“Epidemiology, Pathophysiology and Clinical Diagnosis”
Chief, Cardiovascular Medicine and Nuclear Cardiology
“M.Bufalini-G. Marconi” Hospital
Cesena, Italy
(a categorical teaching seminar presented at the European Association of Nuclear Medicine meeting in Naples, August 2001)
EPIDEMIOLOGY
Pulmonary
embolism (PE) is the third most common cardiovascular disease after acute
ischemic syndromes and stroke and is the first cause of death in hospitalized
patients older than 65 and the first cause of death in women during pregnancy.
PE and deep vein
thrombosis (DVT) should be considered part of the same pathological process,
Venous Thromboembolism, whose real incidence is largely underestimated due to
the following reasons:
-
the clinical
diagnosis is difficult
-
the sub-optimal
accuracy of the first line tests used to support the clinical suspicious
-
the reported
data regarding the incidence of PE are based on different populations and
methods of diagnosis (autopsy; clinical;
clinical + tests)
-
the disease is
managed by physicians in many different specialties (cardiologists,
pneumologists, vascular medicine specialists, general internists, vascular
surgeons)
According to
several Authors the real incidence of the disease is 10 times higher than that
derived from the clinical diagnosis, from the hospital charts, from death
certificates or autoptic results.
Despite the
differences in the epidemiological data the incidence of venous
thromboembolism can be estimated in about 1 in 1000 per year (1-2). By
extrapolation, it can be estimate that more than 250.000 patients are
hospitalized annually in the United States with venous thromboembolism.
Similar data have been reported in Europe.
The average
mortality rate for PE is 10 to 15% (3).
About half of
the patients with pelvic vein thrombosis or proximal leg deep vein thrombosis
have PE which is usually asymptomatic. Similarly, about 70% of patients with
documented PE (angiography or autopsy) have DVT. However only 20 to 35% of
these DVT are clinically evident.
PATHOPHYSIOLOGY
Rudolf
Wirchow postulated more than a century ago that a triad of factors predisposed
to venous thrombosis: 1. Local trauma to the vessel wall; 2.
Hypercoagulability, and 3. Stasis.
Many patients
who suffer pulmonary thromboembolism (PTE) have an underlying inherited
predisposition that remain clinically silent until an acquired stressor occurs
such as surgery, medical illness with immobilization, obesity, pregnancy,
post-partum, oral contraceptives.
The most
frequent inherited predisposition to hypercoagulability is the resistance to
the endogenous anticoagulant protein, activated protein C. This resistance is
related to a mutation in the factor V gene and is designated Factor
V Leiden.
Factor
V Leiden is more common than all other identified inherited hypercoagulable
states including deficiencies of Protein C , protein S, antithrombin III
The embolic risk
of a DVT is related to the following factors:
1.
Location of the DVT proximal or distal to the calf. The
proximal DVP, if not diagnosed, have a rate of embolization of 40% that
decreses to 5% if treated, with <1% of fatal PE. The distal DVT (below the knee) have a much lower rate of PE,
rarely clinically significant. However the distal DVT in 20%-30% of cases tend
to extend proximally within 1-2 weeks of the initial clinical presentation.
2.
Characteristic of the thrombus: floating or adherent.
3.
Presence of an adequate anti-thrombotic therapy. After
the start of the anti-thrombotic therapy the floating thrombi have a similar
risk of PE as the adherent ones.
Embolization:
when venous thrombi become
dislodged from their site of formation, they embolize to the pulmonary
arterial circulation or, paradoxically, to the erterial circulation through a
patent foramen ovale.
Pulmonary
embolism ranges from incidental, clinically unimportant thromboembolism, to
massive embolism with sudden death.
The severity of
the physiopathological and clinical consequences depends from: a) the
respiratory and hemodinamic effect induced by the clot and, b) the
pre-existing cardiovascular and respiratory conditions.
Pulmonary
embolism can have the following effects:
1.
Increased
pulmonary vascular resistance
due to vascular obstruction or neurohormonal agents including serotonin
2.
Impaired
gas exchange due to
increased alveolar dead space from vascular obstruction (hypoxemia)
3.
Alveolar
hyperventilation due to
reflex stimulation of irritant receptors (hypocapnia and respiratory alcalosis)
4.
Increased
airway resistance due to
bronchoconstriction
5.
Decreased
pulmonary compliance due to
loss of surfactant and lung edema
6.
Hemodinamic
effects: Right
ventricular dilatation, atrial dilatation, tricuspid insufficiency.
Consequently the interventricular septum bulges into and compresses an
intrinsecally normal left ventricle. Increased right ventricular wall tension
also compresses the right coronary artery and may precipitate myocardial
ischemia and infarction. Underfilling of the left ventricle may lead to a fall
in left ventricular output and systemic arterial pressure, thereby provoking
myocardial ischemia due to compromised coronary artery perfusion. This can
lead to left ventricular dysfunction and pulmonary edema. However it has to be
noted that this is note the rule. It happens usually in massive or large PE.
In patients without pre-existing cardio-respiratory diseases due to the high
vascular reserve of the pulmonary capillary bed, a vascular obstruction of 30%
induces only a slight increase in the mean pulmonary pressure and an
obstruction > 50% is requested to induce a significant increase in
pulmonary arterial pressure. This explains why in a significant percentage of
patients a PE could be associated only to minimal symptoms and signs.
CLINICAL
DIAGNOSIS
The diagnosis of
venous thromboembolism is difficult. Overdiagnosis is as likely as
underdiagnosis. Approximately only 1/3 of patients with clinical signs
consistent with DVT has actually a DVT at phlebography, and only half of the
patients with documented DVT at phlebography has clinical signs of DVT.
With regard to
PE, in the PIOPED and PISA-PED studies the incidence of false positive
diagnosis was 67% and 61% respectively (4-5)
Several anatomo-clinical
studies have reported that about 75% of patients with PE were misdiagnosed. In
less than 50% of patients who died for PE, the diagnosis was made before the
death . This is a particularly important because the mortality rate for PE can
be markedly reduced in patient in whom the diagnosis is made and are treated
consequently, and because approximately 1/3 of the patients with an initial
non fatal PE will experience a fatal recurrence.
The diagnostic
evaluation for possible PE begins with the clinician’s SUSPICIOUS of the
diagnosis that is triggered by the patient’s presenting features in a
context of risk factors present in a variable proportion in the single
patient. This is the most critical part of the diagnostic process. When a PE
is suspected most of the clinical difficulties are overcome.
Appreciation of
the clinical setting and maintenance of a high degree of clinical suspicious
for possible PE are of paramount importance.
The presentation
is largely variable, depending on the size of the vessel occluded and the
patient’s cardiorespiratory reserve. A small PE in a young adult may cause
little or no symptoms, but could cause significant cardio-pulmonary compromise
in an elderly patient with underlying lung disease.
There are no
powerful diagnostic symptoms and signs. Most of them are non specific and
could be found in several other clinical conditions (pneumonia, congestive
heart failure, myocardial infarction).
In general, a
sudden onset of clinical manifestations suggestive of PE must trigger the
suspicious of PE. When this suspicious occurs in a patient “at risk” for
pulmonary thromboembolism (evidence of DVT or at risk of DVT) the diagnosis of
PE becomes likely, but cannot be considered certain.
The clinical
presentation of PE has prognostic and therapeutic implication.
1. Massive PE:
an obstruction of the arterial blood flow that causes a substantial increase
in right ventricular afterload and consequent elevation of pulmonary arterial
systolic pressure. Such patients are at highest risk of sudden death or, over
a long term, for chronic pulmonary hypertension. These patients present with
systemic hypotension, severe dyspnea and tachycardia , cianosis with distended
neck veins. Cardiogenic shock and cardiac arrest for electromechanical
dissociation may occur. Primary therapy with thrombolysis or embolectomy offer
the greatest chance of survival.
2. Pts with
moderate to large PE have normal
systemic arterial pressure but signs of right ventricular dysfunction (ecocardiography):
the mortality increases as right ventricular failure worsens. Thrombolysis
could be appropriate (6).
3. Pts
with small to moderate PE have
both normal systemic arterial pressure and right ventricular function. They
have a good prognosis.
4. Pulmonary infarction. Usually indicate a small PE. It is very painful
because it lodges near the innervation of pleural nerves.
The most
frequent symptom and signs of PE are non specific: dyspnea, tachypnea,
tachycardia and chest pain can be found in other clinical situations. It is
therefore of paramount importance to suspect the possibility of PE when these
symptoms and signs are associated with clinical risk factors of venous
thromboembolism.
Young and
previously healthy individuals may simply appear anxious even with
anatomically large PE. We should not expect always the presence of the “classic
signs” such as tachycardia, neck vein dystension, cyanosis, increased
intensity of the second heart sound, cough, emoptysis etc. to raise the
suspicious of PE.
Some patients
have PE and a coexisting illness such as pneumonia and heart failure. In such
circumstances clinical improvement will often fail to occur despite standard
medical treatment of the concomitant illness. This situation can serve to
raise the suspicious of the possible coexistence of PE.
The optimal
strategy is an integrated diagnostic approach that includes a methodical
history collection, risk factors analysis and physical examination
supplemented by selective testing when appropriate.
Electrocardiography,
chest radiography and some blood samples should be incorporated into the
clinical diagnostic first workup.
Electrocardiography: the most frequent electrocardiographic abnormality is T-wave inversion
in the anterior leads, especially V1-V4 (7). New-onset right-bundle branch
block or atrial fibrillation are less common. However due to the different
degrees of hemodinamic consequences of PE, the ecg could be largely variable.
From completely normal to mild non specific abnormalities like tachicardia,
mild ST-T abnormalities, small voltages of QRS to clear abnormalities
consistent with right ventricular overload: RBBB, S1-Q3 pattern with negative
T waves in D3 V1-V4.
Chest Radiography: it can exclude the diagnosis of PE when other conditions that can
present with similar symptoms are documented like pneumonia or PNX. It can
show characteristic signs that, although non specific, are frequently
associated with PE: focal oligoemia, enlarged right descending pulmonary
artery, a diaphragm elevation.
Blood tests:
Arterial blood gases: finding of hypoxemia or hypocapnia may increase the physician’s level
of diagnostic suspicion, but these findings are not specific nor sensitive for
PE as demonstrated in the Prospective Investigation of Pulmonary Embolism (PIOPED)
study.
The quantitative
plasma D-Dimer (ELISA method) has a
sensitivity of 96% allowing the exclusion of PE for values < 500 ng/l
with a high negative predictive value. However the D-dimer assay is not
specific because it increases also in patients with myocardial infarction,
sepsis, or almost any systemic illness and therefore it cannot be used to
confirm a suspicious of PE.
In summary:
the clinical assessment alone very rarely allows the diagnosis of PE or DVT.
However it is of paramount importance to detect clinical features suggestive
of pulmonary thromboembolism because the outcome of patients is largely
influenced by the early recognition and treatment of this disease. The “culture”
of the CLINICAL SUSPICIOUS must be always present. We must suspect often PE in
order to confirm its presence sometimes. The final diagnosis must be supported
by objective tests. Relying only on the clinical evaluation is not sufficient.
There is the risk of treating for a long time with anti coagulants patients
who don’t need it and, on the contrary, there is the risk of not treating
patients with DVT with potential fatal PE and not treating patients with PE
with the potential risk of recurrent fatal PE.
References
1.
Anderson FA Jr, Wheeler HB,Goldberg RJ, et al. A
population based perspective of the hospital incidence and case fatality rates
of deep vein thrombosis and pulmonary embolism: The Worcester DVT Study. Arch
Intern Med 1991;151:933-8
2.
Silverstein MD, Heir JA,Mohr DN, Petterson TM, O’Fallon
WM Melton LJ III. Trends in the incidence of deep vein thrombosis and
pulmonary embolism: a 25 year population-based study. Arch Intern Med 1998;
158:585-93
3.
Goldhaber SZ. Pulmonary embolism. The N Engl J Med
1998:339:93-104
4.
The PIOPED Investigators. Value of
Ventilatory/perfusion scan in acute pulmonary embolism: results of the
Prospective Investigation of Pulmonary embolism Diagnosis (PIOPED). JAMA
1990;263:2753-9
5.
Miniati M, Pistolesi M, Marini C et al. Value of
Perfusion Lung Scan in the Diagnosis of Pulmonary Embolism: Results of the
prospective Investigative Study of Acute Pulmonary Embolism Diagnosis
(PISA-PED). Am J Respir Crit Care Med 1996; 154:1387-93
6.
Kasper W, Kostantinides S, Geibel A, et al. Management
strategies and determinants of outcome in acute major pulmonary embolism:
results of a multicenter registry. J Am Coll Cardiol 1997;30:1165-71
7.
Ferrari E, Imbert A, Chevalier T,
et al. The Ecg in pulmonary embolism: predictive value of negative T
waves in precordial leads-80 case report. Chest 1997;111:537-543
Pierluigi
Pieri,MD
Chief, Division
of Cardiovascular Medicine and Nuclear Cardiology
“M.Bufalini-G.Marconi”
Hospital
Phone:0547-352860
Fax:0547-304010
e-mail: mailto:gpieri@ausl-cesena.emr.it
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