Pulmonary emboli and venous thromboses

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Chapter 10 Pulmonary emboli and venous thromboses

George Jelinek, Martin Duffy

PULMONARY EMBOLI

(George Jelinek)

Pulmonary embolism (PE) is a diagnosis to be made in the emergency department. If diagnosed and treated appropriately, the mortality is of the order of 8–10%, with most patients dying of comorbidity. If the diagnosis is not made initially, the mortality rises to about one-third of cases1 and patients have a three-fold higher rate of in-hospital adverse events.2

Clinical features3

The commonest symptoms and signs of patients with PE and the risk factors have been well described for decades.

Commonest symptoms

1. Chest pain

a. Pleuritic
b. Other

2. Dyspnoea
3. Apprehension
4. Cough
5. Haemoptysis
6. Sweats

88%
74%
14%
84%
59%
53%
30%
27%

Commonest signs

1. Tachypnoea (> 16/min)
2. Crackles/rales
3. Loud P2
4. Tachycardia (> 100/min)
5. Fever (> 37.8°C)
6. Diaphoresis
7. Gallop rhythm
8. Deep vein thrombosis (DVT) clinically
9. Peripheral oedema
10. Pulmonary/tricuspid murmur
11. Cyanosis

92%
58%
53%
44%
43%
36%
34%
32%
24%
23%
19%

Risk factors

1. Prolonged immobility
2. Current venous disease
3. Congestive cardiac failure/chronic airflow limitation (CAL)

55%
49%
38%
4. Others (systemic malignancy, trauma to pelvis/lower extremity, surgery, peripartum, oestrogen intake including contraceptives, age > 50, obesity)

Note: Only 6% of patients with PE have no recognised coexistent illness or risk factor.

Diagnosis and differential diagnosis

The diagnosis is often difficult and approaches to diagnosis remain in a state of flux. Classical signs and symptoms occur only occasionally, and most are non-specific. Clinical judgment enhances the ability of investigations to predict PE, and is now used in most PE investigation algorithms, in association with calculation of pre-test probability (PTP) of PE based on symptoms, signs and risk factors.4

Pre-test probability (PTP)2

Points are awarded as follows:

Signs of DVT 3
PE most likely cause 3
Active cancer 1.5
Recent immobilisation (bed rest of 3 days or more, leg plaster for 2 weeks or more, surgery within 3 weeks) 1.5
Tachycardia (PR > 100/min) 1
History of haemoptysis 1

PTP is considered high if over 6, intermediate for a score of 3–6, and low for a score of 2 or less.

PE is a great mimic; there are scores of differential diagnoses. Most concerning are those where anticoagulation would potentially worsen the condition if misdiagnosis as PE occurred, particularly aortic dissection.

PE rule-out criteria (PERC)

A gestalt suspicion of low probability of PE together with a refinement of Wells criteria4 has been developed and trialled to exclude PE in outpatient populations.5,6 These PE rule-out criteria (PERC) are: age < 50 years, pulse < 100/min, SaO2 ≥ 95%, no haemoptysis, no oestrogen use, no surgery/trauma requiring hospitalisation within 4 weeks, no prior venous thromboembolism (VTE) and no unilateral leg swelling.

In a large multicentre study, the combination of low suspicion and negative PERC reduced the probability of VTE to below 2% in those with low suspicion of PE.6

Investigations

The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study found that, although an abnormal (low, intermediate or high probability) ventilation/perfusion lung scan was very sensitive (98%) for PE, it was not nearly as specific (10%) as previously thought, and only a minority of patients with PE had high probability scans.7 Ultrasonography of leg veins (to look for deep vein thrombosis (DVT)) and pulmonary angiography should be used much more liberally when there is strong clinical suspicion of PE.

Increasingly, d-dimer assay and CT pulmonary angiography (CTPA) are being used to refine diagnosis. D-dimer has gone in and out of favour, due to differences in sensitivity of the various testing methods, but with rapid, modern ELISA d-dimers, sensitivity is virtually 100% and the test can be reliably used to exclude PE, provided patient selection is good.

Chest X-ray (CXR)

CXR is usually abnormal, but no changes are specific. Only 7–22% are normal. The commonest findings are:

• Raised hemidiaphragm with atelectasis
• Consolidation/infiltrates/effusion 30–

50%
50%

Hampton’s hump and Westermark’s sign are uncommon.

ECG

The ECG is usually abnormal. Only 13% are normal or unchanged. The commonest findings are:

• Tachycardia (> 100/min)
• ST–T wave changes
• Acute cor pulmonale (S1Q3T3)

44%
42%
12%

Arterial blood gases (ABGs)

ABGs usually reveal hypoxia. Only 10–15% of patients have a PaO2 >80 mmHg, 5% have PaO2 > 90 mmHg. Pulse oximetry, as in other respiratory emergencies, is invaluable.

D-dimer

A negative d-dimer, in conjunction with a low or intermediate PTP, effectively excludes PE in emergency department populations. A d-dimer is, however, unreliable and should not be performed in the following circumstances: for inpatients, in patients with recent (within 2 weeks) invasive surgery or major trauma or with active cancer, or where the duration of symptoms is 7 days or more.

Troponin I

Several studies have suggested the use of troponin I in PE to predict the occurrence of complications. Elevated troponin I appears to reliably predict haemodynamic instability and complicated clinical course.8–10 Others have suggested B-type natriuretic peptide (BNP) may be a better predictor.11

Advanced imaging

Radionuclide ventilation/perfusion lung scan

If normal or near-normal, the diagnosis is reasonably excluded (about 4% will have PE).7

• Low probability PE in
• Medium probability PE in
• High probability PE in

16%
33%
88%

A history of PE decreases the accuracy of diagnosis based on a high-probability scan. If the CXR is abnormal, CT pulmonary angiography (CTPA) is preferred to ventilation/perfusion (V/Q) scanning.

CT pulmonary angiography

CTPA is useful in the setting of patients with abnormal CXRs. It is more sensitive for central than peripheral PEs and has the advantage of detecting other pulmonary pathology if present. Many authorities are now arguing that CTPA may be used as the single diagnostic test in the emergency department after risk stratification and d-dimer testing.12–14 However, small subsegmental emboli may be missed. The rate of subsequent venous thromboembolism after negative results on CTPA, however, appears to be similar to that seen after negative results on pulmonary angiography.15 So it appears safe to withhold anticoagulation after negative CTPA results. MRI is available in a few centres.

Pulmonary angiography

Nearly 100% specific and sensitive, pulmonary angiography is the ‘gold standard’. A negative study essentially excludes the diagnosis of PE. However, morbidity is 1–4% and mortality is 0.1–0.4%.1 It is not often used, but should be when clinical suspicion is very high but other investigations are normal.

Diagnostic pathway

A reasonable approach is to base the use of invasive investigations on a combination of PTP and d-dimer assay. A PTP of 6 or less, together with a negative d-dimer, excludes PE. Otherwise, invasive testing should be undertaken. Alternatively, using the PERC may further minimise the use of investigations.

The choice of test depends on CXR findings. If the CXR is essentially normal, a V/Q scan should be performed; if the CXR is abnormal, a CTPA. Results of these tests should again be interpreted in light of the PTP. A low PTP in association with normal or low-probability V/Q scan or negative CTPA effectively excludes PE. A high-probability V/Q scan, in association with an intermediate or high PTP, makes the diagnosis of PE. For other combinations of PTP and V/Q results, leg ultrasonography and/or pulmonary angiography are needed to definitively make the diagnosis. More and more centres now adopt the alternative strategy of using CTPA as the sole investigation after initial risk stratification and work-up.

Management

Treatment may need to begin on suspicion, particularly if definitive investigations are unavailable out of hours. Conventional anticoagulation with heparin in currently recommended dose regimens (e.g. 5000 units IV stat followed by 800–1600 units/hour by continuous infusion) is still standard therapy in most centres, although low molecular weight heparins now appear to be at least as effective.16 For haemodynamically compromised patients or those with right ventricular dysfunction, thrombolysis should be considered, although evidence of effectiveness is still limited.

Comments

• PE symptoms and signs are very non-specific and PE is the great modern mimic. The diagnosis is more often missed because it is not considered rather than not found on testing.
• ‘Atypical chest pain’ should not be a final diagnosis; a cause should be sought and PE at least considered.
• The role of thrombolytics in PE requires more study.

VENOUS THROMBOEMBOLISM

(Martin Duffy)

Venous thromboembolism is a common disease. The underlying abnormality, as described by Virchow many years ago, is a problem with one or more of the following:

• venous stasis
• injury to the vessel wall
• hypercoagulability.

Although it can occur in any part of the venous system, clinically important sites are the deep veins of the lower limbs and the pelvic veins. Less commonly, the axillary/subclavian veins may be affected.

Patients presenting to the emergency department with possible venous thromboembolism often have a myriad of signs and symptoms making diagnosis a challenging exercise. Importantly, accurate diagnosis is essential. If missed, the patient may suffer significant morbidity or mortality, ranging from postphlebitic syndrome to pulmonary embolism and death. If overdiagnosed, the patient may be exposed to the risks of unnecessary therapy, such as haemorrhage from anticoagulation.

The problem

A typical scenario in the emergency department is the patient who presents with a painful, swollen calf for assessment and management of possible underlying DVT.

In the past, experience had shown us that the clinical examination was unreliable in diagnosing or excluding DVT, hence the mere suggestion of the possibility virtually compelled the doctor to perform some form of medical imaging as part of the diagnostic work-up.

Nowadays, this is no longer the case. The use of a set of standardised clinical criteria enables patients to be stratified according to pre-test probabilities of DVT. Combined with the results of a d-dimer level many patients may not require any further investigation.

Diagnostic approach

Decision-making is based on an assessment of pre-test probability, d-dimer testing and some form of medical imaging. The following algorithm summarises one approach to the investigation of the patient with a possible DVT based on evidence presently available in the literature.

image

Figure 10.1 Approach to the investigation of the patient with a possible DVT

Determine the patient’s pre-test probability

Clinical ‘impression’ alone is not sufficient. Wells and colleagues17 developed and validated a set of clinical criteria incorporating signs, symptoms, risk factors and alternative diagnoses for stratifying a patient’s pre-test probability of DVT into low, moderate or high risk. In their original study, the approximate rates of DVT for these patient populations were as high as 5%, 33% and 85%, respectively. Some authors have argued that the criteria specifically exclude patients with a history of DVT, and are therefore applicable to first-time presentations only, thus limiting their usefulness. However, further research has included such patients and an updated stratification tool now divides patients into ‘likely’ or ‘unlikely’ risk categories, as shown in Table 10.1. However, a notable exclusion is the pregnant patient.

Table 10.1 Clinical model for predicting the pre-test probability of deep-vein thrombosis∗

Clinical characteristic Score
Active cancer (patient receiving treatment for cancer within the previous 6 months or currently receiving palliative treatment) 1
Paralysis, paresis or recent plaster immobilisation of the lower extremities 1
Recently bedridden for 3 days or more, or major surgery within the previous 12 weeks requiring general or regional anaesthesia 1
Localised tenderness along the distribution of the deep venous system 1
Entire leg swollen 1
Calf swelling at least 3 cm larger than that on the asymptomatic side (measured 10 cm below tibial tuberosity) 1
Pitting oedema confined to the symptomatic leg 1
Collateral superficial veins (nonvaricose) 1
Previously documented deep vein thrombosis 1
Alternative diagnosis at least as likely as deep vein thrombosis –2

∗ A score of 2 or higher indicates that the probability of deep vein thrombosis is likely; a score of less than 2 indicates that the probability of deep vein thrombosis is unlikely. In patients with symptoms in both legs, the more symptomatic leg is used.

Reproduced from Wells et al, N Engl J Med 2003; 349:1227–1235, with permission

Determine the d-dimer level

D-dimer is a degradation product from cross-linked fibrin. It rises acutely in the presence of venous thrombosis—and unfortunately it rises in many other conditions as well (advanced age, malignancy, infection, trauma, haemorrhage and even recent major surgery). Numerous assays are currently available—a highly sensitive assay is important.

In patients with an ‘unlikely’ pre-test probability, if the d-dimer is negative then no further investigation for DVT is warranted (risk <1%). The ‘unlikely’ patient with a positive d-dimer level requires further investigation.

Medical imaging

Duplex ultrasonography of the affected lower limb is the most common imaging modality used in the Australasian setting. Sensitivities and specificities of 97% and 94%, respectively, are quoted in the literature. However, it is important to remember two points: (1) the test is operator-dependent; (2) the sensitivity for detecting isolated calf vein DVT is only 73% (20–30% of these may extend proximally).

If the ultrasound is positive for DVT at any stage of the algorithm, treat the patient. In the ‘unlikely’ patient with a positive d-dimer, if the ultrasound is negative then the likelihood of DVT is exceedingly small and treatment can be withheld. However, in the ‘likely’ patient with a positive d-dimer and a negative ultrasound, the evidence would support repeat ultrasonography at 1 week.

Other imaging modalities include:

• impedance plethysmography—non-invasive, but not as accurate as ultrasound—rarely used
• venography (the ‘old’ gold standard)—invasive and has associated complications—rarely used
• CT and MRI—accurate, but place in diagnostic algorithm yet to be determined based on cost, incremental value etc.

Treatment

The treatment of DVT has changed significantly over recent years, with many patients now being treated as outpatients, largely due to the numerous advantages low molecular weight heparin has over unfractionated heparin—i.e. weight-based dosing that does not require any specific monitoring and simple subcutaneous administration once or twice daily.

It is important to remember to look at the ‘whole picture’ when deciding on a treatment plan for each individual, including the following:

• age
• comorbidities—including active bleeding/familial bleeding disorder/marked renal disease/severe liver disease
• proximal versus distal thrombus
• associated pulmonary embolism
• social supports
• ability to access further medical care if/when required.

Patients with cancer, bilateral DVT, renal insufficiency, congestive heart failure, weight less than 70 kg and immobility may be at higher risk of earlier complications (bleeding/recurrence) and should be considered for inpatient therapy.

Baseline investigations

Baseline investigations prior to commencing therapy may include:

• full blood count
• electrolytes/urea/creatinine
• liver function tests
• coagulation profile.

Above-knee DVT

A suitable treatment plan for an above-knee DVT is as follows:

1. Non-drug therapy—mobilisation and TED stockings.
2. Analgesia as required.
3. Enoxaparin 1.5 mg/kg/day as a single dose (if > 100 mg/day, divide the dose into two equal doses). Reduce the dose to 0.75–1.0 mg/kg/day if Hb < 100 g/dL, thrombocytopenia, renal impairment, liver disease or elderly patient.
4. Start warfarin on day 2 or 3 (can be done by local medical officer).
5. Continue enoxaparin until the international normalised ratio (INR) is therapeutic (2–3) for at least 24 hours.
6. Anticoagulate for 3 months.

Below-knee DVT

A suitable treatment plan for a below-knee DVT includes:

1. Non-drug therapy—mobilisation and TED stockings.
2. Analgesia as required.
3. Enoxaparin 1.5 mg/kg/day as a single dose (if > 100 mg/day, divide the dose into two equal doses).
4. Treat for 7–10 days.
5. Repeat lower limb duplex ultrasound at 7–10 days.
6. If ultrasound the same or unchanged, stop anticoagulation.
7. If ultrasound shows progression, treat as for above-knee DVT.

Many new drug therapies for both prophylaxis and treatment of venous thromboembolism are currently undergoing development and testing. Most of these specifically target individual components of the coagulation system. Unfortunately, at this stage, some have not met expectations and none are yet ready for widespread clinical use.

The role of thrombolytics in the management of DVT remains unclear at this point in time. Studies show improvement in clot lysis, but usually at the expense of an increase in haemorrhagic complications. Restricted use in the patient with a massive DVT, after serious consideration of the risk–benefit ratio for the individual patient, seems to be the only scenario when thrombolytics may be considered at present.

Other treatments

1. Vena caval filter. The placement of a filter to prevent pulmonary embolism should be considered in any patient who has a contraindication to anticoagulation, serious bleeding complications on anticoagulation, or disease progression despite adequate anticoagulation.
2. Surgery. Reserved for massive DVTs that threaten limb or life.

Further investigations

Patients with proven DVT, and no obvious reason for the development of such a problem, require further investigation. Apart from the possibility of an underlying hypercoagulable state, always keep in mind the possibility of an undiagnosed malignancy.

Investigations ordered as part of a procoagulant screen include:

• activated protein C resistance
• ANA
• anticardiolipin antibody
• antithrombin III
• factor V Leiden
• homocysteine
• lupus inhibitor
• MTHFR gene mutation
• proteins C and S
• PT20210 gene.

(Note: The use of low-molecular-weight heparin interferes with antithrombin III testing.)

Axillary/subclavian vein thrombosis

Axillary/subclavian vein thrombosis is a much less common clinical problem. The underlying causes are similar to those of other DVTs, though other factors that play a more prominent role include excessive/unusual exercise, intravenous catheters and intravenous drug use. Often there is an underlying predisposing narrowing, e.g. cervical rib. Although commonly thought to be of less concern in terms of embolisation, axillary/subclavian vein thrombosis has been known to occur in up to 30% of cases, and should therefore be treated as aggressively as lower limb DVT.

Comments

• Venous thromboembolism is a common but difficult clinical problem.
• Use Wells’ criteria to risk-stratify patients.
• An ‘unlikely’ pre-test probability and a negative d-dimer rule out DVT.
• Many patients are suitable for outpatient therapy.

REFERENCES

1 Dunmire S.M. Pulmonary embolism. Emergency Medicine Clinics of North America. 1989;7:339-354.

2 Kline J.A., Hernandez-Nino J., Jones A.E., et al. Prospective study of the clinical features and outcomes of emergency department patients with delayed diagnosis of pulmonary embolism. Acad Emerg Med. 2007;14:592-598.

3 Urokinase-streptokinase embolism trial. Phase II results. JAMA. 1974;229:1606-1613.

4 Wells P.S., Ginsberg J.S., Anderson D.R., et al. Use of a clinical model for safe management of patients with suspected pulmonary embolism. Ann Intern Med. 1998;129:997-1005.

5 Wolf S.J., McCubbin T.R., Nordenholz K.E., et al. Assessment of the pulmonary embolism rule-out criteria rule for evaluation of suspected pulmonary embolism in the emergency department. Am J Emerg Med. 2008;26:181-185.

6 Kline J.A., Courtney D.M., Kabrhel C., et al. Prospective multicenter evaluation of the pulmonary embolism rule-out criteria. J Thromb Haemost. 2008;6:772-780.

7 The PIOPED investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA. 1990;263:2753-2759.

8 Aksay E., Yanturali S., Kiyan S. Can elevated troponin I levels predict complicated clinical course and in-hospital mortality in patients with acute pulmonary embolism? Am J Emerg Med. 2007;25:138-143.

9 Palmieri V., Gallotta G., Rendina D., et al. Troponin I and right ventricular dysfunction for risk assessment in patients with nonmassive pulmonary embolism in the Emergency Department in combination with clinically based risk score. Intern Emerg Med. 2008;3(2):131-138.

10 Gallotta G., Palmieri V., Piedimonte V., et al. Increased troponin I predicts in-hospital occurrence of hemodynamic instability in patients with sub-massive or non-massive pulmonary embolism independent to clinical, echocardiographic and laboratory information. Int J Cardiol. 2008;124:351-357.

11 Maziere F., Birolleau S., Medimagh S., et al. Comparison of troponin I and N-terminal-pro B-type natriuretic peptide for risk stratification in patients with pulmonary embolism. Eur J Emerg Med. 2007;14:207-211.

12 Tilli P., Testa A., Covino M., et al. Diagnostic and therapeutic approach to acute pulmonary embolism in an emergency department. Eur Rev Med Pharmacol Sci. 2006;10:91-98.

13 Mountain D. Multislice computed tomographic pulmonary angiography for diagnosing pulmonary embolism in the emergency department: has the ‘one-stop shop’ arrived? Emerg Med Australas. 2006;18:444-450.

14 Emet M., Ozucelik D.N., Sahin M., et al. Computed tomography pulmonary angiography in the diagnosis of acute pulmonary embolism in the emergency department. Adv Ther. 2007;24:1173-1180.

15 Moores L.K., Jackson W.L.Jr., Shorr A.F., et al. Meta-analysis: outcomes in patients with suspected pulmonary embolism managed with computed tomographic pulmonary angiography. Ann Intern Med. 2004;141:866-874.

16 Quinlan D.J., McQuillan A., Eikelboom J.W. Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials. Ann Intern Med. 2004;140:175-183.

17 Wells P., Anderson D. Diagnosis of deep-vein thrombosis in the year 2000. Current Opinion in Pulmonary Medicine. 2000;6(4):309-313.

RECOMMENDED READING

Bates S., Kearon C., Crowther M., et al. A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis. Ann Int Med. 2003;138(10):787-794.

Cornuz J., Ghali W., Hayoz D. Clinical prediction of deep venous thrombosis using two risk assessment methods in combination with rapid quantitative D-dimer testing. Am J Med. 2002;112(3):198-203.

Forster A., Wells P. The rationale and evidence for the treatment of lower-extremity deep venous thrombosis with thrombolytic agents. Current Opinion in Haematology. 2002;9(5):437-442.

Hyers T. Management of venous thromboembolism: past, present, and future. Arch Int Med. 2003;163(7):759-768.

Kelly J., Hunt B. Role of D-dimers in diagnosis of venous thromboembolism. Lancet. 2002;359:456-458.

Kraaijenhagen R., Piovella F., Bernardi E., et al. Simplification of the diagnostic management of suspected deep vein thrombosis. Arch Int Med. 2002;162:907-911.

Minichiello T., Fogarty P. Diagnosis and management of venous thromboembolism. Med Clin N Am. 2008;92:443-465.

Trujillo-Santos J., Herrera S., Page M.A., et al. Predicting adverse outcome in outpatients with acute deep vein thrombosis: findings from the RIETE registry. J Vasc Surg. 2006;44(4):789-793.

Wells P., Anderson D. Diagnosis of deep-vein thrombosis in the year 2000. Current Opinion in Pulmonary Medicine. 2000;6(4):309-313.

Wells P., Anderson D., et al. Evaluation of D-dimer in the diagnosis of suspected deep vein thrombosis N Engl J Med. 2003;349:1227-1235.

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