**5. Risk assessment based on presence of right ventricular dysfunction**

The majority of patients with acute PE are stable at time of diagnosis, but this may not necessarily imply a benign course. Patients may appear stable initially because the development of RV failure and cardiogenic shock can be delayed as the vicious cycle of elevated pulmonary resistance, RV dilatation, and the RV hypokinesis unfolds. In stable patients with acute PE, the presence of RV dysfunction is associated with a high mortality rate (Sanchez et al., 2008).

In addition, RV dysfunction in acute PE predicts recurrent thromboembolic events. During a mean follow-up of three years, patients with persistent RV dysfunction were more likely to have a recurrent PE, deep venous thrombosis or higher PE-related deaths compared with patients without RV dysfunction or had RV dysfunction that resolved at discharge (Grifoni et al., 2006).

#### **5.1 Echocardiography**

Echocardiography is non-invasive and able to provide very useful information promptly. However, it is not recommended as a routine imaging test to diagnose PE because an echocardiogram can appear normal in about 50% of the patients with suspected PE. Despite its limitations, a bedside echocardiogram in a hemodynamically unstable patient is an

Risk Stratification of Patients with Acute Pulmonary Embolism 25

RV hypokinesis by qualitative assessment of the RV wall

Dilated RV cavity (qualitative assessment of RV compared to left ventricle) or RVEDD > 30mm; or when 2 of the

2. TR velocity > 2.5m/s in the absence of inspiratory

1. Dilated RV (RVEDD/LVEDD > 1 or RVEDD >

3. Pulmonary hypertension (Doppler PAT <90ms or

4. Absence of RV hypertrophy (thickness > 7mm)

1. Dilated RV (RVEDD/LVEDD > 1 or RVEDD >

3. Pulmonary hypertension (Doppler PAT <90ms or

1. RVEDD/LVEDD > 0.6 with RV hypokinesis

2. Pulmonary hypertension (Elevated TVPG >30mmHg

5. Loss of inspiratory collapse of the IVC

**Authors Definition of RV dysfunction** 

following were present: 1. TR velocity > 2.8m/s

30mm) 2. Septal dyskinesis

30mm) 2. Septal dyskinesis

Vieillar-Baron et al, 2001 RVEDA/LVEDA > 0.6 with septal dyskinesis

Table 3. Studies evaluating RV dysfunction with echocardiography

collapse of the IVC 3. Dilated RPA (> 12mm/m2) 4. RV wall thickness > 5mm

Presence of any 1 of the following:

RV-RA gradient >30mmHg)

RV-RA gradient >30mmHg)

Presence of any 1 of the following:

with PAT <80ms)

Indirect evidence of RV dysfunction from echocardiography includes raised pulmonary artery systolic pressure (PASP). This can be estimated from the right ventricular systolic pressure (RVSP) according to the formula: PASP = RVSP + estimated right atrial pressure (Figure 5). The RVSP is obtained from the velocity of the tricuspid regurgitant jet (v), such that RVSP = 4v2 and the right atrial pressure is estimated from the size and respiratory

(RVEDD/LVEDD, right to left end-diastolic diameter ratio; RVEDA/LVEDA, right to left ventricular end-diastolic area ratio; RV-RA gradient, right ventricular-right atrial gradient; PAT, pulmonary arterial flow acceleration time; TVPG, tricuspid valve pressure gradient; IVC, inferior vena cava; TR, tricuspid

Presence of any 1 of the following:

motion

Goldhaber et al, 1993, 1999

Ribeiro et al, 1997, Jerjes-Sanchz et al, 2001, Kucher et al, 2003, 2005

Kasper et al, 1997

Grifoni et al, 2000, 2001

Pieralli et al, 2006

Kostrubiec et al, 2005

variation of the inferior vena cava.

regurgitation).

invaluable first-line tool to diagnose other conditions that mimic an acute PE such as myocardial infarction, proximal aortic dissection or a pericardial tamponade. These emergency conditions require management very different from an acute PE.

More importantly, the main role of echocardiography in the setting of an acute PE is to identify a sub-group of stable, non-high-risk patients with RV dysfunction for more aggressive management. The prognostic implications of RV dysfunction detected with echocardiography, even in stable acute PE patients, are clear and this has been illustrated in two separate meta-analyses. In all studies, patients with normal RV function have very good prognosis, with low in-hospital mortality (ten Wolde et al., 2004; Sanchez et al., 2008). Unfortunately, unlike the left ventricle, the anatomy of the RV is complex and assessment of RV function is challenging. Thus, the criteria of RV dysfunction are not well established and differ among published studies (Table 3).

Echocardiography detects both direct and indirect hemodynamic consequences of acute PE (Figure 1). Direct evidence of RV dysfunction includes a dilated RV cavity as compared to the LV. More convincingly, the concomitant presence of RV hypokinesis suggests a failing RV. However, qualitative assessment of RV wall motion is subjective and insufficient in this era of standardization. There is a distinctive two-dimensional echocardiographic finding of regional RV dysfunction that has been described in acute PE. This abnormality is characterized by the presence of normal or hyperdynamic RV apex despite moderate to severe RV free-wall hypokinesis (McConnell sign, Figure 3). Echocardiography may also show flattened inter-ventricular septum or paradoxical motion towards the LV during systole to suggest RV pressure overload (Figure 4).

Fig. 3. Apical four-chamber view demonstrating McConnell sign: hypokinesis of the right ventricle (RV) free wall sparing the apex (arrows). The RV is markedly dilated.

invaluable first-line tool to diagnose other conditions that mimic an acute PE such as myocardial infarction, proximal aortic dissection or a pericardial tamponade. These

More importantly, the main role of echocardiography in the setting of an acute PE is to identify a sub-group of stable, non-high-risk patients with RV dysfunction for more aggressive management. The prognostic implications of RV dysfunction detected with echocardiography, even in stable acute PE patients, are clear and this has been illustrated in two separate meta-analyses. In all studies, patients with normal RV function have very good prognosis, with low in-hospital mortality (ten Wolde et al., 2004; Sanchez et al., 2008). Unfortunately, unlike the left ventricle, the anatomy of the RV is complex and assessment of RV function is challenging. Thus, the criteria of RV dysfunction are not well established and

Echocardiography detects both direct and indirect hemodynamic consequences of acute PE (Figure 1). Direct evidence of RV dysfunction includes a dilated RV cavity as compared to the LV. More convincingly, the concomitant presence of RV hypokinesis suggests a failing RV. However, qualitative assessment of RV wall motion is subjective and insufficient in this era of standardization. There is a distinctive two-dimensional echocardiographic finding of regional RV dysfunction that has been described in acute PE. This abnormality is characterized by the presence of normal or hyperdynamic RV apex despite moderate to severe RV free-wall hypokinesis (McConnell sign, Figure 3). Echocardiography may also show flattened inter-ventricular septum or paradoxical motion towards the LV during

Fig. 3. Apical four-chamber view demonstrating McConnell sign: hypokinesis of the right

ventricle (RV) free wall sparing the apex (arrows). The RV is markedly dilated.

emergency conditions require management very different from an acute PE.

differ among published studies (Table 3).

systole to suggest RV pressure overload (Figure 4).


(RVEDD/LVEDD, right to left end-diastolic diameter ratio; RVEDA/LVEDA, right to left ventricular end-diastolic area ratio; RV-RA gradient, right ventricular-right atrial gradient; PAT, pulmonary arterial flow acceleration time; TVPG, tricuspid valve pressure gradient; IVC, inferior vena cava; TR, tricuspid regurgitation).

Table 3. Studies evaluating RV dysfunction with echocardiography

Indirect evidence of RV dysfunction from echocardiography includes raised pulmonary artery systolic pressure (PASP). This can be estimated from the right ventricular systolic pressure (RVSP) according to the formula: PASP = RVSP + estimated right atrial pressure (Figure 5). The RVSP is obtained from the velocity of the tricuspid regurgitant jet (v), such that RVSP = 4v2 and the right atrial pressure is estimated from the size and respiratory variation of the inferior vena cava.

Risk Stratification of Patients with Acute Pulmonary Embolism 27

An elevated pulmonary artery systolic pressure of more than 50mmHg at time of diagnosis is associated with persistent pulmonary hypertension at 1 year (Ribeiro et al., 1999). In patients with acute PE, the absence of any significant tricuspid regurgitation makes the

Besides the evidence of RV dysfunction and elevated pulmonary arterial pressures, other

1. A right-to-left shunt, such as a patent foramen ovale (PFO). In a prospective study of 139 consecutive patients with acute PE, PFO was diagnosed in 48 patients by contrast echocardiography. Evidence of a PFO in patients with acute PE was associated with higher mortality rate (33% vs. 14%) and higher incidence of peripheral thromboembolic events (Konstantinides et al., 1998). These patients are particularly prone to paradoxical embolism due to increased right-to-left shunt from elevated right-sided pressures. 2. A free-floating right heart thrombus (Figure 6). The prevalence of patients with a right heart thrombus visualized during echocardiography was about 4% (Torbicki et al., 2003). Thrombus from the right heart usually arises from the lower limb veins. These thrombi are highly mobile and often described as having the appearance of a worm, or snake. Free-floating thrombus can embolize at any time and have a dismal prognosis regardless of therapeutic option (Chin et al., 2010). The mortality rate of about 20% within 24 hours of diagnosis, and mortality is significantly linked with the occurrence

Contrast enhanced computer tomography (CT) of the pulmonary arteries is increasingly used as a first-line imaging modality for PE diagnosis. The anatomical distribution and burden of embolic occlusion of the pulmonary arterial bed can be assessed easily by CT (Figure 7). However, the anatomical assessment seems less relevant for risk stratification

Most scanners allow reconstruction of standardized cardiac views and direct measurements of ventricular dimensions can be made. RV enlargement based on RV-to-LV dimension ratio, RVd/LVd, (Figure 8) on the reconstructed CT four-chamber view correlated with RV dysfunction on echocardiogram. Using RVd/LVd > 0.9 as cut-off, the sensitivity and specificity for predicting PE-related adverse events were 83% and 49% on the reconstructed CT, respectively. Comparatively, the sensitivity and specificity of RVd/LVd >0.9 on

In addition to having good correlation with RV dysfunction on echocardiography, assessment of RV enlargement on chest CT in acute PE also predicted patients at risk of death from RV failure (Van der Meer et al., 2005; Schoepf et al., 2004). The greatest role appears to be the

Table 4. Trials reporting RV/LV diameter ratio assessed by CT as a risk marker for 30-day

Sensitivity (%)

Specificity (%)

(RV/LV >1) 100 45 100 10

(RV/LV > 0.9) 78 38 92 16

NPV (%)

PPV (%)

identification of low-risk patients due to its high negative predictive value (Table 4).

than assessment based on functional (hemodynamic) consequences of PE.

echocardiography were 71% and 56%, respectively (Quiroz et al., 2004).

(Cutoff)

SDCT

4 – 16 MDCT

severe pulmonary hypertension less likely.

of cardiac arrest (Chartir et al., 1999).

Author CT equipment

all cause mortality in acute pulmonary embolism.

Van der Meer et

Schoepf et al.,

al., 2005

2004

**5.2 Computed tomography** 

echocardiographic features with prognostic implications include:

Fig. 4. Parasternal short axis view showing an enlarged right ventricle (RV) with a "D" shaped septum, suggesting RV pressure overload.

Fig. 5. Continuous wave Doppler demonstrating peak tricuspid velocity of 3.2m/s, corresponding to a right ventricular systolic pressure of 41mmHg.

An elevated pulmonary artery systolic pressure of more than 50mmHg at time of diagnosis is associated with persistent pulmonary hypertension at 1 year (Ribeiro et al., 1999). In patients with acute PE, the absence of any significant tricuspid regurgitation makes the severe pulmonary hypertension less likely.

Besides the evidence of RV dysfunction and elevated pulmonary arterial pressures, other echocardiographic features with prognostic implications include:


#### **5.2 Computed tomography**

26 Pulmonary Embolism

Fig. 4. Parasternal short axis view showing an enlarged right ventricle (RV) with a "D"

Fig. 5. Continuous wave Doppler demonstrating peak tricuspid velocity of 3.2m/s,

corresponding to a right ventricular systolic pressure of 41mmHg.

shaped septum, suggesting RV pressure overload.

Contrast enhanced computer tomography (CT) of the pulmonary arteries is increasingly used as a first-line imaging modality for PE diagnosis. The anatomical distribution and burden of embolic occlusion of the pulmonary arterial bed can be assessed easily by CT (Figure 7). However, the anatomical assessment seems less relevant for risk stratification than assessment based on functional (hemodynamic) consequences of PE.

Most scanners allow reconstruction of standardized cardiac views and direct measurements of ventricular dimensions can be made. RV enlargement based on RV-to-LV dimension ratio, RVd/LVd, (Figure 8) on the reconstructed CT four-chamber view correlated with RV dysfunction on echocardiogram. Using RVd/LVd > 0.9 as cut-off, the sensitivity and specificity for predicting PE-related adverse events were 83% and 49% on the reconstructed CT, respectively. Comparatively, the sensitivity and specificity of RVd/LVd >0.9 on echocardiography were 71% and 56%, respectively (Quiroz et al., 2004).

In addition to having good correlation with RV dysfunction on echocardiography, assessment of RV enlargement on chest CT in acute PE also predicted patients at risk of death from RV failure (Van der Meer et al., 2005; Schoepf et al., 2004). The greatest role appears to be the identification of low-risk patients due to its high negative predictive value (Table 4).


Table 4. Trials reporting RV/LV diameter ratio assessed by CT as a risk marker for 30-day all cause mortality in acute pulmonary embolism.

Risk Stratification of Patients with Acute Pulmonary Embolism 29

Fig. 7. Computed tomography pulmonary angiogram showing a large embolus within the

Fig. 8. Measurement of the short axes of the RV (47 mm) and LV (39 mm) on computed tomography pulmonary angiogram of the same patient (RV, right ventricle; LV, left

ventricle)

right main pulmonary artery, extending to the main right upper lobe.

Fig. 6. Free floating thrombus (red arrow) transiting from the RA causing acute pulmonary embolism (RA, right atrium; LA, left atrium; LV, left ventricle).

Other CT-derived parameters have also been investigated. The presence of interventricular septal bowing is predictive of PE-related deaths but has low sensitivity and high interobserver variability (Araoz et al., 2007), scores to quantify the extent and location of pulmonary artery obstruction have been developed but not shown to be of prognostic relevance yet (Qanadil et al., 2001; Ghanima et al., 2007).

#### **5.3 Ventilation-perfusion scintigraphy**

Lung ventilation-perfusion scintigraphy (V/Q scan) is a well-established diagnostic test used in patients suspected of PE. Interpretation of the scans can vary, depending on the algorithms used (PIOPED criteria, modified PIOPED criteria, McMaster Clinical criteria and PisaPED criteria) and the experience of the reader. The diagnostic roles and limitations of V/Q scan are beyond the scope and will not be discussed in this chapter.

Fig. 6. Free floating thrombus (red arrow) transiting from the RA causing acute pulmonary

Other CT-derived parameters have also been investigated. The presence of interventricular septal bowing is predictive of PE-related deaths but has low sensitivity and high interobserver variability (Araoz et al., 2007), scores to quantify the extent and location of pulmonary artery obstruction have been developed but not shown to be of prognostic

Lung ventilation-perfusion scintigraphy (V/Q scan) is a well-established diagnostic test used in patients suspected of PE. Interpretation of the scans can vary, depending on the algorithms used (PIOPED criteria, modified PIOPED criteria, McMaster Clinical criteria and PisaPED criteria) and the experience of the reader. The diagnostic roles and limitations of

V/Q scan are beyond the scope and will not be discussed in this chapter.

embolism (RA, right atrium; LA, left atrium; LV, left ventricle).

relevance yet (Qanadil et al., 2001; Ghanima et al., 2007).

**5.3 Ventilation-perfusion scintigraphy** 

Fig. 7. Computed tomography pulmonary angiogram showing a large embolus within the right main pulmonary artery, extending to the main right upper lobe.

Fig. 8. Measurement of the short axes of the RV (47 mm) and LV (39 mm) on computed tomography pulmonary angiogram of the same patient (RV, right ventricle; LV, left ventricle)

Risk Stratification of Patients with Acute Pulmonary Embolism 31

**Sensitivity (%)** 

**Specificity (%)** 

95 57 97 45

95 60 97 48

65 93 94 61

deaths 86 71 99 17

mortality 100 33 100 23

mortality 100 49 100 10

**NPV (%)** 

**PPV (%)** 

**Outcome Definition** 

PE-related

In-hospital death or adverse eventse

In-hospital death or adverse eventse

In-hospital

In-hospital

30-day all cause mortality

(a-cTests used: aShionoria, CIS Bio International; bElecsys, Roche Diagnostics; cTriage, Biosite Technologies. eAdverse events include the need for resuscitation, mechanical ventilation, inotropic

Table 5. Prognostic value of BNP or NT-proBNP in acute pulmonary embolism

Due to the high negative predictive value for PE-related mortality and adverse events, a potential approach consists of a combination of biomarker testing and echocardiography. In the setting of an acute PE, further risk stratification with echocardiography is warranted in patients with elevated cardiac biomarkers due to limited specificity of the assays for predicting RV dysfunction. Conversely, in patients with levels below cut-off,

This approach was demonstrated in a prospective study of 124 patients diagnosed with acute PE. The presence of RV dysfunction on echocardiography in patients with elevated NT-proBNP (cut-off of 1000 pg/mL) or cardiac troponins (cut-off of 0.04 ng/mL) is associated with a 10-fold increase in complication risk compared with patients biomarker

Recurrent PE can occur despite adequate anticoagulation therapy in patients who had

Patients with unprovoked PE (PE occurring in the absence of established risk factors or predisposing illnesses) are at a higher risk for recurrent PE compared to patients with risk factors for PE. In contrast, patients with risk factors of PE have a higher mortality risk (Klok

**Author Test used** 

Ten Wolde et al,

Kucher et al, 2003a

Kucher et al, 2003b

Pruszczyk et al,

Kostrubiec et al,

Binder et al, 2005

2003

2007

2003

**(Threshold)** 

BNP Shionoriaa (21.7 pmol/L)

NT-proBNPb (500 pg/mL)

BNP Triagec (50 pg/mL)

NT-proBNPb (600 pg/mL)

NT-proBNPb (1000 pg/mL)

NT-proBNPb (7500 pg/mL)

echocardiography will likely not add prognostic information.

support, thrombolytics, or embolectomy)

levels below threshold (Binder et al., 2005).

**7. Risk of recurrence** 

survived an acute PE.

Perfusion defects due to PE increase with the number and size of emboli, without corresponding ventilation compromise ("mismatch" defects). However, the prognostic implications of the number and size of defects on a V/Q scan have not been investigated.
