Professional Documents
Culture Documents
conclude with an overview of contemporary concepts in Acute PE increases pulmonary vascular resistance, partly
optimizing prophylaxis. attributable to hypoxic vasoconstriction. In patients without
PE is a common cardiovascular and cardiopulmonary prior cardiopulmonary disease, the mean pulmonary artery
illness with an incidence in the United States that exceeds 1 pressure can double to approximately 40 mm Hg. An addi-
per 1000 and a mortality rate 15% in the first 3 months after tional doubling of pulmonary artery pressure may occur in
diagnosis.1 This makes PE possibly as deadly an illness as patients with prior pulmonary hypertension. Under extreme
acute myocardial infarction. Nevertheless, the lay public has circumstances in patients with chronic thromboembolic pul-
not been well educated about PE. Consequently, early detec- monary hypertension, the pulmonary arterial pressure can
tion and prompt presentation for medical evaluation have exceed the systemic arterial pressure.
lagged far behind the public awareness of acute coronary Increased right ventricular afterload can cause right ven-
syndromes and stroke. Although discussion of the etiology of tricular dilatation, hypokinesis, tricuspid regurgitation with
PE has classically focused on acquired and inherited causes annular dilatation of the tricuspid valve, and ultimately right
of hypercoagulability, there is also an association between ventricular failure. While this pathological process evolves,
atherosclerotic disease and spontaneous venous thrombosis.2 most patients maintain a normal systemic arterial pressure for
The most common reversible risk factor for PE is obesity, 12 to 48 hours and may give the impression of being
an increasing pandemic in our society. Other common revers- hemodynamically stable. Then, often abruptly, pressor-resis-
ible risk factors include cigarette smoking and hypertension. tant systemic arterial hypotension and cardiac arrest may
Nevertheless, public fascination with PE has centered on ensue.
long-haul air travel, a rare cause of venous thromboembo- Right ventricular enlargement attributable to pressure over-
lism.3 PE also occurs in the context of illness attributable to load causes a leftward shift of the interventricular septum,
surgery, trauma, immobilization, cancer,4 oral contracep- which is a manifestation of interventricular dependence.
tives,5 pregnancy, and postmenopausal hormone replacement Right ventricular contraction continues even after the left
therapy,6 as well as medical conditions such as pneumonia ventricle starts relaxing at end-systole. The interventricular
and congestive heart failure. Genetic predisposition to venous septum flattens during systole and then bulges toward the left
thrombosis is being increasingly recognized,7 and twin stud- ventricle, with paradoxical septal motion that distorts the
ies have demonstrated the important contribution of an normally circular left ventricular cavity. There is diastolic left
inherited prothrombotic state.8 Increased levels of clotting ventricular impairment, attributable to septal displacement,
factors and activation peptides contribute to the risk of PE. reduced left ventricular distensibility, and impaired left ven-
Deficiencies of anticoagulant factors also increase thrombotic tricular filling during diastole. Left atrial contraction has a
risk.9 greater than normal contribution to left ventricular filling,
From the Cardiovascular Division (S.Z.G.), Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Mass, and
the Department of Medicine (C.G.E.), Pulmonary and Critical Care Division, LDS Hospital and University of Utah School of Medicine, Salt Lake City,
Utah.
Dr Goldhaber has served as a consultant for Aventis, Pfizer, AstraZeneca, Bayer, Paion, and Procter and Gamble. Dr Elliott has served as a consultant
for Aventis, Pfizer, AstraZeneca, Actelion, and Encysive.
This is Part I of a 2-part article. Part II will appear in the December 9, 2003, issue of Circulation.
Correspondence to Samuel Z. Goldhaber, MD, Cardiovascular Division, Brigham and Womens Hospital, 75 Francis St, Boston, MA 02115. E-mail
sgoldhaber@partners.org
(Circulation. 2003;108:2726-2729.)
2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000097829.89204.0C
2726
Goldhaber and Elliott Acute Pulmonary Embolism: Part I 2727
resulting in a prominent A wave on Doppler that is much oxygen tension gradient are the most common gas exchange
higher than the E wave.10 abnormalities. Total dead space increases. Ventilation and
As right ventricular wall stress increases, cardiac ischemia perfusion become mismatched, with blood flow from ob-
may develop, because increased right ventricular pressure structed pulmonary arteries redirected to other gas exchange
compresses the right coronary artery, diminishes subendocar- units. Shunting of venous blood into the systemic circulation
dial perfusion, and limits myocardial oxygen supply.11 Right may occur.
ventricular microinfarction leads to elevations of troponin,12 Normal tidal volume includes both breathed gas that enters
and right ventricular overload causes elevations of both the gas exchange units (respiratory bronchioles, alveolar
pro-B-type natriuretic peptide13 and B-type natriuretic ducts, and alveolar sacs) and anatomic dead space. In normal
peptide.14,15 lungs, ventilation and perfusion are well matched, and the
ratio of ventilation to the gas exchange structures and blood
Gas Exchange flow to the pulmonary capillaries is approximately 1.0.
Acute PE impairs the efficient transfer of oxygen and carbon Transfer of oxygen is impaired when alveolar ventilation to
dioxide across the lung (Tables 1 and 2). Decreased arterial pulmonary capillaries is reduced relative to blood flow (low
V units); the ratio of ventilation to perfusion falls to 1.0.
/Q
PO2 (hypoxemia) and an increase in the alveolar-arterial
Right-to-left shunting occurs when there is no ventilation to
perfused lung units or when venous blood bypasses the lungs
TABLE 2. Potential Gas Exchange Abnormalities in Pulmonary
and enters the systemic circulation.
Embolism
The transfer of oxygen is a cascade with gas flowing from
Decreased arterial PO2 a high-pressure source (the atmosphere) to a lower-pressure
Increased alveolar to arterial oxygen tension gradient (PAO2PaO2) destination (the mitochondria). The partial pressure of oxygen
Respiratory alkalosis decreases as gas moves from the atmosphere to alveolae to
arterial blood and finally to the tissues. The initial decrease in
Low V/Q units: impaired oxygen transfer to pulmonary capillaries, with
preserved blood flow to pulmonary capillaries; ratio of ventilation to oxygen pressure occurs when air enters humid upper airways,
perfusion is 1.0 where water vapor molecules reduce the partial pressure of
Right-to-left shunting: no ventilation and venous blood enters systemic oxygen. The diffusion of carbon dioxide from capillaries into
circulation gas exchange units additionally decreases alveolar oxygen
Increased anatomic dead space: breathed gas does not enter gas exchange
pressure. The alveolar to arterial oxygen tension gradient
units of the lung represents the inefficiency of oxygen transfer across the
Increased physiologic dead space: ventilation to gas exchange units exceeds
lungs, often as the result of a decreased ratio of ventilation
venous blood flow through the pulmonary capillaries; ratio of ventilation to relative to perfusion in lung gas exchange units.
perfusion 1.0
Increased total dead space: anatomic plus physiologic dead space
Hypoxemia
Several mechanisms explain the presence of arterial hypox-
Decreased carbon monoxide diffusion
emia in the setting of acute PE. Mismatching of ventilation
2728 Circulation December 2, 2003
scoring system has a maximum of 12.5 points, based on 7 3. Lapostolle F, Surget V, Borron SW, et al. Severe pulmonary embolism
variables: 3 points each for clinical evidence of deep vein associated with air travel. N Engl J Med. 2001;345:779 783.
4. Schulman S, Lindmarker P. Incidence of cancer after prophylaxis with
thrombosis and an alternative diagnosis being less likely than warfarin against recurrent venous thromboembolism: Duration of Anti-
PE, 1.5 points each for heart rate 100 per minute, immo- coagulation Trial. N Engl J Med. 2000;342:19531958.
bilization/surgery within 4 weeks, and previous deep vein 5. Vandenbroucke JP, Rosing J, Bloemenkamp KW, et al. Oral contra-
ceptives and the risk of venous thrombosis. N Engl J Med. 2001;344:
thrombosis/PE, and 1 point each for hemoptysis or cancer. A 15271535.
score of 2 points makes PE low probability (2% likelihood), 6. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of
and a score of 6 points makes PE high probability (50% estrogen plus progestin in healthy postmenopausal women: principal
results from the Womens Health Initiative randomized controlled trial.
likelihood). In a consecutive cohort of patients suspected of
JAMA 2002; 288:321333.
PE, almost half had a low probability score. 7. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis.
The D-dimer is elevated in almost all patients with PE N Engl J Med. 2001;344:12221231.
because of endogenous albeit ineffective fibrinolysis, which 8. Rosendaal FR, Bovill EG. Heritability of clotting factors and the revival
of the prothrombotic state. Lancet. 2002;359:638 639.
causes plasmin to digest some of the fibrin clot and release 9. Joffe HV, Goldhaber SZ. Laboratory thrombophilias and venous throm-
D-dimers into the systemic circulation. Among patients pres- boembolism. Vasc Med. 2002;7:93102.
enting to the Emergency Department at Brigham and Wom- 10. Goldhaber SZ. Echocardiography in the management of pulmonary
embolism. Ann Intern Med. 2002;136:691700.
ens Hospital, normal D-dimer ELISA levels have a high 11. Wood KE. Major pulmonary embolism: review of a pathophysiologic
negative predictive value for PE regardless of clinical prob- approach to the golden hour of hemodynamically significant pulmonary
ability.22 Of 1109 consecutive D-dimer assays among patients embolism. Chest. 2002;121:877905.
Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2017
suspected of PE, 547 were normal. Only 2 of 547 had PE 12. Konstantinides S, Geibel A, Olschewski M, et al. Importance of cardiac
troponins I and T in risk stratification of patients with acute pulmonary
despite a normal D-dimer. In this cohort, the sensitivity of the embolism. Circulation. 2002;106:12631268.
D-dimer for acute PE was 96.4%, and the negative predictive 13. Kucher N, Printzen G, Doernhoefer T, et al. Low pro-brain natriuretic
value was 99.6%. By incorporating the D-dimer ELISA into peptide levels predict benign clinical outcome in acute pulmonary
embolism. Circulation. 2003;107:1576 1578.
the diagnostic algorithm, fewer chest CT scans will be 14. ten Wolde M, Tulevski II, Mulder JW, et al. Brain natriuretic peptide as
needed, resulting in improved diagnostic efficiency and cost a predictor of adverse outcome in patients with pulmonary embolism.
reduction. However, these findings do not pertain to inpa- Circulation. 2003;107:20822084.
15. Kucher N, Printzen G, Goldhaber SZ. Prognostic role of BNP in acute
tients suspected of PE.
pulmonary embolism. Circulation. 2003;107:25452547.
In acute PE, the fibrinogen level decreases, probably 16. Itti E, Nguyen S, Robin F, et al. Distribution of ventilation/perfusion
because of activation of endogenous fibrinolysis. As the ratios in pulmonary embolism: an adjunct to the interpretation of venti-
fibrinogen level declines, the D-dimer level increases. In the lation/perfusion lung scans. J Nucl Med. 2002;43:1596 1602.
17. Crapo RO, Jensen RL, Wanger JS. Single-breath carbon monoxide dif-
future, a high ratio of D-dimer to fibrinogen may help to rule fusing capacity. Clin Chest Med. 2001;22:637 649.
in acute PE.23 18. Stein PD, Goldhaber SZ, Henry JW. Alveolar-arterial oxygen gradient in
Chest CT scanning has become the preferred imaging the assessment of acute pulmonary embolism. Chest. 1995;107:139 143.
19. Stein PD, Goldhaber SZ, Henry JW, et al. Arterial blood gas analysis in
modality.20,24 In the absence of PE, the chest CT may yield a the assessment of suspected acute pulmonary embolism. Chest. 1996;109:
previously unsuspected reason for symptoms mimicking PE, 78 81.
such as pneumonia or interstitial fibrosis that were not 20. British Thoracic Society Standards of Care Committee Pulmonary
apparent on the chest radiograph. Lung scanning is being Embolism Guideline Development Group. British Thoracic Society
guidelines for the management of suspected acute pulmonary embolism.
used less frequently because its results are often equivocal. Thorax. 2003;58:470 483.
Lung scanning nevertheless remains the first-line imaging 21. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical
study for patients with anaphylaxis to contrast agent, renal model to categorize patients probability of pulmonary embolism:
increasing the models utility with the SimpliRED D-dimer. Thromb
failure, or pregnancy, as well as in patients with prior PE Haemost. 2000;83:416 420.
diagnosed by lung scan. 22. Dunn KL, Wolf JP, Dorfman DM, et al. Normal D-dimer levels in
Knowing the generation of chest CT scanner that is being emergency department patients suspected of acute pulmonary embolism.
J Am Coll Cardiol. 2002;40:14751478.
used is crucial to interpreting the results of the imaging test.
23. Kucher N, Kohler HP, Dornhofer T, et al. Accuracy of d-dimer/fibrinogen
First-generation scanners have 5-mm resolution and may fail ratio to predict pulmonary embolism: a prospective diagnostic study. J
to detect one third of PEs, especially in the subsegmental Thromb Haemost. 2003;1:708 713.
pulmonary arteries.25 However, third-generation scanners 24. van Strijen MJ, de Monye W, Schiereck J, et al for the Advances in New
Technologies Evaluating the Localisation of Pulmonary Embolism Study
provide 1-mm resolution with a single breath hold. For Group. Single-detector helical computed tomography as the primary di-
institutions without third-generation scanners, a useful alter- agnostic test in suspected pulmonary embolism: a multicenter clinical
native strategy is venous ultrasonography of the legs when management study of 510 patients. Ann Intern Med. 2003;138:307314.
25. Perrier A, Howarth N, Didier D, et al. Performance of helical computed
the chest CT scan shows no evidence of PE.26 tomography in unselected outpatients with suspected pulmonary
embolism. Ann Intern Med. 2001;135:88 97.
References 26. Musset D, Parent F, Meyer G, et al. Diagnostic strategy for patients with
1. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: suspected pulmonary embolism: a prospective multicentre outcome study.
clinical outcomes in the International Cooperative Pulmonary Embolism Lancet. 2002;360:1914 1920.
Registry (ICOPER). Lancet. 1999;353:1386 1389.
2. Prandoni P, Bilora F, Marchiori A, et al. An association between athero- KEY WORDS: thrombosis embolism pulmonary heart disease
sclerosis and venous thrombosis. N Engl J Med. 2003;348:14351441. diagnosis
Acute Pulmonary Embolism: Part I: Epidemiology, Pathophysiology, and Diagnosis
Samuel Z. Goldhaber and C. Gregory Elliott
Circulation. 2003;108:2726-2729
doi: 10.1161/01.CIR.0000097829.89204.0C
Downloaded from http://circ.ahajournals.org/ by guest on February 27, 2017
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2003 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/108/22/2726
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.