**12. Assessment of right ventricle and pulmonary vasculature derangements**

#### **12.1. Electrocardiography**

Electrocardiography (ECG) is an easily obtainable initial study in the evaluation of dyspnea and chest pain. It is often helpful in evaluating for acute coronary syndrome. Unfortunately, ECG has limited diagnostic value for acute PE (Rodger 2000). However, in the setting of known pulmonary thromboembolism, ECG is oftentimes abnormal and may be of some benefit in risk stratification. In 1997, Ferrari et al (Ferrari 1997) reported the results of 80 consecutive ECGs in hospitalized patients with documented pulmonary embolism. T-wave inversion in the precordial leads was shown to be the most common abnormality (68%) and correlated with PE severity. Anterior T wave inversions had a sensitivity of 90% and specificity of 81% for massive PE. The classic finding of acute RV failure with S1Q3 T3 was seen in 50% of ECGs in the setting of confirmed acute PE (Ferrari 1997) which is more frequent than previously reported, 12% (Stein 1975) to 28% (Cutforth 1958).

#### **12.2. Cardiac echocardiography**

Cardiac echocardiography (ECHO) is a useful tool in evaluation of a patient presenting with dyspnea and/or chest pain. Cardiac ECHO should not be used in the evaluation to confirm the diagnosis of acute PE as only 30-40% of all acute pulmonary thromboembolic events are associated with echocardiographic abnormalities (Gibson 2005). However, cardiac ECHO may be used in a supportive role in the diagnostic evaluation and for risk stratification. Several echocardiographic parameters should be assessed in the setting of presumed or confirmed PE including RV size, RV function, presence of RV thrombus, presence of McConnell's sign (midfree wall akinesis but normal apical motion), and estimation of pulmonary artery pressures measured from tricuspid regurgitant jet velocity. RV dilation and dysfunction are associated with poor outcomes in PE accompanied by either normotension or hypotension. In 2005, Gibson et al (Gibson 2005) reported that RV dysfunction occurs in 30-40% of all normotensive patients with acute PE and is a positive predictor for short-term mortality (5%). This finding was also supported by Kucher et al (Kucher 2005) in 2005 who found decreased 30 day survival in patients with RV dysfunction in the setting of normotension (univariate hazard ratio of RV hypokinesis for predicting 30-day mortality of 2.11 (95% CI, 1.41-3.16; P<.001). In the setting of hypotension, RV dysfunction is a strong marker of poor outcome. In a retrospective assessment of 180 patients with acute PE, 70 were found to be hemodynamically stable without RV dysfunction, 74 hemodynamically stable with RV dysfunction and 36 hemodynamically unstable with RV dysfunction. The patients with hemodynamic instability and RV dysfunction had the highest mortality (27.8%, p < 0.05) and PE related deaths (16.7%, p <0.05) (Yoo 2012). McConnell's sign is a distinct pattern of regional RV dysfunction that may be seen in the setting of acute PE. McConnell's sign is characterized by akinesis of the mid-free wall but normal motion at the apex and is 77% sensitive and 94% specific for the diagnosis of acute PE with a positive predictive value of 71% and a negative predictive value of 96% (McConnell 1996).

**13. Biomarkers**

D-dimer, troponin I, troponin T, brain natruretic peptide (BNP) are commonly available biomarkers that are used to evaluate patients with PE. A recent meta-analysis evaluating Ddimer elevation and PE revealed that elevations greater than a defined threshold were associated with significantly increased short-term (3 months) mortality and the degree of pulmonary artery obstruction (Becattini 2012). Elevation in the cardiac biomarker, troponin I, when used in combination with CTPA predicts echocardiographically proven RV dysfunction associated with PE (Meyer 2012). Elevated high-sensitivity troponin T (hsTnT) has also been shown to be associated with poor outcomes in acute PE. hsTnT > 14 pg/ml is a predictor of early death and complications of venous thromboembolic disease. Furthermore, hsTnT, < 14 pg/ml is associated with a low risk of mortality in individuals with PE (Lankeit 2011). Various brain natruretic peptide assays are available for routine use to assess dyspnea. In a multicenter study including 570 patients with acute PE, ProBNP, BNP, and NT-proBNP values were significantly increased in patients with adverse outcomes after acute pulmonary embolism. However, the prognostic performance of proBNP for predicting adverse outcomes was lower

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Optimal management of the dyspneic patient includes rapid assessment for etiologies including PE. Complete history, physical examination and use of clinical prediction rules (CPRs) are essential to the initial evaluation. If the index of suspicion for PE is significant, radiologic imaging with CTPA or V/Q is often employed. If these noninvasive tests are inconclusive, pulmonary angiography is occasionally necessary to obtain a definitive diagno‐ sis. Once PE is confirmed, additional risk assessment with hemodynamic assessment, echo‐ cardiography, CT determination of RV configuration, ECG, and biomarkers should be performed (Tapson 2008, Tapson 2012). Individual patient characteristics, level of hemody‐ namic compromise, and risk assessment should be used to determine optimal management. The 2011 Scientific Statement from the American Heart Association defined acute pulmonary thromboembolism as massive, sub-massive or low risk PE using these criteria: 1. Massive PE: Acute PE with sustained hypotension defined as a systolic blood pressure < 90 mmHg for at least 15 minutes or requiring inotropic support without other etiology; 2. Sub-massive PE: Acute PE without systemic hypotension but at risk of poor outcome based on evidence of either RV dysfunction or myocardial necrosis; 3. Low risk PE: Acute PE without the clinical markers defined in massive or submassive PE that portend a poor prognosis (Jaff 2011). (Table 4)

than that of the other natriuretic peptides (Verschuren 2013).

**14. Management of acute pulmonary embolism**

#### **12.3. Computed tomography pulmonary angiography (CTPA)**

CTPA is a sensitive and specific diagnostic tool for PE (Huisman 2013). More recently, it has also been deemed an important study to assess thrombus burden and functions as a valuable indicator of RV decompensation. Thrombus burden can be assessed utilizing a modified Miller score (MMS) in which thrombus load is evaluated by the number of occluded segmental pulmonary arteries (9 on the right, 7 on the left) (Bankier 1997). In a retrospective analysis of 504 consecutive CTPA proven PE, higher MMS correlated with greater right ventricular (RV) to left ventricular (LV) ratio (RV:LV) indicating RV strain (Wong 2012). Furthermore, CTPA findings of high thrombus burden and RV strain are associated with increased PE mortality. In 81 consecutive patients with CTPA proven PE, RV:LV ratio, the shape of the interventricular septum, and the obstruction index were shown to be significant predictors of mortality (p < 0.001, p = 0.04, p < 0.001 respectively). The negative predictive value for mortality with an RV:LV ratio < or = 1.0 and the obstruction index of < 40% were 100% (Chaosuwannakit 2012).

### **13. Biomarkers**

**12.2. Cardiac echocardiography**

128 Pulmonary Hypertension

Cardiac echocardiography (ECHO) is a useful tool in evaluation of a patient presenting with dyspnea and/or chest pain. Cardiac ECHO should not be used in the evaluation to confirm the diagnosis of acute PE as only 30-40% of all acute pulmonary thromboembolic events are associated with echocardiographic abnormalities (Gibson 2005). However, cardiac ECHO may be used in a supportive role in the diagnostic evaluation and for risk stratification. Several echocardiographic parameters should be assessed in the setting of presumed or confirmed PE including RV size, RV function, presence of RV thrombus, presence of McConnell's sign (midfree wall akinesis but normal apical motion), and estimation of pulmonary artery pressures measured from tricuspid regurgitant jet velocity. RV dilation and dysfunction are associated with poor outcomes in PE accompanied by either normotension or hypotension. In 2005, Gibson et al (Gibson 2005) reported that RV dysfunction occurs in 30-40% of all normotensive patients with acute PE and is a positive predictor for short-term mortality (5%). This finding was also supported by Kucher et al (Kucher 2005) in 2005 who found decreased 30 day survival in patients with RV dysfunction in the setting of normotension (univariate hazard ratio of RV hypokinesis for predicting 30-day mortality of 2.11 (95% CI, 1.41-3.16; P<.001). In the setting of hypotension, RV dysfunction is a strong marker of poor outcome. In a retrospective assessment of 180 patients with acute PE, 70 were found to be hemodynamically stable without RV dysfunction, 74 hemodynamically stable with RV dysfunction and 36 hemodynamically unstable with RV dysfunction. The patients with hemodynamic instability and RV dysfunction had the highest mortality (27.8%, p < 0.05) and PE related deaths (16.7%, p <0.05) (Yoo 2012). McConnell's sign is a distinct pattern of regional RV dysfunction that may be seen in the setting of acute PE. McConnell's sign is characterized by akinesis of the mid-free wall but normal motion at the apex and is 77% sensitive and 94% specific for the diagnosis of acute PE with a positive predictive value of 71% and a negative predictive value of 96% (McConnell 1996).

**12.3. Computed tomography pulmonary angiography (CTPA)**

CTPA is a sensitive and specific diagnostic tool for PE (Huisman 2013). More recently, it has also been deemed an important study to assess thrombus burden and functions as a valuable indicator of RV decompensation. Thrombus burden can be assessed utilizing a modified Miller score (MMS) in which thrombus load is evaluated by the number of occluded segmental pulmonary arteries (9 on the right, 7 on the left) (Bankier 1997). In a retrospective analysis of 504 consecutive CTPA proven PE, higher MMS correlated with greater right ventricular (RV) to left ventricular (LV) ratio (RV:LV) indicating RV strain (Wong 2012). Furthermore, CTPA findings of high thrombus burden and RV strain are associated with increased PE mortality. In 81 consecutive patients with CTPA proven PE, RV:LV ratio, the shape of the interventricular septum, and the obstruction index were shown to be significant predictors of mortality (p < 0.001, p = 0.04, p < 0.001 respectively). The negative predictive value for mortality with an RV:LV ratio < or = 1.0 and the obstruction index of < 40% were 100% (Chaosuwannakit 2012).

D-dimer, troponin I, troponin T, brain natruretic peptide (BNP) are commonly available biomarkers that are used to evaluate patients with PE. A recent meta-analysis evaluating Ddimer elevation and PE revealed that elevations greater than a defined threshold were associated with significantly increased short-term (3 months) mortality and the degree of pulmonary artery obstruction (Becattini 2012). Elevation in the cardiac biomarker, troponin I, when used in combination with CTPA predicts echocardiographically proven RV dysfunction associated with PE (Meyer 2012). Elevated high-sensitivity troponin T (hsTnT) has also been shown to be associated with poor outcomes in acute PE. hsTnT > 14 pg/ml is a predictor of early death and complications of venous thromboembolic disease. Furthermore, hsTnT, < 14 pg/ml is associated with a low risk of mortality in individuals with PE (Lankeit 2011). Various brain natruretic peptide assays are available for routine use to assess dyspnea. In a multicenter study including 570 patients with acute PE, ProBNP, BNP, and NT-proBNP values were significantly increased in patients with adverse outcomes after acute pulmonary embolism. However, the prognostic performance of proBNP for predicting adverse outcomes was lower than that of the other natriuretic peptides (Verschuren 2013).

### **14. Management of acute pulmonary embolism**

Optimal management of the dyspneic patient includes rapid assessment for etiologies including PE. Complete history, physical examination and use of clinical prediction rules (CPRs) are essential to the initial evaluation. If the index of suspicion for PE is significant, radiologic imaging with CTPA or V/Q is often employed. If these noninvasive tests are inconclusive, pulmonary angiography is occasionally necessary to obtain a definitive diagno‐ sis. Once PE is confirmed, additional risk assessment with hemodynamic assessment, echo‐ cardiography, CT determination of RV configuration, ECG, and biomarkers should be performed (Tapson 2008, Tapson 2012). Individual patient characteristics, level of hemody‐ namic compromise, and risk assessment should be used to determine optimal management. The 2011 Scientific Statement from the American Heart Association defined acute pulmonary thromboembolism as massive, sub-massive or low risk PE using these criteria: 1. Massive PE: Acute PE with sustained hypotension defined as a systolic blood pressure < 90 mmHg for at least 15 minutes or requiring inotropic support without other etiology; 2. Sub-massive PE: Acute PE without systemic hypotension but at risk of poor outcome based on evidence of either RV dysfunction or myocardial necrosis; 3. Low risk PE: Acute PE without the clinical markers defined in massive or submassive PE that portend a poor prognosis (Jaff 2011). (Table 4)


(VTE) recommend parenteral anticoagulants or oral factor Xa inhibition with rivaroxaban as the initial therapy for PE. Low-molecular-weight heparin (LMWH) or fondaparinux is endorsed over IV unfractionated heparin or subcutaneous unfractionated heparin. If there are no contraindications to anticoagulation, treatment is recommended for at least 3 months after

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The treatment of submassive PE remains controversial. Patients with submassive PE carry an increased risk of adverse outcomes and early mortality (Piazza 2013); however, there is no clear evidence that thrombolysis in addition to heparin in this subset of patients improves mortality. In 2002, Konstantinides et al (Konstantinides 2002) evaluated 256 patients with submassive PE who were randomly assigned to receive heparin plus alteplase versus heparin plus placebo. Treatment with heparin plus placebo was associated with more frequent clinical deterioration requiring an escalation of treatment (11% versus 25%); however, no change in mortality was detected (Konstantinides 2002). Further study is required to determine appro‐ priate management of this patient population. Currently, comprehensive evaluation weighing risks and benefits of anticoagulation with heparin versus thrombolysis is the usual approach.

The management of massive PE requires a multifaceted approach to resolve pulmonary vascular obstruction, reverse hemodynamic instability, and support respiratory insufficiency (Tapson 2008). Supportive measures often require volume resuscitation, vasopressors, supplemental oxygen, and occasionally mechanical ventilation (Tapson 2012). Current American College of Chest Physicians (ACCP) (Kearon 2012) and American Heart Association (AHA) (Jaff 2011) guidelines support the use of thrombolytic therapy in patients with acute massive PE and no contraindications. A 2004 meta-analysis revealed that thrombolysis significantly reduced recurrent PE and mortality (9.4% versus 19.0%; OR 0.45, 95% CI 0.22 to 0.92; number needed to treat=10) in patients with hemodynamically unstable PE (Wan 2004). There are limited clinical trial data to provide guidance on the best management of massive PE. A small prospective randomized clinical trial evaluating 8 patients with massive PE showed that streptokinase plus heparin improved hemodynamics within the first hour after treatment and survival at 2 years compared with heparin alone (Jerjes-Sanchez 1995). The heparin treated group had 100% mortality 1-3 hours after initial presentation. Autopsy studies in the heparin treated group revealed massive pulmonary emboli with RV infarction and no coronary artery obstruction (Jerjes-Sanchez 1995). Additional studies are required to determine

acute PE with a more prolonged course when indicated (Kearon 2012).

**16. Submassive pulmonary embolism**

**17. Massive pulmonary embolism**

the optimal management of patients with massive PE.

**Table 4.** Definitions of massive, submassive and low risk of pulmonary embolism (based on 2011 American Heart Association Scientific Statement)
