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S u bma s s i ve Pu l mo n ar y

Laurence W. Busse,


Jason S. Vourlekis,


Pulmonary embolism  Submassive  Risk stratification  Thrombolysis 
Intermediate-risk pulmonary embolism  Right ventricular dysfunction
Acute pulmonary embolism (PE) is common and associated with a high degree of
morbidity and mortality. 
PE can present silently or with hemodynamic collapse and cardiac arrest, is difficult to
diagnose, and treatment options depend on accurate and timely risk stratification. 
Severity in PE depends on the amount of clot burden as well as physiologic response to
the clot, and is stratified into low risk, submassive, and massive, with increasing levels of


Acute pulmonary embolism (PE) is part of the spectrum comprising venous thromboembolic disease. In the United States alone there are estimated to be 350,000 to
600,000 cases of venous thromboembolism (VTE) annually with 100,000 to 200,000
related deaths.1,2 PE is associated with a high rate of morbidity and mortality, depending on the clinical presentation and underlying cardiopulmonary status. Mortality
ranges from low in the hemodynamically stable patient to being almost a certainty
in severe cases. In all risk groups, combined in-hospital mortality is estimated at
15%.3 Arguably the single biggest contributor to mortality in PE is failure of diagnosis.4
Long-term morbidity including recurrence, chronic venous insufficiency, and chronic
thromboembolic pulmonary hypertension can occur in up to 12.9%, 7.3%, and 35%
of patients, respectively, at 1 year.5–7
VTE is common in the critical care setting. The frequency depends on the method
of surveillance. Systematic screening for deep vein thrombosis (DVT) by ultrasonography identifies thrombus in as many as 40% of patients.8–10 Patel and colleagues11

Disclosures: The authors have no disclosures to report.
Section of Critical Care Medicine, Department of Medicine, Inova Fairfax Medical Center, 3300
Gallows Road, Falls Church, VA 22042, USA
* Corresponding author.
E-mail address:
Crit Care Clin 30 (2014) 447–473
0749-0704/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.


Busse & Vourlekis

conducted a multicenter, retrospective study of VTE incidence in patients in established intensive care units (ICUs) based on clinical diagnosis. The incidence of DVT
was 1.0% and the incidence of PE was 0.5%, despite most patients having
received pharmacologic prophylaxis. ICU admission is an independent risk factor
for the presence of VTE.12 The economic burden of VTE is considerable, contributing an average additional hospital cost of $8763 per patient (not accounting for
severity of PE) and an attributable length of stay increase of 3 to 4 days.13 PE is
considered preventable and in 2008 the Centers for Medicare and Medicaid Services (CMS) stopped reimbursing hospitals for nosocomial VTE following certain orthopedic procedures. The Federal Agency for Healthcare Quality and Research
adopted postoperative VTE as patient safety indicator, which requires mandatory
reporting of all such events. Given such scrutiny and emphasis, much effort has
been spent on identifying risk factors, educating patients and health care providers,
and putting into place procedures and protocols designed to minimize the occurrence of VTE.
The presentation of PE is complex and variable, and can range from asymptomatic
to fatal. Therefore, much research has gone into the development of clinical decision
tools to aid in the diagnosis of PE. Given the heterogeneity of outcomes, similar attention has been given to the development of risk stratification tools and treatment algorithms that take into account the estimated morbidity and mortality.

PE can be categorized into low-risk, submassive, and massive PE, which correlate
well with increasing levels of mortality and are readily identified with available technology. Massive PE, which accounts for 5% of all PE-related admissions, is characterized
by shock, typically defined as systolic blood pressure less than 90 mm Hg or a reduction of 40 mm Hg in systolic blood pressure from baseline for at least 15 minutes.14
Patients manifest typical signs of organ hypoperfusion including encephalopathy,
oliguria, cold and clammy extremities, or frank cardiac arrest.15,16
Submassive PE denotes the important subset of patients who seem hemodynamically stable, but have evidence of right ventricular strain or dysfunction. Right ventricular dysfunction results from right ventricular pressure overload, and findings
include hypokinesis and dilatation of the right ventricle, flattening and paradoxical
motion of the interventricular septum toward the left ventricle, tricuspid regurgitation,
severe right ventricular free wall hypokinesis and apical sparing (McConnell sign),
loss of respiratory variation in the diameter of the inferior vena cava, and pulmonary
hypertension as identified by a peak tricuspid valve pressure gradient greater than
30 mm Hg or tricuspid regurgitant peak flow velocity greater than 2.5 m/s.17–19 These
findings are supported by varying levels of evidence, and no single finding can predict death. Hence, a combination of findings is routinely used to diagnose right ventricular dysfunction.20,21 Transthoracic echocardiography has long been established
as a valid tool in determining evidence of right ventricular dysfunction, as has
computed tomography (CT) angiography (CTA).19,22 Right ventricular strain is a function of increased wall tension, which results in myocardial cell damage and necrosis.
Myocardial damage can be elucidated by several different criteria, with varying levels
of supporting evidence. Electrocardiographic findings (including complete and
incomplete right bundle branch block and S1Q3T3 pattern) as well as several
biomarkers (troponin, brain natriuretic peptide [BNP] and N-terminal proBNP [NTproBNP], heart-type fatty acid binding protein [H-FABP]) have been studied.
Although right ventricular dysfunction and strain can be identified easily with the

33–0.94 BNP Mortality.61–1.82–84 0.45.75–0. BNP and its analogues.51–0.90 0. major complication.73 0.56.12–0.67 0.25–0.64–0.0 0.68. CTA.41 0.52–0. which is why no dominant approach to diagnosis and risk stratification exists.30–0.37–0.70–1.61 0.Submassive Pulmonary Embolism aforementioned tests.89–0.23–0.58–0.57.55 0.99 CTA Mortality.47–0. major in-hospital complication77.93 complication. ECG.58–0.14 0.99 0. 449 .0 0.86–0.22–0.87 ECG Severe PH from PE.87 BM 1 CTA Mortality.76.05–0.44–0. detection of RVD.41 0.56.0 0. SS. pulmonary perfusion defect 5042.94 0.61–0.64–0.67–0. Patients with submassive PE have an in-hospital mortality of up to 30% compared with low-risk patients with PE who have an estimated in-hospital mortality of only Table 1 Sensitivity.73 — 0. predictive values. These data show that no single test clearly outperforms any other.75–0.72.80 NPV AUC 0.97 0.26–0.82 0. transthoracic echocardiography.76–1.74–0.77. scoring systems.582 Abbreviations: BM. biomarkers (troponin and/or BNP). pulmonary perfusion defect 50%42–44 0.98–0. Table 1 shows the various tests that can be used to identify the presence of right ventricular dysfunction or strain.89–1.11–0.76. major 0. severe PE requiring lysis or embolectomy. there is no gold standard in the diagnosis of submassive PE.58 0.11–0.07–0.129 0. RVD. computed tomography angiography. electrocardiography.81 Mortality.76.70 0.84.92 0. TTE.96 ECG 1 SS 0.0 0. specificity. detection of RVD from PE82–84 0.91 — Pulmonary perfusion defect 50%42 TTE 1 BM Mortality.96 0.57 0.99–1.57. complicated course.38–0.81 H-FABP Mortality.73 0.82.42–0.95 0.79 0.60–0. pulmonary hypertension.58 0.0 0.0 SS Mortality dichotomized between low-risk and high-risk classes. detection of RVD from PE60–64.70 0.1 0. PH. and areas under the curve for the various risk stratification modalities Modality Outcomes Sensitivity Specificity PPV TTE Mortality75.80 0.67.10–0. and the clinician is often left to decide which test or combination of tests is most meaningful. identification of massive PE by Miller index or PH.65–1.28–0.90 0.91 — Troponin 0.82.98 0. major complication56. and hence submassive PE.90 0.72–0. right ventricular dysfunction. detection of RVD from PE54.76.62 — 0.85 0. complicated course.129 0.75 0. detection of RVD from PE51.38 0.44–0.

Approximately 25% occlusion of the pulmonary vasculature is enough to cause an increase in pulmonary arterial pressure and a decrease in arterial oxygen tension. Approximately 20% of calf DVTs migrate to the thighs.14. whether clinically suspected or not. The increase in PVR and ensuing increase in pulmonary artery pressures cause a decrease in right ventricular stroke volume. all of which increase pulmonary vascular resistance (PVR). which is initially compensated by a catecholamine-induced tachycardia.450 Busse & Vourlekis 0. Thus. the degree of clot burden and circulatory occlusion determines the physiologic consequences of a PE.24 Submassive PE may require more aggressive forms of treatment. and only 50% of these embolize to the lungs. and obstruction. 1. and a 35% to 40% occlusion is associated with increased right atrial pressure. Not all DVTs embolize to the pulmonary circulation. accurate and timely risk stratification and treatment are important. Moreover. and right ventricular dilatation.26 A combination of intrinsic and external factors contributes to the initiation and propagation of clot. such as thrombolysis or catheter-directed therapy (CDT).9% (Fig. pulmonary vasoconstriction. . The circulatory failure seen in PE is mediated through a decrease in left ventricular preload. so prompt recognition of the patients with submassive PE can facilitate appropriate treatment and transfer (ie. infarction. the intensivist may need to design and implement proper protocols for the timely and appropriate management of submassive PE.24 Continued increase of right ventricular afterload leads to increased wall stress and oxygen demand on the ventricular tissue and can ultimately lead to ischemia. and endothelial injury.4% to 0. 1).23.27 Once in the lungs. PATHOGENESIS AND PATHOPHYSIOLOGY Most pulmonary emboli start out as lower extremity or pelvic DVTs. A subgroup of patients with right ventricle (RV) dysfunction are deemed submassive. because the complex landscape can be difficult to navigate if a patient decompensates and is on the verge of cardiovascular collapse. and can have mortality in excess of 30%. The presence of shock indicates massive PE. 83% had clots in the lower extremity venous circulation. hypercoagulability. which is highlighted by the classic Virchow triad of circulatory stasis.25 In a large autopsy series of patients with known PE. the ICU) for monitoring. Estimated mortality for PE. indexed by severity.28 PE initiates a cascade of increasing hypoxemia. which is the direct result Fig.

tachycardia.30–34 Once the diagnosis is made. and increased physiologic dead space. echocardiography.24 Most patients present with clinical evidence of alveolar hyperventilation manifested by tachypnea and a low arterial carbon dioxide tension. biomarkers. including clinical decision tools. and seizure. submassive. and ventilation-perfusion scintigraphy. tachycardia may be the only sign of right ventricular strain. RISK STRATIFICATION The diagnosis of PE can be complex and challenging and the reader is referred to several excellent resources in the literature. The presence of hypercapnia may signify a particularly large PE or limited ventilatory reserve. PE. right-to-left shunt. efforts should be undertaken to risk stratify PE into low-risk. acute pulmonary embolism. CTA. such as dyspnea. pleurisy. electrocardiography (ECG). encephalopathy.20 In submassive PE. RV. reduced venous oxygen content. and is a poor prognostic sign. The pathophysiology of massive and submassive PE. PVR. Signs and symptoms of PE.Submassive Pulmonary Embolism Fig. are nonspecific and of little assistance in risk stratification.34. hypoxia. or massive categories. 451 . and these are discussed later.3. pulmonary vascular resistance.29 Concomitant systemic hypoxemia and hypocapnia exist as a result of the ventilation-perfusion mismatch. LV.35 There are several tools available to assist in quantifying the amount of clot burden and corresponding risk of mortality and morbidity. of pulmonary outflow obstruction from clot burden and a reduced left ventricular compliance from shifting of the interventricular septum into the left ventricular cavity (Fig. 2). left ventricle. 2. right ventricle.

44 Jimenez and colleagues45 examined the PESI score along with troponin in 318 hemodynamically stable patients with PE.43 Table 2 shows the originally derived independent risk factors for mortality in the PESI score. and the Geneva score was an independent predictor of mortality in multivariate analysis. The PESI was derived via regression analysis of 11 known patient characteristics that were independently associated with adverse outcome or death.39 These scoring systems have been evaluated against each other. A higher PESI score correlated with the presence of right ventricular dysfunction. Bova and colleagues41 evaluated several prognostic markers in 201 normotensive patients with known PE.0% and 24.31.6% in class I to between 10. and the study was not designed to test the PESI score a priori as an identifier of submassive PE. The PESI score was further examined in a series of 89 patients with nonmassive PE and it predicted mortality when patients were classified according to PESI classification. biomarker analysis. and perform equally well. Hypoxemia. other scoring systems. a higher PESI score correlated with the presence of increased troponin. some efforts have been made to evaluate these clinical decision rules in risk stratification of PE. and the incidence of recurrence. is used to calculate the probability of PE as low. and inotropic support. or high based on several risk factors combined with clinical signs and symptoms.5% in class V. these clinical decision rules were developed and validated in the assessment of the probability of PE. in patients with PE.37 The Wells score likewise evaluates the presence of PE based on pretest probability and a combination of objective (physical examination) and subjective criteria. sepsis. and the need for resuscitation. and the Geneva score. These results suggest that the PESI score has value in identifying the submassive group. the Wells score was evaluated in conjunction with ECG and was nonpredictive of anatomic severity of PE in a retrospective evaluation of patients. The 2002 MAPPET 2 (Management Strategy and Prognosis of Pulmonary Embolism Trial) study showed that high troponin levels correlated with increased in-hospital mortality. and has been shown to be increased in patients with submassive or massive PE. including echocardiography.38.47–49 In addition. both troponin I and troponin T levels correlate well with right ventricular overload and dilatation. Several studies have found that. with mortality ranging from 0% to 1.36.50 Most importantly. Nonetheless.42 One objective index that may be used in risk stratification is the Pulmonary Embolism Severity Index (PESI). Patients are stratified into a risk category based on the PESI score. blood gas. PE-related complications.452 Busse & Vourlekis CLINICAL DECISION TOOLS The Geneva score. Both troponin I and troponin T have been studied in this population and perform similarly. However. In contrast. troponin. mechanical ventilation. intermediate. as originally described in 2001 and simplified in 2008. not the severity of PE.40 However.46 BIOMARKERS Troponin Troponin is a sensitive and specific marker for myocardial injury. cardiogenic shock. troponin has been shown to be an independent predictor of mortality. In fatal events. and clinical gestalt in several studies. PESI has been evaluated in risk stratification. and the PESI score was associated with death. and brain injury). increased troponin in the setting of PE is associated with prolonged hypotension. this analysis included both the submassive and low-risk group.51 A more recent 2007 meta-analysis of 1985 patients from 20 studies concluded . myocarditis. so increased troponin must be interpreted with caution. and the Geneva score predicted in-hospital mortality. However. many other disease processes can present with increased troponins (such as myocardial infarction.

lethargy. A separate systematic review analyzed BNP in a subgroup of patients with acute submassive PE based on echocardiographic assessment and also found an increased odds ratio of 7.2% to 7. class III (intermediate risk). 106 to 125 points. urine output. or coma.51 BNP and NT-proBNP BNP (and the analogue NT-proBNP.53 Like troponin.52 Increased troponin was also able to identify normotensive patients with VTE who were at higher risk of dying. hereafter referred to as BNP) is a neuroprotein that is synthesized and secreted by the myocardium in response to ventricular strain.52 Troponin can be normal in patients with low-risk pulmonary emboli. mortality 4.57). and blood plasma volume. Coutance and colleagues54 found that increased BNP was associated with a higher short-term risk of death (odds ratio. or serious complication attributed to PE. mortality 10.55 453 . stupor. BNP is a nonspecific marker of cardiac injury and its specificity in the diagnosis of PE is limited. respectively. class IV (high risk). class II (low risk). fewer than 65 points. b With or without supplemental oxygen. Stone RA. The PESI may aid the clinician in risk stratifying in submassive PE Prognostic Variables Points Assigned Demographics Age (y) Age Male sex 110 Comorbid Conditions Cancer 130 Heart failure 110 Chronic lung disease 110 Critical Findings Pulse 110 beats per min 120 Systolic blood pressure <100 mm Hg 130 Respiratory rate 30 breaths per min 120 Temperature <36 C 120 Altered mental statusa 160 Arterial oxygen saturation <90%b 120 Total point score obtained by summing the patient’s age with the points given for each applicable prognostic variable.0% to 11.172(8):1041–6. which stratifies patients into increasing levels of mortality. more than 125 points. Risk based on total point score and predicted mortality: class I (very low risk).24. BNP is associated with a higher risk of all-cause mortality. with an odds ratio of 5. death. 86 to 105 points. mortality 0% to 1.6%. et al.4%. a Disorientation.1%. and has been studied as a predictor of survival with a negative predictive value of 92%. class V (very high risk). Adapted from Aujesky D. 66 to 85 points. Moreover. 6. with a sensitivity and specificity to predict death of 93% and 48%.Submassive Pulmonary Embolism Table 2 The PESI score. Am J Respir Crit Care Med 2005.0% to 24. mortality 1.7% to 3. BNP has greater use in risk stratification in established PE. Derivation and validation of a prognostic model for pulmonary embolism. mortality 3. In their comprehensive review.5%. than increased troponin was associated with a higher risk of short-term mortality.90. low BNP had a negative predictive value of 99% in excluding adverse outcome. with an odds ratio for mortality of 5. BNP acts to regulate blood pressure by manipulation of systemic vascular resistance. Obrosky DS.5%.63 for in-hospital mortality.

Measurement of right ventricular dilatation via CTA. but there is no standardized value.9 to as high as 1. It is a small cytoplasmic protein that is present in tissues with active fatty acid metabolism. and positive predictive value for diagnosing right ventricular overload of 92%.32(13):1658. Agnelli G. (From Becattini C. Much like troponin and BNP. specificity. essentially replacing pulmonary angiography. abnormal H-FABP has been associated with a complicated hospital course. Multidetector computed tomography for acute pulmonary embolism: diagnosis and risk stratification in a single test. H-FABP also has been shown to be a valuable prognosticator of adverse outcome. Its low cost and 24-hour availability make it an ideal screening and diagnostic test. In a 2005 systematic review of 15 studies. et al. with a positive predictive value of 92% to 96%. Ventricular diameters are measured as the maximal distance between the ventricular endocardium and the intraventricular septum. With regard to risk stratification. a negative CTA was able to predict the absence of acute PE. 80%.57 Despite these data. Increasing sensitivity. specificity. Eur Heart J 2011.56 In submassive PE.6 have also been proposed (Fig. CTA showed a sensitivity and specificity of 83% and 96%.454 Busse & Vourlekis H-FABP H-FABP is a novel biomarker that has recently been evaluated as an early prognosticator of poor outcomes in acute PE. Vedovati MC.59 CTA may also elucidate alternative diagnoses.0 was representative of right ventricular dilatation.58 In the more recent PIOPED II (Prospective Investigation of Pulmonary Embolism Diagnosis II) study. respectively.) . and ratios of 0. depending on pretest probability. CTA can show right ventricular overload in submassive and massive PE via the measurement of the size of the right ventricle in a cross-sectional picture. negative predictive value. 3. 44%. respectively. and prognostic value have paralleled technological advances in radiographic methods.1%.4 A ratio of right ventricle/left ventricle (RV/LV) size ratio of more than 1. perpendicular to the long axis of the heart. with permission. CTA has been found to have a sensitivity. H-FABP is not routinely used in most institutions as a diagnostic tool or for risk stratification. and 67%. H-FABP was able to outperform troponin and BNP in prognosticating outcome in acute PE. with a negative predictive value of 99. and is released into the circulation (within 90 minutes) during myocardial injury.60–63 Fig. such as myocardium. 3). CTA CTA has emerged in the last decade as the gold standard in the diagnosis of PE.

0. ECHOCARDIOGRAPHY Transthoracic echocardiography (TTE) has a dual role in PE both as a diagnostic study and as a risk stratification tool.68 ECG has been extensively analyzed in risk stratification of PE. a Q wave in lead III. ECG patterns were abnormal in 78% and 94% respectively and neither atrial flutter nor fibrillation was detected in any patient. whereas distal embolization was associated with benign outcome (hazard ratio. and right ventricular enlargement and increased RV/LV ratio on CTA correlate with increased mortality and clinical deterioration. and an inverted T wave in lead III). Other findings on ECG.64 In a recent analysis of 457 patients with acute PE. evidence of right ventricular dilatation.72 ECG scoring systems have been shown to be predictors of right ventricular overload or death. Central (as opposed to lobar or distal) embolization was associated with death or clinical deterioration (hazard ratio. tricuspid 455 .67 who compared perfusion defect volume (PDvol) with CTA-obstruction scores.3). direct visualization of clot is rare and is only seen with very large main pulmonary arteries or intracardiac thrombus. limiting their use. T-wave inversions in the precordial leads have been shown to be predictive of the severity of PE. and adverse events (ICU admission or death). the absence of right ventricular dysfunction on CTA had a negative predictive value for death of 100%. with variable results. such as an S1Q3T3 pattern (an S wave in lead I.61. pulmonary artery diameter. ECG was compared with biomarkers in the detection of right ventricular dysfunction in a retrospective study of 48 patients with acute PE.74 However.68 In a review of 90 patients with submassive or massive PE.Submassive Pulmonary Embolism CTA in risk stratification has been validated in several studies. ECG also outperformed the biomarkers in diagnostic accuracy.70 However. which is neither sensitive nor specific. The prognostic value of CTA-calculated volumetric assessment of clot burden was examined by Apfaltrer and colleagues. and was highly sensitive and specific (75% and 95%). 8. and D-dimer and found them to be highly correlated. valvular disease. and right bundle branch block are less common. and measurement of pulmonary artery systolic pressure via regurgitant flow across the tricuspid valve. Patients with adverse events were more likely to have higher PDvol.71 More recently. and higher CTA-obstruction scores. possible right-to-left shunt via patent foramen ovale. TTE is primarily used in the evaluation of right and left ventricular function. The most common ECG pattern in PE is sinus tachycardia.12). these scoring systems are usually complicated and difficult to recall. but equally insensitive and nonspecific.69.64 CTA-elucidated clot burden was also studied in 516 patients with submassive PE. In PE. Some analyses of ECG tracings in cases of non–risk-stratified pulmonary emboli showed virtually no correlation with hemodynamic compromise.20 Most evidence for diagnosis is indirect (right ventricular dilatation or hypokinesis. ECG is used adjunctively in risk stratification as supporting evidence of right ventricular dysfunction in submassive PE and to evaluate for alternative diagnoses.73. ECG Electrocardiographic abnormalities during PE arise from changes in the impedance of the myocardium and vector of electrical currents through the heart caused by anatomic and functional changes. At present. CTA-elucidated right ventricular dilatation. right precordial T-wave inversions. in patients with known massive PE.65 Okada and colleagues66 used three-dimensionally reconstructed images of 64-section dual-energy CT to compare volumetric assessment of clot burden with pulmonary artery pressure.

82–84 Current guidelines recommend that efforts be made to identify patients with submassive PE. Other studies have evaluated TTE as a predictor of death from PE with similarly equivocal results. in the presence of clinical evidence of instability and failure to improve on anticoagulant therapy. no appreciable benefit was gained when TTE and biomarkers were combined. The role of TTE in risk stratification has been extensively studied in the subset of patients in whom submassive PE is suspected. NT-proBNP. but the decision of thrombolytic therapy should not be made on this determination alone.5. in whom more aggressive treatment (ie.85. and can be performed either by a trained echocardiographer or the clinician (using a point-of-care ultrasound device). compared with CTA-identified right ventricular dysfunction or biomarker-identified right ventricular strain. identifying and differentiating the hemodynamically stable patient with subclinical evidence of right ventricular overload from the hemodynamically stable patient without right ventricular overload) remains an important aspect of management. respectively). ECG. In a population of non–risk-stratified patients with PE. the unadjusted mortality risk ratio of right ventricular dysfunction was 2. Tulevski and colleagues81 were able to show that the combination of increased troponin and BNP in normotensive patients predicted death. Binder and colleagues77 compared TTE with cardiac biomarkers as a means for predicting death from PE. and troponin (with sensitivity and specificity of 81%–93% and 58%–84%. which did not predict adverse outcome.77 CTA in combination with either increased troponin or BNP has been shown to predict right ventricular dilatation better than either CTA or biomarker tests alone and.456 Busse & Vourlekis regurgitation. right ventricular dysfunction as seen on biomarker. TTE was moderately accurate in predicting mortality in the setting of right ventricular dysfunction. The ACCP recommends that tests of right ventricular overload . An analysis of more than 1000 normotensive patients from the International Cooperative Pulmonary Embolism Registry (ICOPER) registry with TTE found that right ventricular hypokinesis was an independent predictor of 30-day mortality. thrombolysis) may be beneficial.75 A 2008 meta-analysis of hemodynamically stable patients examined the prognostic value of TTE-identified right ventricular dysfunction in predicting death. risk stratification (ie.78–80 RISK STRATIFICATION STRATEGIES AND GUIDELINES Because of the mortality implications associated with submassive PE. respectively). respectively. The prognostic value of TTE exceeded that of CTA (with sensitivity and specificity of 65% and 56%. echocardiography. In the 5 studies evaluating TTE. Furthermore. and right ventricular dysfunction on echocardiogram was associated with a 12-fold increased risk of adverse outcome from PE compared with increased BNP. or CT should inform the overall clinical assessment. and that discordant biomarkers (increased BNP and normal troponin) correlated poorly with mortality. more importantly. can predict death and adverse outcome. or paradoxic septal movement) and is largely caused by the presence of right ventricular strain seen in submassive or massive PE. but was inferior to the biomarkers BNP. and clinicians are left to decide which test or combination of tests is best. Hence TTE is most valuable as a tool for risk stratification.86 According to current American College of Chest Physicians (ACCP) guidelines.04 ng/mL) or BNP (1000 pg/mL) with TTE evidence of right ventricular dysfunction was able to identify those with a higher risk of death or major adverse event.76 In contrast. there is no single recommended strategy for this. Numerous efforts have been undertaken to improve the yield on risk stratification by combining biomarkers and radiology. an algorithm combining the presence of increased troponin (0. However. with a sensitivity and specificity of 70% and 57%.

such as underlying comorbidities and propensity of recurrence.Submassive Pulmonary Embolism not be routinely measured. with no required coagulation profile monitoring. ECG. TREATMENT Treatment of PE focuses on 3 major efforts: supportive care. increased biomarkers. level B). or an increased PESI score.85 The American College of Emergency Physicians (ACEP) endorses the use of the PESI as a way to risk stratify patients in the submassive group.40 According to American Heart Association (AHA) guidelines. However. The same argument can be made for biomarkers and right ventricular strain. ECG.89 LMWH is an alternative to heparin and has the added benefit of being dosed by weight once or twice per day. including right ventricular enlargement on CTA. LMWH has been compared with unfractionated heparin in 2 studies of more than 1600 patients with VTE as well as a meta-analysis and it showed no differences in major thromboembolic events or major bleeding. the authors recommend TTE as a confirmatory test.15. Because CTA is typically completed as part of the initial diagnostic work-up. which typically presents with chest pain and shortness of breath. CTA. If any of the aforementioned tests indicate right ventricular dysfunction or strain. and is discussed later. but stops short of committing to treatment decisions based on this analysis. low-molecularweight heparin (LMWH). Anticoagulation The mainstay of treatment of PE is anticoagulation.87 The European Society of Cardiology (ESC) recommends risk stratification of non–high-risk (submassive or low-risk) patents via the use of clinical decision rules. BNP. and hybrid studies (combined tools) may all be used in identifying right ventricular dysfunction. prevention of subsequent clot formation. Confirmation of right ventricular dysfunction on TTE indicates submassive PE and the corresponding treatment algorithm (Fig. In the acute setting. this finding does not always correlate with outcome (see Table 1). imaging. the clinician should seek to identify high-risk features. Only 1 randomized trial comparing unfractionated heparin with placebo was performed in 1960. this is typically accomplished with intravenous heparin administered continuously. this study is usually readily available. such as warfarin or rivaroxaban. However. biomarkers. 5).90–92 Fondaparinux. echocardiography. a newer parenteral synthetic antithrombotic agent with specific anti–factor Xa activity. and ECG are also usually part of the initial diagnostic evaluation of PE. or ECG. or biochemical markers.20. Initiation with an oral anticoagulant. and the reversal of obstructive shock. troponin. Treatment pathways of low-risk PE and massive PE are well defined. CTA. but stops short of endorsing one method rather than another (class IIa. PESI calculation is an easy noninvasive test and should be completed for all confirmed cases of PE. and are discussed elsewhere. clinical scores. Moreover. In the authors’ opinion. the authors propose an algorithm for risk stratification in Fig.86 Some risk stratification algorithms that have been proposed and can be found in the literature. is begun soon thereafter. When PE is diagnosed and shock is absent (indicating low-risk or submassive PE). recurrent 457 . performed similarly to unfractionated heparin with respect to mortality. treatment of submassive PE is not as clear-cut.88 The evidence and guidelines show that no gold standard has emerged for risk stratification in PE. 4. or fondaparinux. The duration of therapy depends on clinical factors. but clinical judgment is required to determine which method is appropriate for the individual patient. and was stopped early when a dramatic reduction in adverse outcome was seen in the heparin group. Although right ventricular dysfunction can easily be identified using TTE.

and bleeding complications in a large. thrombotic events. pulmonary embolism severity index. rivaroxaban. which recently received a US Food and Drug Administration (FDA) indication for DVT and PE. and apixaban) are appealing compared with unfractionated heparin and LMWH in their route of administration and lack of monitoring. 4. PESI. Dabigatran. acute pulmonary embolism. . PE. open-label randomized trial of hemodynamically stable patients. Proposed algorithm for risk stratification of PE. TTE.458 Busse & Vourlekis Fig. transthoracic echocardiography.93 The newer oral anticoagulants (dabigatran.

if there is a possibility of thrombolysis. catheter-directed therapy.87 To date. interventional radiology. inferior vena cava. Proposed algorithm for treatment of submassive PE.96 The use of LMWH and fondaparinux and the novel oral anticoagulant rivaroxaban in submassive PE is controversial. and it was equally effective in preventing recurrence with a similar bleeding risk. was noninferior to the conventional therapy (LMWH and warfarin) for recurrence of thromboembolic disease or death and was superior in bleeding risk. IR. apixaban. 5. which is also under review by the FDA for a venous thromboembolism indication. 459 . CDT.Submassive Pulmonary Embolism Fig.94 Rivaroxaban versus enoxaparin and warfarin was studied in a noninferiority trial of more than 4800 patients and was as efficacious as the standard therapy in preventing symptomatic recurrence with a similar bleeding risk. and most clinicians agree that. no studies have compared the various anticoagulants specifically in the setting of submassive PE. IVC. has been compared with warfarin in a noninferiority trial of more than 2500 patients with acute PE.95 In the recently published AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) study.

patients with massive PE experienced a dramatic reduction in recurrent PE and mortality (9. but takes no stance on this in patients with submassive PE. mortality and major bleeding differences were eliminated. as well as reduced clinical end points at a 6-month interval. Thrombolytics activate plasminogen to plasmin.85–87. Konstantinides and colleagues105 randomized patients with submassive PE to either heparin alone or alteplase plus heparin.97 Subclinical right ventricular dysfunction in a normotensive patient (submassive PE) is associated with higher mortality.99. and the choice of thrombolytic agent is usually institution specific and beyond the scope of this article. current ACCP.98). which may be mitigated with a more aggressive treatment approach.97 .97. However. and found significantly improved right ventricular size and function. level A). 1.98 The ESC recommends unfractionated heparin for patients with massive PE in whom thrombolysis may be used (class I. after 1 week the reduction in vascular obstruction and ventricular dilatation achieved with tPA is no different from that achieved with heparin alone. urokinase. Early studies showed increased mortality in a group of patients with submassive PE treated with thrombolytics. AHA. They have been shown in several trials to reduce clot burden and improve hemodynamics.104 In contrast. because it does not recommend thrombolysis in this group. Unfractionated heparin is the only anticoagulant that has been studied in conjunction with thrombolytic therapy. A 2004 meta-analysis compared mortality and bleeding in 748 non–risk-stratified patients with PE who received thrombolysis versus anticoagulation. Becattini and colleagues106 randomized 58 hemodynamically stable patients with PE and right ventricular dysfunction to single-dose bolus tenectaplase versus placebo and noted a higher rate of resolution of right ventricular dilatation in the thrombolytic group (30% vs 10%). and the combined end point of death or clinical deterioration was significantly higher in the heparin alone group.99–101 However.40. AHA class IIb level C.86 Thrombolysis Thrombolysis of PE is accomplished via intravenous administration of the thrombolytic agent alteplase (recombinant tissue plasminogen activator [tPA]). respectively).103 Given the high morbidity and mortality of hemodynamically unstable patients with PE. most authorities recommend the use of thrombolytics. but there was a significant increase in nonmajor bleeding. ESC class IIb level B). only alteplase has an FDA indication for use in submassive and massive PE. Because of the risk of major adverse events. such as thrombolysis. In the United States. and no fatal or cerebral bleeding occurred in the thrombolytic group. when all patients (massive and nonmassive) were included.102 Clinical outcomes after thrombolysis have also been extensively studied in numerous randomized trials. and ESC guidelines indicate that thrombolysis may be used in hemodynamically stable patients in certain situations when the risk of bleeding is low and the potential for decompensation is high (ACCP grade 2C. In this study.85 The AHA recommends the use of heparin for submassive PE.107 Based on these and prior results.87 The British Thoracic Society (BTS) and the ACCP both recommend that unfractionated heparin be used preferentially rather than LMWH when rapid reversal of effect may be needed (grade C and not rated.85–87 The BTS and ACEP recommend against thrombolysis in nonmassive PE situations (grade B and level B.4% vs 19%) but also a 2-fold greater risk of major bleeding (odds ratio. reteplase. Another study randomized 72 hemodynamically stable patients with PE with TTE-proven right ventricular dysfunction to tenectaplase plus heparin versus heparin alone. and tenecteplase. use of thrombolysis in submassive PE is controversial. respectively).40. resulting in the accelerated lysis of thrombi. Alternatives to tPA include streptokinase.460 Busse & Vourlekis it may be prudent to use short-acting unfractionated heparin.

neurosurgery). with clot removed mechanically under direct visualization. mortality and morbidity benefits were only seen in the younger group.003) were more common in the thrombolysis arm. with the primary endpoint being a composite of death from any cause or hemodynamic decompensation within 7 days of randomization.002).88 ICU monitoring is important and clinicians must be vigilant in surveying for complications that warrant prompt reversal of coagulopathy or emergent consultation (eg. Embolectomy has never Table 3 Absolute and relative contraindications to thrombolytic therapy Absolute Contraindications Relative Contraindications Major trauma within 3 wk Cancer at more than the age of 75 y Major surgery within 3 wk TIA within 6 mo Major head trauma within 3 wk Oral anticoagulation therapy Prior hemorrhagic CVA Noncompressible punctures Ischemic CVA within 6 mo Traumatic resuscitation CNS neoplasm Refractory hypertension GI bleeding within 1 mo Advanced liver disease Active bleeding Infective endocarditis Active peptic ulcer Pregnancy Postpartum state within 1 wk Abbreviations: CNS.001) and hemorrhagic strokes (P 5 .42). There was no difference in all-cause mortality at 7 days (P 5 .6%) in the thrombolytic arm compared with 28 patients (5. hemodynamic decompensation (or collapse). Patients are placed on cardiopulmonary bypass and a median sternotomy is required for access to the heart and central vessels. patients in the thrombolysis arm experienced less hypotension and need for catecholamine vasopressors (P 5 . Surgical Embolectomy Surgical embolectomy is usually reserved for patients with massive PE who have contraindications to thrombolytics. placebo-controlled Pulmonary Embolism Thrombolysis (PEITHO) trial evaluating the use of thrombolytics in submassive PE was recently published.108 The primary endpoint occurred in 13 patients (2. right heart thrombus. CVA.Submassive Pulmonary Embolism The large prospective. gastrointestinal. or a clot in transit. bleeding. multicenter. One thousand and five normotensive patients with intermediate-risk PE (characterized by the presence of right ventricular dysfunction and myocardial injury) were randomized to thrombolysis or placebo with end points of death. and are listed in Table 3. when stratified by age older than 75 years versus 75 years or younger. Nonintracranial major bleeding (P<. alternatives to this therapy exist. central nervous system. cardiovascular accident. paradoxic embolism.6%) in the placebo arm (P 5 . In addition. TIA. Absolute and relative contraindications are mainly related to bleeding risk. and are discussed later. stroke. and informed consent is required in many settings. GI. Thrombolysis must be given with caution. Other trials of thrombolysis have reported intracranial hemorrhage in up to 3% of patients and major bleeding in up to 20%. However. Because of the high risks associated with thrombolysis.42 or at 30 days (P 5 . randomized. and serious adverse events.02). transient ischemic attack. 461 . recurrent pulmonary embolism. failed thrombolytic therapy.

109 Embolectomy compared favorably with repeated thrombolysis with regard to hospital course in a series of 488 patients who failed original thrombolysis (with no statistically significant difference in mortality).112 Another series of 29 patients with submassive PE calculated an 89% survival rate after pulmonary embolectomy. but 77% (10 of 13) survived embolectomy. There were significant differences among the groups. primarily as a result of improved surgical technique and a shift toward a healthier patient population. In addition.85–87 Inferior Vena Cava Filter Inferior vena cava (IVC) filters disrupt the embolization to the lungs of thrombus originating in the deep veins of the lower extremities and pelvis. or 33%). IVC filter may be considered for patients with acute PE and very poor cardiopulmonary reserve (AHA class IIb level C). ESC class IIb level B).85–87. but has decreased over the past 5 decades. controlled trial.20 There are currently no data on the role of IVC filters in submassive PE.97 Outcomes with IVC filters are equivocal.462 Busse & Vourlekis been compared with medical management in a randomized. The AHA recommends that surgical embolectomy only be considered in submassive PE if the patient is deemed to have clinical evidence of adverse prognosis (class IIb level C). respectively). Mortality in pulmonary embolectomy has traditionally been high. Hemorrhage was higher in the medical therapy group and sepsis was higher in the surgical therapy group. whereas the ACCP and ESC recommend pulmonary embolectomy only for patients with massive PE who have contraindications to. In conjunction with thrombolysis. ESC class IIb level B) or if there is a contraindication to anticoagulation (ACCP grade 1B.110 In a case series of patients with PE at a single center.113 Based on similar results. in which a 5% recurrence rate may be expected. including during submassive PE. on weighing the associated prothrombotic effects against the possibility of recurrent or fatal PE. AHA class I level B. but this practice is changing as clinicians gain a better understanding of the mortality implications of subclinical right ventricular failure. and should not be used routinely as an adjunct to anticoagulation or fibrinolysis (AHA class III level C). or 11%) compared with 6 hemodynamically stable patients (submassive PE) who underwent thrombolysis (2 of 6.98.116 There was no observed . Current guidelines regarding embolectomy are discordant. Sukhija and colleagues111 reported a lower mortality in 18 unstable patients (massive PE) who underwent embolectomy (2 of 18. and 67% (16 of 24) survived thrombolysis. Current guidelines call for routine IVC filter use when readily available (BTS grade C). The 2 major indications for IVC filter placement are contraindication to anticoagulation and recurrent DVT formation despite anticoagulation. and placement should be considered on a case-by-case basis.112 Pulmonary embolectomy is indicated in select patients with massive PE and cardiovascular collapse. from more than 50% in the 1960s to 26% in the 1990s to between 10% and 20% currently. but the procedure may regain some of its favor as mortality decreases and patient selection continues to improve. A 2005 series of patients with combined massive (N 5 28) and submassive (N 5 15) PE cited a postprocedure 1-year survival of 86%. Sareyyupoglu and colleagues114 concluded that embolectomy should be considered earlier in the course of the disease. or have failed. but was evaluated in a series of patients with massive PE assigned to medical or surgical management. only if there is recurrent PE (AHA class I level C. IVC filter placement may be associated with a reduction in early PE and death.115 IVC filters also play an important adjunctive role in surgical embolectomy. thrombolysis or CDTs (grade 2C and class I level C. although this finding was associated with a small (N 5 10) subset of patients of the ICOPER trial and may have been confounded by selection bias.

but there are some studies of the submassive population. controlled trials have evaluated CDT against other therapies in reducing clot burden or improving clinical outcome 463 .5% success rate (hemodynamic stabilization. and outcomes were equivocal.118.Submassive Pulmonary Embolism difference in mortality between permanent IVC filters and no filters in an early study by Decousus and colleagues. CDT is thought to mitigate risks associated with systemic thrombolysis or surgical embolectomy. No controlled trials have ever compared surgical embolectomy with CDT. and mortality and the number of complications have improved.124 A 2007 case series evaluated rheolytic thrombectomy (clot dissolution via a high-pressure stream of fluid) with the AngioJet system in addition to local thrombolysis (N 5 1) and IVC filter placement (N 5 4) in 4 patients with submassive PE. To date. Improved flow. no randomized.127. and resolution of hemodynamic compromise can often be observed in real time.120 Most data on CDT are in the massive PE population. and percutaneous thrombectomy. and mainly consist of case series. Historical mortality for CDT ranges from 0% to 25%. local thrombolysis and thrombectomy in 1 procedure). to date. and all uncontrolled) found an 86.121 Systemic thrombolysis was compared with intrapulmonary thrombolysis during pulmonary angiography in an old study (before widespread adoption of CTA for diagnosis). hemodynamics. symptoms. and incidence of bleeding ranges from 0% to 17%. CDT serves as both a diagnostic and therapeutic procedure. data on these techniques are sparse.123 A 2009 meta-analysis comparing modern CDT (<10-French catheter size) with systemic thrombolysis in 594 patients with massive PE (retrospectively. Retrievable filters have been associated with similar complication rates and outcomes as permanent filters. and noted improved hemodynamics (N 5 11) but transient hemoptysis (N 5 3). All 4 patients were weaned from ventilatory assistance within 6 to 8 hours after the procedure.117 with the lower incidence of early PE in the IVC filter group contrasted by an increase in late incidence.128 However.120 Moreover. and can include any or all of the options discussed earlier. Other individual cases and series have been reported with similar findings.121 However. CDT typically is performed by specialists in either interventional radiology or cardiology. because smaller doses of pharmacologic thrombolytics may be exposed to a larger surface area of clot. clot fragmentation. The Greenfield system was evaluated in a case series of 46 patients. embolectomy and pharmacologic thrombolysis) may potentiate the effectiveness of the thrombolytics alone. the only product indicated for use in PE is the Greenfield system. old techniques (such as the 12-French Greenfield suction catheter embolectomy) have largely been replaced by newer techniques that take advantage of smaller devices and improvements in design. citing several procedure-related complications or deaths. improvement of hypoxia. for example. The use of CDT to perform combination procedures (eg.125 Ferrigno and colleagues126 evaluated AngioJet (plus local thrombolytics and IVC filter placement) in 11 patients with submassive PE. and cohort studies. At present. and the FDA has issued a black-box warning for the new AngioJet device.122 The type of procedure available to a patient is usually institution specific. embolectomy. designed to mitigate the prothrombotic characteristics of permanent filters. balloon angioplasty. alone or in combination (ie. and survival were noted in all 4 patients. Retrievable filters. or survival from PE) and 7. have been examined in a multitude of case series.119 Catheter-Directed Therapy Catheter-directed therapy (CDT) includes an array of therapies including pharmacologic thrombolysis. but have never been compared with permanent filters or no filters in a randomized manner. 4 of whom had submassive PE.9% complication rate with CDT. registries. most commonly hemoptysis.

right ventricular hypokinesis or McConnell sign. septal dysfunction.87 The BTS recommends the consideration of invasive approaches (thrombus fragmentation and IVC filter insertion) when facilities and expertise are readily available. aroundthe-clock availability of resources. The optimal treatment of submassive PE relies on appropriate clinical assessment of risk versus benefit of thrombolytics. These algorithms should include a multidisciplinary team approach (including radiology. or major myocardial necrosis) (class IIb level C). and ancillary services). As such. In addition. such as echocardiography. There is no mention of this therapy for submassive PE. systemic thrombolysis. Once diagnosis is made. but does not clarify a patient population (grade C).85 The AHA recommends that catheter embolectomy may be considered for patients with submassive PE who are judged to have clinical evidence of poor prognosis (new hemodynamic instability. It can present silently or with hemodynamic collapse and cardiac arrest. provided that expertise and resources are available (grade 2C). cardiac enzymes and BNP for initial diagnosis of dyspnea or chest pain and as a marker of myocardial damage). the benefits of thrombolysis outweigh the risks. Hybrid CDT therapies (thrombectomy or fragmentation with thrombolysis) are the subject of an emerging field of research. is difficult to . 5). Initial diagnostic results can often assist in risk stratification (CTA for initial diagnosis and evaluation of right ventricular dilatation. increased right ventricular systolic pressure. including obtaining evidence of (1) pending respiratory or circulatory collapse and (2) right ventricular failure. SUMMARY PE is common and is associated with a high degree of morbidity and mortality. or increased biomarkers.115 Submassive PE in particular has been shown to be associated with increased morbidity and mortality. For massive PE. specific treatment strategies must be implemented based on the diagnosis and risk stratification (ie. interventional radiology. appropriate additional risk stratification tools. nursing. should be used. and referral and transfer contingency plans to appropriate PE centers. worsening respiratory failure. emergency medicine. guidelines are vague and noncommittal. an increased Borg score.464 Busse & Vourlekis in submassive PE. pulmonary and internal medicine. the ACCP recommends the use of CDT over no such treatment in patients who have contraindications to. CDT or pulmonary embolectomy should be considered if there is a contraindication to systemic thrombolysis or when systemic thrombolysis has failed.87 Clinical evidence of cardiopulmonary collapse may include hypotension. and thus early and accurate risk stratification must be made based on some or all of the aforementioned tools.86 TREATMENT ALGORITHMS Algorithm-based management strategies can assist the clinician in navigating the complexity and variability of presentation of PE and the multitude of treatment options available. however. cardiothoracic surgery. systemic thrombolysis for submassive PE with features of decompensation or CDT when systemic thrombolysis is contraindicated).97 In addition. a shock index (heart rate in beats per minute divided by systolic blood pressure in millimeters of mercury) of more than 1.87 If. hypoxemia. the ESC recommends that CDT may be considered as an alternative to surgical treatment in patients with high-risk (massive) PE when thrombolysis is absolutely contraindicated or has failed. severe right ventricular dysfunction. or have failed. but does not mention the submassive population (class IIb level C). The authors propose the management algorithm presented later (see Fig. systemic thrombolytics should be administered. but are not universally obtained. in the clinician’s judgment.

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