What every physician needs to know:

Pulmonary embolism (PE) is a common disorder characterized by thrombi obstructing the pulmonary arteries or one of its branches. Overall mortality from PE is high. A recent study reported a 30-day and 1-year mortality of 4% and 13% respectively. Timely diagnosis and treatment reduce the risk of morbidity and mortality associated with pulmonary embolism.

The majority of pulmonary emboli arise in the deep veins of the legs, but they may also arise from the deep veins of the arms, particularly when central venous catheters are present. Other veins, such as renal and pelvic veins, are uncommon sources of pulmonary emboli.

The overall incidence is higher in males compared with females (56 vs. 48 per 100,000 respectively). Blacks and whites have similar age-adjusted rates of pulmonary embolism (approximately 40-50 per 100,000 per year).

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Classification:

One useful clinical classification of pulmonary embolism divides the condition into massive pulmonary embolism, submassive pulmonary embolism, and low-risk (for mortality) pulmonary embolism.

Massive pulmonary embolism or “high-risk” PE is characterized by sustained hypotension (systolic BP < 90 mmHg or requiring pressors) that is not due to another cause.

Submassive pulmonary embolism or “intermediate-risk” PE is characterized by normal blood pressure with evidence of right ventricular dysfunction (RV dilation on echocardiogram; elevation of BNP or N-terminal pro-BNP; EKG evidence of new right bundle branch block, anteroseptal ST elevation, depression, or T-wave inversion) or myocardial necrosis (elevation of troponin).

Low-risk pulmonary embolism occurs without hypotension, RV dysfunction on imaging, or elevation of biomarkers.

Are you sure your patient has pulmonary embolism? What should you expect to find?

New or worsening dyspnea is the most common symptom of acute pulmonary embolism. However, there are many key symptoms and signs of acute pulmonary embolism:

Symptoms:

Dyspnea, particularly abrupt in onset or abruptly worsening

Pleuritic chest pain

Cough

Symptoms of deep venous thrombosis: calf/thigh pain and/or leg swelling

Hemoptysis

Syncope

Signs:

Tachypnea

Tachycardia

Hypotension (especially sustained and unexplained)

Increased intensity of P2

Pleural friction rub

Tenderness over leg veins and/or swelling (particularly asymmetric) of legs or arms

Diagnostic clues:

Hypoxemia (low Pa02 or low Sa02 on pulse oximetry)

EKG abnormalities

Elevated D-dimer

Symptoms, signs, and basic laboratory and imaging studies influence whether pulmonary embolism should be suspected and influence the strength of that suspicion.

The decision to evaluate for suspected pulmonary embolism or to rule out pulmonary embolism can be difficult. Validated practical clinical decision tools are available to assess pre-test probability of PE. Physicians who work in emergency departments may use the pulmonary embolism rule-out criteria (PERC). Patients with symptoms or signs suggestive of pulmonary embolism and who are over fifty years of age, who have had recent (within four weeks) surgery or trauma, who use estrogen, whose oxygen saturation is less than 92 percent at sea level, who have a history of prior deep vein thrombosis or pulmonary embolism, or who have unilateral leg swelling or resting heart rate higher than 99/minute are candidates for further evaluation.

Once the decision has been made to evaluate for pulmonary embolism, the clinician must assess the pre-test probability of pulmonary embolism.

Use of a validated clinical decision rule provides a very useful alternative to clinical gestalt:

Revised Geneva Score (0-3 points = low probability; 4-10 points = intermediate probability; >10 points = high probability)

Age more than 65 years (1 point)

Prior DVT or PE (3 points)

Surgery or fracture in the last month (2 points)

Active malignancy (2 points)

Unilateral leg pain (3 points)

Pain on deep palpation and edema of one leg (4 points)

Hemoptysis (2 points)

Heart rate 75-94 bpm (3 points) or heart rate higher than 94 bpm (5 points)

Traditional Wells Score (< 2 = low probability; 2-6 = moderate probability; > 6 = high probability) or Two-level Wells score (> 4 = likely; < or = 4 = unlikely)

Clinically suspected DVT (3 points)

Alternative diagnosis less likely than PE (3 points)

Heart rate higher than 100 bpm (1.5 points)

Immobilization/surgery in prior four weeks (1.5 points)

Prior DVT or PE (1.5 points)

Hemoptysis (1 point)

Malignancy treated within six months or palliative care (1 point)

When PE probability is low/intermediate based on scoring system, using D-dimer testing helps to exclude the likelihood of PE. If there is a high probability of PE, diagnostic yield is best with CT pulmonary angiography.

Once diagnosed, clinical decision rules such as the Pulmonary Embolism Severity Index (PESI), either the original form with score < 85 or the simplified form (sPESI) with score of 0, can help to risk stratify patients to prevent PE-related morbidity and mortality. These scoring systems are based on clinical information such as age, male sex, history of cancer, history of heart failure, history of chronic lung disease, heart rate, systolic blood pressure, respiratory rate, temperature, and altered mental status.

Beware: there are other diseases that can mimic pulmonary thromboembolism:

Symptoms, signs, laboratory, and imaging abnormalities of pulmonary embolism overlap with many disorders (Table 1). Furthermore, pulmonary embolism can complicate or coexist with many of these disorders.

Table 1.
Pneumonia
Left heart failure
Acute coronary syndromes
Acute lung injury
Postoperative atelectasis
Parenchymal lung disorders, such as obstructive lung disease, interstitial lung diseases, etc.
Pneumothorax
Anemia
Hyperthyroidism

How and/or why did the patient develop pulmonary embolism?

Pulmonary embolism occurs more often in individuals who have one or more risk factors. Tissue endothelial injury, venous stasis, and hypercoagulability are common denominators for the major risk factors of venous thromboembolism.

Which individuals are at greatest risk of developing pulmonary thromboembolism?

Major risk factors for pulmonary embolism include: (1) recent major surgery or trauma within three months, (2) bedrest of three days or more or travel of four hours or more within the past month, (3) active malignancy, especially adenocarcinoma, (4) central vein instrumentation within three months, (5) pregnancy, (6) inherited thrombotic disorders, and/or (7) chronic heart failure or chronic lung disease. The relative risk of pulmonary embolism is higher in women who use oral contraceptives with 50 ug/day of estrogen or more than in women who use lower doses or do not use oral contraceptives, although the absolute risk is low.

Increasing age is a strong risk factor for pulmonary embolism. The relationship between age and the prevalence of pulmonary embolism fits an exponential curve, with the prevalence of pulmonary embolism increasing sharply after age forty. The prevalence of pulmonary embolism increases thirty-fold when individuals in their forties (20/100,000 population) are compared with individuals in their seventies and eighties (300/100,000 population).

Certain racial groups have increased risk for developing pulmonary embolism. Investigators have reported a lower prevalence of pulmonary embolism for Asians, Pacific Islanders, and Native Americans than for whites and African Americans. A lower prevalence of heritable predispositions to embolism (e.g., factor V Leiden) in Asians, Pacific Islanders, and Native Americans may explain these observations.

Pregnancy, abortion, and contraceptives also increase the risk of pulmonary embolism for teenage girls.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

D-dimer: A negative sensitive D-dimer test result combined with a clinical assessment of low or intermediate probability by a validated clinical prediction score excludes pulmonary embolism. Not all D-dimer assays have adequate sensitivity (generally defined as > 85%). Using an age-adjusted D-dimer cutoff (age >50) of 500 μg/L increases the diagnostic yield of likelihood of PE with a positive D-dimer test.

ABG: Low PaO2 in the setting of a normal CXR raises the suspicion for presence of pulmonary embolism. Other abnormalities usually noted are respiratory alkalosis and widened alveolar-arterial oxygen gradient. However, ABG is not to be used as a diagnostic tool since it can be normal in patients with suspected PE.

What imaging studies will be helpful in making or excluding the diagnosis of pulmonary thromboembolism?

Imaging studies are essential for the diagnosis of pulmonary embolism.

CT pulmonary angiography (CTPA) is the most commonly used imaging study for the evaluation of suspected pulmonary embolism. The sensitivity and specificity of CTPA are high. Well designed and executed outcome studies have shown that it is safe to withhold anticoagulants when pulmonary emboli cannot be identified by CTPA.

Lung radionuclide perfusion scans, with or without ventilation scans, can also be very useful for the evaluation of suspected pulmonary embolism, particularly when CTPA examinations are contraindicated. A normal lung perfusion scan allows the clinician to withhold anticoagulants safely. Combining clinical probability, perfusion and ventilation lung scans, and lower extremity venous ultrasonography also allows clinicians to withhold anticoagulants safely. However, lung perfusion scans often lack specificity and require further testing to confirm the diagnosis of pulmonary embolism.

Venous compression ultrasonography can be useful for the evaluation of suspected pulmonary embolism because identification of proximal deep-vein thrombosis confirms the presence of thrombotic disease and allows treatment without exposure to contrast and radiation. However, a negative venous compression ultrasonography study does not allow pulmonary embolism to be excluded.

Conventional pulmonary angiography is also useful for the evaluation of suspected pulmonary embolism, but CTPA has largely replaced this more invasive diagnostic imaging study.

Magnetic resonance pulmonary angiography (MRPA) requires further evaluation. There appears to be considerable variation in its application even among major tertiary referral centers. The use of MRPA should be reserved to centers with experience and proven expertise.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of pulmonary thromboembolism?

In some settings, measurement of P (alveolar-End tidal) CO2 reflects alveolar dead space and combined with clinical pretest probability may be helpful in excluding pulmonary embolism.

What diagnostic procedures will be helpful in making or excluding the diagnosis of pulmonary thromboembolism?

A diagnosis of pulmonary embolism can be made by identifying characteristic features of thromboemboli on CTPA. The clinical probability influences the clinician’s confidence in the diagnosis. Clinicians can have a very high level of confidence when pretest probability is high.

High-probability lung scan patterns can also diagnose pulmonary embolism when the pretest probability is high. However, further testing is necessary to confirm the diagnosis when a high-probability lung scan pattern is identified in a patient for whom the pretest probability is low.

Demonstration of acute deep-vein thrombi on venous compression ultrasonography is sufficient to initiate management of patients for whom pulmonary embolism is suspected.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of pulmonary thromboembolism?

Pathology, cytology, and genetic studies are not used routinely to diagnose pulmonary embolism. Post-mortem examination may confirm the presence of pulmonary embolism as a cause of or contributor to a patient’s death. Rarely, a lung biopsy will show evidence of pulmonary embolism with or without pulmonary infarction.

If you decide the patient has pulmonary thromboembolism, how should the patient be managed?

Prompt anticoagulation is the mainstay of therapy for the majority of patients with pulmonary embolism who do not have a contraindication to anticoagulants. Current guideline statements advocate administration of anticoagulant therapy during the diagnostic workup in the absence of contraindication or high risk for bleeding. Subcutaneous low molecular weight heparin (LMWH), IV unfractionated heparin (UFH), or subcutaneous fondaparinux (F) (Table 2) may be used and should be given for at least 5-10 days overlapping and followed by a vitamin K antagonist (Warfarin), which is adjusted to obtain a therapeutic (2.0 to 3.0) INR.

Table 2.
Unfractionated heparin (UFH)
Bolus 5000 U or 80 U/kg followed by continuous infusion 18 U/ kg/hour to target aPTT
Bolus 333 U/kg followed by 250 U / kg subcutaneously twice daily without aPTT monitoring
Low-molecular-weight heparins*
Enoxaparin 1 mg / kg subcutaneously every twelve hours without monitoring
Tinzaparin 175 U / kg subcutaneously once daily without monitoring
Fondaparinux* 5 mg (patients < 50 kg); 7.5 mg (patients 50-100 kg); 10 mg (patients > 100 kg)

* Excreted by the kidneys. UFH is preferred when creatinine clearance is less than 30 ml/minute

Unfractionated heparin is preferred for patients with a creatinine clearance of less than 30 ml/minute.

LMWH is preferable to warfarin when pulmonary embolism complicates active cancer because the risk of recurrent embolism is lower with LMWH than with warfarin. LMWH or UFH is also preferable for extended anticoagulation during pregnancy.

A meta-analysis showed that novel non–vitamin K-dependent oral anticoagulant agents (NOACs) i.e. apixaban, dabigatran, edoxaban, and rivaroxaban in the treatment of venous thromboembolism are non-inferior to the standard heparin/Vitamin K antagonist regimen, in terms of prevention of VTE recurrence. The NOACs are also probably safer in terms of major bleeding, particularly intracranial and fatal hemorrhage. NOACs are recommended in the 2014 ESC Guidelines as an alternative to the standard heparin/Vitamin K antagonist treatment. It is important to acknowledge that no reversal agents for NOACs have been approved in the US as of early 2017.

The duration of long-term anticoagulation is based upon the risk-to-benefit ratio for individual patients and patient preference. Patients with unprovoked pulmonary embolism, active cancer, or recurrent thromboembolism are candidates for prolonged anticoagulation with periodic reassessment of the risk-to-benefit ratio. Anticoagulants may be discontinued after 3-6 months when they are used to treat provoked pulmonary embolism.

Heparin or LMWH may cause heparin-induced thrombocytopenia, a complication that can cause recurrent venous or arterial thrombi to form, often with devastating consequences. Argatroban, Lepirudin and Bivalirudin (Table 3), are the anticoagulants of choice for patients with proven or suspected heparin-induced thrombocytopenia.

Table 3.
Argatroban Obtain baseline aPTT, then infuse 2 mcg/kg/minute intravenously and adjust until aPTT is 1.5 – 3.0 X baseline.
Lepirudin Bolus 0.4 mg/kg up to 44 mg intravenously over 15 – 20 seconds, then infuse 0.15 mg/kg/hour up to 16.5 mg/hour. Adjust to achieve a PTT ratio of 1.5 to 2.5.
Bivalirudin Obtain baseline aPTT, Initial IV dose: 0.15 to 0.2 mg/kg/hour; adjust to aPTT 1.5 to 2.5 times baseline value.

Besides anticoagulation, several treatment options are available for early reperfusion. Their use is dictated by the severity of the pulmonary embolism, judged by the degree of cardiopulmonary dysfunction and the thrombus burden. In general, massive PE requires early reperfusion, usually systemic thrombolysis (Table 4), but in the face of contraindication to lysis (Table 5), surgical or catheter embolectomy are indicated. For low risk PE, anticoagulation alone is enough. For intermediate risk PE, the best treatment approach is controversial. Multidisciplinary PE teams, so-called Pulmonary Embolism Response Teams, may be useful in making difficult decisions.

Table 4.
Streptokinase 250,000 IU intravenous bolus followed by 100,000 IU/ hour for 12-24 hours
Urokinase 4400 IU/kg bolus followed by 4400 IU/ kg/hour for 12 to 24 hours
Alteplase 100 mg intravenous infusion over two hours
Table 5.
Prior cerebral hemorrhage
Cerebral aneurysm or arteriovenous malformation
Intracranial neoplasm
Ischemic cerebrovascular accident more than three hours but less than three months prior
Other intracranial disease, such as brain abscess
Uncontrolled hypertension
Aortic dissection
Active bleeding or bleeding diathesis (excluding menstruation)
Recent closed-head trauma or facial trauma
Recent (within three weeks) major surgery or trauma

There is weak evidence for reduced/half dose systemic catheter-directed fibrinolysis. These are not routinely recommended for reperfusion treatment for massive or submassive PE, but can be considered under selected circumstances.

Patients with massive pulmonary embolism who are candidates for aggressive management but have absolute or major contraindications to thrombolysis may be managed by surgical embolectomy. Decision making depends upon the clinician’s assessment of risk-to-benefit for the individual patient, the clinical environment, and the availability of skilled specialists.

Catheter-directed reperfusion techniques for removal of obstructing thrombi from the main pulmonary arteries may be an alternative to surgical embolectomy for patients with absolute or relative contraindications to thrombolysis. One of the major limitations to successful outcomes with catheter directed treatment is the need for local expertise to perform the procedure.

Bleeding is the principal risk of anticoagulant therapy. Physicians can identify patients at higher risk for bleeding complications, such as those with recent surgical procedures or major trauma, thrombocytopenia, or history of prior gastrointestinal bleeding. Placement of a vena cava filter is necessary when anticoagulation is contraindicated, the risk for a major bleeding complication is excessive, or major bleeding complicates anticoagulation.

What is the prognosis for patients managed in the recommended ways?

The prognosis for patients diagnosed and treated for acute pulmonary embolism is interwoven with the presence (or absence) of serious comorbidities. The majority of patients survive with few sequelae. However, the case fatality rate for acute pulmonary embolism can range from less than 1 percent to 60 percent, depending upon the clinical presentation.

Death is often the result of comorbid conditions, such as cancer or heart failure. Fatal recurrent pulmonary embolism occurs in less than 5 percent of patients. Chronic thromboembolic pulmonary hypertension is also a rare long-term complication, occurring in less than 5 percent of patients.

What other considerations exist for patients with pulmonary thromboembolism?

Prevention of pulmonary embolism is paramount. Identification of subgroups of patients with risk factors for pulmonary embolism is the first step. (Table 6)

Table 6.
Age greater than seventy years
Obesity (BMI > 30)
Immobility (bed rest or bed rest with bathroom privilege)
Prior venous thromboembolism
Ischemic stroke (especially with paralysis or paresis of a lower limb)
Heart failure (hospitalization)
Severe respiratory disease (hospitalization)Severe inflammatory disease (e.g., SLE or IBD)
Active cancer (within six months of treatment)
Severe infectious disease (e.g., pneumonia, sepsis, meningitis)
Hypercoagulability (acquired or hereditary thrombophilias)
Recent surgery (within the past month)
Ongoing hormone therapy

Current recommendations emphasize the role of institutional plans for identification and prophylaxis of high-risk groups. Prophylaxis against venous thromboembolism must balance the risks and benefits of any method for each individual patient and clinical setting.

Several institutions have developed and implemented risk assessment models (tools) for medical inpatients. (Table 7)

Table 7.
Padua Prediction Score (Score > 3 = increased risk)
Active cancer* 3
Previous VTE 3
Reduced mobility** 3
Known thrombophilia 3
Trauma or surgery (within 1 month) 2
Age over 69 years 1
Heart or respiratory failure 1
Acute MI or ischemic stroke 1
Acute infection or rheumatologic disorder 1
Obesity (BMI > 29) 1
Ongoing hormone therapy 1

* Local or distant metastases and/or radiation or chemotherapy in the past six months.

** Bed rest with bathroom privileges for at least three days.

Surgical populations also require risk-benefit assessment. The Venous Thromboembolism Risk Factor Assessment Tool developed by Joseph Caprini, MD, Ms, FACS, RVT provides a valid approach for risk assessment and can be found at venousdisease.com.

Current consensus statements recommend routine prophylaxis for high-risk surgical groups, such as patients who are undergoing major orthopedic surgical procedures. (Table 8) (Table 9)

Table 8.
General (low risk for VTE) Early frequent ambulation
General (moderate risk for VTE) LMWH, LDUH, or F
General (high- risk for VTE) LMWH, LDUH q 8hrs, or F
General (extreme risk for VTE) LMWH, LDUH q 8hrs, or F and GCS or IPC
Vascular (low risk for VTE) Early frequent ambulation
Vascular (high risk for VTE) LMWH, LDUH, or F
Gynecologic (low risk for VTE) Early frequent ambulation
Gynecologic (laparoscopic) Early frequent ambulation
Gynecologic (laparoscopic and VTE RF) LMWH, LDUH, F, GCS or IPC
Gynecologic (major for benign disease) LMWH, LDUH
Gynecologic (major for cancer) LMWH, LDUH q 8hrs
Urologic (transurethral or low risk for VTE) Early frequent ambulation
Urologic (major, open) LDUH twice or three times daily, GCS or IPC
Bariatric LMWH*, LDUH* three times daily, F, or IPC
*At higher doses than usual
Thoracic LMWH, LDUH, or F
Thoracic (CABG) LMWH, LDUH, or GCS or IPC
Orthopedic (elective hip replacement) LMWH, F, W
Orthopedic (elective knee replacement) LMWH, F, W
Orthopedic (knee arthroscopy without VTE RF) Early mobilization
Orthopedic (knee arthroscopy with VTE RF) LMWH
Orthopedic (hip fracture) F
Orthopedic (leg injury distal to knee) No prophylaxis
Elective spine (without VTE RF) Early frequent ambulation
Elective spine (with VTE RF) IPC or postoperative LDUH or LMWH
Elective spine (with VTE RFs) IPC and postoperative LDUH or LMWH
Neurosurgery IPC
Neurosurgery and high-risk for VTE IPC and postoperative LMWH or LDUH
Major trauma IPC and/or VCF until LMWH is considered safe **
Spinal cord trauma After hemostasis: LMWH or LDUH and IPC
Inpatient rehabilitation LMWH or W

**Mechanical strategies are appropriate for individual patients who are at high risk for bleeding until the risk for bleeding is considered acceptable.

Table 9.
Early frequent ambulation
Graduated compression stockings (GCS)
Venous foot pumps
Intermittent pneumatic compression divides (IPCs)
Vena cava filter (VCF)
Intermittent pneumatic compression of the calf and thigh is recommended over venous foot pumps when anticoagulants are contraindicated.

Clinical trials have led to FDA approval of several medications (Table 10).

Table 10.
Unfractionated heparin (LDUH) 5000 U sc q 12 hrs or q 8 hrs
Enoxaparin (LMWH) 40 mg sc daily
Dalteparin (LMWH) 5000 U sc daily
Fondaparinux (F) 2.5 mg sc daily
Warfarin (W) Dose to target INR 2.5 (range 2-3)

* Unfractionated heparin is preferable for patients with renal failure (creatinine clearance < 30 ml / minute). Doses of these anticoagulants for morbidly obese patients are uncertain, but Enoxaparin 30 mg subcutaneously every twelve hours has been recommended for patients whose BMI is greater than 35. Fondaparinux is very unlikely to cause heparin-induced thrombocytopenia.

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