomen and thighs.189 When present, the petechiae typically emerge 24 to 36 hours after the injury, persist for 3 to 4 days, and then fade rapidly. Additional points favoring fat embolism are the onset of symptoms within hours to a few days after the injury; diffuse, bilateral, “snowstorm-like” densities on chest radiograph simulating pulmonary edema but without pleural effusion or cardiomegaly; a sharp drop in the hematocrit value consequent to intrapulmonary hemorrhage; increased erythrocyte aggregation and hemolysis; thrombocytopenia resulting from platelet aggregation; and demonstration of fat globules in the retinal arterioles, in the cerebrospinal fl uid, or on the surface of the urine.

More typical of PTE are symptoms beginning 1 to 3 weeks after the accident; localized and larger pulmonary parenchymal lesions, often with pleural effusion; pleural friction rub; and signs of venous thrombosis.

Clinical differentiation of fat embolism from PTE can be diffi cult and sometimes impossible. In such cases, imaging of the pulmonary arteries is the best means of resolving the problem.

Amniotic Fluid Embolism

Precipitous hypotension, often accompanied by cardiorespi-ratory embarrassment, is characteristic of amniotic fl uid embolism but occurs in PTE as well. Moreover, accurate premortem distinction between these two types of embolism may be impossible. Guides to amniotic fl uid embolism are multiparity; maternal age over 30 years; onset of symptoms late in labor, during delivery, or in the immediate postpar-tum period; diffi cult or prolonged labor; overweight or still-born infant; radiographic signs of pulmonary edema; or coagulation defects such as thrombocytopenia, hypopro-thrombinemia, and hypofi brinogenemia. By contrast, frank hemoptysis, pleural friction rub, signs of venous thrombosis, and oligemic lung fi elds suggest PTE.

Tumor Embolism

Pulmonary arterial tumor emboli can cause a clinical picture just like that of PTE. Knowledge that the patient has a malig-nancy offers little diagnostic help, because PTE is frequent in persons with cancer. Although cytologic examination of


219 0 c h a p t e r 10 4

blood obtained from the pulmonary artery may show malig-nant cells,190,191 lung biopsy provides the best means of estab-lishing the diagnosis. Recognizing a surgically curable lesion such as myxoma of the right atrium or right ventricle is particularly important; in that regard, echocardiography is indispensable.

Venous Air Embolism

Accidental introduction of air into a systemic vein may result from a variety of diagnostic, therapeutic, or surgical procedures.192 The gas characteristically collects in the right ventricular outfl ow tract or occasionally in the pulmonary arterial tree and, if suffi cient in amount, provokes gasping respirations, cyanosis, chest pain, tachycardia, convulsions, and hypotension. In most cases, death or total recovery ensues within an hour after onset of symptoms. A unique but inconsistent diagnostic sign is a precordial “mill-wheel” murmur—a churning and splashing noise that masks the heart sounds. Palpation of air in the jugular veins or radio-graphic demonstration of air in the right ventricle provides additional diagnostic aid.

Treatment

The ideal treatment of PTE is prevention of the initial throm-bus formation.193–195 Such measures—used singly or in various combinations—include early full ambulation (especially for postoperative and postpartum patients), elastic stockings or intermittent pneumatic compression for bedridden persons and for those undergoing major operative procedures,196 and anticoagulant medication for patients at particular risk for PTE. Current options for preventing deep vein thrombosis in hospitalized patients,194,197–230 in patients discharged after lower extremity arthroplasty,214,215 and in pregnant women21,231 are listed in Table 104.3.

Once PTE has occurred, the type of therapy depends on the severity of the illness, the nature of any associated disease(s), the skill and experience of the physician, and the available facilities. Even considering these factors, it may be diffi cult, at times, to decide on a fi xed course of treatment, primarily because one cannot accurately predict in a given patient whether or when another embolus will occur, whether it will be clinically detectable, or how extensive it will be.

In addition to supportive measures, immediate anti-coagulation with unfractionated or low-molecular-weight heparin is indicated (barring obvious contraindications). Heparin acts largely by binding to antithrombin III.237 The resultant heparin–antithrombin III complex inactivates both thrombin and activated factor X. Because of the heteroge-neous nature of unfractionated heparin, the response to therapy with this agent varies considerably.238 Hence, fre-quent monitoring of the activated partial thromboplastin time (APTT) is necessary.

It is important to achieve a therapeutic threshold rapidly (i.e., an APTT ratio 1.5 times the control).239–241 Failure to do so increases the risk of recurrent PTE.242 We favor an intra-venous bolus of 5000 to 10,000 U of unfractionated heparin followed by a continuous infusion of 1200 to 1500 U/h. Addi-tionally, we recommend that the dose be adjusted every 4 to

6 hours, using the APTT value as a guide. The infusion should be continued for at least 5 days.243

Low-molecular-weight heparin offers several therapeutic advantages over unfractionated heparin: longer half-life, more predictable anticoagulant activity, no need for labora-tory monitoring, and lower incidence of thrombocytope-nia.216,244–250 Moreover, its therapeutic effi cacy in proximal deep vein thrombosis216,245,246 and in PTE248,251–256 is equiva-lent to that of unfractionated heparin. It is administered subcutaneously in a dosage of 1.5 mg/kg once a day or 1 mg/kg every 12 hours.

Treatment of PTE in pregnancy merits special attention. The patient should receive unfractionated or low-molecular-weight heparin as the fi rst step. Unfractionated heparin is administered intravenously for 10 days in the manner previ-ously described and continued subcutaneously throughout gestation.21 The subcutaneous regimen of unfractionated heparin consists of approximately 20,000 U every 12 hours, adjusted to maintain the APTT at 1.5 times the control. The dosage of low-molecular-weight heparin is the same as that in nonpregnant patients and requires weight-based adjust-ment as pregnancy progresses.257,258 Both anticoagulants should be discontinued at the onset of regular uterine contractions. After delivery, anticoagulation with warfarin21 or low-molecular-weight heparin258 is appropriate for at least 6 weeks.

The cornerstone of long-term anticoagulant therapy is warfarin.259 This drug inhibits the enzyme vitamin K epoxide reductase. As a consequence, body stores of vitamin K become depleted, the synthesis of coagulation factors II, VII, IX, and X impaired, and the prothrombin time prolonged.

Warfarin can be administered along with, or shortly after, initiating heparin therapy.243,260,261 The usual recommended therapeutic range is an international normalized ratio (INR) of 2.0 to 3.0.262 But in patients with the antiphospholipid antibody syndrome, the target INR is 3.5.263 Because warfa-rin readily crosses the placenta, its use during pregnancy is contraindicated.

Levels of coagulation factor VII decrease within hours after the initiation of warfarin therapy. It takes about 5 days, however, for levels of the other coagulation factors to decrease.259,264 Therefore, heparin therapy should be contin-ued for several days after the target INR has been reached.

The duration of anticoagulation varies according to the clinical setting.265,266 In patients with a defi nable and revers-ible cause of PTE (e.g., fractured pelvis, postoperative state, or postpartum), 3 months of therapy may suffi ce.267 When the cause cannot be identifi ed, however, therapy should be continued for 6 months262,268,269 or longer.270,271 In that regard, patients with a normal plasma D-dimer value, obtained 1 month after discontinuing anticoagulant therapy, have a low risk for subsequent venous thromboembolism.272 Patients with recurrent PTE and those with the antiphospholipid antibody syndrome require lifelong anticoagulation. For patients with other underlying thrombophilic conditions, the duration of therapy remains uncertain.264,266,273,274

Thrombolytic therapy warrants immediate consideration in patients who are hemodynamically unstable from PTE. Such treatment promotes dissolution of clots much faster than that achieved with anticoagulants alone.154,275–279 The


p u l mon a ry t h rom b oe m b ol i s m 2191

resultant decrease in clot burden relieves strain on the right ventricle, allowing cardiac function to improve.154,159,280,281 This therapy may also reduce the rate of recurrent PTE by dissolving the initiating thrombi. Proof of such an effect, however, is lacking.282

Some patients who are hemodynamically unstable from PTE do not respond to thrombolytic therapy. In such cases, rescue pulmonary embolectomy may be lifesaving.283

A number of patients with PTE are hemodynamically stable but have echocardiographic evidence of right ventricu-lar dysfunction. Their management remains debatable.284 Although thrombolytics in these patients often decrease morbidity,148,149,153,285 they fail to reduce mortality.286 They do, however, improve the scintigraphic, echocardiographic, and angiographic fi ndings.282,287–289

One additional point warrants emphasis. When the pa -tient is in shock and the clinical evidence points strongly to PTE, thrombolytics can be lifesaving and should be admin-istered without seeking absolute diagnostic confi rmation. The potential benefi t of thrombolytics in such cases far outweighs the risk of signifi cant hemorrhage.280,290 Bedside transthoracic or transesophageal echocardiography in this setting is invaluable in demonstrating right ventricular pres-sure overload while excluding other diagnostic consider-ations, such as cardiac tamponade, left ventricular failure, and aortic dissection.148,280

Contraindications to thrombolytic therapy include active internal bleeding, multiple trauma, intracranial hemorrhage, and pregnancy.275 All contraindications become relative, however, when the patient is dying of PTE.

TABLE 104.3. Prophylaxis of venous thromboembolism*

Medical inpatients Unfractionated heparin 5000 U twice daily194,197 (with or without GCS, IPC, or aspirin†198,199) or Low-molecular-weight heparin Enoxaparin 40 mg daily200,232

Intensive care unit Same as medical inpatients201–203

General surgery Unfractionated heparin 5000 U twice daily204–207 or Low-molecular-weight heparin207,208

Enoxaparin 40 mg daily or Dalteparin 2500 to 5000 U daily209,210 or Nadroparin‡ 3100 U daily or Tinzaparin 3500 U daily (Each of the above with or without GCS, IPC, or aspirin)Cardiothoracic surgery Same as medical inpatients211

Hip replacement Low-molecular-weight heparin Enoxaparin 30 mg twice daily212–215 or Heparinoid Danaparoid 750 U twice daily216 or Recombinant hirudin Desirudin 15 U twice daily217,218 or Adjusted-dose unfractionated heparin to maintain APTT ratio 1.5 times that of the control value219 or Adjusted-dose warfarin (target INR 2.5)220 or Fondaparinux 2.5 mg once daily233,234

(Each of the above with or without GCS221 and IPC222)Knee replacement Low-molecular-weight heparin Enoxaparin 30 mg twice daily214,215,223 or Ardeparin 50 U/kg twice daily224 or Fondaparinux 2.5 mg once daily235 or Adjusted dose warfarin (target INR 2.5)236

(Each of the above with or without IPC)Radical prostatectomy Adjusted-dose warfarin (target INR 2.5) with or without GCS and IPC225 or Low-molecular-weight heparin232

Enoxaparin 40 mg daily or Unfractionated heparin 5000 U twice dailyNeurosurgery GCS and IPC226 or GCS with low-molecular-weight heparin Enoxaparin 40 mg daily227

Spinal surgery GCS with or without IPC228

Trauma (excluding brain) GCS and IPC with or without low-molecular-weight heparin Enoxaparin 30 mg twice daily229 or Adjusted-dose unfractionated heparin to maintain APTT ratio 1.5 times that of the control value230

Pregnancy Adjusted-dose unfractionated heparin to maintain APTT ratio 1.5 times that of the control value230 or Low-molecular-weight heparin Dalteparin 5000 U daily231 or Enoxaparin 40 mg daily230

APTT, activated partial thromboplastin time; GCS, graduated compression stockings; INR, international normalized ratio; IPC, intermittent pneumatic compression.

* All listed medications except aspirin and warfarin are administered subcutaneously.

† Dose varies from 80 to 325 mg daily.

‡ Not approved by U.S. Food and Drug Administration.


2192 c h a p t e r 10 4

Whereas the window for thrombolytic therapy in MI is but a few hours,291–293 it is days to weeks in PTE.154,294 Of the three thrombolytic agents currently in use (Table 104.4), recombinant tissue-plasminogen activator is the fastest acting and produces the fewest systemic reactions. No labora-tory monitoring or dose adjustment is necessary, and heparin is not used during the infusion. Anticoagulation is manda-tory, however, on completion of thrombolytic therapy.

Interruption of blood fl ow through the inferior vena cava, either totally (by ligation) or partially (by use of fi lters or various suturing techniques), merits serious consideration when anticoagulant therapy is contraindicated or when PTE recurs despite optimal anticoagulation.60,295,296 Caval inter-ruption is mandatory after pulmonary embolectomy. Addi-tionally, in patients with suppurative pelvic thrombophlebitis and septic pulmonary emboli unresponsive to antibiotic or anticoagulant therapy, ligation of the inferior vena cava and both ovarian or spermatic veins may be lifesaving.

Vena caval fi lters are being used in a wide variety of clini-cal circumstances.296–302 The most popular fi lters are the titanium Greenfi eld, the alternating hook Greenfi eld, the bird’s nest, the Simon nitinol, and the Vena Tech types.303 In some institutions, fi lters specifi cally designed for temporary use are also available.304–308 When combined with standard anticoagulation therapy, caval fi lters may be more effective than anticoagulation alone in preventing PTE.300 But this added protection is short-lived and has not been shown to decrease mortality. Furthermore, the incidence of deep vein thrombosis increases with long-term use of caval fi lters.300 Therefore, indications for vena caval fi lters await better defi nition.309

The role of pulmonary embolectomy remains controver-sial. Some authors have suggested that this procedure should be considered more often,310–312 even in patients with no hemodynamic compromise.311–313 Others have argued that the successful completion of pulmonary arteriography virtu-ally precludes the need for embolectomy.314 Still others have said that there are no indications for pulmonary embolec-tomy.315 In our opinion, this operation is indicated when thrombolytic and anticoagulant agents are contraindicated or have failed, and the patient is either moribund or shows steady deterioration despite vigorous medical management.316 Although conventional arteriography is still the best means of establishing the presence and precise location of surgically accessible pulmonary thromboemboli, CT angiography is now being used for this purpose.311,312 In emergent situations, however, diagnostic confi rmation is sometimes obtained only at operation.311,312

Transvenous pulmonary embolectomy with catheter suction is another method of treating critically ill patients with PTE.317,318 Its in-hospital mortality rate, however, varies from 9% to 30%.319 Furthermore, catheter embolectomy is limited in its ability to remove thrombi that have already become adherent to the wall of the pulmonary artery. Nev-ertheless, techniques of this sort320–322 offer promise for patients who, from old age and coexisting disease, are par-ticularly poor surgical risks, do not have access to cardio-pulmonary bypass facilities, or have contraindications to heparin and thrombolytic therapy.

Pulmonary artery thromboendarterectomy is currently the only effective therapy for patients with chronic major vessel thromboembolic pulmonary hypertension.146,323,324

Course and Prognosis

Pulmonary arteriograms performed serially have shown that major clots can resolve spontaneously and completely within 7325 to 14326 days. In one case, an embolus to a lobar artery resolved almost completely within 30 hours.327 These obser-vations help explain why most patients with PTE survive the initial episode, irrespective of the treatment given.

Deaths from PTE usually occur within the fi rst 2 weeks after diagnosis.328 In fact, about 75% of these deaths occur within the fi rst hour of symptoms.329 Most of the patients who die are either elderly or have a serious underly-ing illness, such as heart failure, chronic lung disease, or cancer.122,328,330

Recurrence of PTE ranges from 3% to 19%122,276,277,329,331 and varies according to the risk factors preceding the initial thrombosis. When these factors are ongoing (e.g., idiopathic PTE, cancer, or thrombophilic disorder), recurrence is four times as high as it is when the factors are transient (e.g., recent surgery).331

The long-term outlook for patients with PTE depends largely on the nature and severity of any underlying disease. The prognosis is good for those without preexisting cardio-pulmonary illness.150,156,332 For example, during a 9-year follow-up study, 12 of 72 patients who had survived massive PTE died, but in no case did death result from chronic pul-monary hypertension or from recurrence of PTE.333 By con-trast, if the patient has echocardiographic evidence of pulmonary hypertension and right ventricular dysfunction after hospitalization, the long-term prognosis is poor.156

Chronic thromboembolic pulmonary hypertension com-plicates about 5% of the cases of PTE122,156—an incidence much higher than was originally thought.146 Patients affected are of younger age, manifest a large perfusion defect at pre-sentation, or have idiopathic pulmonary embolism.122

Although some battles have been won, the war against venous thrombosis and pulmonary embolism is far from over. This disease continues to pose problems for both the patient and the doctor. Its incidence is still uncertain, its diagnosis often in doubt, and its treatment unsettled.

Few conditions in medicine have been subjected to so much analysis with so little elucidation.

Michael E. DeBakey334

Written in 1954, those words remain true today.

TABLE 104.4. Thrombolytic treatment protocols for pulmonary thromboembolism

Agent Loading dose* Maintenance dose*

Streptokinase 250,000 U over 30 min 100,000 U/h for 24 hUrokinase 4400 IU/kg over 4400 IU/kg/h for 10 min 12–24 hRecombinant None 50 mg/h for 2 h tissue-

plasminogenactivator

* Intravenous.



References

1. Moser KM. Venous thromboembolism. Am Rev Respir Dis 1990;141:235–249.

2. Bell WR, Simon TL. Current status of pulmonary thromboem-bolic disease: pathophysiology, diagnosis, prevention, and treat-ment. Am Heart J 1982;103:239–262.

3. Lilienfeld DE, Chan E, Ehland J, Godbold JH, Landrigan PJ, Marsh G. Mortality from pulmonary embolism in the United States: 1962 to 1984. Chest 1990;98:1067–1072.

4. Goyette EM. The diagnosis and management of pulmonary embolism and infarction. Dis Chest 1954;25:15–20.

5. Rexrode WO. Massive pulmonary embolism in an otherwise healthy young patient. Respir Care 1986;31:803–806.

6. Emery JL. Pulmonary embolism in children. Arch Dis Child 1962;37:591–595.

7. Ramirez LM. Thromboembolic disease in adolescence. JAMA 1959;170:1808–1811.

8. Anderson FA Jr, Spencer FA. Risk factors for venous thrombo-embolism. Circulation 2003;107(23 suppl 1):I9–I16.

9. Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classifi cation system. Ann Intern Med 2003;138:128–134.

10. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001;344:1222–1231.

11. Juul K, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004;140:330–337.

12. Heit JA, Sobell JL, Li H, Sommer SS. The incidence of venous thromboembolism among Factor V Leiden carriers: a commu-nity-based cohort study. J Thromb Haemost 2005;3:305–311.

13. Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000;343:1846–1850.

14. Hughes GR. The antiphospholipid syndrome: ten years on. Lancet 1993;342:341–344.

15. Kuter DJ. Thrombotic complications of central venous cathe-ters in cancer patients. Oncologist 2004;9:207–216.

16. Rosovsky RP, Kuter DJ. Catheter-related thrombosis in cancer patients: pathophysiology, diagnosis, and management. Hematol Oncol Clin North Am 2005;19:183–202.

17. Venous thromboembolic disease and combined oral contracep-tives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardio-vascular Disease and Steroid Hormone Contraception. Lancet 1995;346:1575–1582.

18. Effect of different progestogens in low oestrogen oral contracep-tives on venous thromboembolic disease. World Health Orga-nization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995;346:1582–1588.

19. Grady D, Wenger NK, Herrington D, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/Progestin Replacement Study. Ann Intern Med 2000;132:689–696.

20. Clahsen PC, van de Velde CJ, Julien JP, Floiras JL, Mignolet FY. Thromboembolic complications after perioperative chemother-apy in women with early breast cancer: a European Organiza-tion for Research and Treatment of Cancer Breast Cancer Cooperative Group study. J Clin Oncol 1994;12:1266–1271.

21. Toglia MR, Weg JG. Venous thromboembolism during preg-nancy. N Engl J Med 1996;335:108–114.

22. Greer IA. The challenge of thrombophilia in maternal-fetal medicine. N Engl J Med 2000;342:424–425.

23. Zornberg GL, Jick H. Antipsychotic drug use and risk of fi rst-time idiopathic venous thromboembolism: a case-control study. Lancet 2000;356:1219–1223.

24. Tapson VF. Risk of venous thromboembolism with use of anti-psychotic drugs. Lancet 2000;356:1206.

25. Ehrenforth S, Nemes L, Mannhalter C, et al. Impact of envi-ronmental and hereditary risk factors on the clinical manifes-tation of thrombophilia in homozygous carriers of factor V:G1691A. J Thromb Haemost 2004;2:430–436.

26. den Heijer M, Koster T, Blom HJ, et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996;334:759–762.

27. Selhub J, D’Angelo A. Relationship between homocysteine and thrombotic disease. Am J Med Sci 1998;316:129–141.

28. Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary throm-boembolism in Asians/Pacifi c Islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med 2004;116:435–442.

29. Klatsky AL, Baer D. What protects Asians from venous throm-boembolism? Am J Med 2004;116:493–495.

30. Decensi A, Maisonneuve P, Rotmensz N, et al. Effect of tamox-ifen on venous thromboembolic events in a breast cancer pre-vention trial. Italian Tamoxifen Study Group. Circulation 2005;111:650–656.

31. Goldhaber SZ. Tamoxifen: preventing breast cancer and placing the risk of deep vein thrombosis in perspective. Circulation 2005;111:539–541.

32. Gore I, Tanaka K. Phlebothrombosis, pulmonary embolization and pulmonary hypertension. Am J Med Sci 1962;244:351–361.

33. Sevitt S, Gallagher N. Venous thrombosis and pulmonary embolism. A clinico-pathological study in injured and burned patients. Br J Surg 1961;48:475–489.

34. Chakko S, Richards F III. Right-sided cardiac thrombi and pul-monary embolism. Am J Cardiol 1987;59:195–196.

35. Fred HL, Harle TS. Septic pulmonary embolism. Dis Chest 1969;55:483–486.

36. Harley DP, White RA, Nelson RJ, Mehringer CM. Pulmonary embolism secondary to venous thrombosis of the arm. Am J Surg 1984;147:221–224.

37. Moran TJ. Pulmonary embolism in nonsurgical patients with prostatic thrombosis. Am J Clin Pathol 1947;17:205–208.

38. Marks J, Truscott BM, Withycombe JF. Treatment of venous thrombosis with anticoagulants: review of 1135 cases. Lancet 1954;2:787–791.

39. Gorham LW. A study of pulmonary embolism. I. A clinico-pathological investigation of 100 cases of massive embolism of the pulmonary artery; diagnosis by physical signs and differen-tiation from acute myocardial infarction. Arch Intern Med 1961;108:8–22.

40. Gorham LW. A study of pulmonary embolism. II. The mechanism of death; based on a clinicopathological inves-tigation of 100 cases of massive and 285 cases of minor embo-lism of the pulmonary artery. Arch Intern Med 1961;108:189–207.

41. Gorham LW. A study of pulmonary embolism. III. The mecha-nism of pain; based on a clinicopathological investigation of 100 cases of minor and 100 cases of massive embolism of the pulmonary artery. Arch Intern Med 1961;108:418–426.

42. Olazabal F Jr, Roman-Irizarry LA, Oms JD, Conde L, Marchand EJ. Pulmonary emboli masquerading as asthma. N Engl J Med 1968;278:999–1001.

43. Fred HL, Yang M. Sudden loss of consciousness, dyspnea, and hypoxemia in a previously healthy young man. Circulation 1995;91:3017–3019.

44. Miller R, Berry JB. Pulmonary infarction: a frequently missed diagnosis. Am J Med Sci 1951;222:197–206.

45. Kollef MH, Schacter DT. Acute pulmonary embolism triggered by the act of defecation. Chest 1991;99:373–376.


219 4 c h a p t e r 10 4

46. Sagall EL, Bornstein J, Wolff L. Clinical syndrome in patients with pulmonary embolism. Arch Intern Med 1945;76:234–238.

47. Stevens AE. The late appearance of leg symptoms in pulmo-nary embolus. Lancet 1961;2:1005–1007.

48. Smith GT, Dammin GJ, Dexter L. Postmortem arteriographic studies of the human lung in pulmonary embolization. JAMA 1964;188:143–151.

49. Israel HL, Goldstein F. The varied clinical manifestations of pulmonary embolism. Ann Intern Med 1957;47:202–226.

50. Murray HW, Ellis GC, Blumenthal DS, Sos TA. Fever and pul-monary thromboembolism. Am J Med 1979;67:232–235.

51. Fred HL. Bacterial pneumonia or pulmonary infarction? Dis Chest 1969;55:422–425.

52. Parker BM, Smith JR. Pulmonary embolism and infarction: a review of the physiologic consequences of pulmonary arterial obstruction. Am J Med 1958;24:402–427.

53. Kugel MA, Lichtman SS. Factors causing clinical jaundice in heart disease. Arch Intern Med 1933;52:16–29.

54. Fleischner FG. Pulmonary embolism. Clin Radiol 1962;13:169–182.

55. Smith MJ. Roentgenographic aspects of complete and incom-plete pulmonary infarction. Dis Chest 1953;23:532–546.

56. Erkan L, Fyndyk S, Uzun O, Atycy AG, Light RW. A new radio-logic appearance of pulmonary thromboembolism: multilocu-lated pleural effusions. Chest 2004;126:298–302.

57. Perkins RB, Bradshaw HH. Pulmonary infarction mistaken for bronchogenic carcinoma. JAMA 1953;151:545–548.

58. Moser KM, Auger WR, Fedullo PF. Chronic major-vessel throm-boembolic pulmonary hypertension. Circulation 1990;81:1735–1743.

59. Beall AC Jr, Fred HL, Cooley DA. Pulmonary embolism: cause, consequences, prevention and treatment. Curr Probl Surg 1964:1–47.

60. Kucher N, Walpoth N, Wustmann K, Noveanu M, Gertsch M. QR in V1—an ECG sign associated with right ventricular strain and adverse clinical outcome in pulmonary embolism. Eur Heart J 2003;24:1113–1119.

61. Goodwin JF, Harrison CV, Wilcken DE. Obliterative pulmo-nary hypertension and thrombo-embolism. Br Med J 1963;1:701–711, 777–783.

62. Afzal A, Noor HA, Gill SA, Brawner C, Stein PD. Leukocytosis in acute pulmonary embolism. Chest 1999;115:1329–1332.

63. Bynum LJ, Wilson JE III. Characteristics of pleural effusions associated with pulmonary embolism. Arch Intern Med 1976;136:159–162.

64. Dantzker DR, Bower JS. Alterations in gas exchange following pulmonary thromboembolism. Chest 1982;81:495–501.

65. Cvitanic O, Marino PL. Improved use of arterial blood gas analysis in suspected pulmonary embolism. Chest 1989;95:48–51.

66. Stein PD, Goldhaber SZ, Henry JW, Miller AC. Arterial blood gas analysis in the assessment of suspected acute pulmonary embolism. Chest 1996;109:78–81.

67. Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic fi ndings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 1991;100:598–603.

68. Stein PD, Goldhaber SZ, Henry JW. Alveolar-arterial oxygen gradient in the assessment of acute pulmonary embolism. Chest 1995;107:139–143.

69. Ely EW, Smith JM, Haponik EF. Pulmonary embolism and normal oxygenation: application of PIOPED-derived likelihood ratios. Am J Med 1997;103:541–544.

70. Perrier A, Desmarais S, Goehring C, et al. D-Dimer testing for suspected pulmonary embolism in outpatients. Am J Respir Crit Care Med 1997;156:492–496.

71. Perrier A. D-dimer for suspected pulmonary embolism: whom should we test? Chest 2004;125:807–809.

72. Goldstein NM, Kollef MH, Ward S, Gage BF. The impact of the introduction of a rapid D-dimer assay on the diagnostic evalu-ation of suspected pulmonary embolism. Arch Intern Med 2001;161:567–571.

73. Brown MD, Rowe BH, Reeves MJ, Bermingham JM, Goldhaber SZ. The accuracy of the enzyme-linked immunosorbent assay D-dimer test in the diagnosis of pulmonary embolism: a meta-analysis. Ann Emerg Med 2002;40:133–144.

74. Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a sys-tematic review. Ann Intern Med 2004;140:589–602.

75. Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: manage-ment of patients with suspected pulmonary embolism present-ing to the emergency department by using a simple clinical model and D-dimer. Ann Intern Med 2001;135:98–107.

76. Dunn KL, Wolf JP, Dorfman DM, Fitzpatrick P, Baker JL, Gold-haber SZ. Normal D-dimer levels in emergency department patients suspected of acute pulmonary embolism. J Am Coll Cardiol 2002;40:1475–1478.

77. Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003;349:1227–1235.

78. Bates SM, Kearon C, Crowther M, et al. A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis. Ann Intern Med 2003;138:787–794.

79. Kearon C, Ginsberg JS, Douketis J, et al. Management of sus-pected deep venous thrombosis in outpatients by using clinical assessment and D-dimer testing. Ann Intern Med 2001;135:108–111.

80. Rathbun SW, Whitsett TL, Raskob GE. Negative D-dimer result to exclude recurrent deep venous thrombosis: a manage-ment trial. Ann Intern Med 2004;141:839–845.

81. Pruszczyk P, Bochowicz A, Torbicki A, et al. Cardiac troponin T monitoring identifi es high-risk group of normotensive patients with acute pulmonary embolism. Chest 2003;123:1947–1952.

82. Kucher N, Wallmann D, Carone A, Windecker S, Meier B, Hess OM. Incremental prognostic value of troponin I and echocar-diography in patients with acute pulmonary embolism. Eur Heart J 2003;24:1651–1656.

83. Kruger S, Graf J, Merx MW, et al. Brain natriuretic peptide predicts right heart failure in patients with acute pulmonary embolism. Am Heart J 2004;147:60–65.

84. Kucher N, Printzen G, Doernhoefer T, Windecker S, Meier B, Hess OM. Low pro-brain natriuretic peptide levels predict benign clinical outcome in acute pulmonary embolism. Circu-lation 2003;107:1576–1578.

85. Kucher N, Printzen G, Goldhaber SZ. Prognostic role of brain natriuretic peptide in acute pulmonary embolism. Circulation 2003;107:2545–2547.

86. Goldhaber SZ. Cardiac biomarkers in pulmonary embolism. Chest 2003;123:1782–1784.

87. Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratifi ca-tion of patients with acute pulmonary embolism. Circulation 2003;108:2191–2194.

88. Hull RD, Hirsh J, Carter CJ, et al. Diagnostic value of ventila-tion-perfusion lung scanning in patients with suspected pul-monary embolism. Chest 1985;88:819–828.

89. Alderson PO, Martin EC. Pulmonary embolism: diagnosis with multiple imaging modalities. Radiology 1987;164:297–312.

90. Hull RD, Raskob GE, Coates G, Panju AA. Clinical validity of a normal perfusion lung scan in patients with suspected pul-monary embolism. Chest 1990;97:23–26.



91. Webber MM, Gomes AS, Roe D, La Fontaine RL, Hawkins RA. Comparison of Biello, McNeil, and PIOPED criteria for the diagnosis of pulmonary emboli on lung scans. AJR Am J Roent-genol 1990;154:975–981.

92. The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA 1990;263:2753–2759.

93. Moser KM, Fedullo PF, LitteJohn JK, Crawford R. Frequent asymptomatic pulmonary embolism in patients with deep venous thrombosis [published correction appears in JAMA 1994;271:1908]. JAMA 1994;271:223–225.

94. McNeil BJ. Ventilation-perfusion studies and the diagnosis of pulmonary embolism: concise communication. J Nucl Med 1980;21:319–323.

95. Hull RD, Hirsh J, Carter CJ, et al. Pulmonary angiography, ventilation lung scanning, and venography for clinically sus-pected pulmonary embolism with abnormal perfusion lung scan. Ann Intern Med 1983;98:891–899.

96. Kipper MS, Moser KM, Kortman KE, Ashburn WL. Long-term follow-up of patients with suspected pulmonary embolism and a normal lung scan. Perfusion scans in embolic suspects. Chest 1982;82:411–415.

97. Kelley MA, Carson JL, Palevsky HI, Schwartz JS. Diagnosing pulmonary embolism: new facts and strategies. Ann Intern Med 1991;114:300–306.

98. Alderson PO, Rujanavech N, Secker-Walker RH, McKnight RC. The role of 133Xe ventilation studies in the scintigraphic detec-tion of pulmonary embolism. Radiology 1976;120:633–640.

99. Cheeley R, McCartney WH, Perry JR. The role of noninvasive tests versus pulmonary angiography in the diagnosis of pulmo-nary embolism. Am J Med 1981;70:17–22.

100. Goodman LR, Lipchik RJ. Diagnosis of acute pulmonary embo-lism: time for a new approach. Radiology 1996;199:25–27.

101. Mayo JR, Remy-Jardin M, Muller NL, et al. Pulmonary embo-lism: prospective comparison of spiral CT with ventilation-perfusion scintigraphy. Radiology 1997;205:447–452.

102. Cross JJ, Kemp PM, Walsh CG, Flower CD, Dixon AK. A ran-domized trial of spiral CT and ventilation perfusion scintigra-phy for the diagnosis of pulmonary embolism. Clin Radiol 1998;53:177–182.

103. van Erkel AR, Pattynama PM. Cost-effective diagnostic algo-rithms in pulmonary embolism: an updated analysis. Acad Radiol 1998;5(suppl 2):S321–S327.

104. Perrier A, Desmarais S, Miron M-J, et al. Non-invasive diagno-sis of venous thromboembolism in outpatients. Lancet 1999;353:190–195.

105. Kruip MJ, Leclercq MG, van der Heul C, Prins MH, Buller HR. Diagnostic strategies for excluding pulmonary embolism in clinical outcome studies. A systematic review. Ann Intern Med 2003;138:941–951.

106. Perrier A, Nendaz MR, Sarasin FP, Howarth N, Bounameaux H. Cost-effectiveness analysis of diagnostic strategies for suspected pulmonary embolism including helical computed tomography. Am J Respir Crit Care Med 2003;167:39–44.

107. Khan A, Cann AD, Shah RD. Imaging of acute pulmonary emboli. Thorac Surg Clin 2004;14:113–124.

108. Kanne JP, Lalani TA. Role of computed tomography and magnetic resonance imaging for deep venous thrombosis and pulmonary embolism. Circulation 2004;109(12 suppl 1):I15–I21.

109. Ferretti GR, Bosson JL, Buffaz PD, et al. Acute pulmonary embolism: role of helical CT in 164 patients with intermediate probability at ventilation-perfusion scintigraphy and normal results at duplex US of the legs. Radiology 1997;205:453–458.

110. Garg K, Welsh CH, Feyerabend AJ, et al. Pulmonary embolism: diagnosis with spiral CT and ventilation-perfusion scanning—

correlation with pulmonary angiographic results or clinical outcome. Radiology 1998;208:201–208.

111. van Strijen MJ, de Monye W, Schiereck J, et al. Advances in New Technologies Evaluating the Localisation of Pulmonary Embolism Study Group. Single-detector helical computed tomography as the primary diagnostic test in suspected pulmo-nary embolism: a multicenter clinical management study of 510 patients [published correction appears in Ann Intern Med 2003;139(5 pt 1):387]. Ann Intern Med 2003;138:307–314.

112. Remy-Jardin M, Remy J, Wattinne L, Giraud F. Central pulmo-nary thromboembolism: diagnosis with spiral volumetric CT with the single-breath-hold technique—comparison with pul-monary angiography. Radiology 1992;185:381–387.

113. Schoepf UJ, Kucher N, Kipfmueller F, Quiroz R, Costello P, Goldhaber SZ. Right ventricular enlargement on chest com-puted tomography: a predictor of early death in acute pulmo-nary embolism. Circulation 2004;110:3276–3280.

114. Kipfmueller F, Quiroz R, Kucher NC, Costello P, Goldhaber SZ, Schoepf UJ. Reversal of right ventricular enlargement on mul-tidetector-row chest CT following thrombolysis or surgical embolectomy in patients with acute pulmonary embolism. Cir-culation 2004;110(17 suppl 3):III370.

115. Teigen CL, Maus TP, Sheedy PF II, et al. Pulmonary embolism: diagnosis with contrast-enhanced electron-beam CT and com-parison with pulmonary angiography. Radiology 1995;194:313–319.

116. Remy-Jardin M, Remy J, Deschildre F, et al. Diagnosis of pul-monary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology 1996;200:699–706.

117. Moores LK, Jackson WL Jr, Shorr AF, Jackson JL. Meta-analysis: outcomes in patients with suspected pulmonary embolism managed with computed tomographic pulmonary angiography. Ann Intern Med 2004;141:866–874.

118. Perrier A, Howarth N, Didier D, et al. Performance of helical computed tomography in unselected outpatients with suspected pulmonary embolism. Ann Intern Med 2001;135:88–97.

119. Hansell DM, Flower CD. Imaging pulmonary embolism. A new look with spiral computed tomography. BMJ 1998;316:490–491.

120. Rathbun SW, Raskob GE, Whitsett TL. Sensitivity and specifi c-ity of helical computed tomography in the diagnosis of pulmo-nary embolism: a systematic review. Ann Intern Med 2000;132:227–232.

121. Schoepf UJ, Goldhaber SZ, Costello P. Spiral computed tomog-raphy for acute pulmonary embolism. Circulation 2004;109:2160–2167.

122. Pengo V, Lensing AW, Prins MH, et al. Thromboembolic Pul-monary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257–2264.

123. Gottschalk A, Stein PD, Goodman LR, Sostman HD. Overview of Prospective Investigation of Pulmonary Embolism Diagno-sis II. Semin Nucl Med 2002;32:173–182.

124. Cronan JJ. Venous thromboembolic disease: the role of US. Radiology 1993;186:619–630.

125. Turkstra F, Kuijer PM, van Beek EJ, Brandjes DP, ten Cate JW, Buller HR. Diagnostic utility of ultrasonography of leg veins in patients suspected of having pulmonary embolism. Ann Intern Med 1997;126:775–781.

126. Lensing AW, Doris CI, McGrath FP, et al. A comparison of compression ultrasound with color Doppler ultrasound for the diagnosis of symptomless postoperative deep vein thrombosis. Arch Intern Med 1997;157:765–768.

127. Birdwell BG, Raskob GE, Whitsett TL, et al. The clinical valid-ity of normal compression ultrasonography in outpatients sus-pected of having deep venous thrombosis. Ann Intern Med 1998;128:1–7.


219 6 c h a p t e r 10 4

128. Kearon C, Julian JA, Newman TE, Ginsberg JS. Noninvasive diagnosis of deep venous thrombosis. McMaster Diagnostic Imaging Practice Guidelines Initiative [published correction appears in Ann Intern Med 1998;129:425]. Ann Intern Med 1998;128:663–677.

129. Kearon C, Ginsberg JS, Hirsh J. The role of venous ultrasonog-raphy in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. Ann Intern Med 1998;129:1044–1049.

130. Bone RC. Ventilation/perfusion scan in pulmonary embolism. “The emperor is incompletely attired.” JAMA 1990;263:2794–2795.

131. ACCP Consensus Committee on Pulmonary Embolism. Opin-ions regarding the diagnosis and management of venous throm-boembolic disease. Chest 1996;109:233–237.

132. Perrier A, Roy PM, Aujesky D, et al. Diagnosing pulmonary embolism in outpatients with clinical assessment, D-dimer measurement, venous ultrasound, and helical computed tomog-raphy: a multicenter management study. Am J Med 2004;116:291–299.

133. Musset D, Parent F, Meyer G, et al. Evaluation du Scanner Spirale dans l’Embolie Pulmonaire study group. Diagnostic strategy for patients with suspected pulmonary embolism: a prospective multicentre outcome study. Lancet 2002;360:1914–1920.

134. Bockenstedt P. D-dimer in venous thromboembolism. N Engl J Med 2003;349:1203–1204.

135. Katz DS, Loud PA, Bruce D, et al. Combined CT venography and pulmonary angiography: a comprehensive review. Radio-graphics 2002;22(spec):S3–S19.

136. Mayo JR, Ketai LH. In discussion of: Combined CT venography and pulmonary angiography: a comprehensive review. Radio-graphics 2002;22(spec):S20–S24.

137. Weinmann EE, Salzman EW. Deep-vein thrombosis. N Engl J Med 1994;331:1630–1641.

138. Hull R, Hirsh J, Sackett DL, et al. Clinical validity of a negative venogram in patients with clinically suspected venous throm-bosis. Circulation 1981;64:622–625.

139. Agnelli G, Ranucci V, Veschi F, Rinonapoli E, Lupattelli L, Nenci GG. Clinical outcome of orthopaedic patients with nega-tive lower limb venography at discharge. Thromb Haemost 1995;74:1042–1044.

140. Anderson DR, Gross M, Robinson KS, et al. Ultrasonographic screening for deep vein thrombosis following arthroplasty fails to reduce posthospital thromboembolic complications: the Postarthroplasty Screening Study (PASS). Chest 1998;114(2 suppl):119S–122S.

141. Alexander JK, Gonzalez DA, Fred HL. Angiographic studies in cardiorespiratory diseases. Special reference to thromboembo-lism. JAMA 1966;198:575–578.

142. Ferris EJ, Stanzler RM, Rourke JA, Blumenthal J, Messer JV. Pulmonary angiography in pulmonary embolic disease. Am J Roentgenol Radium Ther Nucl Med 1967;100:355–363.

143. Lowman RM, Reardon J, Hipona FA, Stern H, Toole AL. The role of pulmonary angiography in pulmonary embolism. A com-prehensive review of the roentgen fi ndings. Angiology 1967;18:291–305.

144. Peterson KL, Fred HL, Alexander JK. Pulmonary arterial webs. A new angiographic sign of previous thromboembolism. N Engl J Med 1967;277:33–35.

145. Auger WR, Fedullo PF, Moser KM, Buchbinder M, Peterson KL. Chronic major-vessel thromboembolic pulmonary artery obstruction: appearance at angiography. Radiology 1992;182:393–398.

146. Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thrombo-embolic pulmonary hypertension. N Engl J Med 2001;345:1465–1472.

147. Wolfe MW, Lee RT, Feldstein ML, Parker JA, Come PC, Gold-haber SZ. Prognostic signifi cance of right ventricular hypoki-nesis and perfusion lung scan defects in pulmonary embolism. Am Heart J 1994;127:1371–1375.

148. Kasper W, Konstantinides S, Geibel A, et al. Management strat-egies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 1997;30:1165–1171.

149. Goldhaber SZ. Pulmonary embolism thrombolysis: broadening the paradigm for its administration. Circulation 1997;96:716–718.

150. Goldhaber SZ. Echocardiography in the management of pulmo-nary embolism. Ann Intern Med 2002;136:691–700.

151. Grifoni S, Vanni S, Pieralli F, et al. Prevalence, risk factors, and long-term outcome of patients with pulmonary embolism and persistent right ventricular dysfunction. Circulation 2004;11(17 suppl 3):III454.

152. Ribeiro A, Lindmarker P, Juhlin-Dannfelt A, Johnsson H, Jor-feldt L. Echocardiography Doppler in pulmonary embolism: right ventricular dysfunction as a predictor of mortality rate. Am Heart J 1997;134:479–487.

153. Konstantinides S, Geibel A, Olschewski M, et al. Association between thrombolytic treatment and the prognosis of hemody-namically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation 1997;96:882–888.

154. Goldhaber SZ, Haire WD, Feldstein ML, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assess-ing right-ventricular function and pulmonary perfusion. Lancet 1993;341:507–511.

155. Goldhaber SZ. Pulmonary embolism for cardiologists. J Am Coll Cardiol 1997;30:1172–1173.

156. Ribeiro A, Lindmarker P, Johnsson H, Juhlin-Dannfelt A, Jorfeldt L. Pulmonary embolism: one-year follow-up with echocardiography Doppler and fi ve-year survival analysis. Cir-culation 1999;99:1325–1330.

157. Konstantinides S, Geibel A, Kasper W, Olschewski M, Blumel L, Just H. Patent foramen ovale is an important predictor of adverse outcome in patients with major pulmonary embolism. Circulation 1998;97:1946–1951.

158. Kasper W, Meinertz T, Henkel B, et al. Echocardiographic fi nd-ings in patients with proved pulmonary embolism. Am Heart J 1986;112:1284–1290.

159. Come PC. Echocardiographic evaluation of pulmonary embo-lism and its response to therapeutic interventions. Chest 1992;101(4 suppl):151S–162S.

160. Rittoo D, Sutherland GR, Samuel L, Flapan AD, Shaw TR. Role of transesophageal echocardiography in diagnosis and manage-ment of central pulmonary artery thromboembolism. Am J Cardiol 1993;71:1115–1118.

161. McConnell MV, Solomon SD, Rayan ME, Come PC, Goldhaber SZ, Lee RT. Regional right ventricular dysfunction detected by echocardiography in acute pulmonary embolism. Am J Cardiol 1996;78:469–473.

162. Chartier L, Bera J, Delomez M, et al. Free-fl oating thrombi in the right heart: diagnosis, management, and prognostic indexes in 38 consecutive patients. Circulation 1999;99:2779–2783.

163. Pruszczyk P, Torbicki A, Pacho R, et al. Noninvasive diagnosis of suspected severe pulmonary embolism: transesophageal echocardiography vs spiral CT. Chest 1997;112:722–728.

164. White RD, Winkler ML, Higgins CB. MR imaging of pulmo-nary arterial hypertension and pulmonary emboli. AJR Am J Roentgenol 1987;149:15–21.

165. Gupta A, Frazer CK, Ferguson JM, et al. Acute pulmonary embolism: diagnosis with MR angiography. Radiology 1999;210:353–359.

166. Meaney JF, Weg JG, Chenevert TL, Stafford-Johnson D, Hamil-ton BH, Prince MR. Diagnosis of pulmonary embolism with



magnetic resonance angiography. N Engl J Med 1997;336:1422–1427.

167. Ellis D. Acute pulmonary embolism: advances in imaging. Br J Hosp Med 1997;58:393–396.

168. Yucel EK. Pulmonary MR angiography: is it ready now? Radiol-ogy 1999;210:301–303.

169. Evans AJ, Sostman HD, Witty LA, et al. Detection of deep venous thrombosis: prospective comparison of MR imaging and sonography. J Magn Reson Imaging 1996;6:44–51.

170. Fraser DG, Moody AR, Morgan PS, Martel AL, Davidson I. Diagnosis of lower-limb deep venous thrombosis: a prospective blinded study of magnetic resonance direct thrombus imaging. Ann Intern Med 2002;136:89–98.

171. Uchida Y, Oshima T, Hirose J, Sasaki T, Morizuki S, Morita T. Angioscopic detection of residual pulmonary thrombi in the differential diagnosis of pulmonary embolism. Am Heart J 1995;130:854–859.

172. Sagar KB, Rhyne TL, Greenfi eld LJ. Echocardiographic tissue characterization and range-gated Doppler ultrasound for the diagnosis of pulmonary embolism. Circulation 1983;67:365–370.

173. Kato C, Matsuyama H, Kondo T, et al. Clinical evaluation of acute and chronic pulmonary thromboembolism using intra-vascular ultrasound and angioscopy [in Japanese]. J Cardiol 1999;34:317–324.

174. Simonneau G, Azarian R, Brenot F, Dartevelle PG, Musset D, Duroux P. Surgical management of unresolved pulmonary embolism. A personal series of 72 patients. Chest 1995;107(1 suppl):52S–55S.

175. Good CA, Holman CB. Cavitary carcinoma of the lung: roent-genographic features in 19 cases. Dis Chest 1960;37:289–293.

176. Dodd GD, Boyle JJ. Excavating pulmonary metastases. Am J Roentgenol Radium Ther Nucl Med 1961;85:277–293.

177. Sherrick DW, Kincaid OW, DuShane JW. Agenesis of a main branch of the pulmonary artery. Am J Roentgenol Radium Ther Nucl Med 1962;87:917–928.

178. Ahdout DJ, Damani P, Ultan LB. Recurrent acute pulmonary emboli in association with acute myocardial infarction. Chest 1989;96:682–684.

179. Barritt DW, Jordan SC. Clinical features of pulmonary embo-lism. Lancet 1961;1:729–732.

180. Richards P. Pulmonary oedema and intracranial lesions. Br Med J 1963;2:83–86.

181. Surawicz B. Electrocardiographic pattern of cerebrovascular accident. JAMA 1966;197:913–914.

182. Ireland P, Sapira JD, Templeton B. Munchausen’s syndrome. Review and report of an additional case. Am J Med 1967;43:579–592.

183. Bluemle LW Jr. Acute tubular necrosis: analysis of one hundred cases with respect to mortality, complications, and treatment with and without dialysis. Arch Intern Med 1959;104:180–197.

184. Krachman SL, Lodato RF, D’Alonzo GE. Managing the acute chest syndrome in sickle cell patients. J Crit Illn 1994;9:375–392.

185. Stahl RL, Javid JP, Lackner H. Unrecognized pulmonary embo-lism presenting as disseminated intravascular coagulation. Am J Med 1984;76:772–778.

186. Fred HL, Allred DP, Garber HE, Retiene K, Lipscomb H. Pheo-chromocytoma masquerading as overwhelming infection. Am Heart J 1967;73:149–154.

187. Richmond J, Frazer SC, Millar DR. Paroxysmal hypotension due to an adrenaline-secreting phaeochromocytoma. Lancet 1961;2:904–906.

188. Sproule BJ, Phillipson EA, Couves CM, Brownlee RT. Acute pulmonary hypertension in idiopathic lactic acidosis. Can Med Assoc J 1966;94:141–143.

189. Stephens JH, Fred HL. Petechiae associated with systemic fat embolism. Arch Dermatol 1962;86:515–517.

190. Masson RG, Ruggieri J. Pulmonary microvascular cytology. A new diagnostic application of the pulmonary artery catheter. Chest 1985;88:908–914.

191. Babar SI, Sobonya RE, Snyder LS. Pulmonary microvascular cytology for the diagnosis of pulmonary tumor embolism. West J Med 1998;168:47–50.

192. Bailey H. Air embolism. J Int Coll Surg 1956;25:675–688. 193. Hirsh J. Antithrombotic therapy in deep vein thrombosis and

pulmonary embolism. Am Heart J 1992;123:1115–1122. 194. Clagett GP, Anderson FA Jr, Heit J, Levine MN, Wheeler HB.

Prevention of venous thromboembolism. Chest 1995;108(4 suppl):312S–334S.

195. Prevention of venous thromboembolism. International Con-sensus Statement (guidelines according to scientifi c evidence). Int Angiol 1997;16:3–38.

196. Morehead RS, Tzouanakis AE, Berger R. Preventing VTE: a guide to nonpharmacologic therapies. J Crit Illn 1998;13:486.

197. Halkin H, Goldberg J, Modan M, Modan B. Reduction of mor-tality in general medical in-patients by low-dose heparin pro-phylaxis. Ann Intern Med 1982;96:561–565.

198. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. BMJ 1994;308:235–246.

199. Cohen AT, Skinner JA, Kakkar VV. Antiplatelet treatment for thromboprophylaxis: a step forward or backwards? BMJ 1994;309:1213–1215.

200. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous throm-boembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999;341:793–800.

201. Hirsch DR, Ingenito EP, Goldhaber SZ. Prevalence of deep venous thrombosis among patients in medical intensive care. JAMA 1995;274:335–337.

202. Ryskamp RP, Trottier SJ. Utilization of venous thromboembo-lism prophylaxis in a medical-surgical ICU. Chest 1998;113:162–164.

203. Goldhaber SZ. Venous thromboembolism in the intensive care unit: the last frontier for prophylaxis. Chest 1998;113:5–7.

204. Abernethy EA, Hartsuck JM. Postoperative pulmonary embo-lism. A prospective study utilizing low dose heparin. Am J Surg 1974;128:739–742.

205. Prevention of fatal postoperative pulmonary embolism by low doses of heparin. An international multicentre trial. Lancet 1975;2:45–51.

206. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med 1988;318:1162–1173.

207. Nurmohamed MT, Rosendaal FR, Buller HR, et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992;340:152–156.

208. Jorgensen LN, Wille-Jorgensen, Hauch O. Prophylaxis of post-operative thromboembolism with low molecular weight hepa-rins. Br J Surg 1993;80:689–704.

209. Bergqvist D, Matzsch T, Burmark US, et al. Low molecular weight heparin given the evening before surgery compared with conventional low-dose heparin in prevention of thrombo-sis [published correction appears in Br J Surg 1988;75:1077]. Br J Surg 1988;75:888–891.


219 8 c h a p t e r 10 4

210. Caen JP. A randomized double-blind study between a low molecular weight heparin Kabi 2165 and standard heparin in the prevention of deep vein thrombosis in general surgery. A French multicenter trial. Thromb Haemost 1988;59:216–220.

211. Ramos R, Salem BI, De Pawlikowski MP, Coordes C, Eisenberg S, Leidenfrost R. The effi cacy of pneumatic compression stock-ings in the prevention of pulmonary embolism after cardiac surgery. Chest 1996;109:82–85.

212. Turpie AG, Levine MN, Hirsh J, et al. A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery. N Engl J Med 1986;315:925–929.

213. Mohr DN, Silverstein MD, Murtaugh PA, Harrison JM. Prophy-lactic agents for venous thrombosis in elective hip surgery. Meta-analysis of studies using venographic assessment. Arch Intern Med 1993;153:2221–2228.

214. Leclerc JR, Gent M, Hirsh J, Geerts WH, Ginsberg JS. The incidence of symptomatic venous thromboembolism during and after prophylaxis with enoxaparin: a multi-institutional cohort study of patients who underwent hip or knee arthro-plasty. Canadian Collaborative Group. Arch Intern Med 1998;158:873–878.

215. Hirsh J. Evidence for the needs of out-of-hospital thrombosis prophylaxis: introduction. Chest 1998;114(2 suppl):113S–114S.

216. de Valk HW, Banga JD, Wester JW, et al. Comparing subcutane-ous danaparoid with intravenous unfractionated heparin for the treatment of venous thromboembolism. A randomized con-trolled trial. Ann Intern Med 1995;123:1–9.

217. Eriksson BI, Ekman S, Kalebo P, Zachrisson B, Bach D, Close P. Prevention of deep-vein thrombosis after total hip replace-ment: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996;347:635–639.

218. Eriksson BI, Wille-Jorgensen P, Kalebo P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997;337:1329–1335.

219. Leyvraz PF, Richard J, Bachmann F, et al. Adjusted versus fi xed-dose subcutaneous heparin in the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 1983;309:954–958.

220. Lieberman JR, Wollaeger J, Dorey F, et al. The effi cacy of pro-phylaxis with low-dose warfarin for prevention of pulmonary embolism following total hip arthroplasty. J Bone Joint Surg Am 1997;79:319–325.

221. Imperiale TF, Speroff T. A meta-analysis of methods to prevent venous thromboembolism following total hip replacement [published correction appears in JAMA 1995;273:288]. JAMA 1994;271:1780–1785.

222. Hull RD, Raskob GE, Gent M, et al. Effectiveness of intermit-tent pneumatic leg compression for preventing deep vein thrombosis after total hip replacement. JAMA 1990;263:2313–2317.

223. Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of venous thromboembolism after knee arthroplasty. A random-ized, double-blind trial comparing enoxaparin with warfarin. Ann Intern Med 1996;124:619–626.

224. Levine MN, Gent M, Hirsh J, et al. Ardeparin (low-molecular-weight heparin) vs graduated compression stockings for the prevention of venous thromboembolism. A randomized trial in patients undergoing knee surgery. Arch Intern Med 1996;156:851–856.

225. Chandhoke PS, Gooding GA, Narayan P. Prospective random-ized trial of warfarin and intermittent pneumatic leg compres-sion as prophylaxis for postoperative deep venous thrombosis in major urological surgery. J Urol 1992;147:1056–1059.

226. Turpie AG, Hirsh J, Gent M, Julian D, Johnson J. Prevention of deep vein thrombosis in potential neurosurgical patients. A

randomized trial comparing graduated compression stockings alone or graduated compression stockings plus intermittent pneumatic compression with control. Arch Intern Med 1989;149:679–681.

227. Agnelli G, Piovella F, Buoncristiani P, et al. Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elec-tive neurosurgery. N Engl J Med 1998;339:80–85.

228. Catre MG. Anticoagulation in spinal surgery. A critical review of the literature. Can J Surg 1997;40:413–419.

229. Geerts WH, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996;335:701–707.

230. Green D, Lee MY, Ito VY, et al. Fixed- vs adjusted-dose heparin in the prophylaxis of thromboembolism in spinal cord injury. JAMA 1988;260:1255–1258.

231. Hunt BJ, Doughty HA, Majumdar G, et al. Thromboprophy-laxis with low molecular weight heparin (Fragmin) in high risk pregnancies. Thromb Haemost 1997;77:39–43.

232. Leizorovicz A, Mismetti P. Preventing venous thromboembo-lism in medical patients. Circulation 2004;110(24 suppl 1):IV13–19.

233. Lassen MR, Bauer KA, Eriksson BI, Turpie AG. European Pen-tasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elec-tive hip-replacement surgery: a randomised double-blind com-parison. Lancet 2002;359:1715–1720.

234. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Superiority of fondaparinux over enoxaparin in preventing venous thrombo-embolism in major orthopedic surgery using different effi cacy end points. Chest 2004;126:501–508.

235. Bauer KA, Eriksson BI, Lassen MR, Turpie AG. Steering Com-mittee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345:1305–1310.

236. Lieberman JR, Sung R, Dorey F, Thomas BJ, Kilgus DJ, Finerman GA. Low-dose warfarin prophylaxis to prevent symp-tomatic pulmonary embolism after total knee arthroplasty. J Arthroplasty 1997;12:180–184.

237. Hirsh J, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, effi cacy, and safety. Chest 1992;102(4 suppl):337S–351S.

238. Brill-Edwards P, Ginsberg JS, Johnston M, Hirsh J. Establishing a therapeutic range for heparin therapy. Ann Intern Med 1993;119:104–109.

239. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986;315:1109–1114.

240. Cruickshank MK, Levine MN, Hirsh J, Roberts R, Siguenza M. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991;151:333–337.

241. Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern Med 1993;119:874–881.

242. Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA. Rela-tion between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 1997;157:2562–2568.

243. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990;322:1260–1264.



244. Tapson VF, Hull RD. Management of venous thromboembolic disease. The impact of low-molecular-weight heparin. Clin Chest Med 1995;16:281–294.

245. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecu-lar-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proxi-mal deep-vein thrombosis. N Engl J Med 1996;334:677–681.

246. Koopman MM, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group [published correction appears in N Engl J Med 1997;337:1251]. N Engl J Med 1996;334:682–687.

247. Weitz JI. Low-molecular-weight heparins [published correction appears in N Engl J Med 1997;337:1567]. N Engl J Med 1997;337:688–698.

248. Koopman MM, Buller HR. Low-molecular-weight heparins in the treatment of venous thromboembolism. Ann Intern Med 1998;128:1037–1039.

249. Antman EM, Handin R. Low-molecular-weight heparins: an intriguing new twist with profound implications. Circulation 1998;98:287–289.

250. Aguilar D, Goldhaber SZ. Clinical uses of low-molecular-weight heparins. Chest 1999;115:1418–1423.

251. Merli G, Spiro TE, Olsson CG, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Enoxaparin Clinical Trial Group. Ann Intern Med 2001;134:191–202.

252. Hull RD, Raskob GE, Brant RF, et al. Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. American-Canadian Thrombosis Study Group. Arch Intern Med 2000;160:229–236.

253. ACCP Consensus Committee on Pulmonary Embolism. Amer-ican College of Chest Physicians. Opinions regarding the diag-nosis and management of venous thromboembolic disease. Chest 1998;113:499–504.

254. Schafer AI. Low-molecular-weight heparin—an opportunity for home treatment of venous thrombosis. N Engl J Med 1996;334:724–725.

255. Simonneau G, Sors H, Charbonnier B, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinza-parine ou Heparine Standard: Evaluations dans l’Embolie Pul-monaire. N Engl J Med 1997;337:663–669.

256. The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997;337:657–662.

257. Bates SM, Ginsberg JS. How we manage venous thromboembo-lism during pregnancy. Blood 2002;100:3470–3478.

258. Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 suppl):627S–644S.

259. Hirsh J, Dalen JE, Deykin D, Poller L. Oral anticoagulants. Mechanism of action, clinical effectiveness, and optimal thera-peutic range. Chest 1992;102(4 suppl):312S–326S.

260. Gallus A, Jackaman J, Tillett J, Mills W, Wycherley A. Safety and effi cacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 1986;2:1293–1296.

261. Rosiello RA, Chan CK, Tencza F, Matthay RA. Timing of oral anticoagulation therapy in the treatment of angiographically proven acute pulmonary embolism. Arch Intern Med 1987;147:1469–1473.

262. Schulman S, Rhedin AS, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after

a fi rst episode of venous thromboembolism. Duration of Anti-coagulation Trial Study Group. N Engl J Med 1995;332:1661–1665.

263. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphos-pholipid-antibody syndrome. N Engl J Med 1995;332:993–997.

264. Hull RD, Pineo GF. Current concepts of anticoagulation therapy. Clin Chest Med 1995;16:269–280.

265. Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pul-monary embolism. Lancet 1992;340:873–876.

266. Hirsh J. The optimal duration of anticoagulant therapy for venous thrombosis. N Engl J Med 1995;332:1710–1711.

267. Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 suppl):401S–428S.

268. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a fi rst episode of idiopathic venous thromboembolism [published cor-rection appears in N Engl J Med 1999;341:298]. N Engl J Med 1999;340:901–907.

269. Schafer AI. Venous thrombosis as a chronic disease. N Engl J Med 1999;340:955–956.

270. Agnelli G, Prandoni P, Santamaria MG, et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. N Engl J Med 2001;345:165–169.

271. Agnelli G, Prandoni P, Becattini C, et al. Extended oral antico-agulant therapy after a fi rst episode of pulmonary embolism. Warfarin Optimal Duration Italian Trial Investigators. Ann Intern Med 2003;139:19–25.

272. Palareti G, Legnani C, Cosmi B, et al. Predictive value of D-dimer test for recurrent venous thromboembolism after anti-coagulation withdrawal in subjects with a previous idiopathic event and in carriers of congenital thrombophilia. Circulation 2003;108:313–318.

273. Goldhaber SZ. Pulmonary embolism. N Engl J Med 1998;339:93–104.

274. Bauer KA. The thrombophilias: well-defi ned risk factors with uncertain therapeutic implications. Ann Intern Med 2001;135:367–373.

275. Stein PD, Hull RD, Raskob G. Risks for major bleeding from thrombolytic therapy in patients with acute pulmonary embo-lism. Consideration of noninvasive management. Ann Intern Med 1994;121:313–317.

276. Urokinase Pulmonary Embolism Trial. Phase 1 results. A coop-erative study. JAMA 1970;214:2163–2172.

277. Urokinase-Streptokinase Embolism Trial. Phase 2 results. A cooperative study. JAMA 1974;229:1606–1613.

278. Goldhaber SZ, Kessler CM, Heit J, et al. Randomised controlled trial of recombinant tissue plasminogen activator versus uro-kinase in the treatment of acute pulmonary embolism. Lancet 1988;2:293–298.

279. Meyer G, Sors H, Charbonnier B, et al. Effects of intravenous urokinase versus alteplase on total pulmonary resistance in acute massive pulmonary embolism: a European multicenter double-blind trial. The European Cooperative Study Group for Pulmonary Embolism. J Am Coll Cardiol 1992;19:239–245.

280. Arcasoy SM, Kreit JW. Thrombolytic therapy of pulmonary embolism: a comprehensive review of current evidence. Chest 1999;115:1695–1707.

281. Come PC, Kim D, Parker JA, Goldhaber SZ, Braunwald E, Markis JE. Early reversal of right ventricular dysfunction in patients with acute pulmonary embolism after treatment with intravenous tissue plasminogen activator. J Am Coll Cardiol 1987;10:971–978.


2 2 0 0 c h a p t e r 10 4

282. Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmo-nary embolism: is it effective? Is it safe? When is it indicated? Arch Intern Med 1997;157:2550–2556.

283. Meneveau N, Blonde MC, Legalery P, et al. Rescue surgical embolectomy compared with repeat thrombolysis after unsuc-cessful thrombolysis in acute pulmonary embolism. Circula-tion 2004;110(17 suppl 3):III453.

284. Kreit JW. The impact of right ventricular dysfunction on the prognosis and therapy of normotensive patients with pulmo-nary embolism. Chest 2004;125:1539–1545.

285. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W; Management Strategies and Prognosis of Pulmonary Embo-lism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143–1150.

286. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 2004;110:744–749.

287. Levine M, Hirsh J, Weitz J, et al. A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen acti-vator in patients with acute pulmonary embolism. Chest 1990;98:1473–1479.

288. A collaborative study by the PIOPED Investigators. Tissue plas-minogen activator for the treatment of acute pulmonary embo-lism. Chest 1990;97:528–533.

289. Dalla-Volta S, Palla A, Santolicandro A, et al. PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen Activator Italian Multicenter Study 2. J Am Coll Cardiol 1992;20:520–526.

290. Ahearn GS, Hadjiliadis D, Tapson VF, Govert JA. Thrombolytic therapy with tissue plasminogen activator (TPA) in the fi rst trimester of pregnancy after massive pulmonary embolism (PE). Chest 1999;116(4 suppl 2):405S–406S.

291. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397–402.

292. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous strepto-kinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349–360.

293. Bobbio M, Bergerone S, Maggioni AP, et al. Administration of thrombolytic therapy to 17,944 patients with acute myocardial infarction: the GISSI-3 database. GISSI-3 Investigators. Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocar-dio. Am Heart J 1998;135:443–448.

294. Daniels LB, Parker JA, Patel SR, Grodstein F, Goldhaber SZ. Relation of duration of symptoms with response to thrombo-lytic therapy in pulmonary embolism. Am J Cardiol 1997;80:184–188.

295. Bomalski JS, Martin GJ, Hughes RL, Yao JS. Inferior vena cava interruption in the management of pulmonary embolism. Chest 1982;82:767–774.

296. Greenfi eld LJ, Proctor MC. Current indications for caval inter-ruption: should they be liberalized in view of improving tech-nology? Semin Vasc Surg 1996;9:50–58.

297. Mansour M, Chang AE, Sindelar WF. Interruption of the infe-rior vena cava for the prevention of recurrent pulmonary embo-lism. Am Surg 1985;51:375–380.

298. Cohen JR, Tenenbaum N, Citron M. Greenfi eld fi lter as primary therapy for deep venous thrombosis and/or pulmonary embo-lism in patients with cancer. Surgery 1991;109:12–15.

299. Arnold TE, Karabinis VD, Mehta V, Dupont EL, Matsumoto T, Kerstein MD. Potential of overuse of the inferior vena cava fi lter. Surg Gynecol Obstet 1993;177:463–467.

300. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval fi lters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med 1998;338:409–415.

301. Rogers FB, Strindberg G, Shackford SR, et al. Five-year follow-up of prophylactic vena cava fi lters in high-risk trauma patients. Arch Surg 1998;133:406–411; discussion 412.

302. Haire WD. Vena caval fi lters for the prevention of pulmonary embolism. N Engl J Med 1998;338:463–464.

303. Streiff MB. Vena caval fi lters: a comprehensive review. Blood 2000;95:3669–3677.

304. Bovyn G, Gory P, Reynaud P, Ricco JB. The Tempofi lter: a multicenter study of a new temporary caval fi lter implantable for up to six weeks. Ann Vasc Surg 1997;11:520–528.

305. Neill AM, Appleton DS, Richards P. Retrievable inferior vena caval fi lter for thromboembolic disease in pregnancy. Br J Obstet Gynaecol 1997;104:1416–1418.

306. Vos LD, Tielbeek AV, Bom EP, Gooszen HC, Vroegindeweij D. The Gunther temporary inferior vena cava fi lter for short-term protection against pulmonary embolism. Cardiovasc Intervent Radiol 1997;20:91–97.

307. Neuerburg JM, Gunther RW, Vorwerk D, et al. Results of a multicenter study of the retrievable Tulip Vena Cava Filter: early clinical experience. Cardiovasc Intervent Radiol 1997;20:10–16.

308. Kercher K, Sing RF. Overview of current inferior vena cava fi lters. Am Surg 2003;69:643–648.

309. Shure D. Vena caval fi lters: what do we really know? Pulmon Perspect 2004;21(3):8–10.

310. Stoschitzky K, Stark G, Dacar D. Massive pulmonary embo-lism. N Engl J Med 1997;337:1561.

311. Aklog L, Williams CS, Byrne JG, Goldhaber SZ. Acute pulmo-nary embolectomy: a contemporary approach. Circulation 2002;105:1416–1419.

312. Yalamanchili K, Fleisher AG, Lehrman SG, et al. Open pulmo-nary embolectomy for treatment of major pulmonary embo-lism. Ann Thorac Surg 2004;77:819–823; discussion 823.

313. Glassford DM Jr, Alford WC Jr, Burrus GR, Stoney WS, Thomas CS Jr. Pulmonary embolectomy. Ann Thorac Surg 1981;32:28–32.

314. Crane C, Hartsuck J, Birtch A, et al. The management of major pulmonary embolism. Surg Gynecol Obstet 1969;128:27–36.

315. Sautter RD, Myers WO, Ray JF III, Wenzel FJ. Pulmonary embo-lectomy: review and current status. Prog Cardiovasc Dis 1975;17:371–389.

316. Fred HL, Natelson EA. Selection of patients for pulmonary embolectomy. Dis Chest 1969;56:139–142.

317. Timsit JF, Reynaud P, Meyer G, Sors H. Pulmonary embolec-tomy by catheter device in massive pulmonary embolism. Chest 1991;100:655–658.

318. Greenfi eld LJ, Proctor MC, Williams DM, Wakefi eld TW. Long-term experience with transvenous catheter pulmonary embolectomy. J Vasc Surg 1993;18:450–457; discussion 457–458.

319. Meyer G, Koning R, Sors H. Transvenous catheter embolec-tomy. Semin Vasc Med 2001;1:247–252.

320. Schmitz-Rode T, Janssens U, Duda SH, Erley CM, Gunther RW. Massive pulmonary embolism: percutaneous emergency treat-ment by pigtail rotation catheter. J Am Coll Cardiol 2000;36:375–380.

321. Koning R, Cribier A, Gerber L, et al. A new treatment for severe pulmonary embolism: percutaneous rheolytic thrombectomy. Circulation 1997;96:2498–2500.

322. Fava M, Loyola S, Flores P, Huete I. Mechanical fragmentation and pharmacologic thrombolysis in massive pulmonary embo-lism. J Vasc Intervent Radiol 1997;8:261–266.


p u l mon a ry t h rom b oe m b ol i s m 2 2 01

323. Moser KM, Auger WR, Fedullo PF, Jamieson SW. Chronic thromboembolic pulmonary hypertension: clinical picture and surgical treatment. Eur Respir J 1992;5:334–342.

324. Jamieson SW. Pulmonary thromboendarterectomy. Heart 1998;79:118–120.

325. Fred HL, Axelrad MA, Lewis JM, Alexander JK. Rapid resolu-tion of pulmonary thromboemboli in man. An angiographic study. JAMA 1966;196:1137–1139.

326. Dalen JE, Banas JS Jr, Brooks HL, Evans GL, Paraskos JA, Dexter L. Resolution rate of acute pulmonary embolism in man. N Engl J Med 1969;280:1194–1199.

327. Sautter RD, Fletcher FW, Ousley JL, Wenzel FJ. Extremely rapid resolution of a pulmonary embolus. Report of a case. Dis Chest 1967;52:825–827.

328. Carson JL, Kelley MA, Duff A, et al. The clinical course of pulmonary embolism. N Engl J Med 1992;326:1240–1245.

329. Donaldson GA, Williams C, Scannell JG, Shaw RS. A reap-praisal of the application of the Trendelenburg operation to massive fatal embolism. Report of a successful pulmonary-artery thrombectomy using a cardiopulmonary bypass. N Engl J Med 1963;268:171–174.

330. Peterson KL. Acute pulmonary thromboembolism: has its evo-lution been redefi ned? Circulation 1999;99:1280–1283.

331. Kearon C. Natural history of venous thromboembolism. Semin Vasc Med 2001;1:27–37.

332. Paraskos JA, Adelstein SJ, Smith RE, et al. Late prognosis of acute pulmonary embolism. N Engl J Med 1973;289:55–58.

333. Hall RJ, Sutton GC, Kerr IH. Long-term prognosis of treated acute massive pulmonary embolism. Br Heart J 1977;39:1128–1134.

334. De Bakey ME. A critical evaluation of the problem of throm-boembolism. Int Abstr Surg 1954;98:1–27.


1 pulmonary 0 thromboembolism -...

Documents