Pulmonary embolism

Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved
from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may
include shortness of breath, chest pain particularly upon breathing in, and coughing up blood.
Symptoms of a blood clot in the leg may also be present such as a red, warm, swollen, and painful
leg. Signs of a PE include low blood oxygen levels, rapid breathing, rapid heart rate, and sometimes
a mild fever. Severe cases can lead to passing out, abnormally low blood pressure, and sudden
death.

PE usually results from a blood clot in the leg that travels to the lung. The risk of blood clots is
increased by cancer, prolonged bed rest, smoking, stroke, certain geneticconditions, estrogen-based
medication, pregnancy, obesity, and after some types of surgery. A small proportion of cases are
due to the embolization of air, fat, or amniotic fluid. Diagnosis is based on signs and symptoms in
combination with test results. If the risk is low a blood test known as a D-dimer will rule out the
condition. Otherwise a CT pulmonary angiography, lung ventilation/perfusion scan, or ultrasound of
the legs may confirm the diagnosis. Together deep vein thrombosis and PE are known as venous
thromboembolism (VTE).

Efforts to prevent PE include beginning to move as soon as possible after surgery, lower leg
exercises during periods of sitting, and the use of blood thinners after some types of surgery.
Treatment is typically with blood thinners such as heparin or warfarin. Often these are
recommended for six months or longer. Severe cases may require thrombolysis using medication
such as tissue plasminogen activator (tPA), or may require surgery such as a pulmonary
thrombectomy. If blood thinners are not appropriate, a vena cava filter may be used.

Pulmonary emboli affect about 430,000 people each year in Europe, In the United States between
300,000 and 600,000 cases occur each year, which results in between 50,000 and 200,000 deaths.
Rates are similar in males and females. They become more common as people get older.

Signs and symptoms

Symptoms of pulmonary embolism are typically sudden in onset and may include one or many of the
following: dyspnea (shortness of breath), tachypnea (rapid breathing), chest pain of a "pleuritic"
nature (worsened by breathing), cough and hemoptysis (coughing up blood). More severe cases can
include signs such as cyanosis (blue discoloration, usually of the lips and fingers), collapse,
and circulatory instability because of decreased blood flow through the lungs and into the left side of
the heart. About 15% of all cases of sudden death are attributable to PE. While PE may present
with syncope, less than 1% of syncope cases are due to PE.

On physical examination, the lungs are usually normal. Occasionally, a pleural friction rub may be
audible over the affected area of the lung (mostly in PE with infarct). A pleural effusion is sometimes
present that is exudative, detectable by decreased percussion note, audible breath sounds, and
vocal resonance. Strain on the right ventricle may be detected as a left parasternal heave, a
loud pulmonary component of the second heart sound, and/or raised jugular venous pressure. A
low-grade fever may be present, particularly if there is associated pulmonary hemorrhage or
infarction.

As smaller pulmonary emboli tend to lodge in more peripheral areas without collateral circulation
they are more likely to cause lung infarction and small effusions (both of which are painful), but not
hypoxia, dyspnea or hemodynamic instability such as tachycardia. Larger PEs, which tend to lodge
centrally, typically cause dyspnea, hypoxia, low blood pressure, fast heart rate and fainting, but are
often painless because there is no lung infarction due to collateral circulation. The classic
presentation for PE with pleuritic pain, dyspnea and tachycardia is likely caused by a large
fragmented embolism causing both large and small PEs. Thus, small PEs are often missed because
they cause pleuritic pain alone without any other findings and large PEs often missed because they
are painless and mimic other conditions often causing ECG changes and small rises in troponin and
BNP levels.

PEs are sometimes described as massive, submassive and nonmassive depending on the clinical
signs and symptoms. Although the exact definitions of these are unclear, an accepted definition of
massive PE is one in which there is hemodynamic instability such as sustained low blood
pressure, slowed heart rate, or pulselessness.

About 90% of emboli are from proximal leg deep vein thromboses (DVTs) or pelvic vein thromboses.
DVTs are at risk for dislodging and migrating to the lung circulation. The conditions are generally
regarded as a continuum termed venous thromboembolism (VTE).

The development of thrombosis is classically due to a group of causes named Virchow's

triad (alterations in blood flow, factors in the vessel wall and factors affecting the properties of the
blood). Often, more than one risk factor is present.
 Alterations in blood flow: immobilization (after surgery, long-haul flight), injury, pregnancy (also
procoagulant), obesity (also procoagulant), cancer (also procoagulant)
 Factors in the vessel wall: surgery, catheterizations causing direct injury ("endothelial injury")

Underlying causes
After a first PE, the search for secondary causes is usually brief. Only when a second PE occurs,
and especially when this happens while still under anticoagulant therapy, a further search for
underlying conditions is undertaken. This will include testing ("thrombophilia screen") for Factor V
Leiden mutation, antiphospholipid antibodies, protein C and S and antithrombinlevels, and later
prothrombin mutation, MTHFR mutation, Factor VIII concentration and rarer
inherited coagulation abnormalities.

Diagnosis

In order to diagnose a pulmonary embolism, a review of clinical criteria to determine the need for
testing is recommended. In those who have low risk, age less than 50, heart rate less than 100
beats per minute, oxygen level more than 94% on room air, and no leg swelling, coughing up of
blood, surgery or trauma in the last four weeks, previous blood clots, or estrogen use, further testing
is not typically needed.

If there are concerns this is followed by testing to determine a likelihood of being able to confirm a
diagnosis by imaging, followed by imaging if other tests have shown that there is a likelihood of a PE
diagnosis.

The diagnosis of PE is based primarily on validated clinical criteria combined with selective testing
because the typical clinical presentation (shortness of breath, chest pain) cannot be definitively
differentiated from other causes of chest pain and shortness of breath. The decision to perform
medical imaging is based on clinical reasoning, that is, the medical history, symptoms and findings
on physical examination, followed by an assessment of clinical probability.

Probability testing
The most commonly used method to predict clinical probability, the Wells score, is a clinical
prediction rule, whose use is complicated by multiple versions being available. In 1995, Philip Steven
Wells, initially developed a prediction rule (based on a literature search) to predict the likelihood of
PE, based on clinical criteria. The prediction rule was revised in 1998 This prediction rule was further
revised when simplified during a validation by Wells et al. in 2000. In the 2000 publication, Wells
proposed two different scoring systems using cutoffs of 2 or 4 with the same prediction rule. In 2001,
Wells published results using the more conservative cutoff of 2 to create three categories. An
additional version, the "modified extended version", using the more recent cutoff of 2 but including
findings from Wells's initial studies were proposed. Most recently, a further study reverted to Wells's
earlier use of a cutoff of 4 points to create only two categories.

There are additional prediction rules for PE, such as the Geneva rule. More importantly, the use
of any rule is associated with reduction in recurrent thromboembolism.

The Wells score:

 clinically suspected DVT — 3.0 points

 alternative diagnosis is less likely than PE — 3.0 points
 tachycardia (heart rate > 100) — 1.5 points
 immobilization (≥ 3d)/surgery in previous four weeks — 1.5 points
 history of DVT or PE — 1.5 points
 hemoptysis — 1.0 points
 malignancy (with treatment within six months) or palliative — 1.0 points

Traditional interpretation

 Score >6.0 — High (probability 59% based on pooled data)

 Score 2.0 to 6.0 — Moderate (probability 29% based on pooled data)
 Score <2.0 — Low (probability 15% based on pooled data)

Alternative interpretation

 Score > 4 — PE likely. Consider diagnostic imaging.

 Score 4 or less — PE unlikely. Consider D-dimer to rule out PE.

Recommendations for a diagnostic algorithm were published by the PIOPED investigators; however,
these recommendations do not reflect research using 64 slice MDCT. These investigators
recommended:

 Low clinical probability. If negative D-dimer, PE is excluded. If positive D-dimer, obtain MDCT
and based treatment on results.
 Moderate clinical probability. If negative D-dimer, PE is excluded. However, the authors were not
concerned that a negative MDCT with negative D-dimer in this setting has a 5% probability of
being false. Presumably, the 5% error rate will fall as 64 slice MDCT is more commonly used. If
positive D-dimer, obtain MDCT and based treatment on results.
 High clinical probability. Proceed to MDCT. If positive, treat, if negative, more tests are needed
to exclude PE. A D-dimer of less than 750 ug/L does not rule out PE in those who are at high
risk.

Pulmonary embolism rule-out criteria

The pulmonary embolism rule-out criteria (PERC) helps assess people in whom pulmonary
embolism is suspected, but unlikely. Unlike the Wells score and Geneva score, which are clinical
prediction rules intended to risk stratify people with suspected PE, the PERC rule is designed to rule
out risk of PE in people when the physician has already stratified them into a low-risk category.

People in this low risk category without any of these criteria may undergo no further testing for PE:
low oxygen saturations — SaO <95%, unilateral leg swelling, coughing up blood, prior DVT or PE,
2

recent surgery or trauma, age >50, hormone use, fast heart rate. The rationale behind this decision
is that further testing (specifically CT angiogram of the chest) may cause more harm (from radiation
exposure and contrast dye) than the risk of PE. The PERC rule has a sensitivity of 97.4% and
specificity of 21.9% with a false negative rate of 1.0% (16/1666).

Blood tests
In people with a low or moderate suspicion of PE, a normal D-dimer level (shown in a blood test) is
enough to exclude the possibility of thrombotic PE, with a three-month risk of thromboembolic events
being 0.14%. D-dimer is highly sensitive but not specific (specificity around 50%). In other words, a
positive D-dimer is not synonymous with PE, but a negative D-dimer is, with a good degree of
certainty, an indication of absence of a PE. The typical cut off is 500 μg/L, although this varies based
on the assay. However, in those over the age of 50, changing the cut-off value to the person's age
multiplied by 10 μg/L (accounting for assay which has been used) is recommended as it decreases
the number of falsely positive tests without missing any additional cases of PE.

When a PE is being suspected, several blood tests are done in order to exclude important
secondary causes of PE. This includes a full blood count, clotting status (PT, aPTT, TT), and some
screening tests (erythrocyte sedimentation rate, renal function, liver enzymes, electrolytes). If one of
these is abnormal, further investigations might be warranted.

Troponin levels are increased in between 16–47% with pulmonary embolism.

Imaging

Selective pulmonary angiogramrevealing clot (labeled A) causing a central obstruction in the left main
pulmonary artery. ECG tracing shown at bottom.

In typical people who are not known to be at high risk of PE, imaging is helpful to confirm or exclude
a diagnosis of PE after simpler first-line tests are used. Medical societies recommend tests such as
the D-dimer to first provide supporting evidence for the need for imaging, and imaging would be
done if other tests confirmed a moderate or high probability of finding evidence to support a
diagnosis of PE.

CT pulmonary angiography is the recommended first line diagnostic imaging test in most people.

Historically, the gold standard for diagnosis was pulmonary angiography, but this has fallen into
disuse with the increased availability of non-invasive techniques. Ultrasound of the legs can confirm
the presence of a PE but cannot rule it out.

CT pulmonary angiography

CT pulmonary angiography (CTPA) is a pulmonary angiogram obtained using computed

tomography (CT) with radiocontrast rather than right heart catheterization. Its advantages are clinical
equivalence, its non-invasive nature, its greater availability to people, and the possibility of
identifying other lung disorders from the differential diagnosis in case there is no pulmonary
embolism.

Prevention
Further information: Thrombosis prophylaxis

Pulmonary embolism may be preventable in those with risk factors. People admitted to hospital may
receive preventative medication, including unfractionated heparin, low molecular weight
heparin (LMWH), or fondaparinux, and anti-thrombosis stockings to reduce the risk of a DVT in the
leg that could dislodge and migrate to the lungs.

Following the completion of warfarin in those with prior PE, long-term aspirin is useful to prevent
recurrence.

Treatment
Anticoagulant therapy is the mainstay of treatment. Acutely, supportive treatments, such
as oxygen or analgesia, may be required. People are often admitted to hospital in the early stages of
treatment, and tend to remain under inpatient care until the INR has reached therapeutic levels.
Increasingly, however, low-risk cases are managed at home in a fashion already common in the
treatment of DVT. Evidence to support one approach versus the other is weak.

Anticoagulation
Usually, anticoagulant therapy is the mainstay of treatment. Unfractionated heparin (UFH), low
molecular weight heparin (LMWH), or fondaparinux is administered initially,
while warfarin, acenocoumarol, or phenprocoumontherapy is commenced (this may take several
days, usually while the patient is in the hospital). LMWH may reduce bleeding among people with
pulmonary embolism as compared to UFH according to a systematic review of randomized
controlled trials by the Cochrane Collaboration. According to the same review, LMWH reduced the
incidence of recurrent thrombotic complications and reduced thrombus size when compared to
heparin. There was no difference in overall mortality between participants treated with LMWH and
those treated with unfractionated heparin.

Warfarin therapy often requires a frequent dose adjustment and monitoring of the international
normalized ratio (INR). In PE, INRs between 2.0 and 3.0 are generally considered ideal. If another
episode of PE occurs under warfarin treatment, the INR window may be increased to e.g. 2.5–3.5
(unless there are contraindications) or anticoagulation may be changed to a different anticoagulant
e.g. LMWH.

In patients with an underlying malignancy, therapy with a course of LMWH is favored over warfarin; it
is continued for six months, at which point a decision should be reached whether ongoing treatment
is required.

Similarly, pregnant women are often maintained on low molecular weight heparin until at least six
weeks after delivery to avoid the known teratogenic effects of warfarin, especially in the early stages
of pregnancy.

Warfarin therapy is usually continued for 3–6 months, or "lifelong" if there have been previous DVTs
or PEs, or none of the usual risk factors is present. An abnormal D-dimer level at the end of
treatment might signal the need for continued treatment among patients with a first unprovoked
pulmonary embolus. For those with small PEs (known as subsegmental PEs) the effects of
anticoagulation is unknown as it has not been properly studied as of 2014.

Thrombolysis
Massive PE causing hemodynamic instability (shock and/or low blood pressure, defined as a systolic
blood pressure <90 mmHg or a pressure drop of 40 mmHg for >15 min if not caused by new-onset
arrhythmia, hypovolemia or sepsis) is an indication for thrombolysis, the enzymatic destruction of the
clot with medication. In this situation, it is the best available treatment in those without
contraindications and is supported by clinical guidelines. It is also recommended in those in cardiac
arrest with a known PE.

Catheter-directed thrombolysis (CDT) is a new technique found to be relatively safe and effective for
massive PEs. This involves accessing the venous system by placing a catheter into a vein in the
groin and guiding it through the veins by using fluoroscopic imaging until it is located next to the PE
in the lung circulation. Medication that breaks up blood clots is released through the catheter so that
its highest concentration is directly next to the pulmonary embolus. CDT is performed
by interventional radiologists, and in medical centers that offer CDT, it may be offered as a first-line
treatment. Catheter-based ultrasound-assisted thrombolysis is being investigated.

The use of thrombolysis in non-massive PEs is still debated. Some have found that the treatment
decreases the risk of death and increases the risk of bleeding including intracranial hemorrhage.
Others have found no decrease in the risk of death.

Surgery
Surgical management of acute pulmonary embolism (pulmonary thrombectomy) is uncommon and
has largely been abandoned because of poor long-term outcomes. However, recently, it has gone
through a resurgence with the revision of the surgical technique and is thought to benefit certain
people. Chronic pulmonary embolism leading to pulmonary hypertension(known as chronic
thromboembolic hypertension) is treated with a surgical procedure known as a pulmonary
thromboendarterectomy.

Epidemiology
Pulmonary emboli occur in more than 600,000 people in the United States each year. It results in
between 50,000[7] and 200,000 deaths per year in the United States.[9] The risk in those who are
hospitalized is around 1%. The rate of fatal pulmonary emboli has declined from 6% to 2% over the
last 25 years in the United States.
Prognosis
Less than 5 to 10% of symptomatic PEs are fatal within the first hour of symptoms.

There are several markers used for risk stratification and these are also independent predictors of
adverse outcome. These include hypotension, cardiogenic shock, syncope, evidence of right heart
dysfunction, and elevated cardiac enzymes. Some ECG changes including S1Q3T3 also correlate
with worse short-term prognosis. There have been other patient-related factors such as COPD and
chronic heart failure thought to also play a role in prognosis.

Prognosis depends on the amount of lung that is affected and on the co-existence of other medical
conditions; chronic embolisation to the lung can lead to pulmonary hypertension. After a massive
PE, the embolus must be resolved somehow if the patient is to survive. In thrombotic PE, the blood
clot may be broken down by fibrinolysis, or it may be organized and recanalized so that a new
channel forms through the clot. Blood flow is restored most rapidly in the first day or two after a
PE. Improvement slows thereafter and some deficits may be permanent. There is controversy over
whether small subsegmental PEs need treatment at all and some evidence exists that patients with
subsegmental PEs may do well without treatment.

Once anticoagulation is stopped, the risk of a fatal pulmonary embolism is 0.5% per year.

Mortality from untreated PEs was said to be 26%. This figure comes from a trial published in 1960 by
Barrit and Jordan, which compared anticoagulation against placebo for the management of PE.
Barritt and Jordan performed their study in the Bristol Royal Infirmary in 1957. This study is the only
placebo controlled trial ever to examine the place of anticoagulants in the treatment of PE, the
results of which were so convincing that the trial has never been repeated as to do so would be
considered unethical. That said, the reported mortality rate of 26% in the placebo group is probably
an overstatement, given that the technology of the day may have detected only severe PEs.

Predicting mortality
The PESI and sPESI scoring tools can estimate mortality of patients. The Geneva prediction rules
and Wells criteria are used to calculate a pre-test probability of patients to predict who has a
pulmonary embolism. These scores are tools to be used with clinical judgment in deciding diagnostic
testing and types of therapy. The PESI algorithm comprises 11 routinely available clinical variables.
It puts the subjects into one of five classes (I-V), with 30-day mortality ranging from 1.1% to 24.5%.
Those in classes I and II are low-risk and those in classes III-V are high-risk.