Pulmonary Embolism

Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Deep vein thrombosis (DVT) is diagnosed in > 50% of patients presenting with symptoms, in whom the lower-extremity deep-venous system is the most common source of thrombus. Some individuals are asymptomatic, but the most common presenting symptom is dyspnea. The symptoms can be acute or chronic, and diagnosis is usually based on radiographic findings. Initial management is supportive and focuses on restoring oxygenation and hemodynamic stability. Both medical (systemic anticoagulants) and interventional therapies (catheter-based approach, surgery) are used to reestablish vessel patency.

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Overview

Definition

Pulmonary embolism (PE) is the intraluminal obstruction of a main pulmonary artery or any of its branches by a thrombus, air, amniotic fluid, or fat.

Epidemiology

  • Incidence: approximately 112 per 100,000 in the United States
    • Common in the elderly (> 500 per 100,000 in individuals > 75 years of age)
    • Approximately 100,000–300,000 deaths annually
  • Slight male predominance

Etiology

The most common cause is an obstruction in the pulmonary artery system by a migratory thrombus (most commonly: deep vein thrombosis (DVT)).

Origin of embolus is associated with frequency of embolism:

  • Proximal leg (most common):
    • Iliac, femoral, and popliteal veins 
    • Concurrent PE in > 50% at presentation
  • Distal leg: tibial and peroneal veins
  • Upper extremity:
    • Subclavian and brachial veins
    • Foreign bodies (e.g., catheters) usually present
  • Right side of the heart:
    • Thrombus related to foreign bodies (e.g., pacemaker leads)
    • Air (from intravenous injection)
  • Pelvic and renal veins:
    • Amniotic fluid during pregnancy
    • Air due to vascular injury
    • Fat due to trauma (e.g., orthopedic surgery)

Risk factors:

  • Virchow’s triad (predictive for developing DVT):
    • Stasis
    • Endothelial injury
    • Hypercoagulable state
  • Genetic: 
    • Factor V Leiden mutation
    • Prothrombin gene mutation
    • Protein C and Protein S deficiencies
  • Acquired:
    • Immobilization
    • Recent surgery 
    • Malignancy
    • Trauma 
    • Obesity
    • Smoking

Pathophysiology

Anatomy

  • Saddle embolus:
    • At the bifurcation of the main pulmonary artery
    • May extend into the right or left main pulmonary artery
    • 3%–6% of all cases
  • Most emboli move beyond the bifurcation:
    • Lobar
    • Segmental
    • Subsegmental branches

Pathophysiology

Ventilation/perfusion (V/Q) mismatch:

  • Obstruction of vascular flow
  • Imbalance in ventilation (V) and blood flow (Q) within the alveoli leads to an inflammatory response and further imbalance:
    • Shunting (perfusion without ventilation):
      • Decreased surfactant production
      • Atelectasis
      • Bronchoconstriction due to the release of inflammatory mediators
      • Decreased airflow to the alveoli
    • Dead space (ventilation without perfusion):
      • Vasoconstriction due to the release of inflammatory mediators
      • Decreased blood flow to the alveoli

Hemodynamic instability:

  • Right-sided heart failure:
    • Increased pulmonary vascular resistance (PVR)
    • Decreased ejection from the right ventricle (RV) with subsequent increased central venous pressure (CVP)
    • Ultimately leads to prolonged RV strain, distention, and decreased contractility
  • Left-sided heart failure:
    • “Right heart failure begets left heart failure.”
    • Acute condition occurring with larger (i.e., central) emboli, and later with peripheral disease
    • Decreased RV ejection fraction results in decreased left ventricular end-diastolic volume (LVEDV).
    • Decreased LVEDV results in decreased cardiac output, which manifests clinically as hypotension and tachycardia.

Pulmonary infarction:

  • Occurs in about 10% of patients
  • Associated with small emboli in the segmental and subsegmental branches, causing ischemia of lung tissue

Illustration of pulmonary embolism

Image: “Illustration of pulmonary embolism” by Baedr-9439. License: CC0

Clinical Presentation

Timeline

  • Acute: immediate development of symptoms
  • Subacute: development of symptoms within days to weeks
  • Chronic: 
    • No immediate symptoms
    • Patients gradually develop pulmonary hypertension (over years).

Symptoms

Presentation varies significantly. High suspicion must be maintained given the risks of complications and mortality.

  • Can be asymptomatic (incidentally found on imaging)
  • Massive PE presents with hemodynamic instability/shock.
  • Most common symptom: dyspnea at rest and/or during exertion
  • Cough
  • Pulmonary infarcts:
    • Hemoptysis 
    • Pleuritic chest pain
  • Symptoms of DVT: 
    • Calf pain and/or tenderness
    • Extremity swelling
    • Palpable cord
    • Erythema
    • Rubor

Diagnosis

Physical exam

  • Tachypnea
  • Tachycardia
  • Rales and/or decreased breath sounds
  • Hypotension 
  • Loud 2nd heart sound (P2)
  • Jugular vein distention

Pulse oximetry

  • Room-air oxygen saturation (O2 sat) < 95%
  • Low O2 sat is associated with more complications.

Electrocardiography

  • Arrhythmia:
    • Sinus tachycardia is most common.
    • Atrial fibrillation
  • S1Q3T3 (rare but pathognomonic):
    • Prominent S wave in lead I
    • Q wave in lead III
    • Inverted T wave in lead III

Laboratory studies

  • CBC: Leukocytosis may be present.
  • Troponin may be elevated in 50% of patients with moderate-to-large emboli.
  • D-dimer (< 500 ng/mL is normal):
    • By-product of crosslinked fibrin degradation
    • Indication of thrombus breakdown
    • > 95% sensitivity when elevated
  • Arterial blood gas (ABG) on room air:
    • Hypoxemia: PaO2 < 80 mm Hg
    • Hypocapnia: PaCO2 < 35 mm Hg
    • Respiratory alkalosis: pH > 7.45

Modified Wells score

  • PE probability assessment is used with clinical evaluation to guide diagnostic workup.
  • If PE unlikely (modified Wells score ≤ 4), a D-dimer can be ordered:
    • D-dimer normal (< 500): PE excluded
    • D-dimer elevated: Order CT chest with contrast (or V/Q scan).
  • If PE is likely (modified Wells score > 4), CT chest with contrast is the best initial test.
Table: Modified Wells criteria
Major criteriaScore
Signs/symptoms of DVT3.0
PE clinically more likely than other diagnoses3.0
Tachycardia1.5
Prolonged immobilization1.5
History of PE or DVT1.5
Hemoptysis1.0
Malignancy1.0
Probability assessment:
Score > 4: PE likely
Score ≤ 4: PE unlikely

DVT: deep vein thrombosis
PE: pulmonary embolism

Imaging

  • Chest radiography:
    • Nonspecific
    • Atelectasis or parenchymal abnormality
    • Effusion
    • Cardiomegaly
  • Chest CT pulmonary angiography (CTPA) with contrast or spiral CT:
    • Best initial test if modified Wells score > 4
    • Current “gold standard” in PE investigation
    • Shows filling defects in the pulmonary vasculature
  • V/Q scan: 
    • 2nd-line diagnostic modality
    • Used if CT scan is contraindicated, not available, or inconclusive
    • 2 or more perfusion defects within normally ventilated pulmonary areas 
  • Venous ultrasonography (US):
    • Does not definitively diagnose PE, but indicates DVT
    • Loss of normal venous compressibility detected using ultrasound probe
    • Turbulent or retrograde flow on Doppler imaging
    • Not useful for central veins obscured by skeletal structures (e.g., subclavian vein)
  • Echocardiogram:
    • Can show RV strain
    • Can show cardiac thrombus (“in transit” embolus)
    • Does not yield a definitive diagnosis, but can be considered for bedside use in patients who are unstable
  • Pulmonary angiography:
    • Direct injection of iodine contrast into the main pulmonary artery via a central catheter
    • Largely replaced by CTPA, but used if:
      • CT scan is inconclusive
      • Planning a catheter-directed thrombolysis or embolectomy

Management and Prognosis

Respiratory support

  • Supplemental oxygen therapy to improve O2 sat > 95%
  • Nasal cannula, non-rebreather mask, mechanical ventilation

Hemodynamic support

  • Small amount of IV fluids to improve preload, but avoid fluid overload
  • Inotropic agents
  • Vasopressin
  • Selection of cardiac drugs should be based on the presence and severity of heart failure and hemodynamics.

Anticoagulants

  • Majority of patients with PE are managed with anticoagulants, including warfarin and heparin:
    • Majority of patients are initially started on heparin (regular or low-molecular-weight heparin (LMWH)).
    • Patients are continued on oral warfarin for at least 3 months or longer depending on the risk profile.
  • Always assess for bleeding risks:
    • Advanced age
    • Frequent falls
    • History of liver or renal failure
    • Thrombocytopenia
    • History of bleeding disorders or hemorrhagic stroke
    • Recent surgery or trauma
  • Empiric treatment is initiated with subcutaneous LMWH if:
    • Pre-test probability of PE is high.
    • Diagnostic imaging is delayed.

Reperfusion therapy

  • Thrombolytic therapy:
    • Infusion of a lytic agent (e.g., streptokinase) through a catheter tip directed at the embolus in an attempt to lyse the thrombus
    • For hemodynamically unstable patients with a massive embolus
  • For hemodynamically stable patients with adverse outcomes (i.e., RV dysfunction) or patients unresponsive to systemic anticoagulants
  • Embolectomy consists of removal of the embolus: 
    • Catheter-based or surgical procedure
    • Indicated for hemodynamically unstable patients with massive emboli, who are not suitable candidates for thrombolytic therapy, or in cases of failed thrombolytic therapy

Inferior vena cava (IVC) filter

  • Used to prevent PE in patients with DVT
  • Barrier placed within the IVC to prevent passage of the migratory thrombus into the pulmonary arterial system
  • Not useful for DVT in the upper extremities
  • Indications:
    • Contraindications to anticoagulants
    • Failed systemic anticoagulants
    • Complications of systemic anticoagulants

Prognosis

  • Estimated mortality of untreated PE is approximately 30%. 
  • Recurrence:
    • More likely in patients with unresolved risk factors (i.e., cancer)
    • Highest in the 1st 2 weeks after presentation 
  • Chronic thromboembolic pulmonary hypertension (CTEPH) is a long-term sequel that rarely occurs:
    • Patients complain of progressive dyspnea and/or exercise intolerance.
    • May result from an undissolved thrombus or parenchymal damage

Pulmonary emboli in both pulmonary arteries revealed after the autopsy of a patient who died of pulmonary embolism:
A: macroscopic thrombus (arrows)
B: 20-cm long thrombus
C: microscopic thrombi (arrows), hematoxylin and eosin staining, magnification X100

Image: “Pulmonary emboli” by Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. License: CC BY 4.0

Differential Diagnosis

  • Acute heart failure: an acute reduction in cardiac function. Acute heart failure commonly presents with dyspnea, low room-air O2 sat levels, and lower-extremity edema, which is more likely to be bilateral as opposed to unilateral. Elevated BNP and Trop I are commonplace and echocardiography findings aid in the diagnosis. Chest X-ray may show pulmonary edema. Management relies on medical optimization.
  • Myocardial infarction: acute ischemia of the myocardium. Myocardial infarction can result in tachyarrhythmia, right-sided heart failure, and hypotension depending on the severity and location. The chest pain that occurs during a heart attack is most commonly substernal in location and not usually pleuritic. Serially elevated cardiac enzymes and ST-segment changes on the ECG are usually diagnostic. Management involves stabilization, anticoagulant, and reperfusion therapies.
  • Pneumonia: an inflammation of the lung parenchyma usually caused by respiratory infection. Pneumonia may cause pleuritic chest pain with accompanying low room-air O2 sat levels. Chest X-ray commonly reveals parenchymal lesions, which are usually absent in PE unless a parenchymal infarct is present. Treatment is with antibiotics and respiratory support in advanced cases.
  • Chronic obstructive pulmonary disease (COPD) exacerbation: an acute exacerbation of chronic disease of the lower respiratory tract causing respiratory impairment. Chronic obstructive pulmonary disease presents with marked dyspnea and is commonly accompanied by wheezing. Chest pain is an unlikely symptom in the absence of concomitant pneumonia. Diagnosis is established based on a combination of history, clinical symptoms, and pulmonary function tests. Symptoms generally improve with supplemental oxygen therapy and a combination of steroidal treatments.

References

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  2. Tapson, V.F., Weinberg, A.S. (2020). Treatment, prognosis, and follow-up of acute pulmonary embolism in adults. UpToDate. Retrieved December 6, 2020, from https://www.uptodate.com/contents/treatment-prognosis-and-follow-up-of-acute-pulmonary-embolism-in-adults
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  4. Hollander, J.E., Chase, M. (2020). Evaluation of the adult with chest pain in the emergency department. UpToDate. Retrieved December 9, 2020, from https://www.uptodate.com/contents/evaluation-of-the-adult-with-chest-pain-in-the-emergency-department
  5. Thompson, B.T., Kabrhel, C., Pena, C. (2020). Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism. UpToDate. Retrieved December 9, 2020, from https://www.uptodate.com/contents/clinical-presentation-evaluation-and-diagnosis-of-the-nonpregnant-adult-with-suspected-acute-pulmonary-embolism
  6. Lip, G.Y.H., Hull, R.D. (2020). Overview of the treatment of lower extremity deep vein thrombosis (DVT). UpToDate. Retrieved December 11, 2020, from https://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt
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