Pulmonary embolism

Pulmonary embolism (PE) is the obstruction of one or more pulmonary arteries by solid, liquid, or gaseous masses. In most cases, the embolism is caused by blood thrombi, which arise from the deep vein system in the legs or pelvis (deep vein thrombosis) and embolize to the lungs via the inferior vena cava. Risk factors include immobility, inherited hypercoagulability disorders, pregnancy, puerperium, and recent surgery. The clinical presentation is variable and, depending on the extent of vessel obstruction, can range from asymptomatic to obstructive shock. Symptoms are often nonspecific, including chest pain, coughing, dyspnea, and tachycardia. The diagnosis of PE is based primarily on the clinical findings and is confirmed by the detection of an embolism in CT pulmonary angiography (CTPA). Arterial blood gas analysis typically shows evidence of respiratory alkalosis with low partial oxygen pressure, low partial carbon dioxide pressure, and elevated pH. Another commonly performed test is the measurement of D-dimer levels, which can rule out PE if negative. Anticoagulation with heparin is initiated to prevent further thromboembolisms as well as to promote the gradual dissolution of the embolism and the underlying thrombosis. In massive PE with obstructive shock, the thrombus is resolved with thrombolytic agents or embolectomy.

• Pulmonary embolism (PE): luminal obstruction of one or more pulmonary arteries, typically due to blood thrombi from deep vein thrombosis (DVT)
• Venous thromboembolism (VTE): an umbrella term that encompasses PE and DVT (see also “Hypercoagulable states”)
  • Recurrent VTE: VTE that recurs in a patient after the completion of the first 2 weeks of antithrombotic therapy ^[1]
  • Provoked VTE: VTE in an individual with ≥ 1 risk factor for VTE
  • Unprovoked VTE (idiopathic VTE): VTE in an individual without risk factors for VTE

• Incidence ^[2]
  • ∼ 1–2 venous thromboembolism per 1,000 in the United States per year
  • Rises with age
• Sex: overall ♂ > ♀ but women have a slight increase during the reproductive years ^[2]
• Mortality: Venous thromboembolism accounts for ∼ 100,000 deaths in the US per year. ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Deep vein thrombosis (most common cause; see “Risk factors for venous thromboembolism.”) ^[2]
• Fat embolism
• Air embolism
• Amniotic fluid embolism
• Others: bacterial embolism, pulmonary tumor embolism, pulmonary cement embolism

PE is FATAL: PE caused by Fat, Air, Thrombus, Amniotic fluid, and Less common, i.e., bacterial, tumor, and cement.

• Mechanism: thrombus formation (see “Virchow's triad.”) → deep vein thrombosis in the legs or pelvis (most commonly iliac vein) → embolization to pulmonary arteries via inferior vena cava ; → partial or complete obstruction of pulmonary arteries ^[2]
• Pathophysiologic response of the lung to arterial obstruction ^[2]
  • Infarction and inflammation of the lungs and pleura
    • Causes pleuritic chest pain and hemoptysis
    • Leads to surfactant dysfunction → atelectasis → ↓ PaO₂ ^[3]
    • Triggers respiratory drive → hyperventilation and tachypnea → respiratory alkalosis with hypocapnia (↓ PaCO₂)
  • Impaired gas exchange
    • Mechanical vessel obstruction → ventilation-perfusion mismatch → arterial hypoxemia (↓ PaO₂) and elevated A-a gradient (See “Diagnostics” below.)
  • Cardiac compromise
    • Elevated pulmonary artery pressure (PAP) due to blockage → right ventricular pressure overload → forward failure with decreased cardiac output → hypotension and tachycardia
• Pulmonary vasoconstriction: thromboxane A₂, prostaglandins, adenosine, thrombin, and serotonin secreted by activated platelet and the thrombus → pulmonary vasoconstriction and bronchospasm ^[4]

• Features of PE ^[2][5]
  • Acute onset of symptoms, often triggered by a specific event (e.g., on rising in the morning, sudden physical strain/exercise)
  • Dyspnea and tachypnea (> 50% of cases)
  • Sudden pleuritic chest pain (∼ 50% of cases), worse with inspiration
  • Cough and hemoptysis
  • Possibly decreased breath sounds, dullness on percussion, split second heart sound audible in some cases
  • Tachycardia; (∼ 25% of cases), hypotension
  • Jugular venous distension; and Kussmaul sign (in the event of a massive pulmonary embolism)
  • Low-grade fever
• Features of DVT: unilaterally painful leg swelling
• Features of massive PE: syncope and obstructive shock with circulatory collapse (e.g., due to a saddle thrombus)
• Features of PE under anesthesia during surgery ^[6]
  • Increasing heart rate
  • Drop in blood pressure
  • Drop in partial pressure of end-tidal CO₂ (PetCO₂) in capnography.
  • Drop in PaO₂ saturation end

Consider PE as a differential diagnosis in recurring or progressive dyspnea of uncertain etiology.

There are several externally validated decision tools that can be used to assess the pretest probability of PE. These include the original Wells score and modified Wells score, revised Geneva score, and pulmonary embolism rule-out criteria (PERC). None of these scoring systems have been found to have greater levels of accuracy than the others. ^[7][8]

Wells criteria for pulmonary embolism ^[9]

The Wells score is a diagnostic algorithm for assessing the probability of PE and has been validated in inpatient and outpatient settings. Note that a different version is used for determining the probability of DVT. (See “Wells criteria for DVT.”)

Revised Geneva score ^[12]

The revised Geneva score utilizes objective clinical variables. It has been externally validated and was initially studied in emergency department outpatients.

Pulmonary embolism rule-out criteria (PERC) ^[8][13][14]

PERC is only used for patients who have a low pretest probability of PE based on either their Wells score for pulmonary embolism or revised Geneva score.

PERC should only be used in patients with a low pretest probability of PE.

Diagnostic approach ^[5][8]

1. Assess for hemodynamic stability.
   • Stable patients: systolic BP > 90 mm Hg
   • Unstable patients: systolic BP < 90 mm Hg for > 15 minutes, evidence of shock, or BP drop > 40 mm Hg for > 15 minutes
2. Assess the pretest probability of PE.
   • Low: modified Wells score for PE ≤ 4, Wells score for PE < 2, or revised Geneva score < 4
   • Intermediate: modified Wells score for PE ≤ 4, Wells score for PE 2–6, or revised Geneva score 4–10
   • High: modified Wells score for PE > 4, Wells score for PE > 6, or revised Geneva score > 10
3. Obtain other laboratory studies or imaging as needed.
   • Stable patient and low probability of PE: Assess whether patient meets pulmonary embolism rule-out criteria (PERC).
     • Stable patient and PERC not met or intermediate probability of PE: Obtain D-dimer.
       • D-dimer ≥ 500 ng/mL: CTPA or V/Q scan
       • D-dimer < 500 ng/mL: PE is unlikely; consider other causes of symptoms (see “Differential diagnosis”).
   • Unstable patients and/or high probability of PE: Obtain CTPA or V/Q scan for a definitive diagnosis.
   • Critically ill patients who cannot be safely transported: bedside echocardiography

Laboratory studies ^[8]

D-dimer levels ^[8]

• Indication: pretest probability of PE is either low and does not meet PERC OR is intermediate
• Findings
  • Normal levels: < 500 ng/mL
  • If ≥ 500 ng/mL: Further testing is required (see below).
  • If the patient is > 50 years of age, adjust for age: age x 10 ng/mL = cut off value in ng/mL
• Interpretation
  • High sensitivity and negative predictive value: A negative D-dimer test most likely rules out PE.
  • Low specificity: positive results in all forms of fibrinolysis

Normal D-dimer values can usually rule out PE or DVT in patients with unremarkable history and physical examination! A positive D-dimer is nonspecific, since it may be elevated in any situation where there is increased fibrinolysis.

Additional testing

• Arterial blood gas (ABG): Limited utility in the diagnosis of suspected PE ^[15][16]
  • Hypoxemia: ↓ SaO₂ and PaO₂ < 80 mm Hg
  • ↑ Alveolar-arterial gradient
  • Respiratory alkalosis may be present : ↓ paCO₂, ↑ pH
  • May be normal
• CBC: mild leukocytosis may be present
• BMP: assessment of serum creatinine and eGFR
• Troponin: may be elevated ^[17]
• B-type natriuretic peptide (BNP) or NT-proBNP ^[18]
  • May be elevated
  • Elevated BNP is a risk factor for poor in-hospital outcomes and death.

Imaging

CT pulmonary angiography (CTPA)

• Definition: contrast-enhanced imaging of the pulmonary arteries
• Indications: most definitive diagnostic test for PE; high sensitivity, specificity, and immediate evidence of pulmonary arterial obstruction ^[5]
  • Unstable patients with a high pretest probability of PE who can be safely transported
  • Stable patients with a high pretest probability of PE or D-dimer ≥ 500 ng/mL
• Contraindications ^[19]
  • Renal insufficiency
  • Contrast allergy
  • Pregnancy
• Findings ^[20]
  • Visible intraluminal filling defects of pulmonary arteries
  • Wedge-shaped infarction with pleural effusion is almost pathognomonic for PE.

Ventilation/perfusion scintigraphy (V/Q scan) ^[20]

• Indications: an alternative to CT pulmonary angiography in patients with renal insufficiency and/or contrast allergy
• Procedure: detects areas of ventilation/perfusion (V/Q) mismatch via perfusion and ventilation scintigraphy
• Findings ^[21]
  • Perfusion failure in the normally ventilated pulmonary area (mismatch) suggests PE.
  • Discordance between V/Q scan results and the clinical pretest probability necessitates further evaluation.

Echocardiography ^[22]

• Indication: suspected right heart strain, critically-ill patients with suspected PE ^[19]
  • Prognostic tool in a hemodynamically stable patient
  • Rapid presumptive diagnostic tool in hemodynamically unstable patients
• Findings
  • Increased right atrial pressure
  • Dilatation and hypokinesis of the right ventricle, McConnell sign
  • Venous reflux with dilation of inferior vena cava (with corresponding liver congestion seen on ultrasound of the abdomen)
  • Tricuspid regurgitation (tricuspid valve insufficiency)
  • ↑ Pulmonary artery systolic pressure

Lower extremity venous ultrasound ^[20]

• Indications ^[5][8]
  • Symptoms of deep venous thrombosis and pulmonary embolism
  • Contraindications to CTPA (e.g., contrast allergy and renal insufficiency)
  • Pregnant women
• Findings: See “Deep vein thrombosis.”
  • Low sensitivity for the diagnosis of probable PE
  • A negative ultrasound may not be sufficient to rule out PE. ^[23][24]

Chest x-ray ^[20]

• Indication: initially often performed to rule out other causes (e.g., pneumonia, pneumothorax, pericarditis, aortic dissection)
• Findings
  • Signs of pulmonary embolus (rare)
    • Hampton hump: wedge-shaped opacity in the peripheral lung with its base at the thoracic wall; caused by pulmonary infarction and not specific for PE
    • Westermark sign: An embolus leads to diminished perfusion of downstream lung tissue, which has a hyperlucent appearance on x-ray.
    • Fleischner sign: prominent pulmonary artery caused by vessel distension due to a large pulmonary embolus (common in massive PE)
  • Other findings that may indicate PE
    • Atelectasis
    • Pleural effusions
    • Cardiomegaly

Pulmonary angiography ^[20]

• Definition: an invasive radiological procedure performed with contrast dye to visualize the pulmonary vasculature
• Procedure: Right heart catheterization → insertion of a catheter into a pulmonary artery→ angiography following administration of contrast agent
• Indications
  • Planning of concomitant endovascular treatment ^[20]
  • Suspicion for PE is high despite negative findings. ^[19]
• Findings: intraluminal filling defects in pulmonary arteries

Magnetic resonance pulmonary angiography ^[25]

• Indications: when standard imaging (CTPA or V/Q scan) cannot be performed
• Findings: similar to CTPA ^[20]

Additional diagnostics

Electrocardiography (ECG) ^[26]

• Findings
  • May be normal ^[27]
  • Arrhythmias: sinus tachycardia (> 100/min) , bradycardia (< 60/min) , atrial fibrillation ^[28][29]
  • Signs of right heart strain
    • S_IQ_IIIT_III-pattern
    • New right bundle branch block (incomplete or complete)
    • Right axis deviation or extreme right axis deviation
  • Other non-specific findings: P pulmonale , ST-segment elevation or depression, T-wave inversions in the anterior precordial leads (V1–V4) ^[30][31]
• Predictors of adverse outcome ^[26]
  • Atrial fibrillation
  • Sinus bradycardia
  • S_IQ_IIIT_III-pattern
  • New RBBB
  • ST-segment elevation in aVR
  • T-wave inversions in V1–V4
  • Inferior Q waves in lead II, III, and aVF

Identifying the underlying cause

• Evaluation for thrombophilia ^[32]
  • Indicated in younger patients with any of the following
    • No or weak risk factors
    • Family history
    • Recurrence of venous thrombosis
  • Timing: after the completion of therapy
  • See “Hypercoagulable states.”
• Evaluation for malignancies: age-appropriate screening studies

Approach

1. Stabilize the patient and provide supportive care.
   • Pulseless patient with suspected PE: Start ACLS and consider administration of thrombolytics (e.g., tPA ). ^[33][34].
2. Assess bleeding risk (see risk factors for bleeding in patients with VTE).
3. Consider empiric parenteral anticoagulation while awaiting a definitive diagnosis.
4. Risk stratify the patient based on prognostic models (see risk stratification of pulmonary embolism).
5. Consult pulmonary embolism response team (PERT), if available. ^[35]
6. Initiate therapy based on risk stratification and bleeding risk.
   • Massive PE: thrombolytic therapy or embolectomy
   • Submassive and nonmassive PE: anticoagulation or IVC filter

Supportive care

• Hemodynamic support: in patients with hypotension and obstructive shock ^[36]
  • IV fluids
    • Gentle bolus (e.g., normal saline ≤ 500 mL)
    • Avoid volume overload, which may be harmful in cases of right ventricular strain
  • Consider vasopressors (norepinephrine is most commonly used) if there is no improvement following fluid administration.
• Respiratory support
  • Oxygen supplementation in patients with SpO₂ < 90% ^[36]
  • For patients with respiratory failure: airway management and/or mechanical ventilation
• Analgesics: for patients with pain
  • See pain management.
  • Avoid NSAIDs if patient receiving anticoagulation or thrombolytics
  • Consider one of the following:
    • Morphine
    • Oxycodone

Hypervolemia can be harmful if right ventricle strain is present.

Assessment of bleeding risk

There are currently no scoring systems with sufficient prediction outcomes for the bleeding risk from anticoagulant therapy in patients with PE. The HAS-BLED score is sometimes used but it was designed and validated for anticoagulant therapy in patients with atrial fibrillation. See risk factors for bleeding in patients with VTE. ^[37]

Empiric parenteral anticoagulation for pulmonary embolism

• Indications: consider starting empiric anticoagulation in patients awaiting a definitive diagnosis, depending on the risk of bleeding, the pretest probability of PE, and the expected timing of the diagnostic study ; ^[34][36]
  • Low probability of PE and diagnostic study is expected to be delayed > 24 hours ^[34]
  • Intermediate probability of PE and diagnostic study is expected to be delayed > 4 hours ^[34]
  • High probability of PE
• Absolute contraindication: high bleeding risk
• Choice of medication ^[34][36]
  • Stable patients: LMWH ^[34]
  • Unstable patients or patients with renal insufficiency: UFH ^[38]

An absolute contraindication for empiric anticoagulation is a high risk of bleeding (e.g., recent surgery, hemorrhagic stroke, active bleeding).

Risk stratification of pulmonary embolism

Risk categories based on the risk of adverse outcomes ^[39][40]

• Massive pulmonary embolism (high-risk PE)
  • Persistent hypotension (shock)
  • Right ventricular failure
• Submassive pulmonary embolism (intermediate-risk PE)
  • Stable blood pressure (SBP > 90 mm Hg)
  • Right ventricular dysfunction or evidence of myocardial necrosis
• Nonmassive pulmonary embolism (low-risk PE)
  • Normotensive
  • No right ventricular dysfunction
  • Normal cardiac biomarkers

Pulmonary Embolism Severity Index (PESI) and simplified PESI (sPESI) ^[41][42]

The Pulmonary Embolism Severity Index stratifies the risk of mortality or adverse outcomes and is used to assist in decisions on inpatient vs. outpatient management.

Treatment of massive pulmonary embolism

Initiate directed therapy based on bleeding risk and the presence of any contraindications to thrombolytic therapy in massive pulmonary embolism.

• Low bleeding risk: systemic thrombolytic therapy
• High bleeding risk: catheter-directed thrombolytic therapy
• If thrombolytic therapy is contraindicated or unsuccessful: embolectomy

Thrombolytic therapy in pulmonary embolism

Systemic thrombolysis ^[38]

• Indications
  • Massive PE causing right heart failure associated with hypotension and a low bleeding risk
  • Nonmassive PE if the patient deteriorates after the initiation of anticoagulation but has not yet developed hypotension and has a low bleeding risk
• Contraindications: See contraindications to thrombolytic therapy in massive pulmonary embolism below.
• Procedure: thrombolysis, preferably with recombinant tissue-type plasminogen activator (tPA), e.g., alteplase
  • Most commonly systemic infusion via peripheral IV catheter ^[38]
  • Thrombolytic agents
    • tPA (alteplase)
    • Streptokinase
    • Urokinase
  • In patients receiving anticoagulation ^[43]
    • Discontinue anticoagulation prior to thrombolysis
    • Check aPTT 2 hours after completion of thrombolysis.
    • Resume anticoagulation when aPTT is < 2 times the upper normal limit.
• Complication: risk of hemorrhage during thrombolytic treatment ^[44]

Catheter-directed thrombolysis ^[38]

• Indication: patients with persistent hypotension who have high bleeding risk, obstructive shock, and/or failed systemic thrombolysis
• Contraindications: See contraindications to thrombolytic therapy in massive pulmonary embolism below.
• Procedure: ultrasound-assisted direct infusion of thrombolytics into pulmonary artery via pulmonary arterial catheter

Contraindications to thrombolysis

Embolectomy in pulmonary embolism ^[34]

• Indication: : treatment of last resort when thrombolysis is contraindicated or unsuccessful
• Procedure: surgical embolectomy (removal of an embolus by opening up an artery with an incision) or catheter-based thrombus removal

Treatment of nonmassive pulmonary embolism and submassive pulmonary embolism

Initiate directed therapy based on the bleeding risk on anticoagulation for VTE.

• Low to moderate bleeding risk: anticoagulation for pulmonary embolism
• High bleeding risk (anticoagulation is contraindicated): Consider IVC filter. ^[34]

Anticoagulation for pulmonary embolism ^{[34][38][40][45]}

• Initial parenteral anticoagulation (first 5–10 days): not required if long-term anticoagulation is planned with rivaroxaban or apixaban ^[38]
  • Low molecular weight heparin (LMWH) (e.g., enoxaparin ) or fondaparinux ; ^[34][40]
    • Preferred in patients with normal renal function
    • LMWH is especially preferred in patients with cancer.
  • Unfractionated heparin (UFH) ; ^[45]
    • In patients with renal failure
    • In patients with inadequate subcutaneous absorption (i.e., obesity)
    • In patients who might still require thrombolysis
• Long-term anticoagulation (up to 3 months)
  • DOAC: preferred over VKA in the general population
    • No initial parenteral anticoagulation required: rivaroxaban or apixaban
    • Initial parenteral anticoagulation required: dabigatran or edoxaban
  • Vitamin K antagonist (warfarin; , target INR 2–3): If DOAC cannot be given, VKA is preferred over LMWH. ^[45]
  • LMWH: preferred in cancer patients and pregnant women
• Reassessment of need for anticoagulation
  • After 3 months of anticoagulation, then annually
  • Indications for extended anticoagulation ^[38]
    • Unprovoked PE with a low to moderate risk of bleeding
    • Patients with cancer with any level of bleeding risk

Specific populations ^[38]

• Recurrent VTE
  • Assess for true recurrence, medication compliance, and underlying malignancy.
  • If on VKA or DOAC, switch to LMWH at least temporarily (usually at least for 1 month).
  • If there is a recurrence while on LMWH, increase the dose by one-quarter to one-third.
• Subsegmental PE
  • If there is a low risk for recurrence , anticoagulation is not necessary.
  • Otherwise, initiate anticoagulation.
  • Ultrasound of lower extremities to rule out proximal DVT.
• Low-risk PE based on risk stratification (see risk stratification of pulmonary embolism)
  • Patients with adequate home circumstances may be treated at home or discharged early (after 5 days of treatment).

Initial management

• Hemodynamic support in patients with hypotension
• Supplemental oxygen as needed
• Analgesics
• Consult Pulmonary Embolism Response Team (PERT). ^[35]

Nonmassive and submassive pulmonary embolism

• Assess bleeding risk and consider empiric parenteral anticoagulation while awaiting definitive diagnosis.
• If bleeding risk is low to moderate, start anticoagulation (see anticoagulation for pulmonary embolism).
• If bleeding risk is high, consider IVC filter placement.
• Consider continuous pulse oximetry and/or continuous telemetry.
• In select patients with very low-risk PE (e.g., sPESI = 0): Consider outpatient therapy.
• In patients with subsegmental PE with low risk of recurrent VTE: Consider clinical surveillance only.

Massive pulmonary embolism

• Evaluate need for mechanical ventilation.
• Have a crash cart at the bedside.
• Check for contraindications to thrombolytic therapy in massive pulmonary embolism.
• If there are no absolute contraindications: Initiate thrombolytic therapy in pulmonary embolism.
• If thrombolytic therapy is ineffective or absolute contraindications are present: Consult interventional radiology and/or surgery for embolectomy (see embolectomy in pulmonary embolism).
• Continuous telemetry and pulse oximetry
• Transfer to ICU.

Pulseless patient with suspected PE

• Start ACLS.
• Consider administration of reduced dose of tPA.

• See “Differential diagnosis of chest pain” and “Differential diagnosis of dyspnea.”
• Postoperative atelectasis
• Anxiety disorders

• High risk of recurrence: Without anticoagulant treatment, the risk of recurrence is ∼ 10% in the first year and ∼ 5% per year after. ^[5]
• Right ventricular failure and secondary pulmonary arterial hypertension
• Sudden cardiac death due to pulseless electrical activity
• Atelectasis (∼ 20% of cases)
• Pleural effusion
• Pulmonary infarction (∼ 10% of cases)
  • Embolisms of smaller segmental arteries can lead to wedge-shaped hemorrhagic pulmonary infarctions
  • Right ventricular failure, increased bronchial venous pressure, and preexisting pulmonary diseases increase the risk.
  • Patients may present with pneumonia following pulmonary infarction, detected by peripheral infiltration on chest X-ray (typically wedge-shaped = Hampton's hump).
• Arrhythmia

We list the most important complications. The selection is not exhaustive.

• Purpose: distinguishing cause of embolism (See “Etiology” above.)
• Histological findings ^[46]
  • Lines of Zahn: alternating layers of platelets mixed with fibrin (light pink layers) and red blood cells (dark red layers)
  • Only appear premortally (help distinguish a premortal thrombus from a postmortem one)

• One-Minute Telegram 9-2020-3/3: Commonly used scores for pulmonary embolism are only moderately useful in predicting short-term mortality

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