Pulmonary Medicine

Acute Pulmonary Embolism: Prevention and Treatment

What every physician needs to know:

Pulmonary thromboembolism is a common disorder characterized by thrombi obstructing the pulmonary arteries. Untreated pulmonary thromboembolism recurs and kills approximately a fourth of affected individuals.Timelydiagnosis and treatment reduce the risk of death caused by pulmonary thromboembolism.

The majority (> 90%) of pulmonary thromboemboli 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 thromboemboli.

Pulmonary thromboembolism affects men and women equally. However, there are disparities in the incidence of pulmonary thromboembolism based upon race. Blacks and whites have similar age-adjusted rates of pulmonary embolism (approximately 40-50 per 100,000 per year), whereas Asians and Japanese have lower rates of pulmonary thromboembolism.

Classification:

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

Massive pulmonary thromboembolism is characterized by sustained hypotension (systolic BP < 90 mmHg or requiring pressors) that is not due to another cause.

Submassive pulmonary thromboembolism is characterized by right ventricular dysfunction (RV dilation shown by RV / LV diameter >0.9 on four-chamber echocardiogram or CT image; elevation of BNP or N-terminal pro-BNP; or electrocardiographic evidence of new right bundle branch block, anteroseptal ST elevation, depression, or T-wave inversion) or myocardial necrosis (elevation of troponin).

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

Patients with massive pulmonary thromboembolism are candidates for more aggressive therapeutic interventions, such as thrombolysis or pulmonary embolectomy. In contrast, patients with submassive or low-risk pulmonary thromboembolism require management with anticoagulants.

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

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

Symptoms

Dyspnea, particularly abrupt in onset or abruptly worsening

Pleuritic chest pain

Hemoptyis

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

Presence of a central venous catheter

Laboratory clues

Hypoxemia (low Pa02 or low Sa02 on pulse oximetry)

EKG abnormalities

Elevated troponin

Symptoms, signs, and basic laboratory and imaging studies influence whether pulmonary thromboembolism 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, and physicians often rely on their intuition. However, validated practical clinical decision rules are available. Physicians who work in emergency departments may use the pulmonary embolism rule-out criteria (PERC). Patients with symptoms or signs suggestive of pulmonary thromboembolism and who are over fifty years of age, who have hemoptysis, who have had recent (within four weeks) surgery or trauma, who use estrogen, whose oxygen saturation is less than 95 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 thromboembolism, the clinician must assess the pretest probability of pulmonary thromboembolism. Clinical gestalt may suggest that pulmonary thromboembolism is either highly likely or unlikely.

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)

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

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

Table 1

Disorders overlapping with pulmonary thromboembolism
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 thromboembolism?

Pulmonary thromboembolism is the third most common acute cardiovascular disease. Pulmonary thromboembolism occurs more often in individuals who have one or more risk factors. Tissue injury, immobility, 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 thromboembolism include: (1) recent major surgery or trauma within three months, (2) bed rest 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, and/or (5) chronic heart failure or chronic lung disease. The relative risk of pulmonary thromboembolism is higher in women who use oral contraceptives with 50 ug/day 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 thromboembolism fits an exponential curve, with the prevalence of pulmonary thromboembolism increasing sharply after age forty. The prevalence of pulmonary thromboembolism 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 thromboembolism. Investigators have reported a lower prevalence of pulmonary thromboembolism for Asians, Pacific Islanders, and Native Americans than for whites and African Americans. A lower prevalence of heritable predispositions to thromboembolism (e.g., factor V Leiden) in Asians, Pacific Islanders, and Native Americans may explain these observations.

Gender is not a strong risk factor for the development of pulmonary thromboembolism. Pulmonary thromboembolism occurs more frequently in women than in men because of estrogen use and pregnancy.

Pregnancy, abortion, and contraceptives also increase the risk of pulmonary thromboembolism 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 excludes pulmonary thromboembolism. Not all D-dimer assays have adequate sensitivity (generally defined as > 85%). A positive D-dimer assay does not confirm the diagnosis of pulmonary thromboembolism but indicates the need for further testing.

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

Imaging studies are essential for the diagnosis of pulmonary thromboembolism.

CT pulmonary arteriography (CTPA) is the most commonly used imaging study for the evaluation of suspected pulmonary thromboembolism. 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 thromboemboli 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 thromboembolism, 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 thromboembolism.

Venous compression ultrasonography can be useful for the evaluation of suspected pulmonary thromboembolism 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 thromboembolism to be excluded.

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

Magnetic resonance pulmonary arteriography requires expertise and experience. A recent major study showed 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 dead space combined with pretest probability may be helpful in excluding pulmonary thromboembolism.

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

A diagnosis of pulmonary thromboembolism 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 the pretest probability is high.

High-probability lung scan patterns can also diagnose pulmonary thromboembolism 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 thromboembolism 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 thromboembolism. Postmortem examination may confirm the presence of pulmonary thromboembolism as a cause of or contributor to a patient's death. Rarely, a lung biopsy will show evidence of pulmonary thromboembolism 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 management for the majority of patients with pulmonary thromboembolism who do not have a contraindication for 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) (Table 2), intravenous or subcutaneous unfractionated heparin (UFH) either with monitoring of a PTT or weight-based without monitoring of a PTT (Table 2), or subcutaneous fondaparinux (F) (Table 2) may be used and should be given for at least five days. Unfractionated heparin is preferable for patients with a creatinine clearance of less than 30 ml/minute.

Table 2

Anticoagulants used to treat acute pulmonary embolism
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)

A vitamin K antagonist (typically warfarin) is initiated as soon as possible and is overlapped with UFH, LMWH, or F until at least five days of UFH, LMWH, or F are provided, and the international normalized ratio (INR) is 2.0 or higher for at least 24 hours.

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

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

Argatroban (Table 3), lepirudin (Table 3), and danaparoid (not available in the United States) are the anticoagulants of choice for patients with proven or suspected heparin-induced thrombocytopenia.

Table 3

Agents used to treat heparin-induced thrombocytopenia with FDA-approved doses
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

Patients with massive pulmonary thromboembolism are candidates for treatment with thrombolysis (Table 4), provided that they do not have absolute contraindications (Table 5). Patients with massive pulmonary thromboembolism--who are candidates for aggressive management--who have absolute or major contraindications to thrombolysis may be managed by 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.

Table 4

Thrombolytic agents with FDA approved doses
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

Absolute and Major Contraindications to Thrombolysis
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

Bleeding is the principal risk of anticoagulant therapy. Uncontrolled bleeding contraindicates anticoagulation. Physicians can identify patients at higher risk for bleeding complications, such as those with recent surgical procedures or major trauma, thrombocytpenia, 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.

Heparin or LMWH may cause heparin-induced thrombocytopenia, a complication that can cause recurrent venous or arterial thrombi to form, often with devastating consequences.

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

The prognosis for patients diagnosed and treated for acute pulmonary thromboembolism 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 thromboembolism 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 thromboembolism occurs in less than 5 percent of patients. Chronic thromboembolic pulmonary hypertension is also a rare complication, occurring in less than 5 percent of patients.

What other considerations exist for patients with pulmonary thromboembolism?

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

Table 6

Risk factors for pulmonary embolism
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

Risk assessment model for medical inpatients
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

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

Prophylaxis strategies for specific surgical populations
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
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

Table 9

Mechanical Methods
Early frequent ambulation
Graduated compression stockings (GCS)
Venous foot pumps
Intermittent pneumatic compression divides (IPCs)
Vena cava filter (VCF)

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

Table 10

FDA-approved medications for prevention of pulmonary thromboembolism*
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)

What’s the evidence?

Stein, PD, Matta, F. "Epidemiology and incidence: the scope of the problem and risk factors for development of venous thromboembolism". Clin Chest Medicine. vol. 31. 2010. pp. 611-628.

Jaff, MR, McMurtry, MS, Archer, SL. "Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association.". Circulation. vol. 123. 2011. pp. 1788-1830.

A comprehensive and updated review of the treatment of venous thrombosis from the American Heart Association.

Agnelli, G, Becattini, C. "Current concepts: acute pulmonary embolism.". N Engl J Med. vol. 363. 2010. pp. 266-274.

This concise review includes an informative algorithm for diagnosis.

Torbicki, A, Perrier, A, Konstantinides, S. "Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC).". Eur Heart J. vol. 29. 2008. pp. 2276-2315.

The European perspective is presented in this guideline from the European Society of Cardiology.

Kearon, C, Kahn, SR, Agnelli, G, Goldhaber, S, Raskob, GE, Comerota, AJ. "Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).". Chest. vol. 133. 2008. pp. 454S-545S.

The standard for antithrombotic therapy

Goldhaber, SZ. "Thrombolysis for pulmonary embolism.". N Engl J Med. vol. 347. 2002. pp. 1131-1132.

Goldhaber, SZ, Visani, L, De Rosa, M. "Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER).". Lancet. vol. 353. 1999. pp. 1386-1389.

Gandara, E, Wells, PS. "Diagnosis: use of clinical probability algorithms". Clin Chest Med. vol. 31. 2010. pp. 629-639.

Elliott, CG, Lovelace, TD, Brown, LM, Adams, D. "Diagnosis: imaging techniques". Clin Chest Med. vol. 31. 2010. pp. 641-657.

Pendleton, RC, Rodgers, GM, Hull, RD. "Established venous thromboembolism therapies: heparin, low molecular weight heparins, and vitamin K antagonists, with a discussion of heparin-induced thrombocytopenia". Clin Chest Med. vol. 31. 2010. pp. 691-706.

Kearon, C. "Long-term anticoagulation for venous thromboembolism: duration of treatment and management of warfarin therapy". Clin Chest Med. vol. 31. 2010. pp. 719-730.

Marik, PE. "Venous thromboembolism in pregnancy". Clin Chest Med. vol. 31. 2010. pp. 731-740.

Stevens, SM, Douketis, JD. "Deep vein thrombosis prophylaxis in hospitalized medical patients: current recommendations, general rates of implementation, and initiatives for improvement.". Clin Chest Med. vol. 31. 2010. pp. 675-689.

Geerts, WH, Bergqvist, D, Pineo, GF, Heit, JA, Samama, CM, Lassen, MR, Colwell, CW. "Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).". Chest. vol. 133. 2008. pp. 381S-453S.

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