Pulmonary Embolism

Pulmonary embolism is an obstruction or blockage that affects the pulmonary artery (main artery to the lung) or one of its branches in the lung by an embolus, usually a blood clot that has formed as a result of deep vein thrombosis. In cases in which the embolus is large enough to block the main pulmonary artery or if there are many clots, it may lead to cardiac arrest and require emergency resuscitation.

A pulmonary embolism results when one or more emboli (fragments of material) break off from a blood clot, usually in a vein, and are carried, via the heart, to the lungs. The effects mainly depend on the size and numbers of emboli but also on the general health of the person’s lungs and heart.

Causes and symptoms

Pulmonary embolism is more likely to occur after recent surgery, pregnancy, oestrogen treatment – for example with the combined pill or hormone replacement therapy (HRT) – and immobility, including long-haul flights. It may also be linked to thrombophilia (a genetic tendency for blood to clot too readily). A massive embolus can cause sudden death. Smaller emboli may cause severe shortness of breath, rapid pulse, dizziness, chest pain that is made worse by breathing, and coughing up of blood. Tiny emboli may not produce any symptoms, but, if recurrent, they may eventually lead to pulmonary hypertension (high blood pressure in the arteries that supply the lungs). After having a first embolism, the risk of developing further emboli is significantly increased.

Diagnosis

A diagnosis may be made using procedures including chest X-rays, radionuclide scanning, and pulmonary angiography. An ECG and analysis of arterial blood gases may also be performed.

Treatment

Treatment depends on the size and severity of the embolus. A small clot gradually dissolves; thrombolytic drugs may be given to speed up this process. Surgery may be needed to remove larger clots. Anticoagulant drugs reduce the chance of developing further clots. If the condition recurs, however, tests are needed to investigate the possibility of blood clotting disorders. Affected females should stop using combined oral contraceptives and HRT.

Pulmonary embolism in more detail - technical

Essentials

Acute pulmonary embolism (PE) is the third most common cardiovascular problem after coronary heart disease and stroke. It is a complication of DVT, with emboli originating in the legs in 80% or more of cases. Immobilization, irrespective of the cause, is the most frequent predisposing factor.

Common symptoms are dyspnoea (c.75%), pleuritic chest pain (c.50%), cough (c.35%), and calf or thigh pain or swelling (c.40%). Circulatory collapse (systolic blood pressure <80 mmHg or loss of consciousness) is an uncommon (8–15%) mode of presentation in patients entered into clinical trials, but likely to be more frequent in routine clinical practice. Tachypnoea (respiratory rate ≥20 cycles/min or greater) is the most common physical sign (50–70%), and abnormalities may be found on respiratory (30–50%) or cardiac (20–30%) examination.

Investigation—algorithms similar to those used to guide management of patients with suspected DVT are used when PE is suspected or needs to be excluded. Patients with a low clinical probability and negative D-dimer are not investigated further. Patients with a moderate or high clinical probability, and patients with an elevated D-dimer, proceed to tests for the presence of pulmonary emboli, typically by contrast-enhanced spiral CT in combination (in many centres) with CT venous-phase imaging.

Management—treatment with anticoagulants while awaiting the outcome of diagnostic tests may be appropriate, particularly if the tests cannot be obtained immediately. All patients who are hypoxic should be given supplementary oxygen at high concentration. Anticoagulation is as described for DVT. Thrombolytic therapy is not indicated for routine treatment, but is advised for those that are hypotensive or have continuing hypoxemia whilst receiving high-flow oxygen.

Inferior vena cava filter—this is recommended for patients with proximal DVT or PE if anticoagulants are contraindicated, PE has recurred whilst on adequate anticoagulant therapy, or PE is severe and any recurrent PE may be fatal.

A very few survivors of acute PE (0.1–0.2%) develop chronic pulmonary thromboembolic hypertension

Introduction

Deep venous thombosis (DVT) and pulmonary embolism (PE) are sometimes described together using the term ‘thromboembolism’. PE is a complication of DVT, with thrombi in 80% or more of cases originating in the legs. Management strategies have been developed that are based on the diagnosis of either PE or DVT, provided the patient has good respiratory reserve. Treatment with anticoagulants is the same for both, although some physicians believe that patients can be managed better if it is known whether acute PE is present, even if a diagnosis of DVT is already established.

Incidence

Acute PE is the third most common cardiovascular problem after coronary heart disease and stroke. In 2006, 0.8% of patients ≥18 years hospitalized in short-stay hospitals in the United States of America had PE. This represented 110 patients / 100,000 adult population.

Age-adjusted rates were similar in men and women. Silent PE, on average, was diagnosed in 32% of patients with DVT. The incidence of acute PE increases exponentially with age and is much more frequent in adults than in children, but it is not rare in children.

In autopsy studies encompassing university as well as nonuniversity hospitals, when the pathologist judged that PE contributed to death or caused death, the diagnosis was unsuspected ante-mortem in over one-half of cases. Some of these were in patients who died of malignancy, in whom a diagnosis of PE may (appropriately) not have been actively pursued. However, the time-honoured point remains as valid today as ever: a high index of suspicion is necessary to reduce the number of patients with unsuspected PE.

Predisposing factors

Immobilization, irrespective of the cause, is the most frequent predisposing factor (Table 1). Immobilization of even 1 or 2 days may predispose to PE and most patients with PE are immobilized less than 2 weeks. Obesity is also a risk factor.

Table 1 Predisposing factors for PE in all patients irrespective of previous cardiac or pulmonary disease (n = 383)
Predisposing factor Cases (%)
Immobilization 54
Surgery 42
Lung disease 27
Malignancy 18
Coronary heart disease 20
Thrombophlebitis—ever 19
Myocardial infarction 13
Trauma—lower extremities 12
Heart failure 12
Chronic obstructive pulmonary disease 10
Stroke 10
Asthma 7
Pneumonia—acute 7
Prior pulmonary embolism 6
Oestrogen 6
Collagen vascular disease 4
Postpartum—3 months or less 2
Interstitial lung disease 2

Pregnancy-associated DVT has increased in recent years, the rate being over twice that in nonpregnant women. The rate of DVT following caesarean section is twice the rate following vaginal delivery. By contrast, higher rates of PE have not been shown in pregnancy, but this may be because of reluctance to perform imaging studies in pregnant women. Thromboembolic events have been linked to oestrogen-containing oral contraceptives, but the absolute risk is low and their frequency has been reduced with the use of preparations that contain less than 50 μg of oestrogen. Oral contraceptives may increase the risk of venous thromboembolism after surgery even if their oestrogen content is low.

There has been much interest in the subject of genetic predisposition to thromboembolism. Heterozygosity for the factor V Leiden mutation increases susceptibility three- to eight-fold in a variety of circumstances. Other genetic and acquired thrombophilic factors include protein C deficiency, protein S deficiency, antithrombin deficiency, prothrombin 20 201A, high concentration of factor VIII, hyperhomocystinaemia, heparin cofactor II deficiency, dysfibrinogenaemia, decreased levels of plasminogen, decreased levels of plasminogen activators, antiphoslipid antibodies, heparin-induced thrombocytopenia, and myeloproliferative disorders.

Clinical features

The clinical characteristics of acute PE have been derived from prospectively acquired data of patients recruited in trials of diagnostic investigations or therapies such as the Prospective Investigation of PE Diagnosis (PIOPED) studies. Such trials clearly only include those in whom there was sufficient clinical suspicion to lead physicians to obtain diagnostic tests: whether subtle PE was overlooked is undetermined. The specificity of signs, symptoms, and ordinary clinical tests was low among patients with suspected PE in whom the diagnosis was eventually excluded.

Symptoms

In patients in whom the diagnosis is not confused by pre-existing cardiac or pulmonary disease, dyspnea is the most common symptom, occurring in 73% of cases both in PIOPED and PIOPED II (Table 2), with dyspnoea only on exertion in 16%. Dyspnoea (at rest or during exertion) and orthopnoea were more frequent in patients with PE in main or lobar pulmonary arteries than in patients in whom the largest vessel with PE was a segmental pulmonary artery. The onset of dyspnoea occurred within seconds or minutes in 72% of cases, and within seconds, minutes, or hours in 83%. In some, however, the onset of dyspnoea occurred over days.

Table 2 Symptoms of PE in patients without pre-existing cardiac or pulmonary disease
Symptoms PE (%)
PIOPED I (n=117) PIOPED II (n=127–133)
Dyspnea    
 Dyspnea (rest or exertion) 73 73
 Dyspnea (at rest)   55
 Dyspnea (exertion only)   16
 Orthopnea (≥2 pillow)   28
Pleuritic pain 66 44
Chest pain (not pleuritic) 4 19
Cough 37 34
 Haemoptysis 13  5a
 Purulent   5
 Clear   5
 Nonproductive   20
Wheezing 9 21
Palpitations 10  
Calf or thigh swelling   41
Calf swelling only 28 33
Calf and thigh swelling   7
Thigh swelling only   1
Calf or thigh pain   44
Calf pain only 26b 23
Calf and thigh pain   17
Thigh pain only   3

a Haemoptysis, patients with PE: 2, slightly pinkish; 4, blood-streaked; 1, all blood (<1 teaspoonful).

b‘Leg pain’.

Data from Stein PD, et al. (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest, 100, 598–603 Stein PD, et al. (2007). Clinical characteristics of patient with acute pulmonary embolism: data from PIOPED II. Am J Med, 120, 871–9

Pleuritic chest pain (66% of patients with PE and no pre-existing cardiopulmonary disease in PIOPED and 44% in PIOPED II) occurred much more often than haemoptysis (13% in PIOPED and 5% in PIOPED II).

Prevention of deep vein thrombosis and pulmonary embolism 

For recommendations for prevention of DVT and PE see Tables 3, 4, 5 and 6.

For more tables with details of prevention of DVT (1. Recommendations for prevention of deep venous thrombosis in patients undergoing general, vascular, gynecological, urological and laparoscopic surgery & 2. Recommendations for prevention of DVT during long-distance air travel) see the article on deep vein thrombosis

Table 3 Recommendations for prevention of DVT in patients undergoing orthopaedic surgery

Surgical procedure Recommendation
Elective total hip replacement LMWH (at a usual high-risk dose, started 12 h before surgery or 12–24 h after surgery, or 4–6 h after surgery at half the usual high-risk dose and then increasing to the usual high-risk dose the following day) for 10–35 days
  • or
  • Fondaparinux, (2.5 mg started 6–24 h after surgery) for 10–35 days
  • or
  • Vitamin K antagonist started preoperatively or on the evening after surgery (INR 2.0–3.0) for 10–35 days
  • or
  • Mechanical thromboprophylaxis if high risk of bleeding
Elective total knee arthroplasty As with total hip replacement, although intermittent pneumatic compression is an alternative
Hip fracture surgery Fondaparinux or LMWH at usual high-risk dose or vitamin K antagonist (INR 2.0–3.0) or low dose unfractionated heparin for 10–35 days
If surgery is delayed—low dose unfractionated heparin or LMWH while waiting
Mechanical prophylaxis if high risk of bleeding

INR, international normalized ratio; LMWH, low molecular weight heparin.

Adapted from Geerts WH, et al. (2008). Prevention of venous thromboembolism: the Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 133(Suppl): 381S–453S.

Table 4 Recommendations for prevention of DVT in patients undergoing neurosurgery
Surgical procedure Recommendation
Elective spine surgery
  • No additional risk factors
  • Additional risk factors (advanced age, malignancy, neurological deficit, previous VTE, or an anterior surgical approach)
  • Early and persistent mobilization
  • Low dose unfractionated heparin or LMWH or perioperative intermittent pneumatic compression or perioperative graduated compression stockings or perioperative intermittent pneumatic with compression stockings
Neurosurgery
No additional risk factors
  • Intermittent pneumatic compression ± graduated compression
  • Alternatively, low dose unfractionated heparin or postoperative LMWH
High risk Graduated compression stockings and/or intermittent pneumatic compression) and low dose unfractionated heparin or LMWH

LMWH, low molecular weight heparin.

Adapted from Geerts WH.,et al. (2008). Prevention of venous thromboembolism: the Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 133(Suppl): 381S–453S.

Table 5 Recommendations for prevention of DVT in patients following trauma, acute spinal cord injury and burns
Indication Recommendation
Trauma
  • LMWH. Continue after hospital discharge with LMWH or a vitamin K antagonist (INR 2.0 to 3.0) if major impaired mobility
  • Intermittent pneumatic compression ±, graduated compression stockings if bleeding or a high risk for bleeding
Acute spinal cord injury
  • LMWH after primary hemostasis
  • Intermittent pneumatic compression with low dose unfractionated heparin or LWMH
  • Intermittent pneumatic compression and/or graduated compression stockings is recommended if anticoagulant prophylaxis is contraindicated
  • During rehabilitation phase if impaired mobility continue LMWH or convert to oral vitamin K antagonist (INR 2.0–3.0).
  • Burns
  • if advanced age, morbid obesity, extensive or lower extremity burns, concomitant lower extremity trauma, use of a femoral venous catheter, and/or prolonged immobility
  • Low dose unfractionated heparin or LMWH
  • Intermittent pneumatic compression ±, graduated compression stockings if high risk for bleeding

INR, international normalized ratio; LMWH, low molecular weight heparin.

Adapted from Geerts WH, et al. (2008). Prevention of venous thromboembolism: the Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 133(Suppl): 381S–453S.

Table 6 Recommendations for prevention of DVT in patients hospitalized with medical conditions and in critical units
Medical conditions in hospital Recommendation
  • Heart failure or severe respiratory disease
  • Patients confined to bed and have cancer, previous VTE, sepsis, acute neurological disease, or inflammatory bowel disease
  • Low dose unfractionated heparin, LMWH or fondaparinux
  • Compression stockings or intermittent pneumatic compression if high risk of bleeding
Critical care
Moderate risk (medically ill or postoperative) Low dose unfractionated heparin or LMWH
Higher risk (major trauma or orthopaedic surgery) LMWH
High risk of bleeding Compression stockings and/or intermittent pneumatic compression

LMWH, low molecular weight heparin.

Adapted from Geerts WH, et al. (2008). Prevention of venous thromboembolism: the Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 133(Suppl): 381S–453S.

Cough was common (37% and 34% in PIOPED and PIOPED II) among patients with PE and no pre-existing cardiopulmonary disease. This was nonproductive or productive of bloody (typically blood-streaked, but it can be pure blood or blood-tinged) or purulent (5% of cases) sputum.

Signs

Tachypnoea (respiratory rate 20/min or greater) was the most common sign of acute PE among patients with no prior cardiac or pulmonary disease (70% of patients in PIOPED and 54% in PIOPED II) (Table 7). Tachycardia (heart rate greater than 100/min) occurred in 30% and 24% of patients with PE in PIOPED and PIOPED II, and the pulmonary component of the second sound was accentuated in 23% and 15% of cases. DVT was clinically apparent in 11% of patients with PE in PIOPED, but more frequently in PIOPED II (47%). A right ventricular lift, third heart sound, or pleural friction rub were uncommon, each occurring in 4% or less of patients with PE.

Table 7 Signs of PE in patients without pre-existing cardiac or pulmonary disease
Signs PE (%)
PIOPED I (n=117) PIOPED II (n=127–133)
General
 Tachypnea (≥20/min) 70 54
 Tachycardia (>100/min) 30 24
 Diaphoresis 11 2
 Cyanosis 1 0
 Temperature >38.5°C (>101.3°F) 7 1
Cardiac examination (any) 21
 Increased P2 23 15
 Third heart sound 3  
 Fourth heart sound 24  
 Right ventricular lift 4 4
 Jugular venous distension   14
Lung examination (any abnormality)   29
 Rales (crackles) 51 18
 Wheezes 5 2
 Rhonchi   2
 Decreased breath sounds   17
 Pleural friction rub 3 0
DVT
 Calf or thigh 11 47a
 Calf only   32
 Calf and thigh   14
 Thigh only   2
 Homans’ sign 4  

P2, pulmonary component of second sound.

a Number of patients with PE who had one or more signs of DVT: oedema, 55; erythema, 5; tenderness, 32; palpable cord, 2.

Data from Stein PD et al, (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest 100, 598–603 and Stein PD, et al. (2007). Clinical characteristics of patient with acute pulmonary embolism: data from PIOPED II. Am J Med, 120, 871–9

Most patients with PE who had rales (crepitations) had pulmonary parenchymal abnormalities, atelectasis, or a pleural effusion on the chest radiograph.

Among patients with PE and no other source of fever, temperature below 39.9°C was present in 12% and fever of 39.9°C or higher occurred in 2%. Fever in patients with pulmonary haemorrhage/infarction was not more frequent than among those with no pulmonary haemorrhage/infarction. Clinical evidence of DVT was often present in patients with PE and otherwise unexplained fever.

Circulatory collapse (systolic blood pressure <80 mmHg or loss of consciousness) was an uncommon mode of presentation: 15% in PIOPED and in 8% in PIOPED II. However, patients with circulatory collapse may not be candidates for recruitment into trials of diagnostic investigations or therapies, and patients with circulatory collapse often die within the first few hours, hence it may be that the incidence of circulatory collapse as determined from published series is falsely low. Patients with pulmonary infarction have less severe PE than patients with isolated dyspnoea, and those with circulatory collapse probably have the most severe of all.

Combinations of symptoms and signs

Dyspnoea or tachypnoea (respiratory rate 20/min or greater) was present in 90% and 84% of patients with acute PE and no pre-existing cardiac or pulmonary disease in PIOPED and PIOPED II. Dyspnoea or tachypnoea or pleuritic pain was present in 97% and 92% respectively. Dyspnea or tachypnea or pleuritic pain or radiographic evidence of atelectasis or a parenchymal abnormality was present in 98%. The remaining patients usually had either DVT or an unexplained low PaO2. PE was rarely diagnosed in the absence of dyspnoea or tachypnoea or pleuritic pain.

Dyspnea or tachypnea occurred in 92% of all patients with PE (irrespective of pre-existing cardiopulmonary disease) in whom the pulmonary emboli were in main or lobar pulmonary arteries, but in only 65% of patients in whom the largest PE was in segmental pulmonary arteries. Dyspnoea or tachypnoea or pleuritic pain occurred in 97% of patients with proximal PE and 77% of patients with pulmonary emboli in only segmental pulmonary arteries.

Accuracy of clinical assessment

To emphasize the point that the diagnosis of PE is difficult to make, senior staff physicians and postgraduate fellows taking part in the PIOPED study were uncertain of the diagnosis in most patients. Using individual judgement without any specific predetermined criteria, senior staff were correct in the diagnosis in 88% of cases when their clinical assessment indicated a high probability of PE. When their clinical assessment indicated a low probability of PE, senior staff correctly excluded PE in 86%. Postgraduate fellows, on the basis of clinical assessment, were more accurate in excluding PE than they were in making the diagnosis. Objective scoring systems for the probability of acute PE give probability assessments similar to those of experienced physicians and do not require experience or clinical judgement. An example of an objective scoring system is shown in Table 8.

Table 8 A model to determine the clinical probability of PE according to Wells and associates
Clinical feature Score (points)
Clinical signs and symptoms of DVT (objectively measured leg swelling and pain with palpation in the deep vein system) 3.0
Heart rate>100/min. 1.5
Immobilization ≥3 consecutive days (bed rest except to access bathroom) or surgery in previous 4 weeks 1.5
Previous objectively diagnosed PE or DVT 1.5
Haemoptysis 1.0
Malignancy (cancer patients receiving treatment within 6 months or receiving palliative treatment) 1.0
PE as likely or more likely than alternative diagnosis (based on history, physical examination, chest radiograph, ECG, and blood tests) 3.0

Score: <2.0, low probability; ≤4, unlikely probability; >4, likely probability; >6.0, high probability.

Data from Wells PS, et al. (2000). Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost, 83, 416–20

Differential diagnosis

The commonest presentation of acute PE is with dyspnoea and/or pleuritic chest pain. There are several other possible causes of these symptoms, the commonest being musculoskeletal pain and pneumonia. Musculoskeletal chest pain can be very similar to that caused by pleurisy, and splinting of the chest can lead to a perception of breathlessness that may be exacerbated by anxiety. If there is an obvious history of local trauma to the chest, then the patient will rarely present to the physician, but it is worthwhile to ask specifically whether there has been any trauma or unaccustomed physical activity, whether the pain can be brought on by particular movements, and to examine carefully for local tenderness of the ribs, muscles, or costal margins. Tenderness can sometimes be found in cases of pleurisy. Appropriate history often supports a diagnosis of musculoskeletal pain.

Pneumonia complicated by pleurisy can cause dyspnoea and chest pain. Important features to look for in the history include preceding systemic upset (‘flu-like’ symptoms), high fever, and rigors, and on examination, high fever, ‘toxic appearance’, and chest signs of pneumonic consolidation. If a positive diagnosis of another cause of dyspnoea and/or pleuritic chest pain cannot be made, then the default position should be to assume that the patient has PE until proven otherwise.

Investigation

Detection of evidence of thrombus within the circulation: D-dimer

As when considering the diagnosis of DVT, a ‘negative’ D-dimer test is useful for excluding PE in patients who are clinically thought to be at low risk, but a ‘positive’ result does not establish the diagnosis. Hence, when used in the appropriate clinical context, D-dimer testing is useful in defining a group of patients with suspected PE who do not require further investigation.

In ranking the D-dimer assays according to their sensitivity values and likelihood of increasing certainty for ruling out PE, the enzyme-linked immunosorbent assay (ELISA) and quantitative rapid ELISA assays are significantly superior to the semiquantitative latex and whole blood agglutination assays. The quantitative rapid ELISA assay is more convenient than the conventional ELISA and provides a high level of certainty for a negative diagnosis of PE as well as DVT. A particle enhanced immunoturbidometric assay (quantitative latex agglutination) gives results comparable to the rapid ELISA.

The 3-month risk of PE in untreated patients with a negative rapid ELISA D-dimer measurement and low or intermediate clinical probability Geneva score was 0% (0 of 220). With a negative D-dimer by rapid ELISA or quantitative latex agglutination assay and an unlikely (≤ 4) Wells score, PE occurred in 0.4% (4 of 1028).

Detection of the physical presence of thrombus in the pulmonary circulation
Ventilation–perfusion lung scans
 
By 2001 in the United States of America the use of CT pulmonary angiography surpassed the use of ventilation–perfusion lung scans for the diagnosis of acute PE, the use of ventilation-perfusion lung scans having fallen into disfavour after the PIOPED trial because in most patients they led to an indeterminate result. Now, two decades since PIOPED was published, advances have been made in imaging equipment, improved methods of interpretation, and new radiopharmaceuticals.With such advances, and recognizing the risk of radiation with CT angiography, radionuclear imaging is receiving renewed interest.

Based on the results of PIOPED, a high probability lung ventilation–perfusion scan indicates PE in 87% of patients (Table 9) and a normal scan excludes PE. In the absence of any other information an intermediate probability scan indicates a 30% chance of PE and a low probability scan 14%. A low probability ventilation–perfusion scan by the criteria used in PIOPED does not therefore exclude PE. Intermediate and low probability interpretations may be grouped as ‘nondiagnostic’, which was frequently the case in PIOPED.

Table 9 The probability of PE using clinical assessment in combination with ventilation–perfusion lung scans
Clinical science probability (%) 80–100 20–79 0–19 All probabilities
Scan category PE+/No of patientsa % PE+/No of patients % PE+/No of patients % PE+/No of patients %
High probability 28/29 96 70/80 88 5/9 56 103/118 87
Intermediate probability 27/41 66 66/236 28 11/68 16 104/345 30
Low probability 6/15 40 30/191 16 4/90  4 40/296 14
Near normal/normal 0/5  0 4/62  6 1/61 2 5/128 4
Total 61/90 68 170/569 30 21/228 9 252/887 28

a PE+ indicates angiogram reading that shows PE or determination of PE by the outcome classification committee on review. PE status is based on angiogram interpretation for 713 patients, on angiogram interpretation and outcome classification committee reassignment for 4 patients, and on clinical information alone (without definitive angiography) for 170 patients.

Reproduced from A National Investigation by the PIOPED Investigators (1990). Value of the ventilation/perfusion scan in acute pulmonary embolism - results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). Copyright 1990 American Medical Association.

Prior clinical assessment in combination with interpretation of the ventilation–perfusion scan improves diagnostic validity (Table 10). If the ventilation–perfusion scan is interpreted as high probability for PE, and if the clinical impression is concordantly high, then the positive predictive value for PE is 96%. If the ventilation–perfusion scan is low probability and the clinical suspicion is concordantly low, then PE is excluded in 96% of patients.

The probability of PE can be determined based on the number of mismatched defects. Since PIOPED, criteria for the interpretation of very low probability lung scans (positive predictive value <10%) have been developed and tested. Fewer mismatched perfusion defects are required to diagnose PE among patients with no prior cardiopulmonary disease. Adding clinical assessment to the stratification results in a more accurate evaluation.

Using revised PIOPED criteria, some have shown that in patients with suspected acute PE and a normal chest radiograph the perfusion lung scan was diagnostic (high probability, normal or very low probability) in 89% of patients (Table 10). There were no non-diagnostic perfusion scans when interpreted by the PISAPED criteria (Table 11). After elimination of non-diagnostic scans, sensitivity with modified PIOPED criteria was 86% and specificity was 93%. With PISAPED criteria, sensitivity was 72% and specificity was 97%. It may be, therefore, that with updated techniques, perfusion scintigraphy in a patient with a normal chest radiograph can provide diagnostic accuracy similar to CT angiography at a lower cost and with a lower radiation dose.

Table 10  Modified PIOPED II scintigraphic criteria
Diagnosis Criteria
PE present High probability (≥2 segments of perfusion scan-chest radiograph mismatcha)
PE absent Normal perfusion

Very low probability:

  • Nonsegmental lesion, e.g. prominent hilum, cardiomegaly, elevated diaphragm, linear atelectasis, costophrenic angle effusion with no other perfusion defect in either lung
  • Perfusion defect smaller than radiographic lesion
  • 1–3 small segmental defects
  • A solitary chest radiographic–perfusion scan matched defect in the mid or upper lung zone confined to a single segment
  • Stripe sign around perfusion defect (best tangential view)
  • Pleural effusion ≥ 1/3 of the pleural cavity with no other perfusion defect in either lung
Not diagnostic All other findings

a May be ≥2 large segmental mismatches, or 1 large and 2 moderate mismatches or 4 moderate segmental mismatches. Modified from Sostman et al. (2008). Sensitivity and specificity of perfusion scintigraphy combined with chest radiography for acute pulmonary embolism in PIOPED II. J Nucl Med, 49, 1741-8.

Table 11 PISAPED scintigraphic criteria
Diagnosis Criteria
PE present One or more wedge-shaped perfusion defects
PE absent Normal or near normal perfusion

Contour defect caused by enlarged heart, mediastinum, or diaphragm

Perfusion defect, not wedge-shaped

Not diagnostic Cannot classify as PE-positive or PE-negative

Modified from Sostman et al. (2008). Sensitivity and specificity of perfusion scintigraphy combined with chest radiography for acute pulmonary embolism in PIOPED II. J Nucl Med, 49, 1741–8.

Although not routine practice in most centers, it can be useful to obtain a post-therapy baseline ventilation–perfusion lung scan for use in the event of suspected recurrent PE. This will assist in determining if abnormalities subsequently discovered on a ventilation– perfusion scan are new or residual. A residual abnormality of perfusion 1 year after PE is more frequent among patients with prior cardiopulmonary disease than among patients with none.

SPECT ventilation–perfusion lung scan Imaging

Single-photon emission computed tomography (SPECT) ventilation–perfusion lung scan imaging may further improve the accuracy of pulmonary scintigraphy. SPECT offers the advantages of tomographic sections over traditional planar ventilation–perfusion imaging. The ability to obtain SPECT lung scans was still in its relatively early stages when the PIOPED investigation of planar lung scans was published. Dual- and triple-headed gamma cameras with ultra-high-resolution collimators have been developed, as have new radiopharmaceuticals for ventilatory studies, prominent among which is 99mTc technegas (Cyclomedica, Lucas Heights, Australia), which consists of ultrafine carbon particles that behave physiologically like a gas.

Many investigators have found SPECT ventilation–perfusion lung scan imaging to be better than planar imaging. Among its advantages are the avoidance of overlapping of small perfusion defects by normal tissue and a higher contrast resolution than planar scans. It can, therefore, detect abnormalities—particularly at the subsegmental level and in the lung bases - where the segments are tightly packed. Review showed that the sensitivity of SPECT was higher than planar lung scans in 4 of 5 investigations, and specificity was generally higher, equal, or only somewhat lower than planar ventilation–perfusion lung scans. Non-diagnostic SPECT lung scans were reported in ≤3% by most investigators.

Pulmonary angiography

Pulmonary angiography is useful and remains the diagnostic gold standard for PE. However, it is associated with serious complications in about 1% of patients and has been generally replaced by contrast-enhanced CT.

Contrast-enhanced spiral computed tomography

The sensitivity of single-slice CT angiography for the diagnosis of acute PE, based on pooled data, was 73%. Those with 3 mm collimation showed a sensitivity of 78% and specificity was 90%. Data with single-slice CT using 5 mm collimation showed a sensitivity of 68% and specificity of 83%.

The sensitivity of multidetector CT angiography alone and in combination with CT venous-phase venography were investigated in PIOPED II. The CT angiogram among 824 patients was of insufficient quality for a conclusive interpretation in 6.2%. Among 773 patients with an adequate CT angiogram, the sensitivity of CT angiography was 83% and specificity was 96%: positive predictive value was 86% and negative predictive value was 95%. Positive predictive values were 97% for PE in a main or lobar artery, 68% in those in whom the largest vessel with PE was a segmental pulmonary artery, and 25% among only a few patients in whom the largest PE was in a subsegmental branch.

The combination CT angiogram with venous-phase imaging of the pelvic and thigh veins (CT venogram) among 824 patients was of insufficient quality for a conclusive interpretation in 11%. Among the 737 patients with an adequate CT angiogram/CT venogram combination, the sensitivity was 90% and specificity was 95%, with positive predictive value 85% and negative predictive value 97%.

As with ventilation–perfusion scans, better prediction can be made if imaging results are interpreted in the light of clinical information (Table 12). Among patients with a high or intermediate probability prior clinical assessment based on the Wells score, a positive CT angiogram had a positive predictive value for PE of 96% and 92% respectively. In patients with a low or intermediate probability prior clinical assessment and a negative CT angiogram, the negative predictive values for exclusion of PE were 96% and 89% respectively. Positive and negative predictive values were considerably reduced when scan results were discordant with clinical probabilities.

Table 12 Positive and negative predictive values of CT pulmonary angiography in relation to prior clinical assessment
 
  • High clinical probability
  • (Wells score >6)
  • n/N (%)
  • Intermediate clinical
  • Probability
  • (Wells score 2–6)
  • n/N (%)
  • Low clinical
  • probabilitya
  • (Wells score <2)
  • n/N (%)
  • CTA positive
  • (positive predictive value)
22/23 (96) 93/101 (92) 22/38 (58)
  • CTA or CTV positive
  • (positive predictive value)
27/28 (96) 100/111 (90) 24/42 (57)
  • CTA negative
  • (negative predictive value)
9/15 (60) 121/136 (89) 158/164 (96)a
  • CTA and CTV negative
  • (Negative Predictive Value)
9/11 (82) 114/124 (92) 146/151 (97)a

a To avoid bias for calculation of the negative predictive value in patients with a low probability prior clinical assessment, only patients with a reference test diagnosis by V/Q scan or conventional pulmonary digital subtraction angiography were included.

CTA, computed tomographic pulmonary angiography; CTV = computed tomographic venous-phase imaging.

Modified from Stein PD et al. (2006). PK for the PIOPED II Investigators. Multidetector computed tomography for acute pulmonary embolism. N Eng J Med 354:2317–2327

MRI

Potential advantages of gadolinium-enhanced magnetic resonance (MR) angiography are that it does not involve the use of iodinated contrast agents, it is minimally invasive, and patients are not exposed to ionizing radiation. In small studies it shows a sensitivity for PE in proximal or segmental branches that ranges from 77% to 100% and specificity that ranges from 95 to 98%, but sensitivity for sub-segmental branches has not been evaluated. Gadolinium-enhanced venous-phase imaging of the veins of the pelvis and thighs in combination with imaging of the pulmonary arteries would permit a comprehensive study for thromboembolism comparable to the combination of contrast-enhanced spiral CT of the pulmonary arteries in combination with venous-phase CT of the veins of the lower extremities.

The PIOPED III trial of the accuracy of gadolinium-enhanced MR pulmonary angiography showed that most centers had difficulty in obtaining adequate quality MR pulmonary angiograms (MRA). The investigators defined an adequate quality MRA as adequate opacification through subsegmental vessels. Among 371 patients, adequate quality images were obtained in the main or lobar pulmonary arteries in 91%, of the segmental pulmonary arteries in 87%, and of the subsegmental branches in 73%. Averaged across participating centers, MR pulmonary angiograms were technically inadequate in 25%, but the figure at one center was only 11%. Including patients with technically inadequate images, MRA identified 57% with PE. Technically adequate MRA had a sensitivity of 78% and specificity of 99%, and the sensitivity of MRA for detecting PE in a main or lobar pulmonary artery was 79%. Pulmonary embolism was rarely identified by MRA when the largest PE was in a segmental or subsegmental branch. Specificity was 98% to 100%, irrespective of the order of the vessel. The combination of a technically adequate MRA with magnetic resonance venography (MRA/MRV) had a higher sensitivity than MRA alone, 92%, while maintaining a high specificity of 96%. However, either MRA or MRV was technically inadequate in 52% of patients. This led the investigators to conclude that MRA should only be considered at centers that routinely perform it well, and for patients who have contraindications to standard tests. Nephrogenic systemic fibrosis (also known as nephrogenic fibrosing dermopathy) has been reported in patients with moderate or severe renal failure and in patients on dialysis following MR angiography with gadolinium-containing contrast agents. Other diagnostic approaches are recommended in such patients.Other tests

Electrocardiography

Electrocardiographic abnormalities are common in acute PE (Table 13), with a normal electrocardiogram found in only 30% of patients. Acute ventricular dilatation is speculated to be the most likely cause of the electrocardiographic changes. Abnormalities of the ST segment and T wave are by far the most frequent observation, with nonspecific ST segment or T wave changes seen in about 50% of patients in whom the severity of PE ranged from mild to severe. Atrial flutter or atrial fibrillation in patients with acute PE is nearly always limited to individuals with prior heart disease.

Table 13  Electrocardiographic manifestations of pulmonary embolisms in patients without prior cardiac or pulmonary disease (n=89)
Patients with electrocardiographic findingsa (%)
Rhythm disturbances
Atrial flutter 1
Atrial fibrillation 4
Atrial premature contractions 4
Ventricular premature contractions 4
P wave
P pulmonale 2
QRS abnormalities
Right axis deviation 2
Left axis deviation 13
Incomplete right bundle branch block 4
Complete right bundle branch block 6
Right ventricular hypertrophy 2
Pseudoinfarction 3
Low voltage (frontal plane) 3
ST segment and T wave
Nonspecific ST segment or T wave abnormalities 49

a Some patients had more than one abnormality.

Data from Stein PD, et al. (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest, 100, 598–603

Electrocardiographic manifestations of acute cor pulmonale (S1Q3T3, complete right bundle branch block, P pulmonale, or right axis deviation) are less common than ST segment or T wave changes. One or more of these abnormalities occurred in 26% of patients with submassive or massive acute PE not associated with cardiac or pulmonary disease (32% of patients with massive PE). Left axis deviation occurs more frequently than right axis deviation.

The electrocardiogram may simulate an inferior infarction with Q waves and T wave inversion in leads II, III, and aVF, or anteroseptal infarction characterized by QS or QR waves in V1 and T-wave inversion in the right precordial leads. The development of Q waves and extensive T wave inversion in the anterior and lateral leads has also been observed. However, a pseudoinfarction pattern is seen in only 3% of patients.

Inversion of the T waves is the most persistent electrocardiographic abnormality, disappearing in only 22% of patients 5 or 6 days after the PE was diagnosed, although resolving in 49% by 2 weeks. Depression of the ST segment tends to resolve somewhat faster, and abnormalities of depolarization resolve more quickly than abnormalities of repolarization. Well over half of the electrocardiograms that showed pseudoinfarction, S1S2S3, S1Q3T3, right ventricular hypertrophy or right bundle branch block no longer show these abnormalities 5 or 6 days after the diagnosis is made.

Patients with ST segment abnormalities, T wave inversion, pseudoinfarction patterns, S1Q3T3 patterns, incomplete right bundle branch block, right axis deviation, right ventricular hypertrophy, or ventricular premature beats have larger perfusion defects on the lung scan or larger defects on the pulmonary arteriogram than those with normal electrocardiograms. Such patients have higher pulmonary arterial pressures and in general have a low partial pressure of oxygen in arterial blood.

Chest radiography

The findings on the plain chest radiograph—when used together with the history, physical examination, electrocardiogram and simple laboratory tests—assist in identifying PE. The chest radiograph, when normal in a patient who is dyspneic, hints that PE is a diagnostic possibility. Among patients with no prior cardiopulmonary disease a normal chest radiograph is found in 16% (Table 14). Atelectasis or a pulmonary parenchymal abnormality are the most frequent abnormalities present (68%). Pleural effusions are found in about half of cases and are usually small, with most limited to blunting of the costophrenic angle. In some studies, an elevated hemidiaphragm is the most frequent abnormality. Westermark’s sign (a prominent central pulmonary artery and decreased pulmonary vascularity) is identified by radiologists in only 7% of patients with PE.

Table 14  Chest radiograph findings in pulmonary embolism in patients with no previous cardiac or pulmonary disease (n =117)
Patients with radiographic finding (%)
Atelectasis or pulmonary parenchymal abnormality 68
Pleural effusion 48
Pleural based opacity 3
Elevated diaphragm hemidiaphragm 24
Decreased pulmonary vascularity 21
Prominent central pulmonary artery 15
Cardiomegaly 12
Westermark’s signa 7

a Prominent central pulmonary artery and decreased pulmonary vascularity.

Data are modified from Stein PD et al, (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest, 100, 598–603

In cases of PE, those with a normal plain chest radiograph have the lowest pulmonary artery mean pressures. The highest pulmonary artery mean pressures are in patients with a prominent central pulmonary artery or cardiomegaly.

Echocardiography

Echocardiography may show right ventricular dilatation and evidence of pulmonary hypertension, which—in the proper clinical setting—may strengthen the clinical impression that PE has occurred. Transesophageal echocardiography sometimes may show proximal pulmonary emboli, but it has limited value in this regard.

Arterial blood gases and alveolar–arterial oxygen difference

A low partial pressure of oxygen in arterial blood (PaO2) is typical of acute PE and supports the diagnosis, but patients with acute PE can have a normal PaO2. Among patients with acute PE and no prior cardiopulmonary disease who have measurements of the PaO2 while breathing room air, 24% have a PaO2 of 80 mmHg (10.5 kPa) or higher, and even among patients with submassive or massive acute PE, 12% have a PaO2 of this level or higher. A normal alveolar–arterial oxygen difference (alveolar–arterial oxygen gradient) does not exclude acute PE. No value of the alveolar–arterial oxygen difference is diagnostic of PE, and no value can exclude the diagnosis.

Other routine blood tests

Among patients in whom a possible or definite cause for leucocytosis is eliminated, 80% of patients with PE have a normal white blood cell count, 6% a count of 10.1–11.9 × 109/litre, and 13% a count of higher than this. A white blood cell count of 20 x 109/litre or greater is rarely if ever seen. Leucocytosis is not more frequent in patients with the pulmonary haemorrhage/infarction syndrome than in other patients with acute PE.

Biomarkers

Cardiac troponin I (cTnI) and creatine kinase isoenzyme MB (CK-MB) are useful for assessment of prognosis in stable patients with acute PE who have right ventricular (RV) dilatation. Patients with a dilated RV have a mortality from PE of 13% to 29% if cardiac biomarkers are elevated, compared with 4% if they are not. Elevated biomarkers are not prognostically significant if RV size is normal. Only a few patients with PE had an abnormal CK-MB, which limits its value if used as the only indicator of prognosis.

Strategy for diagnosis

With increasing severity of PE, from pulmonary infarction to isolated dyspnoea to circulatory collapse, trends suggest that the prevalence of signs and symptoms increases, but generally recognized symptoms may be absent, even in patients with large pulmonary emboli. Clues that can assist the physician in assessing the possibility of PE, and avoiding inadvertent exclusion of the diagnosis are as follows:

  • ◆ Dyspnoea—onset is usually, but not always, within minutes or hours, and may be present only on exertion. Frequent in patients with large pulmonary emboli, but often absent in those with small pulmonary emboli
  • ◆ Orthopnea—often present in dyspnoeic patients with PE
  • ◆ Circulatory collapse—may occur with PE in patients who do not have dyspnoea or tachypnoea or pleuritic pain
  • ◆ Tachypnoea—frequent in patients with large pulmonary emboli, but often absent in those with small pulmonary emboli
  • ◆ Crepitations (rales)—common among patients with pulmonary infarction, but less so in those with isolated dyspnoea or circulatory collapse; they occur in those with radiographic evidence of a parenchymal abnormality
  • ◆ Electrocardiogram—a normal ECG is frequent in patients with the pulmonary infarction syndrome, but uncommon in those with isolated dyspnoea; nonspecific ST segment and T wave changes are the most frequent abnormality
  • ◆ Chest radiograph—abnormalities are more common among patients with pulmonary infarction but are often observed in those with isolated dyspnoea; patients with circulatory collapse may have a normal chest radiograph
  • ◆ Ventilation–perfusion scan—a high probability interpretation occurs in a minority of patients with the pulmonary infarction syndrome but in the majority of those with the isolated dyspnea syndrome; a low probability scan may occur in patients with PE and circulatory collapse
  • ◆ Oxygenation—a PaO2 higher than 80 mmHg (10.5 kPa) is not uncommon in patients with the pulmonary infarction syndrome, but such levels are uncommon in those with the isolated dyspnoea syndrome

Subjecting all patients who might have a PE to complex, expensive and/or invasive tests is best avoided. Management algorithms have been developed to identify those at very low risk, who can then be spared imaging tests. These algorithms typically use scoring systems to stratify the clinical probability that the particular patient has a PE, proceeding to D-dimer testing of those with a clinical probability that is not high. Untreated patients with a low or intermediate clinical probability by Geneva score or “unlikely” clinical probability by Wells score and negative D-dimer by rapid ELISA or quantitative latex agglutination test had a 3-month incidence of PE of 0% to 0.4%. There was no fatal PE on follow-up. Patients with such a clinical probability and D-dimer need not to be investigated further. Patients with a high clinical probability and patients with an elevated D-dimer proceed to tests for the presence of pulmonary emboli, typically by contrast-enhanced spiral CT in combination with CT venous-phase imaging. Recommendations for the approach to the diagnosis of acute PE based on use of a pretest scoring system (Table 8) and D-dimer followed by imaging are discussed below. Recommendations for the diagnostic approach to patients in whom PE is not excluded by clinical assessment in combination D-dimer test depend on clinical probability, age, gender, pregnancy, the complexity of associated lung disease as determined from the plain chest radiograph and the severity of illness.

For patients with an elevated D-dimer and patients with a high probability clinical assessment irrespective of the D-dimer, CT pulmonary angiography is recommended for most patients.

If CT angiography is negative and clinical probability is low or intermediate, treatment is unnecessary but a venous ultrasound is recommended if clinical assessment is intermediate or high probability. In those with a high probability clinical assessment additional options include serial venous ultrasound examinations, pulmonary scintigraphy, and pulmonary digital subtraction angiography.

If CT angiography shows main or lobar pulmonary emboli, treatment is indicated irrespective of the clinical probability. With segmental or subsegmental pulmonary emboli the certainty of the CT diagnosis should be re-assessed if clinical probability is low or intermediate, but treatment is indicated if the clinical probability is high. In those with segmental or subsegmental PE and a low or intermediate probability clinical assessment, pulmonary scintigraphy, a single venous ultrasound examination, or serial venous ultrasound examinations are optional. CT angiography should be repeated if image quality is poor.

Most believe that CT venography is unnecessary with CT pulmonary angiography because the risk from radiation outweighs the benefits of additional diagnoses. In patients with a high risk of lower extremity DVT or elderly patients with low risk of radiation effects and limited cardiopulmonary reserve, CT venography is recommended by some.

Other considerations

A venous ultrasound examination prior to imaging with CT angiography or prior to imaging with a ventilation–perfusion lung scan is optional and may guide treatment if positive. However, about 50% of patients with PE have negative noninvasive leg tests for DVT, even though DVT is the source of the PE.

Scintigraphy as the first imaging test

It may be that with updated techniques, perfusion scintigraphy in a patient with a normal chest radiograph can provide diagnostic accuracy similar to CT angiography at a lower cost and with a lower radiation dose. Opinion is divided on whether perfusion lung scans or CT angiograms should be obtained as a first imaging test in patients with a nearly normal chest radiograph. Some opt for perfusion imaging only if the patient is pregnant or young or has a contraindication to CT angiography, as with chronic kidney disease. Patients with emphysema, chronic obstructive pulmonary disease, or poorly controlled asthma may require a ventilation scan in addition to a perfusion scan even if the chest radiograph appears nearly normal. Some suggest use of the PISAPED criteria for interpretation. Some now favor the use of SPECT scintigraphy over planar ventilation-perfusion lung scans.

Recommendations for women of reproductive age

In women of reproductive age with a normal chest radiograph, if D-dimer is positive, most recommend either a perfusion lung scan as the first diagnostic test, or venous ultrasound to be followed by a perfusion lung scan. If the chest radiograph is abnormal, most recommend a CT pulmonary angiogram.

Recommendations for patients who are pregnant

Most investigators recommend venous ultrasound before imaging tests with ionizing radiation in patients who are pregnant. The European Association for Nuclear Medicine recommends a perfusion scan without a ventilation scan, and a lower dose of radioisotope. Others believe that rapid diagnosis is crucial and radiation is a secondary issue. If a CT pulmonary angiogram is performed, imaging should be strictly limited to the thoracic cavity, and low kVp, if applicable, should be utilized.

Recommendations for hemodynamically stable young men

The effect of radiation on male reproduction is uncertain. In young men with a normal chest radiograph, opinions differ on which imaging test should be performed. In young men with an abnormal chest radiograph, most recommend CT pulmonary angiography as the first imaging test.

Recommendations for hemodynamically stable older men and women

The risk of radiation-induced cancer is small with older men and women. Most recommend CT pulmonary angiography as the first imaging test in such patients, irrespective of whether the chest radiograph is normal. Opinion differs, however, and scintigraphy is recommended by many, particularly if the chest radiograph is normal.

Recommendations for patients with allergy to iodinated contrast material

D-dimer with clinical assessment is recommended to exclude pulmonary embolism. Patients with mild iodine allergies may be treated with steroids prior to CT imaging. Venous ultrasound and pulmonary scintigraphy are recommended as alternative diagnostic tests in patients with severe iodine allergy. Serial venous ultrasound is an option, as is gadolinium enhanced CT angiography.

Recommendations for patients with impaired renal function

D-dimer with clinical assessment is recommended to exclude pulmonary embolism. If further investigation is warranted, venous ultrasound is recommended, followed by treatment if positive, with pulmonary scintigraphy if venous ultrasound is negative. Serial venous ultrasound is an option if scintigraphy is nondiagnostic. However, as always it is a matter of balancing benefits and risks, and if the index of suspicion is high, then many physicians will proceed with CT pulmonary angiography.

Recommendations for patients in extremis

Bedside echocardiography in combination with bedside leg ultrasonography are generally recommended as rapidly obtainable bedside tests. In an appropriate clinical setting, either right ventricular enlargement or poor right ventricular function, or a positive venous ultrasound, can be interpreted as resulting from pulmonary embolism. Others recommend a portable perfusion scan or immediate transfer to an interventional catheterization laboratory, but in many instances neither of these will be available. A combination of a negative bedside echocardiogram and venous ultrasound would suggest that the patient may be in extremis for some other reason than pulmonary embolism, but the diagnosis of PE can be pursued with CT angiography, if this is feasible, and such imaging may be appropriate if and when the patient stabilizes.

Serial noninvasive leg tests

Instead of imaging the lungs, an alternative strategy for the diagnosis of PE is to detect and treat DVT. Such a strategy can only be applied to patients with adequate cardiorespiratory reserve, because even a small recurrent PE might be dangerous if this is poor. In practice this means obtaining serial ultrasonography of the legs over a period of 2 weeks, and treating if DVT is shown. Among patients with suspected PE who had a nondiagnostic ventilation-perfusion lung scan, and negative noninvasive leg tests (one study required low or intermediate probability clinical assessment and another normal cardiorespiratory reserve), PE at 3 months follow-up occurred in only 0.4% to 0.6%. However, most now believe that with many safe and accurate imaging options available, serial noninvasive leg tests are rarely (if ever) indicated.

Treatment—general measures

All patients who are hypoxic should be given supplementary oxygen at high concentration (enough to restore normal PaO2). In the early stages continuous monitoring of arterial oxygen tension by pulse oximetry is advised, with particularly careful clinical and arterial blood gas monitoring of those with coincident chronic chest disease in case CO2 retention is problematic.

Resuscitation

Patients with massive PE and circulatory collapse may look as though they are about to die, with cool peripheries, cyanosis, profound hypotension, and marked elevation of the jugular venous pulse. Features typical of long-standing pulmonary hypertension (palpable right ventricular heave, right ventricular gallop, loud P2, hepatomegaly, ascites, peripheral oedema) are unlikely to be present. This dramatic haemodynamic picture may not be simply due to the direct anatomical effects of occlusion of main pulmonary vessels (the same picture is not seen after pneumonectomy, when one pulmonary artery is tied off completely), but also secondary to pulmonary neurogenic reflexes and local release of vasoactive substances, including 5-hydroxytryptamine and thromboxane from activated platelets.

Every effort should be made to support the circulation until measures designed to deal with the embolus (usually thrombolysis—see below) can be applied and take effect.

Treatment—antithrombotic

It is common and sensible to begin anticoagulant treatment as soon as the diagnosis of PE is suspected unless there are serious concerns about the potential side effects of anticoagulation or imaging is immediately available. The antithrombotic regimen is the same as for DVT: see Table 15.

Table 15  Recommendations for treatment of DVT and/or pulmonary thromboembolism
Condition Treatment
High clinical suspicion of DVT or PE Give anticoagulants while awaiting outcome of diagnostic tests
Confirmed DVT or PE
  • LMWH or intravenous heparin (or subcutaneous unfractionated heparin with DVT or nonmassive PE) or fondaparinux for ≥5 days
  • Intravenous unfractionated heparin–aPTT prolongation corresponding to plasma heparin levels 0.3–0.7 IU/ml anti-Xa activity by the amidolytic assay. If large doses fail to achieve therapeutic aPTT, measure anti-Xa level for dose guidance
  • Subcutaneous unfractionated heparin–an initial dose of 17500 U twice daily SC, with subsequent dosing to maintain the aPTT in the therapeutic range
  • LMWH - subcutaneously once or twice daily as an outpatient if possible for DVT.
  • If severe renal failure, intravenous unfractionated heparin is preferred.
  • Start vitamin K antagonists with LMWH or unfractionated heparin on first treatment day and discontinue heparin when INR is stable and >2.0 for 24 h
  • Ambulate as tolerated
Nonmassive PE LMWH preferred over unfractionated heparin
Massive PE, hemodynamically unstable Systemic thrombolytic therapy, short infusion time preferred
Massive PE, highly compromised patients unable to receive thrombolytic therapy or whose critical status does not allow sufficient time to infuse thrombolytic therapy Catheter extraction or fragmentation or pulmonary embolectomy
Extensive DVT Catheter-directed thrombolysis: followed by balloon angioplasty and stents or systemic thrombolytic therapy. Thrombus fragmentation and/or aspiration if expertise and resources are available.
PE or DVT and contraindication to anticoagulants or recurrent thromboembolism despite adequate anticoagulation Inferior vena cava filter
Condition Duration of treatment
First episode DVT or PE, reversible risk factor Vitamin K antagonist for 3 months
First episode, idiopathic DVT or PE Vitamin K antagonist for 3 months; then consider indefinite treatment (INR 2.0–3.0)
DVT or PE and cancer LMWH for 3-6 months followed by indefinite duration of anticoagulation or until cancer is resolved.
Two or more episodes DVT or PE Indefinite treatment

aPTT =activated partial thromboplastin, LMWH, low molecular weight heparin.

Adapted from Kearon C, et al. (2008). Antithrombotic Therapy for Venous Thromboembolic Disease: the Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 133(Suppl): 454S-545S

Complications

Resolution rate with anticoagulants:

Most patients (81%) treated with anticoagulants show complete CT angiographic resolution after 28 days, with emboli resolving at a faster rate in main or lobar pulmonary arteries than in segmental branches. Among patients with no prior cardiopulmonary disease who are treated with anticoagulants, resolution of 90% or more on perfusion lung scans is shown at 1 year in 91% of cases, compared with only 72% of those with prior cardiopulmonary disease.

Thrombolytic therapy

Thrombolytic therapy is not indicated for the routine treatment of PE. Hypotension and continuing hypoxemia whilst receiving high fractions of inspired oxygen (FiO2) are indications for intervention. Right ventricular dysfunction on the echocardiogram may indicate impending hemodynamic instability.

A more rapid lysis of pulmonary thromboemboli occurs with thrombolytic agents than occurs spontaneously in patients treated only with anticoagulants, but pulmonary reperfusion as demonstrated on perfusion lung scans is similar after 2 weeks in patients treated with thrombolytic agents and patients treated with anticoagulants.

In 1973 the Urokinase Pulmonary Embolism Trial showed no improvement of mortality and no difference of the rate of recurrence of PE among stable patients treated with thrombolytic therapy and patients treated with anticoagulants. There have been no subsequent prospective randomized trials to contradict these results, although a trend suggesting a lower rate of recurrent PE has been shown among patients with right ventricular dysfunction who were treated with tissue plasminogen activator.

Thrombolysis has risks. Based on pooled data the frequency of major bleeding from tissue plasminogen activator among patients with PE in randomized trials was 14.7%. This occurred despite the fact that all studies excluded patients at a high risk of bleeding, such those with recent surgery, recent biopsy, peptic ulcer disease, blood dyscrasia, or severe hepatic or renal disease. The risk of intracranial haemorrhage with tissue plasminogen activator (2%) was higher among patients with PE than among patients who received tissue plasminogen activator for myocardial infarction.

Regimens of thrombolytic therapy

Regimens approved by the United States Food and Drug Administration for treatment of acute PE are:

  • ◆ streptokinase 250 000 IU over 30 min followed by 100 000 IU/h for 24 h
  • ◆ urokinase 4400 IU/kg over 10 min followed by 4400 IU/kg per h for 12 to 24 h
  • ◆ tissue plasminogen activator (alteplase) 100 mg (50 million IU)/2 h. In Europe, rt-PA is administrated using a 10mg bolus, followed by a 90mg continuous IV infusion with concomitant UFH.

Potentially advantageous regimens of thrombolytic therapy that have not been fully evaluated for treatment of PE are:

  • ◆ urokinase 3 000 000 U/2 h
  • ◆ streptokinase 1 500 000 U/1–2 h
  • ◆ reteplase 10 U, repeat 10 U in 30 min
  • ◆ saruplase 80 mg/30 min
  • ◆ staphylokinase 20 mg/30 min
  • ◆ tenecteplase single bolus in 5 to 10s, 30–50 mg depending on weight
  • ◆ anistreplase 5 or 10 mg × 3 doses

It is recommended that heparin be discontinued during thrombolytic therapy and reinstituted upon discontinuation of thrombolytic therapy. None of the regimens approved by the United States Food and Drug Administration utilize concomitant heparin.

Inferior vena cava occlusion

An inferior vena cava filter is recommended in a patient with proximal DVT or PE if anticoagulants are contraindicated, PE has recurred while on adequate anticoagulant therapy, or PE is severe (hypotension, right ventricular failure on physical examination) and any recurrent PE may be fatal. Insertion of an inferior vena cava filter is also strongly recommended in patients following pulmonary embolectomy.

Routine insertion of an inferior vena cava filter is not indicated only on the basis of a continuing predisposition for DVT, although in special circumstances this may be the best approach, e.g. in high-risk patients with DVT, severe pulmonary hypertension, and minimal cardiopulmonary reserve.

Several vena cava filters have been designed for percutaneous insertion and many are retrievable. They differ in outer diameter of the delivery system, maximal caval diameter into which they can be inserted, hook design, retrievability, biocompatibility, and filtering efficiency. They may be effective alone in preventing PE, but anticoagulant therapy after insertion of a filter is recommended.

Complications of permanent vena cava filters include improper anatomic placement, filter deformation, filter fracture, insufficient opening of the filter, and filter migration; also perforation, thrombosis, and stenosis of the cava wall. Symptomatic occlusion of the inferior vena cava is the most frequent complication, occurring in about 9% of patients. Complications at the site of insertion of the catheter do not differ from complications observed locally with other catheter techniques. DVT at the puncture site generally has been reported in 8% to 25%. Retrievable vena cava filters typically are successfully removed after 1 to 3 months, but some have been successfully removed after 1 year.

PE after insertion of an inferior vena cava filter is uncommon (1%), and fatal embolism is rare. Possible mechanisms that can explain PE after filter insertion are (1) ineffective filtration, especially with tilting of the filter, (2) growth of trapped thrombi through the filter, (3) thrombosis on the proximal side of the filter, (4) filter migration, (5) filter retraction from the caval wall, (6) embolization through collaterals, (7) embolization from sites other than the inferior vena cava, and (8) incorrect position of the filter. Over the last two decades, the use of inferior vena cava filters in the United States of America has increased markedly in patients with PE, patients with DVT alone, and patients at risk who had neither PE nor DVT. The use for primary prevention in patients who do not have DVT or PE has accelerated. Extensive use of permanent and retrievable vena cava filters indicates a liberalization of indications, but despite the benefits of retrievability, retrieval has been attempted in only a minority of patients.

Catheter interventions

Catheter-tip devices for the extraction or the fragmentation of PE have the potential of producing immediate relief from massive PE. Such interventions may be particularly useful in patients in whom there is a contraindication to thrombolytic therapy. A suction-tip device for extraction of PE has been used in some patients, and thrombus fragmentation with a guide wire, angiographic catheter, balloon catheter, or specially designed devices has been reported in small case series or case reports. The release of fragmented thromboemboli into the distal pulmonary arterial branches is not a problem. A registry of management strategies used by hospitals throughout Germany showed use of thrombus fragmentation in 1.3% to 6.8% of patients with PE, depending on severity.

Although originally it was thought that catheter embolectomy or fragmentation could substitute for thrombolytic therapy, it now appears to be an adjunct to thrombolysis, allowing a larger surface area of the fragmented emboli to be exposed to thrombolytic agent. Among patients who undergo fragmentation with standard angiographic catheters, the rate of successful clinical outcome with a local infusion of thrombolytic agents in combination with fragmentation is higher than with a systemic infusion.

Pulmonary embolectomy

Medical therapy is likely to give better results than embolectomy, although the latter may have life-saving potential in some instances. The average operative mortality among 253 patients operated from 1985 to 2006 was 20%, and higher in those who experienced a preoperative cardiac arrest. A candidate for pulmonary embolectomy should meet the following criteria: (1) massive PE, angiographically documented if possible, (2) haemodynamic instability (shock) despite heparin therapy and resuscitative efforts, and (3) failure of thrombolytic therapy or a contraindication to its use.

Chronic pulmonary thromboembolic hypertension

The vast majority of PE resolve because of natural thrombolytic processes. Residual emboli, if any, undergo fibrovascular organization causing chronic obstruction to pulmonary arterial blood flow. In a very few patients—0.1 to 0.2 % of survivors of acute PE—this process results in chronic pulmonary thromboembolic hypertension.

Further reading

Top

Agnelli G and Becattini C. (2010). Acute pulmonary embolism. N Engl J Med, 363, 266–274.

Buller HR et al. (2004). Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest, 126 Suppl, 401–28S.

Collaborative Study by the PIOPED Investigators (1990). Value of the ventilation/perfusion scan in acute pulmonary embolism—results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA, 263, 2753–59.

Doyle RL, et al. (2004). Surgical treatments/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest, 126 Suppl, 63–71S.

Geerts WH, et al. (2004). Prevention of venous thromboembolism. American College of Chest Physicians evidence-based clinical guidelines (8th edition), Chest, 133, 381S–453S.

Geerts WH, et al. (2004). Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest, 126 Suppl, 338–400S.

Kearon CJS, et al. (2001). Management of suspected deep venous thrombosis in outpatients by using clinical assessment and D-dimer testing. Ann Intern Med, 135, 108–11.

Kearon C, et al. (2008). Antithrombotic therapy for venous thromboembolic disease. American College of Chest Physicians evidence-based clinical guidelines (8th edition), Chest, 133, 454S–545S.

National Cooperative Study (1973). The Urokinase Pulmonary Embolism Trial. Circulation, 47 Suppl II, II-1–108.

Perrier A , et al. (2005). Multidetector-row computed tomography in suspected pulmonary embolism. N Engl J Med, 28, 1760–1768.

Sostman HD, et al. (2008). Sensitivity and specificity of perfusion scintigraphy combined with chest radiography for acute pulmonary embolism in PIOPED II. J Nucl Med 2008; 49:1741–1748

Stein PD (2007). Pulmonary embolism, 2nd edition. Blackwell, Oxford.

Stein PD and Matta F (2010). Acute pulmonary embolism. Current Problems in Cardiology, 35, 314–376

Stein PD, et al. (1991). Clinical, laboratory, roentgenographic and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest, 100, 598–603.

Stein PD, et al. (2004). D-dimer for the exclusion of deep venous thrombosis and acute pulmonary embolism: a systematic review. Ann Intern Med, 140, 589–602.

Stein PD, et al. (2004). Venous thromboembolism in pregnancy: 21 year trends. Am J Med, 117, 121–5.

Stein PD, et al. (2006). Diagnostic pathways in acute pulmonary embolism: Recommendations of the PIOPED II investigators. Am J Med, 119, 1048–55.

Stein PD, et al. (2006). Multidetector computed tomography for acute pulmonary embolism. N Engl J Med, 354, 2317–27.

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