Pulmonary embolism: An unsuspected killer

Article (PDF Available)inEmergency Medicine Clinics of North America 22(4):961-83 · December 2004with40 Reads
DOI: 10.1016/j.emc.2004.05.011 · Source: PubMed
  • 18.07 · Mayo Foundation for Medical Education and Research
  • 27.65 · Mayo Foundation for Medical Education and Research
Abstract
The presentation of PE is often subtle and may mimic other diseases. Many pulmonary emboli invariably preclude diagnosis by their occult nature or by leading to rapid death from cardiopulmonary arrest. In patients who do manifest symptoms from PE, accurate diagnosis is essential. Often it is difficult to distinguish the vague symptoms of PE from other diagnoses, such as acute coronary syndrome, pneumonia, COPD, CHF,aortic dissection, myocarditis or pericarditis, pneumothorax, and musculo-skeletal or gastrointestinal causes. Regardless of the presentation, the most fundamental step in making the diagnosis of PE is first to consider it. Historical clues and risk factors should raise the clinician's suspicion.PE is an unsuspected killer with a nebulous presentation and high mortality. In all likelihood, PE will remain an elusive diagnosis despite advances in technology and a wealth of research. A high index of suspicion is required, but no amount of suspicion would eliminate all missed cases. Patients with significant underlying cardiopulmonary disease seem to be the most challenging. Patients with significant comorbidity have poor reserve and are likely to have poor outcomes, especially if the diagnosis is not made and anticoagulation is not initiated early. Controversy exists over the best diagnostic approach to PE. A battery of diagnostic studies is available, with few providing definitive answers. Studies such as CT may be helpful at some institutions but offer poor predictive value at others. Other diagnostic tests are not universally available. It is hoped that further research and improvements in current diagnostic modalities will clear some of the current confusion and controversy of this ubiquitous and deadly disease.
Pulmonary embolism: an
unsuspected killer
Torrey A. Laack, MD
a,b,c,d,
*, Deepi G. Goyal, MD
b,c
a
Department of Pediatric and Adolescent Medicine, Mayo Medical School,
Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
b
Department of Emergency Medicine, Mayo Medical School, Mayo Clinic,
200 First Street SW, Rochester, MN 55905, USA
c
Mayo Emergency Medicine Residency, Mayo Medical School, Mayo Clinic,
200 First Street SW, Rochester, MN 55905, USA
d
Department of Pediatrics, Mayo Medical School, Mayo Clinic,
200 First Street SW, Rochester, MN 55905, USA
The accurate diagnosis of pulmonary embolism (PE) is crucia l. PE is
currently the third leading cause of death in the United States with 50,000
to 100,000 estimated deaths per year and an incidence of 0.5 to 1 per 1000
[1–4]. PE is a leading cause of unexpected deaths in hospitalized patients and
a major source of medical malpractice lawsuits [5]. However, the diagnosis is
missed more often than it is made. One author conservatively estimates that
more than half of fata l PE cases are not even suspected antemortem [6].
Prior autopsy studies consistently have shown the rate to be even higher, at
approximately 70% [7–11]. Conversely, in patients in whom the diagnosis is
considered, the prevalence of PE is only 25% to 35% [12,13]. Therefore,
clinicians generally miss PE when it is present and suspect it when it is not.
PE is truly an unsuspected killer with profound clinical implications.
Although patients in whom PE is diagnosed and treated have a mortality
rate of only 3% to 8% [3,14,15], those in whom the diagnosis is missed have
a fourfold to sixfold greater mortality [3,6,15].
Before the use of heparin, surgical interventions were the only treatment
options available for PE with a mortality rate approaching 100% [16].
Heparin first was administered to treat PE in the 1930s, but concerns over its
safety in this setting prevented more widespread use. It was not until 1960
that the benefits of anticoagulation therapy were confirmed [17]. Beginning
* Corresponding author. Department of Emergency Medicine, Mayo Medical School,
Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
E-mail address: laack.torrey@mayo.edu (T.A. Laack).
0733-8627/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.emc.2004.05.011
Emerg Med Clin N Am
22 (2004) 961–983
in the 1960s, the use of fibrinolytics was studied; fibrinolytics were reserved
primarily for unstable patients with PE [16]. With the advent of effective
therapy, the accurate diagnosis of thromboembolic disease became vital.
Although many deaths are attributed to undiagnosed pulmonary emboli,
the actual incidence of PE in the general population and the risk of
mortality or morbidity from an individual pulmonary embolus are un-
known. A high incidence of asymptomatic PE has been shown in patients
with deep venous thrombosis (DVT) [18–22], suggesting that PE may be
common and only infrequently may lead to death. Although some studies
have found mortality rates from untreated PE ranging from 25% to 30%,
these studies involved patients with other comorbidities that likely
contributed to the adverse outcomes [17,23,24].Other studies involving pa-
tients without coexisting cardiopulmonary disease ha ve found that mortality
even with untreated or recurrent PE was significantly lower [22,24–27].
A follow-up study of the untreated patients with PE from the Prosp ective
Investigation of Pulmonary Embolism Diagnosis (PIOPED) revealed
a mortality rate from PE of only 5% (1 in 20) [27] .
Given the fact that anticoagulation carries with it significant bleeding
risks and that not all cases of PE cause morbidity or mortality, the risk of
misdiagnosis of PE is not limited to missing the diagnosis. Incorrectly diag-
nosing PE in patients in whom it is absent or inconsequential unnecessarily
exposes them to the risks inherent with long-term anticoagulation therapy.
Because the accurate diagnosis of PE is crucial to maximizing patient
outcomes, this article focuses on atypical presentations, unique challenges in
certain patient populations, and current diagnostic strategies for PE.
Background
Venous thromb oembolism (VTE) is a diseas e with a spectrum of mani-
festations that include thrombophlebitis, DVT, and PE. Most pulmonary
emboli have their origin in clots in the iliac, deep femoral, or popliteal veins.
Pulmonary emboli also can originate from sources in the upper extremities,
central vascular access devices, heart, and vena caval filters [28–30]. The site
of the DVT does not seem to be as important as previously was thought
because PE can occur from any site of DVT formation [31]. Calf vein
thrombosis, previously considered relatively benign, propagates above the
knee in approximately 80% and may cause PE without first extending
proximally [16]. Likewise, although superficial thrombophlebitis is generally
benign, it can extend into the deep venous system and pose a risk for PE
[32]. In many instances of PE, no peripheral source of thrombosis is ever
identified.
Virchow first described the process of thrombosis as involving a triad of
stasis, hypercoagulability, and endothelial injury [33]. Risk factors for PE
can be inherited or acquired (Box 1) and must be considered when
assessing a patient’s probability of PE [29,30,35]. The strongest risk factor of
962 T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
VTE seems to be a history of prior thromboembolic disease [35].In
addition, malignancy and surgery are well known to be associated with
VTE. Certain malignancies, such as tumors affecting the lung, brain,
ovaries, and pancreas, are especially prone toward predisposing patients to
VTE [29], as are neurosurgical and orthopedic surgical procedures [34].
Major trauma patients are a high-r isk patient population that deserves
particular attention because PE is the third most common cause of death in
these patients [2,36]. One study of victims of major trauma revealed that
nearly 60% had a DVT, most of whom were asymptomatic [37].
Despite the clinical significance of risk factors for VTE, Morgenthaler
and Ryu [9] found that 12% (11 of 92) of patients with PE as the cause of
death at autopsy lacked any known risk factor. Risk factors must be taken
into account in conjunction with the patient’s history and presentation, but
an absence of risk factors does not reliably exclude the diagnosis of PE.
Clinical presentation
The presentation of PE is occasionally dramatic, but more commonly
patients present with subtle clinical findings, or they may be completely
Box 1. Risk factors predisposing to venous thromboembolism
Inherited risk factors
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden mutation
Acquired risk factors
Prior history of venous thromboembolism
Malignancy
Surgery
Trauma
Central venous access devi ces
Pregnancy and the puerperium
Immobilization (travel, paralysis, bedridden state)
Congestive heart failure
Myocardial infarction
Stroke
Advanced age
Smoking
Obesity
Oral contraceptives/hormone replacement therapy
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asymptomatic. This situation contributes to the large number of cases that
are missed on initial presentation. The class ic findings of hemoptysis,
dyspnea, and chest pain are insensitive and nonspecific for a diagnosis of
PE, with fewer than 20% having this classic triad. The incidence of common
symptoms in patients suspected of having PE is depicted in Table 1 [38]. One
prospective observational study found that the single historical finding most
sensitive for PE was unexplained dyspnea. Even this finding was absent,
however, in 8% of the patients studied [39]. Althou gh unexplained chest
pain or dyspnea always should lead to the consideration of PE, the fact that
presentations of PE are often subtle mandates that the clinician not over-
look the diagnosis based on a lack of these symptoms.
No single physical examination finding is sensitive or specific for PE.
Table 1 shows the prevalence of various signs in patients suspected of having
PE [38]. Although other studies reveal tachypnea to be the most sensitive
clinical sign, it is absent in 5% to 13% of cases of PE [34,40]. Tachycardia is
even less sensitive, especially in younger patients, with 70% of PE patients
younger than 40 years old and 30% of patients older than 40 having heart
rates less than 100 beats/min [40]. Fever tends to be low grade, and its
presence may mislead the clinician into suspecting an infectious etiology.
Table 1
Symptoms and signs in 500 patients with clinically suspected pulmonary embolism
PE present n=202 PE absent n = 298
No. % No. % P
Symptoms
Dyspnea (sudden onset) 158 78 87 29 \.00001
Dyspnea (gradual onset) 12 6 59 20 .00002
Orthopnea 2 1 27 9 .00004
Chest pain (pleuritic) 89 44 89 30 .002
Chest pain (substernal) 33 16 29 10 .04
Fainting 53 26 38 13 .0002
Hemoptysis 19 9 16 5 .12
Cough 22 11 45 15 .22
Palpitations 36 18 46 15 .56
Signs
Tachycardia [100/min 48 24 69 23 .96
Cyanosis 33 16 44 15 .73
Hypotension \90 mm Hg 6 3 5 2 .15
Neck vein distention 25 12 28 9 .36
Leg swelling (unilateral) 35 17 27 9 .009
Fever [38
C 14 7 63 21 .00003
Crackles 37 18 76 26 .08
Wheezes 8 4 39 13 .001
Pleural friction rub 8 4 11 4 .93
Abbreviation: PE, pulmonary embolism.
From Miniati M, Prediletto R, Fromichi B, et al. Accuracy of clinical assessment in the
diagnosis of pulmonary embolism. Am J Respir Crit Care Med 1999;159:866; with permission.
964 T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
Stein et al [41] found fever with no other source present in 14% of patients
with PE.
Data from the PIOPED found that in patients diagnosed with PE, 97%
had the presence of dyspnea, chest pain, or tachypnea [13]. Dyspnea, chest
pain, and tachypnea are all nonspecific symptoms, however, that are found
more commonly with diseases other than PE. This finding is likely subject to
considerable selection bias because only patients in whom the diagnosis was
suspected were enrolled in the PIOPE D study, whereas patients with silent
or atypical presentations of PE would have been missed and their symptoms
not recorded. The symptoms of dyspnea, pleuritic chest pain, and tachypnea
are not only nonspecific, but also they may be insensitive when generalized
to all patients with PE [4].
Patients traditionally have been described as having one of three classic
syndromes: pulmonary infarction, isolated dyspnea, or circulatory collapse.
This is an oversimplification of the clinical presentation of PE that does not
account for atypical presentati ons and occult pulmonary emboli. Patients in
whom the diagnosis is suspected tend to present, however, with one of these
three syndromes. Although one should not limit clinical suspicion only to
patients in these categories, it is extremely difficult to diagnose PE reliably in
patients outsi de of this simplified scheme.
Patients with pulmonary infarction commonly present with chest pain
secondary to irritation of the pleura. It may be difficult to differentiate
between PE and pneumonitis or pleuritis. Hemoptysis usually is self-limited
and occurs in approximately one third of these patients. Pulmonary infarc-
tion is much more common in older patients with underlying cardiopul-
monary disease, and they tend to present with pleuritic chest pain more
frequently [30,42]. PE may be present in 20% of young patients, however,
without specific risk factors for VTE who present with a complaint of
pleuritic chest pain [16]. Pulmonary infarct is associated with submassive
and less severe PE than isolated dyspnea or circulatory collapse [42,43].
In patients with isolated dyspnea, the severity of symptoms is related to
the degree of vascular obstruction and their underlying cardiopulmonary
reserve. Even with obstruction of 50%, patients may remain asymptomatic
[42]. PE may be difficult to distinguish from other causes of dyspnea, such as
congestive heart failure (CHF), hyperventilation, reactive airway disease, or
obstructive lung disease. Patients with circulatory collapse have the most
severe form of PE. They may present with syncope, hemodynamic in-
stability, or full cardiopulmonary arrest.
Atypical presentations
Atypical presentations of PE are common, with symptoms such as
abdominal pain, back pain, fever, cough, atrial fibrillation, and hiccoughs
[16]. As noted earlier, most fatal pulmonary emboli are never suspected and
965T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
go undiagnosed. Many of these misses may involve patients with other sig-
nificant comorbid disease to which their symptoms are attributed incorrectly.
A signi ficant percentage of these misses may be due to clinically silent or
occult presentations and pulmonary emboli causing sudden cardiopulmonary
arrest. Given that only a few cases of PE are suspected, these ‘‘atypical’’
presentations seem to represent most fatal cases of PE. Atypical presentations
that are explored in more detail include occult PE, syncope, and PE in the
setting of cardiopulmonary arrest.
Occult PEs are known to exist in asymptomatic patients in high-risk
groups. Of asymptomatic surgical patients, 15% have been shown to have
evidence of PE on lung scans [24]. In patients with known DVT but without
symptoms suggesting PE, 40% to 60% have lung scan or angiogram
findings suggesting PE [19–21]; this has led some authors to propose that all
patients diagnosed with DVT have a baseline ventilation-perfusion (V/Q)
scan [18,21]. Because the risk of recurrent VTE is low in patients adequately
treated and because of the unclear clinical significance of these abnormal V/
Q scans, other authors do not think that baseline lung scans are indicated
for all patients diagnosed with DVT [20,44–46]. The rate of asymptomatic
PE in the general population or in patie nts with occult DVT is unknown. It
is possible that healthy individuals frequently have small emboli that
dissolve rapidly and never become symptomatic.
Of patients presenting with syncope, Sarasin et al [47] found PE to be the
cause in about 1%. Meanwhile, syncope is present in 8% to 13% of all
patients with PE [48]. It is presumed to be secondary to right ventricular
outflow obstruction causing transient hypotension. In a study of 92 patients
at autopsy with PE as the cause of death, more than one quarter had a
history of syncope [9]. Patient s with PE who present with syncope carry
a worse prognosis than patients who do not [48]; this may be due to the fact
that larger pulmonary emboli are necessary to cause the outflow obstruction
required to induce syncope. In a study by Bell et al [49], syncope occurred in
20% of patients with massive PE compared with only 4% of patients with
submassive PE.
PE may cause right ventricular outflow obstruction with subsequent
decreased left ventricular filling and cardiac output, leading to hypotension,
shock, and cardiac arrest. One study found that of all patients presenting to
the emergency department in cardiac arrest, PE was responsible in 4.8%
[50]. In younger patients, who tend to have a lower baseline risk of cardiac
disease, the percentage of cardiac arrests due to PE is likely even higher,
with one author estimating it at 10%. In this study, patients with PE were
more likely to have pulseless electrical acti vity and wi tnessed arrest than
patients with other causes of death [51]. In another study, 63% of patients
with PE-induced cardiac arrest had pulseless electrical activity as the
presenting rhythm [52]. It is theorized that patients have time to seek aid
during a gradual progression to pulselessness with maintained electrical
activity. Conversely, in patients presenting with pulseless electrical activity
966 T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
and cardiac arrest, approximately one third to one half have been found to
have PE at autopsy [51,52].
Despite the frequency with which they occur, most missed PEs are
unsuspected (Fig. 1) [4]. Some authorities argue, as expressed in an editorial
by Egermayer [53], ‘‘There can be only a limited advantage to encouraging
increased alertness for a disease that is usually asymptomatic.’ Egermayer’s
recommendation was to place an increased emphasis on prevention rather
than diagnosis and treatment [53]. Although no amount of increased alert-
ness woul d allow a clinician to diagnose all cases of PE, it is only with
increased cognizance an d development of improved diagnostic algorithms
that clinicians can enhance their ability to diagnose this deadly but treatable
disease.
Specific patient populations
Pediatrics
VTE in children usually is associated with hereditary or acquired co-
agulation abnormalities. Hereditary deficiencies include factor V Leiden
mutation; sickle cell disease; and deficiencies of protein C, protein S, and
antithrombin III. Thrombosis tends to be most pronounced in the neonatal
period and at adolescence. There are numerous causes of acquired VTE,
including surgery, malignancy, trauma, central venous catheter placement,
infection, renal disease, autoimmune diseases, vasculitis, congenital heart
disease, and severe inflammatory bowel disease [54]. Central vascular access
devices seem to be the most common acquired risk factor in children [55].A
Fig. 1. Schema of relationship between suspected and actual cases of pulmonary embolism
(PE). (From Ryu JH, Olson EJ, Pellikka PA. Clinical recognition of pulmonary embolism:
problem of unrecognized and asymptomatic cases. Mayo Clin Proc 1998;73:877; with
permission.)
967T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
retrospective study of 61 children with thrombosis found an association with
central vascular access in 25% [56].
Overall, VTE is rare in children. Rohrer et al [57] found an incidence of
lower extremity DVT of only 0.05% (1 of 93 cases, in a 17-year-old) in
hospitalized children with at least two independent risk factors for
thrombosis. A study of pediatric intensive care unit patients found 4% to
have DVT [58], whereas at autopsy the rate of PE in children was ap-
proximately 4% [59]. A review of the literature on VTE in children revealed
that 98% had a precipitating factor, although it was not always known on
initial presentation [60]. Although rare, the diagnosis of PE should be con-
sidered in children manifesting suspicious symptoms, especially in older
children and children with risk factors. Children diagnosed with VTE
require anticoagulation and an extensive workup in search of a potential
underlying cause.
Pregnancy
PE is the leading cause of maternal mortality in developed countries
[61,62]. Although the incidence of PE in individuals older than age 45 is
higher in men than in women, numerous studies have shown that in young
adults, women have a significantly higher rate of PE [29]. Pregnancy and the
postpartum period are well-known risk factors for PE [63], with the risk of
PE five times higher in pregnant compared with nonpregnant women [34].
During the postpartum period, there is an even greater risk of thrombosis
than during pregnancy [29]. Although a high level of suspicion is necessary,
the prevalence of PE in pregnant patients in whom the diagnosis is
considered is quite low [64].
The diagnosis of PE in pregnancy is particularly difficult because dyspnea
may be a normal finding. Causes of dyspnea in pregnancy include upward
pressures on the diaphragm secondary to an intra-abdominal mass effect
and increased oxygen consumption requiring increased cardiac output. By
the third trimester, 75% of pregnant women have dyspnea, and most women
have symptoms beginning by the 20th week. The physiologic dyspnea of
pregnancy may be difficult to differentiate from more worrisome causes such
as PE. Physiologic dyspnea tends to be mil d without limiting daily activities,
it tends to be absent at rest, and it generally does not worsen as pregnancy
progresses. Symptoms such as syncope, he moptysis, and chest pain should
not be attributed to physiologic dyspnea [65]. Likewise, dyspnea that has
a rapid onset should raise suspicion for PE.
During pregnancy, failure to diagnose PE places the mother and the fetus
in jeopardy. Likewise, overdiagnosing PE places both patients at risk by
exposing them to anticoagulation and hospitalization. Although it is desir-
able to minimize fetal radiation exposure, the importance of making the
correct diagnosis mandates that the appropriate diagnostic studies be
performed. Although a negative D-dimer test can be helpful in patients with
968 T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
a low pretest probability of PE, it is not helpful in patients whose pretest
probability is estimated to be moderate or high. Because ultrasound poses no
risk to the fetus, bilateral lower extremity ultrasound is considered by some
authors to be the initial study of choice. If ultrasound is positive for DVT, PE
is implied, and the patient should be treated accordingly with no further
testing necessary. In pregnant patients being evaluated for PE without
specific symptoms of DVT, however, ultrasound is rarely positive [66–68].
Many authorities advocate the use of V/Q scanning as the next step.
During pregnancy, especially in patients without prior history of pulmonary
disease, many scans are normal or near-normal in the absence of PE. The
radiation exposures from V/Q scan and chest x-ray are well below the
maximal recommended dose in pregnancy and can be decreased even further
without compromising the study [62,64]. Although the use of helical CT
historically has been discouraged, there is increasing evidence that next-
generation CT scanners subject the patient to less radiation than does V/Q
scanning [69,70]. This evidence has led to the preferential use of CT over
V/Q scanning in pregnant patients at the authors’ institution. If pulmonary
angiography is required, the abdomen can be shielded in an attempt to
reduce radiation exposure to the fetus. If PE is discovered, warfarin is
contraindicated because it is a known teratogen [71], and the patient
requires admission and daily administration of unfractionated heparin or
low-molecular-weight heparin for the duration of pregnancy.
Elderly
Elderly patients are at an increased risk of developing PE, but it is unclear
if this is because age is an independent risk factor or secondary to a higher
prevalence of underlying diseas e and recent surgery in this patient popula-
tion. The mean age of patients presenting with PE is approximately 60 years
with a rate 10 times higher in patients older than 75 compared with patients
younger than 40 [29,36]. Elderly patients with PE have higher mortality
compared with younger patients. The reason is multifactorial and likely due
to the fact that diagnosis is more difficult and the higher incidence of
underlying disease in this patient population. In addition, the elderly have
more bleeding complications from therapy with a resulting increased
likelihood of having anticoagulants withheld [28].
The specifici ty of some diagnostic tests is decreased in the elderly. The
specificity of D dimer was found to be 67% in patients younger than 40, but
only 10% in patients age 80 and older. In addition, the number of non-
diagnostic V/Q scans increased from 32% to 58% in these same age groups
[72]. There is no single diagnostic test that is ideal for the diagnosis of PE
in elderly patients. When a diagnosis of VTE is made in an elderl y patient, the
patient should be treated with anticoagulation unless he or she has a specific
contraindication. Age should not preclude thrombolytic therapy when
appropriate [73,74].
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Comorbid diseases
Patients with multiple medical problem s often pr esent diagnostic
challenges in the workup of PE. As previously discussed, symptoms of PE
are notoriously nonspecific, and symptoms of a patient’s underlying disease
may be impossible to distinguish from that of PE. A coexisting illness may
be assumed to be the cause of the patient’s symptoms and the presence of PE
may go undiagnosed in patients who can least tolerate it. Cardiopulmonary
illnesses may present with similar sympt oms and similar diagnostic and
laboratory studies. To complicate matters further, many illnesses are in-
dependent risk factors for VTE, such as CHF, myocar dial infarction, and
cancer. Severe illness also leads to prolonged immobilization, an increased
likelihood of surgery, and the use of central vascular access devices. Two
examples of comorbid diseases that can complicate the diagnosis of PE are
chronic obstructive pulmonary disease (COPD) and CHF.
Patients with COPD are at high risk for PE. These patients tend to be
older smokers who also may have immob ility, CHF, and lung malignancy.
Autopsy studies reveal a rate of PE ranging from 28% to 51% in patients
with CO PD [75]. Differentiating the symptoms of a COPD exacerbation
from PE can be extremely challenging given the similarity of symptoms. PE
may precipitate an exacerbation of COPD causing additional diagnostic
uncertainty with overlapping symptoms from both disorders. Patients with
COPD and a pulmonary embolus found at autopsy were much less likely to
have had the diagnosis made ante mortem compared with patients without
COPD [6] . For these reasons , it is important to maintain a high index of
suspicion in patients with COPD who present with shortness of breath that
is acute in onset or differs from prior exacerbations.
The diagnostic workup in patients with COPD is complicated by an
increased likelihood of obtaining nondiagnostic V/ Q scans. In patients with
COPD, less than 10% of scans are diagnostic (either normal/near-normal or
high probability of PE) [75]. CT may be the study of choice in these patients
with less associated risk compared with angiogram and greater likelihood of
revealing a definitive answer compared with V/Q scan. CT has the advantage
of revealing alternative diagnoses, and abnormalities from infec tious and
neoplastic processes common ly are presen t in patients with COPD.
As with COPD, the symptoms of PE can mimic the symptoms of CHF
and can trigger CHF exacerbations. Because it is associated with a low-flow
state, CHF predisposes patients to stasis and VTE. Beca use of the inherent
activity limitation of CHF patients, they often are relatively immobile,
which further increases their risk for PE. One must always consider PE in
the differential diagnosis of patients with an exacerbation of CHF and
should be extremely suspicious of symptoms that have an acute or new onset
with no clear predisposing events, vary considerably from previous symp-
toms, or do not respond to conventional therapy. As with COPD, clinical
and laboratory findings are rarely helpful, and V/Q scans only rarely give
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definitive results. CT may help diagnose PE and altern ative diagnoses, such
as pericardial effusion.
Although human immunodeficiency virus (HIV) infection is considered
by some to be a risk factor for PE secondary to the hypercoagulable state
associated with the infection, VTE is actually uncommon in HIV-positive
patients. Many HIV-positive patients present with symptoms due to
respiratory infections that are difficult to distinguish from PE. The diagnosis
of PE still should be considered in HIV-positive patients with presumed
respiratory infections who do not respond to antimicrobial therapy [76].
Diagnostic approac h
Given the lack of a single diagnostic test or clinical finding with adequate
sensitivity and specificity, the diagnosis of PE generally involves in-
terpretation of multiple data points in light of the emergency physician’s
assessment of an estimated pretest probability. The authors’ current method
of diagnosing PE relies heavily on subjective assessment of risk. In some
cases, the diagnosis is made easily, but many more cases require the treating
physician to make a diagnosis based on uncertain information.
The frustration of examiners was emphasized in a 1999 poll of 623
emergency physicians who identified the evaluation of PE as the clinical
problem that would benefit most from a decision rule [77]. A nonvalidated
decision rule was proposed in 1990 by the PIOPED investigators, who used
the pretest assessment of risk combined with results from V/Q scanning.
This rule allowed for the noninvasive diagnosis or exclusion of PE in only
a few patients, however, with most requiring angiography [13] . Studies at
academic and private hospitals have shown a poor compliance with the
PIOPED approach [24,78,79].
The PIOPED recommendations require interpretation of the V/Q result
in terms of pretest probability. Accurately assigning pretest probability can
be difficult, however. No scoring system was devised initially, and clinical
estimates of pretest probability have been met with considerable inter-
observer variability [80, 81]. Siegel et al [81] reported instances in which the
same patient was assigned a low pretest probability of PE by one examiner
and high probability by another. Several algorithms have been devised to
address this problem. Two of the most popular scoring systems are the Wells
and Geneva criteria (Table 2) [82–84].
Validation studies of these decision rules reveal that they are predictive of
which patients have PE [84,85]. They do not give definitive results, however,
or obviate the need for further diagnostic tests, and they have not been
proved to be superior to implicit clinical judgment. The prevalence of PE in
the population to which these rules are applie d affects the success of these
scoring systems [84]. These de cision rules are best suited for risk stratifying
patients to estimate a pretest likelihood of PE before diagno stic studies.
971T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
If one follows the PIOPED recommendations, most patients being
evaluated for PE require angiography. The rate of pulmonary angiography
performed in these patients is typically less than 12%, however, with most
physicians unwilling or unable to obtain angiography routinely in the
workup of PE [24,78,79,86,87]. Some authors believe that failure to obtain
angiography in all cases that have nondiagnostic studies is unacceptable due
to the likelihood of missed pulmonary emboli. Follow-up studies have
shown, however, that PE is unlikely in patients discharged after a low-
probability V/Q scan [26]. Wolfe and Hartsell [24] argued that an outcome-
based approach is more important than diagnosis of all PE cases. They
pointed out that in patients with adequate cardiopulmonary reserve, occult
VTE not diagnosed by noninvasive testing does not seem to affect outcome
[24,25,82,88,89]. This situati on has led to the formation of an alternative
algorithmic approach, which attempts to reduce the number of recom-
mended angiogr aphy studies (Fig. 2) [24]. Although currently lacking
Table 2
Prediction rules for suspected pulmonary embolism
Geneva score [13] Points Wells’ score [14] Points
Previous pulmonary embolism or
deep vein thrombosis
þ2 Previous pulmonary embolism or
deep vein thrombosis
þ1.5
Heart rate [100 beats p/min þ1 Heart rate [100 beats p/min þ1.5
Recent surgery þ3 Recent surgery or immobilization þ1.5
Age (y) Clinical signs of deep vein
thrombosis
þ3
60–79 þ1 Alternative diagnosis less likely than þ3
80 þ2 pulmonary embolism
Hemoptysis þ1
Cancer þ1
Pa
CO
2
\4.8 pKa (36 mm Hg) þ2
4.8–5.19 pKa (36–38.9 mm Hg) þ1
PaO
2
\6.5 pKa (48.7 mm Hg) þ4
6.5–7.99 pKa (48.7–59.9 mm Hg) þ3
8–9.49 pKa (60–71.2 mm Hg) þ2
9.5–10.99 pKa
(71.3–82.4 mm Hg)
þ1
Atelectasis þ1
Elevated hemidiaphragm þ1
Clinical probability Clinical probability
Low 0–4 Low 0–1
Intermediate 5–8 Intermediate 2–6
High –9 High 7
Abbreviations: Pa
O
2
, partial pressure of oxygen, arterial; PaCO
2
, partial pressure of carbon
dioxide, arterial.
From Chagnon I, Bounameaux H, Aujesky D, et al. Comparison of two clinical prediction
rules and implicit assessment among patients with suspected pulmonary embolism. Am J Med
2002;113:270; with permission.
972 T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
Fig. 2. Proposed diagnostic algorithm for the evaluation of suspected pulmonary embolism
(PE). CTA, computed tomography angiography; DVT, deep venous thrombosis; ELISA,
enzyme-linked immunosorbent assay; V/Q, ventilation-perfusion. (Adapted from Wolfe TR,
Hartsell SC. Pulmonary embolism: making sense of the diagnostic evaluation. Ann Emerg Med
2001;37:509; with permission.)
973T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
prospective validation, such an algorithm better fits current practice and
avoids the need for angiograms in most patients.
Diagnostic tests
Electrocardiogram, arterial blood gas, chest radiography
Electrocardiogram, arterial blood gas analysis, and chest radiography all
have a limited role in the evaluation of PE. The primary utility of the
electrocardiogram is its ability to point to an alternate diagnosis, such as
acute coronary syndrome or pericarditis. Classic findings, such as S
1
Q
3
T
3
,
lack sensitivity and specificity (54% and 62%), whereas the most common
electrocardiogram abnormality, found in 68%, is T-wave inversion in the
precordial leads [90]. Chest radiography similarly has its primary utility in
detecting alternative diagnoses, such as pneumothorax, CHF, and pneumo-
nia. Chest x-ray findi ngs can be misleading, however, and must be inter-
preted carefully because findings suggesting CHF or pneumonia may coexist
with a pulmonary embolus. In a study of patients ultimately diagnosed with
PE, 76% of chest x-rays were abnormal, but the noted abnormalities tended
to be nonspecific [91]. Arterial blood gas analysis has a limited role in the
evaluation of PE. It is a relatively invasive procedure that lacks the sen-
sitivity or specificity to rule in or out disease [92].
D dimer
D-dimer testing has been proposed by some authorities as a convenient,
noninvasive way to exclude or to increase suspicion for VTE. Specificity is
known to be low secondary to false-positive results from numerous causes,
such as trauma, postoperative state, sepsis, and myocardial infarction [30].
It also is less likely to be helpful in elderly patients and patie nts with sig-
nificant comorbid disease. The role of D dimer generally has been reserved
for ruling out disease in low-risk patients. Wells et al [93] found that patien ts
with a low clinical probability of VTE and a negative D-di mer assay could
be discharged safely with only 0.4% found to have VTE on follow-up
examination. However, The numerous different assays available and insti-
tutional variability in terms of the assays used have led to confusion and
precluded the universal adoption of D-dimer assays as screening tests for
PE. Readers are referred to a review by Sadosty et al [94] for a more in-
depth analysis of D-dimer assays and to a meta-analysis by Brown et al [95]
regarding enzyme-linked immunosorbent assay D-dimer testing.
Ventilation-perfusion scintigraphy
V/Q is a two-part study involving a ventilation and a perfusion phase. A
radioisotope is injected, and areas of pulmonary perfusion are identified
using a gamma camera. A radiopharmaceutical is inhaled to identify areas
974 T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
of ventilation. The areas of perfusion and ventilation are compared to
identify foci of mismatch. Areas with ventilation but without perfusion
increase the suspicion for PE because thrombus obstruction of a pulmonary
artery would cause hypoperfusion to the affected lung segment without
affecting ventilation. The test must be interpreted in light of the patient’s
pretest probability. It is most helpful when there is concordance between the
pretest probability and the scan results (ie, a low pretest probability and
a normal/near-normal scan or a high pretest probability with a high
probability study (Table 3) [96]. Interpreting the study without factoring in
the pretest probability would lead to overdiagnosis and underdiagnosis of
PE: Of patients who have a high-pr obability V/Q scan but a low pretest
probability, 44% would have angiograms negative for PE, whereas in
patients with a low-probability scan but a high pretest probability, 40%
would be found to have PE on angiogram (see Table 3) [13,96]. Because of
these interpretive factors and because patients with preexisting lung disease
often have abnormal studies, V/Q scan provides a definitive answer
regarding whether or not a patient should be started on anticoagulation
therapy in only 25% to 40% of cases [12].
Spiral computed tomography
CT is becoming increasingl y accepted in the evaluation of PE. Fig. 3
shows a large proximal pulmonary embolus in the pulmonary artery. CT is
rapid, noninvasive, and widely available. It is more likely to be diagnostic
than V/Q scanning and is less expensive than V/Q scanning, magnetic
resonance angiography, and pulmonary angiography. CT also has the
advantage of being able to elucidate alternative diagnoses, such as infectious
or neoplastic processes. Its primary limitations relate to the need for
potentially nephrotoxic intravenous contrast material, which is contra-
indicated in patients with a contras t allergy or renal failure. Many
investigators have questioned whether the sensitivity of CT is sufficient to
Table 3
Clinical assessment and ventilation-perfusion scan probability in PIOPED*
Clinical probability
Ventilation-perfusion
scan (probability) High likely (80–100%) Uncertain (20–79%) Unlikely (0–19%)
High 28/29
y
(96%) 70/80 (88%) 5/9 (56%)
Intermediate 27/41 (66%) 66/236 (28%) 11/68 (16%)
Low 6/15 (40%) 30/191 (16%) 4/90 (4%)
Near-normal/normal 0/5 (0%) 4/62 (6%) 1/61 (2%)
Total 61/90 (68%) 170/569 (30%) 21/228 (9%)
* PIOPED = Prospective Investigation of Pulmonary Embolism Diagnosis.
y
Number of patients with proven pulmonary embolism per number of patients with the
specific scan result.
From American Thoracic Society. The diagnostic approach to acute venous thromboem-
bolism: clinical practice guideline. Am J Respir Crit Care Med 1999;160:1055; with permission.
975T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
rule out definitively the possibility of PE [97]. Perrier et al [12] found the
sensitivity and specificity to be only 70% and 91%, whereas others have
reported sensitivities of 88% to 100% with negative predictive values of
89% to 95% [98–100].
Despite its potential promi se, the role of CT in the diagnosis of PE is not
clear. Isolated subsegmental emboli and horizontal vessels are not visualized
well on CT, and lymph nodes may be misinter preted as emboli with false-
positive results [24,30,69]. Subsegmental emboli are not visualized well on
angiogram either [24,101]. Newer thin-collimation multislice CT scanners
have increased speed and allow improved visualization with less motion
artifact [68]. The clinical significance of isolated subsegmental emboli is
uncertain and has been questioned [102]. If these emboli are not clinically
important, failed diagnosis would be beneficial because unnecessary anti-
coagulation therapy could be avoided. However, If subsegmental emboli are
clinically relevant, fals e-negative results could lead to poor outcomes or
possible untoward future e vents.
Three studies have concluded that withholding anticoagulant therapy on
the basis of a negative helical CT scan is safe [100,102,103]. Swensen et al
[99] and Donato et al [102] found that only 8 of 993 and 4 of 239 patients
developed VTE within 3 months of a negative CT scan. In patients with CT
results negative for PE, there were 189 deaths (118, 33, and 38 deaths in the
Swenson et al [100], Donato et al [102], and van Strijen et al [102] studies),
with only 5 of these deaths thought to be secondary to PE. Wh ether occult
PE played a role in the remaining 184 deaths is unknown but could affect
significantly the data interpretation. These studies used superior CT tech-
nology and experienced radiologic interpretation that may not be available
Fig. 3. Pulmonary embolus (PE) located in the proximal pulmonary artery (PA) as seen on
spiral CT.
976 T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
at all centers. Given all the variables affecting the quality of CT evaluation,
the practitioner is left to determine whether or not CT is a reliable means of
detecting PE at his or her institution.
Pulmonary angiog raphy
Although pulmonary angiograph y is considered the gold standard in the
diagnosis of PE, it has numerous disadvantages. It is expensive, it requires
the use of potentially nephrotoxic intravenous contrast material, and it is
invasive with complications occurring in 6.5% and death in 0.5% [102,104].
It also is time-consuming and requires transport of the patient away from
the emergency depa rtment to the angiography department. Additionally,
angiography may not be readily available at many center s. These limitations
may explai n the reluctance of clinicians to follow through with angiography
despite other nondiagnostic testing. Patients can undergo pulmonary an-
giography safely even after receiving intravenous contrast material for a CT
scan [24].
Magnetic resonance angiography
Magnetic resonance angiography is expensive (although less so than
pulmonary angiography), is time-consuming, and has limited availability.
Access to the patient is limited, which makes it impractical for potentially
unstable patients. Contraindications include implanted metallic objects,
morbid obesity, and claustrophobia [30]. Magnetic resonance angiogr aphy
has the advantage of using a safer contrast agent and does not expose the
patient to ionizing radiation. A study by Oudkerk et al [105] comparing
magnetic resonance angiography with CT reported similar results between
the two modalities. Given the many disadvantages, however, the role of
magnetic resonance angiography remains limited.
Alveolar dead space measurements
When alveoli are ventilated but not perfused second ary to the presence of
a pulmonary embolus, blood flow is obstructed, while ventilation continues
resulting in dead space. Under normal conditions, there is no alveolar dead
space. Alveolar dead space measurements may play a future role in the
diagnosis of PE, especially in conjunction with other testing. Although
studies have shown that indices of alveolar dead space volume are predictive
of the presence of PE [106], further study and better availability of these
bedside tests are needed before measurement of alveolar dead space obtains
more widespread use [3,30].
Summary
The presentation of PE is often subtle and may mimic other diseases.
Many pulmonary emboli invariably preclude diagnosis by their occult
977T.A. Laack, D.G. Goyal / Emerg Med Clin N Am 22 (2004) 961–983
nature or by leading to rapid death from cardiopulmonary arrest. In pa-
tients who do manifest symptoms from PE, accurate diagnosis is essential.
Often it is difficult to distinguish the vague symptoms of PE from other
diagnoses, such as acute c oronary syndrome, pneumonia, COPD, CHF,
aortic dissection, myocarditis or pericarditis, pneumothorax, and musculo-
skeletal or gastrointestinal causes. Regardless of the presentation, the most
fundamental step in making the diagnosis of PE is first to consider it.
Historical clues and risk factors should raise the clinician’s suspicion.
PE is an unsuspected killer with a nebulous presentation and high mor-
tality. In all likelihood, PE will remain an elusive diagnosis despite advances
in technology and a wealth of research. A high index of suspicion is required,
but no amount of suspicion would eliminate all missed cases. Patients with
significant underlying cardiopul monary disease seem to be the most chal-
lenging. Patients with significant comorbidity have poor reserve and are
likely to have poor outcomes, especially if the diagnosis is not made and
anticoagulation is not initiated early.
Controversy exists over the best diagnostic approach to PE. A battery of
diagnostic studies is available, with few providing definitive answers. Studies
such as CT may be helpful at some institutions but offer poor predictive
value at others. Other diagnostic tests are not universally available. It is
hoped that further research and improvement s in current diagnostic modal-
ities will clear some of the current confusion and controversy of this
ubiquitous and deadly disease.
Acknowledgments
The authors thank Judith Roberson and Dr. Nadia Laack, for their
assistance in the preparation of this article.
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    • "In USA, the incidence of all DVT/PE events is 300,000–600,000 cases per year (approximately 1–2 per 1000 persons per year) and the mortality rates of all DVT/PE events is 60,000–100,000 cases per year (Beckman et al. 2010). However, it is difficult to estimate accurate mortality rates of the PE, because of the presence of related diseases and the large proportion of undiagnosed PE (Laack and Goyal 2004). With the improvement of its diagnosis and the development of access to healthcare, VT in Asian populations is now thought to be rising (Roberts et al. 2009; Zakai and McClure 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: To evaluate SNPs (single nucleotide polymorphism) in PROC (protein C gene) associated with pulmonary embolism (PE) susceptibility in North Chinese Han population. A case-control study design was used, and patients with PE and healthy participants were enrolled from the Emerging Department of the several hospitals in Weifang, Shandong, China. SNPs in PROC were genotyped using Mass ARRAY system. The allele frequency of rs199469469 was significantly different between PE patients and the control [OR (95 % CI) = 5.00 (1.66–15.12), P = 0.004], and the difference remained significantly after controlling for age and gender [OR (95 % CI) = 5.34 (1.47–19.39), P = 0.011). The G(del)G in the haplotype includes rs1799809|rs199469469|rs2069928 was of a significantly difference (P = 0.016) among PE patients and the controls, and remained significant (P = 0.015) after adjustment for age and sex. Our study reports that PROC SNPs (rs199469469) might be associated with PE susceptibility, with the G allele of rs199469469 serving as the protective factors for incidence of PE. These findings may contribute to the understanding and primary prevention of PE.
    Full-text · Article · Dec 2016
    • "Despite the development of several diagnostic and treatment methods for acute pulmonary embolism acute (PE), the condition continues to be a significant cause of cardiovascular morbidity and mortality [1, 2]. According to current guideline recommendations, risk stratification of patients with acute PE is mandatory to allow assessment of the individual prognosis and to guide therapeutic decision making. "
    [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to examine the Tpeak-Tend (Tpe/corrected Tpe) interval, which is an indicator of transmural myocardial repolarization, measured non-invasively via electrocardiogram in patients with acute pulmonary embolism (PE), and to investigate the relationship with 30-day mortality and morbidity. The study included 272 patients diagnosed with acute PE, comprising 154 females and 118 males, with a mean age of 63.1 ± 16.8 years. Tpe/cTpe intervals were calculated from the electrocardiograms with a computer program after using a ruler or vernier caliper manual measuring tool to obtain highly sensitive measurements. The relationship between the electrocardiogram values and 30-days mortality and morbidity were measured. The study group was divided into three groups according to cTpe intervals: Group 1, < 113 ms; Group 2, 113-133 ms; and Group 3, > 133 ms. White blood cell count and troponin T levels, corrected QT intervals with QRS complex durations, percentage of right ventricle dilatation with right/left-ventricular ratio, 30-day death, and combinations of these values were seen at a higher rate in Group 3 patients compared to the other groups. Kaplan-Meier analysis showed that the cTpe interval measured at > 126 ms could be used as a cut-off value in the prediction of mortality and morbidity. The cTpe cut-off values of 126 ms had sensivity, specificity, negative predictive value, and positive predictive value of 80.56 %, 59.32 %, 95.2 %, and 23.2 %, respectively. cTpe interval could be a useful method in early risk stratification in patients with acute PE.
    Full-text · Article · Sep 2015
    • "Numerous ECG findings have been reported, with sinus tachycardia being the most common [2]. Findings such as the S1Q3T3 pattern lack sensitivity and specificity, and also show no correlation with the severity of PE [2, 3]. Several studies have stated that T-wave inversion in lead III, aVF and precordial leads is most often associated with massive PE and/or PE with RV dysfunction, ascribing a high sensitivity, specificity, positive and negative predictive value to these findings3456. "
    Full-text · Dataset · Aug 2014 · BMC Cardiovascular Disorders
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