Acute pulmonary embolism: risk stratification in the emergency department

Transcription

1 Intern Emerg Med (2007) 2: DOI /s y 119 REVIEW C. Becattini G. Agnelli Acute pulmonary embolism: risk stratification in the emergency department Received: 16 October 2006 / Accepted in revised form: 18 December 2006 / Published online: 27 June 2007 Abstract Pulmonary embolism is a common disease associated with a high mortality rate. Death due to pulmonary embolism occurs more commonly in undiagnosed patients before hospital admission or during the initial in-hospital stay. Thus, mortality could be reduced by prompt diagnosis, early prognostic stratification and more intensive treatment in patients with adverse prognosis. Mortality is particularly high in patients with pulmonary embolism presenting with arterial hypotension or cardiogenic shock. In patients with pulmonary embolism and normal blood pressure, a number of clinical features and objective findings have been associated with a high risk of adverse in-hospital outcome. Advanced age and concomitant cardiopulmonary disease are clinical risk factors for in-hospital mortality. The Bburden of thromboembolism, as assessed by lung scan or spiral CT, and right ventricle overload, as assessed by echocardiography and probably spiral CT, have been claimed to be risk factors for in-hospital mortality. Elevated serum levels of troponins have been shown to be associated with right ventricular overload and adverse in-hospital outcomes in patients with pulmonary embolism. Despite the currently available evidence, no definite prognostic value can be assigned to any of the individual risk factors or cluster of C. Becattini G. Agnelli ( ) Sezione di Medicina Interna e Cardiovascolare Dipartimento di Medicina Interna Università di Perugia Via G. Dottori 1, I Perugia, Italy agnellig@unipg.it them. Large prospective trials should be carried out to validate individual risk factors or clusters of risk factors able to identify patients with acute pulmonary embolism at high risk for in-hospital mortality. These patients could afford the trade-off of an increased risk of side effects related to a more aggressive treatment, such as thrombolysis or surgical or interventional procedures. Keywords Pulmonary embolism Venous thromboembolism Thrombolysis Anticoagulants Introduction Pulmonary embolism accounts for between and deaths in the USA every year [1, 2]. In patients with pulmonary embolism, the risk of death is particularly high during the acute phase and then decreases over time. Twoweek mortality or in-hospital clinical worsening in patients with undiagnosed pulmonary embolism ranges between 25 and 38% [3], while mortality in properly treated patients is lower, as it ranges from less than 1% to 20%. Thus, mortality due to pulmonary embolism could be reduced by prompt diagnosis and treatment in the emergency department (ED). The utility of rapidly available tools for diagnosis of venous thromboembolism in the emergency setting has been discussed previously [4, 5]. Mortality is about 30% in patients with acute pulmonary embolism presenting with arterial hypotension or cardiogenic shock. In about 5% 10% of patients with pulmonary embolism and normal blood pressure at admission, haemodynamic deterioration occurs during the firstinitial days of the hospital stay. Haemodynamic deterioration is conceptually sustained by early recurrence of additional emboli, or by acute failure of the right ventricle. Thus, early prognostic stratification and the identification of patients at high risk for haemodynamic deterioration and in-hospital death are crucial in the emergency department. Patients at high risk for

2 120 adverse outcome could be selected for admission to intensive care units and/or for more aggressive treatment, such as thrombolysis or mechanical revascularisation. On the other hand, patients at low risk for adverse outcome could be candidates for less intensive care or even for home treatment with low-molecular-weight heparin. This review will focus on currently available evidence regarding prognostic factors for in-hospital outcome in patients with acute pulmonary embolism. In-hospital clinical outcome in patients with pulmonary embolism In-hospital mortality in patients with pulmonary embolism largely varies among the different reports, this inconsistency being due to differences in study design, clinical presentation and initial treatment of the observed patients (Table 1). Recent trials on anticoagulation in patients with pulmonary embolism reported low mortality rates, while recent clinical practice-based registries confirmed an in-hospital mortality of about 15%. It is conceivable that strict inclusion and exclusion criteria used in intervention clinical trials lead to the selection of patients with pulmonary embolism at low risk of in-hospital death. The International Cooperative Pulmonary Embolism Registry (ICOPER) remains the largest available registry of patients with acute pulmonary embolism, with an overall study population of 2454 patients [6]. Patients were followed up to 90 days from the index event. Mortality is 11.4% and 17.5% at two weeks and three months, respectively. Pulmonary embolism accounts for 45.1% of deaths. Similarly, 69 out of 719 patients with pulmonary embolism (9.6%) included in the Management and Prognosis in Pulmonary Embolism Trial (MAPPET) Registry died during hospital stay [7]. Of these, 94.2% (9.0% of the overall population) died due to pulmonary embolism. The 1-year mortality of the 399 patients with confirmed pulmonary embolism included in the Prospective Investigation of Pulmonary Table 1 Incidence of in-hospital mortality in registries and randomised trials in patients with acute pulmonary embolism In-hospital mortality % Registries ICOPER (4) 11.4 Haemodynamically unstable 58.3 Haemodynamically stable 15.1 MAPPET (5) 9.6 RCTs MAPPETT III (6) 2.7 MATISSE PE (7) 0.9 Thesee (8) 1.0 C. Becattini, G. Agnelli: Acute pulmonary embolism Embolism Diagnosis (PIOPED) project is 23.8% [11]. Ten patients died due to pulmonary embolism (10.5% of the overall mortality), 9 within two weeks from diagnosis of the index embolic event. In a large cohort of patients with venous thromboembolism, one-day and seven-day survivals are 97.0% and 96.2% among patients with deep vein thrombosis and 63.6% and 59.1% among patients with pulmonary embolism [12]. In conclusion, all these registry data consistently show that death due to pulmonary embolism remains high and occurs most commonly during the initial in-hospital stay. In addition to death, haemodynamic deterioration has been recently taken into account to evaluate the short-term clinical course of patients with acute pulmonary embolism. Recent studies aimed at assessing the short-term clinical course of patients with pulmonary embolism have considered haemodynamic deterioration as a composite study end-point including: (1) new onset of haemodynamic collapse, (2) need for treatment upgrading, as thrombolysis or emergency surgical embolectomy or catheter thrombus fragmentation, (3) need for endotracheal intubation or cardiopulmonary resuscitation, (4) need for cathecholamine infusion. Haemodynamic deterioration could be due to both treatment failure and an early recurrence of additional emboli. Early recurrence of pulmonary embolism is quite common (about 16% of patients at 30 days) and associated with high in-hospital mortality (33.7% vs. 8.5% in patients without recurrence) [6, 7]. Prognostic stratification: clinical features Clinical risk factors for adverse outcome can be classified as clinical conditions pre-existing the index event or clinical signs at admission. Among the clinical conditions pre-existing the index event, age over 70, a history of bed rest for 5 days or more, cancer, chronic obstructive pulmonary disease (COPD) and renal failure are shown to be risk factors for mortality in patients with pulmonary embolism in the ICOPER registry [6]. Consistently, increasing age, male gender, lower body mass index, confinement to bed, congestive heart failure, COPD, major neurological diseases and cancer awere independent predictors of reduced short-term survival in a North American large observational study [12]. In the MAPPET registry, a correlation is found at univariate analysis between mortality and a history of congestive heart failure or COPD, which is not confirmed at multivariate analysis (OR=1.37; 95% CI and OR=1.60; 95% CI ) [7]. In a recent study, the mean age of patients discharged alive from the hospital is 61.9±15.4 years compared with 66.8±13.1 years in those who die to the diseased (p=0.002) [13]. In this study, history of chronic cardiac or pulmonary diseases is more common in

3 C. Becattini, G. Agnelli: Acute pulmonary embolism 121 patients who die, while no difference between survivors and non-survivors is observed with regard to history of recent surgery or major trauma, previous venous thrombosis or pulmonary embolism, cancer, stroke or pregnancy. In conclusion and conceivably, age, cancer, severe COPD or severe heart failure are predictors of mortality in acute pulmonary embolism, while a potential role can be hypothesised for milder diseases. Among the clinical signs at admission, symptoms and signs related to the haemodynamic status are established predictors of prognosis. In the ICOPER registry, mortality is 58.3% in the 103 haemodynamically unstable patients and 15.1% in the 2351 haemodynamically stable patients [6]. A recent meta-analysis shows higher mortality rates, regardless of treatment intensity, in studies that included haemodynamically unstable patients with pulmonary embolism in comparison to studies that excluded this patient category (9.4% vs. 2.8%) [14]. In the MAPPET registry, arterial hypotension (12.6% vs. 7.3%, p=0.021) and tachycardia (11.1% vs. 6.3%, p=0.06) are significantly associated with death at 30 days at univariate analysis [7]. However, none of these clinical signs are independent predictors of mortality by logistic regression analysis. In a recent study, arterial hypotension, shock or syncope at presentation weare all significantly associated with a higher death rate [13]. Syncope is the predominant clinical presentation in about 10% of patients with pulmonary embolism. Of note, the MAPPET registry shows that patients with syncope due to pulmonary embolism have a higher risk of death at 30 days (14.4% and 7.3%, p=0.012). Whether syncope in patients with pulmonary embolism is due to a dramatically reduced cardiac output or to a vaso-vagal mechanism is still unknown. In an observational study, 10 patients having syncope as the primary symptom of pulmonary embolism hadve a higher prevalence of emboli in the main pulmonary arteries and a significant reduction in systolic and/or diastolic blood pressure compared to 60 patients without syncope (contingency coefficient=0.301, p<0.04) [15]. In a retrospective review of 154 consecutive patients with acute pulmonary embolism, patients with or without syncope have similar epidemiological and clinical features (including respiratory failure, right heart failure and arterial hypotension), and hospital mortality [16]. No specific prognostic significance has been attributed to changes in blood gas analysis. The only available data on the prognostic value of respiratory function derive from a prospective study in 53 subjects with suspected pulmonary embolism [17]. In subjects with pulmonary embolism the alveolar dead space volume correlatesd with lung perfusion defect and pulmonary artery pressures (r 2 =0.41 and r 2 =0.59, respectively). These findings support the potential for alveolar dead space volume to quantify the embolic burden of pulmonary embolism. However, as this procedure requires an invasive manoeuvre, it has failed to be adopted in the clinical practice. In conclusion, shock and systemic blood pressure are currently the only established clinical predictors of shortterm mortality in patients with pulmonary embolism. The presence of shock requires the use of aggressive treatment strategies in order to reduce mortality. Prognostic stratification: clinical features-based algorithms The prognostic value of individual clinical features has been used to derive prognostic models to optimise the first-line evaluation of patients with pulmonary embolism (Table 2). Prognostic scores would be clinically useful if able to identify patients with pulmonary embolism eligible for outpatient or in-hospital management and for standard or intensive care. The first of these scores was derived in Geneva by the prospective evaluation of 296 consecutive patients with pulmonary embolism admitted to an emergency ward [18]. Thirty patients (10.1%) had one or more adverse events during their 3-month follow-up period: 25 patients (8.4%) died, 10 patients had recurrent thromboembolic events (3.4%) and 5 patients presented major bleeding (1.7%). At multivariate analysis, cancer, heart failure, previous deep vein thrombosis, systolic blood pressure <100 mmhg, arterial PaO 2 <8 kpa and presence of deep vein thrombosis on ultrasound are associated with an adverse outcome at 3 months. A risk score was calculated by adding 2 points for cancer and hypotension, and 1 point each for the other risk factors. Of 180 lowrisk patients (score 2), only 4 have adverse outcomes (2.2%) compared to 23 of 88 (26.1%) high-risk patients (score 3). By retrospectively evaluating a cohort of inpatients with a discharge diagnosis of pulmonary embolism, Aujesky et al. developed a model for risk stratification for pulmonary embolism [19]. Data routinely available at initial examination were considered as variables predictive of 30-day mortality. The final model consistsed of 10 factors: age over 70, history of cancer, heart failure, COPD, chronic renal disease, cerebrovascular disease, heart rate over 110 beats/min, systolic blood pressure lower than 100 mmhg, altered mental status and arterial oxygen saturation lower than 90%. The derived rule is able to stratify patients with pulmonary embolism into five severity classes associated with an increasing mortality (class I, 0% 1.6%; class II, 1.7% 3.5%; class III, 3.2% 7.1%; class IV, 4.0% 11.4%; class V, 10.0% 24.5%). Patients with none of these factors weare at low risk for 30-day mortality and non-fatal adverse outcomes [20]. Should one of these rules be prospectively validated and implemented, the initial management of patients with pulmonary embolism would be more easily guided, thus avoiding more sophisticated instrumental examinations.

4 122 C. Becattini, G. Agnelli: Acute pulmonary embolism Table 2 A comparison between clinical scoring systems for patients with acute pulmonary embolism Model 1 (16) Points Model 2 (17) Points Demographics Demographics Age, per year Age in yr Age, 60 79/>80 1 Gender +10 Comorbidity Comorbidity Heart failure +10 Heart failure 1 Cancer +30 Cancer 2 COPD +10 Recent surgery 1 Previous VTE 1 Clinical status Clinical status Heart rate > Systolic BP < Systolic BP <100 2 Respiratory rate > Temperature <36 C +20 Altered mental status +60 Arterial oxygen Sat <90% +20 Arterial oxygen pressure <8 kpa 1 DVT at ultrasound 1 For Model 1 low risk 85 points, high risk 106 points For Model 2 low risk 2 points, high risk 3 points Prognostic stratification: ECG changes ECG signs suggestive of right ventricular strain (S 1 Q 3 T 3 complex, right bundle block, pulmonary P waves, T-waves inversion in right precordial leads) have been correlated with the extent of the perfusion defect as assessed by lung scan or pulmonary angiography [21]. In a landmark prospective study, T-wave inversion in right precordial leads (V 1 V 4 ) wais found in 90% of patients with a Miller index over 17, as assessed by pulmonary angiography [22]. In this study, 81% of patients with a new onset T-wave inversion in the right precordial leads haved a mean pulmonary artery pressure higher than 30 mmhg. The correlation between ECG abnormalities and the extent of the perfusion defect, as assessed by perfusion lung scan, was evaluated in a prospective study in 229 patients with high-probability ventilation/perfusion scans [23]. An ECG score was calculated on examinations obtained within 48 h from the lung scan. The mean ECG score is 2.6 (standard deviation 2.8) in patients with <30% perfusion defect, 3.2 (standard deviation 2.9) in patients with 30% 50% perfusion defect and 5.3 (standard deviation 3.7) in patients with >50% perfusion defect. An ECG score 3 predicts >50% perfusion defect with a sensitivity of 70% (95% CI 59% 81%), and a specificity of 59% (95% CI 51% 67%). In an autopticsy series, an association is found between new onset of right bundle branch block and main pulmonary artery obstruction [24]. The impact of individual ECG findings at admission on 30-day mortality was evaluated in 508 patients with acute pulmonary embolism [25]. Atrial arrhythmias, complete right bundle branch block, peripheral low voltage, pseudoinfarction pattern (Q waves) in leads III and avf, and ST segment changes (elevation or depression) over the left precordial leads are all significantly more frequent in patients who hadve a fatal outcome. Overall, in-hospital death occurrs in 29% of the patients presenting at least one ECG abnormality related to pulmonary embolism on admission as compared to 11% of patients with a normal ECG. The presence of at least one of the above ECG findings is an independent predictor of outcome at multivariate analysis. The prognostic value of inverted T-waves was assessed in a prospective study of 40 patients with acute pulmonary embolism [26]. Patients were classified into 3 groups according to the number of leads with inverted T waves found on the admission ECG (<3, 4 6, 7). The prevalence of right ventricular dysfunction on echocardiography (47%, 92% and 100%, p<0.01), along with the incidence of in-hospital adverse events (including death or need for catecholamine support, cardiopulmonary resuscitation or mechanical cardiovascular support for haemodynamic instability) (0%, 8% and 46%, p=0.004) increases proportionally with the number of leads presenting the T-wave inversion. On multivariate analysis, arterial hypotension (OR 8.96, p=0.049) and inverted T waves in 7 leads on the ECG at admission (OR 16.8, p=0.037) are independent predictors of in-hospital adverse events. The blind evaluation of ECGs from 151 patients with suspected pulmonary embolism shows a higher prevalence of Qr in V1 (14 vs. 0 in controls; p<0.0001) and ST elevation in V1 1 mv (15 vs. 1 in controls; p=0.0002) in patients with pulmonary embolism [27]. Three of five patients who died in-hospital and 11 of 20 patients with a complicated course hadve a Qr in V1. In this study, a Qr in V1 (OR 8.7, 95% CI ; p=0.02) is an independent predictor of adverse outcome after adjustment for other indicators of right ventricular strain.

5 C. Becattini, G. Agnelli: Acute pulmonary embolism 123 In conclusion, a number of ECG findings have been shown to be associated with adverse outcome events in the short-term course of patients with pulmonary embolism, in particular T-wave inversion in the right precordial leads. The prognostic value of ECG has been usually demonstrated for abnormalities of recent onset. Unfortunately, previous ECGs are often not available in the initial phases of patient management. This is the main limit for prognostic stratification done through the ECG. Prognostic stratification: imaging techniques The size of emboli, assessed by the extent of the perfusion defects at diagnostic imaging, seems to be an objective measure of the severity of pulmonary embolism (Table 3). The Miller index was generated to quantify the extent of vascular obstruction by pulmonary angiography. In 144 patients with pulmonary embolism, Alpert observedd a mortality of 5% and 16% in the two groups of patients with Miller index <50% or 50%, respectively [28]. Nowadays, pulmonary angiography is rarely used, as it is invasive and associated with a high risk of complications. Thus, the extent of perfusion defect is more commonly assessed by lung scan or CT scan. The correlation between the extent of perfusion defect at lung scan and death due to pulmonary embolism was evaluated in a cohort study in patients with suspected pulmonary embolism [29]. Mortality is 1.1% in 508 patients with normal lung scan or sub-segmental perfusion defect; 0% in 33 adequately treated patients with intermediate-probability lung scan; and 5.8% in 103 adequately treated patients with a high-probability lung scan. A number of methods have been proposed to quantify the extension of perfusion defect by using a spiral CT scan. The CT severity score was evaluated in 36 consecutive patients, without underlying cardiopulmonary disease, undergoing spiral CT and echocardiography for a high clinical suspicionappearance of pulmonary embolism [30]. All 36 patients had pulmonary embolism confirmed at spiral CT. Spiral CT and echocardiography were performed both at the time of diagnosis and after 10 days. The CT severity scores were calculated as the percentages of obstructed surface of each central and peripheral pulmonary arterial section using a 5-point scale (1: <25%; 2: 25% 49%; 3: 50% 74%; 4: 75% 99%; 5: 100%). The sum of the detailed scores attributed to 5 mediastinal, 6 lobar and 20 segmental arteries per patient led to the determination of central, peripheral and global CT severity scores and the subsequent determination of percentage of obstruction of pulmonary circulation. The mean percentage of pulmonary artery obstruction at admission is significantly higher in 22 patients with right ventricular overload at echocardiography than in those without it (56±13 vs. 28±32%; p<0.001). A significant reduction in the mean percentage of pulmonary artery obstruction is observed in the 19 patients experiencing a 10-day resolution of right ventricular overload at echocardiography compared to those who diddo not have this positive effect (57±14% vs. 7±11%; p<0.001). The mean pulmonary artery pressure is reported to be significantly higher in 26 patients with more than 50% pulmonary artery obstruction at admission (45±15 mmhg) compared to the 10 patients with less than 50% pulmonary artery obstruction (31±11 mmhg; p<0.01). The currently accepted method for the assessment of the extent of vascular obstruction by CT scan is the vascular obstruction index. This index is calculated as the number of blocked segmental artery branches corrected by a factor of one for partial blockage or by a factor of two for completely obstructive thromboemboli [31]. With this scoring system, the maximum score is 40 (thrombus completely obstructing the pulmonary trunk), which corresponds to a 100% obstruction index. This index was validated in a prospective study in 158 patients, of whom 56 had confirmed pulmonary embolism. In this study the obstruction index (29±17%) and the Miller index (43±25%) are well correlated (r=0.867, p<0.0001). A CT obstruction index higher than 40% is observed in more than 90% of the patients with right ventricular dilatation. More recently, the ratio of the right to left ventricle short axis diameters (RV/LV), as assessed by helical CT scan, has been proposed as a prognostic factor for short-term adverse outcome in patients with pulmonary embolism [32 35]. In a recent retrospective study in 120 patients with pulmonary embolism, seven patients died of pulmonary embolism. Both, the RV/LV ratio and the obstruction index are shown to Table 3 In-hospital mortality based on the presence of right ventricle dysfunction (RVD) in patients with acute pulmonary embolism Trans-thoracic echocardiography Study design Mortality % No RVD RVD Kasper, 1997 Prospective Ribeiro, 1997 Prospective Grifoni, 2000 Prospective Vieillard-Baron, 2001 Retrospective 0 23 Kucher, 2006 Retrospective

6 124 be risk factors for 3-month mortality (p=0.04 and 0.01, respectively) [36]. No relationships are found between (1) the ratio of pulmonary artery to ascending aorta diameters (p=0.66) and the 3-month mortality and (2) the shape of the interventricular septum (p=0.20) and 3-month mortality. A RV/LV ratio 1.0 has a 100% (lower 95% CI: 94.3%) negative predictive value for uneventful outcome. Patients with an obstruction index 40% have a 11.2-fold increased risk of death due to pulmonary embolism (95% CI: ). In a study on 431 consecutive patients, right ventricle dilation on spiral CT scan (right ventricle diameter/left ventricle diameter 0.9) shows a 3.36 (95% CI, ; p=0.029) hazard ratio for 30-day mortality [37]. On multivariable analysis, right ventricle dilation is a predictor of 30- day mortality (hazard ratio, 5.17; 95% CI, ; p=0.005) after adjusting for age and other risk factors. Should these data be confirmed in a large ad hoc study, spiral CT scan would be the only examination needed to be performed in the ED in patients with acute pulmonary embolism to achieve both a rapid diagnosis and a prognostic stratification for adverse outcome. Prognostic stratification: echocardiography Nowadays, echocardiography is considered the gold standard for the assessment of right ventricle dysfunction in patients with pulmonary embolism [38]. Signs of right heart overload at echocardiography include right ventricle dilation, increased left/right ventricular diameter ratio, right ventricular wall hypokinesis (classified as mild, moderate and severe) and dilation of the right pulmonary artery. Echocardiography may also be used to estimate pulmonary artery systolic pressure, by measuring the peak velocity flow through the regurgitant tricuspid valve. Hypokinesis of the mid-apical, right ventricular free wall (McConnell sign) is an uncommon, probably hyper-emphasised, sign of acute right ventricular overload [39]. None of these parameters is able to distinguish chronic from acute right side overload. Hypertrophy of the right ventricle wall (thickness >7 mm) is a commonly accepted sign of chronic pulmonary hypertension. Right ventricle overload at echocardiography was correlated with the extent of perfusion defect, as assessed by lung scan, in 90 patients with acute pulmonary embolism [40]. In this study 92% of patients with an impairment of more than 30% of the pulmonary vascular cross-sectional area at lung scan have signs of right ventricular overload at echocardiography. Concerning the prognostic value of echocardiography, some consensus exists that direct evidence of thrombi in the right heart at echocardiography is diagnostic for pulmonary embolism and highly associated with an elevated incidence of adverse short-term outcome [41]. In fact, in a case series of patients with right heart emboli in transit, short-term C. Becattini, G. Agnelli: Acute pulmonary embolism death occurs in over 50% of patients with thrombi in the right heart as assessed by echocardiography [42]. In a prospective study involving 126 patients with acute pulmonary embolism, echocardiography was obtained at hospital admission in all patients [43]. In-hospital mortality due to pulmonary embolism is 7.9%. All patients who died in-hospital hadve echocardiographic evidence of severe right ventricular dysfunction. In a further prospective study, inhospital mortality due to pulmonary embolism is reported to beat 12.6% and 0.9% in patients with pulmonary embolism with and without right ventricular overload at hospital admission, respectively (p<0.001) [44]. Echocardiography was obtained at hospital admission in 209 patients with confirmed pulmonary embolism included in a prospective study [45]. Right ventricle dysfunction was defined as the presence of one among right ventricular dilatation, paradoxical movement of the interventricular septum or pulmonary hypertension, all in the absence of right ventricular thickness >7 mm. Patients were divided into four groups based on systolic arterial pressure (> or <90 mmhg) and on the presence of right ventricle dysfunction at echocardiography (patients presenting with shock, patients with hypotension, patients with blood pressure >90 mmhg and right ventricle dysfunction, patients with blood pressure >90 mmhg and no signs of right ventricle dysfunction). In-hospital mortality is 32% in patients with shock. The presence of right ventricular dysfunction is associated with a 5% mortality and 10% incidence of adverse in-hospital outcome, independent of blood pressure. None of the patients with blood pressure >90 mmhg without signs of right ventricle dysfunction experienced an adverse clinical outcome during follow-up. Kucher et al. have recently addressed the issue of echocardiography-based prognosis in normotensive patients by reviewing the database of the ICOPER registry [46]. All 1035 patients with blood pressure 90 mmhg who underwent echocardiography within 24 h from diagnosis were included in a post hoc analysis. In patients with right ventricle hypokinesis (n=405), the initial blood pressure is lower (125±22 vs. 131±22 mmhg; p<0.001), and the initial heart rate is higher (104±21 vs. 99±22 beats/min; p<0.001) than in patients without right ventricle hypokinesis (n=630). The 30-day survival rates are 83.7% and 90.6% in patients with and without right ventricle hypokinesis, respectively (log-rank p value <0.001). Right ventricle hypokinesis is an independent predictor of 30-day mortality (hazard ratio, 1.94; 95% CI, ) after adjusting for cancer, congestive heart failure, chronic lung disease, age older than 70 years, systolic arterial pressure of 100 mmhg or lower, administration of thrombolytic therapy and heart rate greater than 100 beats/min. A recent systematic review has confirmed that echocardiographic right ventricle dysfunction at hospital admission is associated with an increased risk of short-term mortality in normotensive patients with pulmonary embolism [47] (Table 3).

7 C. Becattini, G. Agnelli: Acute pulmonary embolism 125 Prognostic stratification: cardiac biomarkers The role of troponins as indicators of myocardial cell injury has been firmly established in patients with acute myocardial infarction [48] and consistently proposed in patients with pulmonary embolism. The reasons for elevated blood levels of troponin in pulmonary embolism are not completely defined. In patients with myocardial infarction, even in non- ST segment elevation events, troponins remain elevated for at least 7 days, thus suggesting irreversible injury to cardiomyocytes. In patients with pulmonary embolism the period of marker elevation is 2 3 days in most of the cases, thus suggesting cells injury, while irreversible cell necrosis seems to be uncommon in this clinical setting [49]. Myocardial damage resulting from pulmonary embolism is probably due to the reduction of cardiac output and of coronary blood flow through the acute increase of right ventricular afterload [50]. Unchanged coronary arteries have beenare found in the postmortem examination of patients who had died due to massive pulmonary embolism. In most of the studies examining patients with acute pulmonary embolism, elevated troponin levels weare associated with older age, lower blood pressure and higher heart rate. In an observational study in patients with acute pulmonary embolism, the mean systemic blood pressure wais significantly lower in patients with elevated levels of troponin I on admission than in patients without elevation (77±19 vs. 93±17 mmhg, p=0.015) [51]; right bundle branch block wais more common in patients with high levels of troponin (33% vs. 10%, p=ns); whereas the S1Q3T3 pattern wais more common in patients with normal levels of troponin (6% vs. 20%, p=ns). In this study right ventricle overload, as assessed by echocardiography, wais more common in patients with elevated levels of troponin I than in patients without elevation (67% vs. 15%, p=0.004). Similarly, right ventricle systolic pressures weare significantly higher in the troponin I positive group (51±8 vs. 40±9 mmhg, p=0.002). In a similar study, the presence of T waves inversion in the right pre-cordial leads wais shown to be related wittoh elevated levels of serum troponin T [52]. Troponin I elevation wais associated with a greater perfusion defect, as detected by lung scan, than normal levels of troponin I (p=0.0002) [53]. In this study, high serum levels of troponin I weare observed in the 62.5% of patients with acute pulmonary embolism and echocardiographic right ventricular dilatation, in comparison to 28.6% of patients with normal right ventricular diameter (p=0.009; RR=2.18; 95% CI ). The association between elevated levels of serum troponin T and right ventricular strain, as assessed by ECG or echocardiography, wahas recently been confirmed [54]. The prognostic role of troponin elevation in patients with pulmonary embolism was first assessed in a prospective study in 56 consecutive patients with confirmed diagnosis [55]. Troponin T was measured within 12 h after admission and patients were stratified according to a clinically based scoring system for the severity of pulmonary embolism. Troponin is elevated in 32% of patients with massive and moderate, but not in patients with mild pulmonary embolism. Elevated troponin is more common in patients with signs of right ventricular overload at echocardiography. In-hospital death (OR 29.6, 95% CI ), prolonged hypotension and cardiogenic shock (OR 11.4, 95% CI ) and need for resuscitation (OR 18.0, 95% CI ) are all more common in patients with elevated troponin levels. Patients with elevated troponin more often needed inotropic support (OR 37.6, 95% CI ) and mechanical ventilation (OR 78.8, 95% CI ). Troponin is an independent predictor of 30-day mortality at multivariate regression analysis (OR 15.2, 95% CI ). In a similar study in 106 patients with acute pulmonary embolism, logistic regression analysis confirms that the mortality risk is significantly elevated only in patients with high ctni (p=0.019) or ctnt (p=0.038) levels [56]. Furthermore, the risk of a complicated in-hospital course is almost 5 times higher (15.47 vs. 3.16) in the highctni group compared to patients with moderate ctni elevation. These data are confirmed in 64 patients with pulmonary embolism and normal blood pressure (systolic blood pressure >90 mmhg) [52]. In this study, elevated troponin levels are strongly associated with in-hospital mortality (p=0.0048), while normal levels of troponin T revealed a high negative predictive value for the cumulative end-point of adverse in-hospital outcomes (in-hospital death, cardiopulmonary resuscitation, thrombolysis or the need for catecholamine infusion). In particular, only one of 32 patients with normal levels of troponin T experiences at least one outcome event in comparison with 14 out of 32 patients with high levels of troponin (p=0.001). In a retrospective study including 141 patients with acute pulmonary embolism, troponin is significantly more elevated in patients who died from pulmonary embolism within 30 days [57]. The combination of elevated troponin and right ventricle dysfunction has a positive predictive value of 38% and a negative predictive value of 89% for 30-day mortality. The association of elevated troponin and right ventricle dysfunction predicts mortality even in normotensive patients (HR 5.6; 95% CI ). The incremental prognostic value of right ventricular dysfunction at echocardiography and elevated troponin levels are confirmed in a study in 91 patients with pulmonary embolism [58]. In this study, the ability of predicting in-hospital outcome by troponin and echocardiography, calculated by the area under the receiveroperating characteristic (ROC) curve from multivariate regression models, is incremental: 0.77 without including troponin I and echocardiography, 0.89 with troponin I alone, 0.86 with echocardiography alone, and 0.90 with the combination of troponin and echocardiography. More recently, the prognostic value of serum levels of the B-type natriuretic peptide (BNP) has been evaluated in

8 126 patients with acute pulmonary embolism. BNP is secreted by the left ventricle in response to volume expansion and pressure overload. The utility of BNP in differentiating dyspnoea due to congestive heart failure from dyspnoea due to lung disease was demonstrated in a study in 321 patients presenting to the emergency department with acute dyspnoea [59]. In this study, a breakdown of patients with pulmonary disease reveals the highest levels of BNP in 3 patients with acute pulmonary embolism compared to patients with COPD, asthma, acute bronchitis, pneumonia and lung cancer. The role of plasma BNP as a predictor of fatal pulmonary embolism at three-month follow-up was evaluated in 110 consecutive patients with acute pulmonary embolism [60]. A 17% risk of death related to pulmonary embolism (95% CI ) wais found in patients with BNP levels >21.7 pmol/l. The negative predictive value for uneventful outcome of a BNP value <21.7 pmol/l iwas 99% (95% CI ). In a further study, BNP levels were measured in 73 patients with acute pulmonary embolism within 4 h of hospital admission [61]. Adverse clinical outcome was defined as in-hospital death or need of at least one of the following: cardiopulmonary resuscitation, mechanical ventilation, cathecholamine infusion, thrombolysis, catheter fragmentation or surgical embolectomy. BNP levels are lower in the 53 patients with a benign clinical outcome than in 20 patients with adverse clinical outcome. The negative predictive value of BNP levels <500 pg/ml for adverse clinical outcome is 97% (95% CI 84 99). BNP remaineds an independent predictor for adverse clinical outcome (OR 14.6; 95% CI ; p=0.02) after adjusting for severity of pulmonary embolism (submassive/massive), troponin T levels, age >70 years, gender and history of congestive heart failure. The authors concluded that low BNP levels can be used to identify patients with acute pulmonary embolism at low risk for adverse short-term events and thus potential candidates for outpatient treatment. In 61 patients with a first documented episodes of acute pulmonary embolism without shock or previous left ventricular dysfunction at echocardiography, rapid BNP testing was obtained on admission [62]. Overall, 35 patients (57%) have echocardiographic evidence of right ventricle dysfunction, and the prevalence increases progressively with increasing levels of BNP (0% in the lower tertile of BNP values, 75% in the middle tertile and 100% in the upper tertile). Overall, 11 patients (18%) of the upper tertile progressed to shock during admission, 4 of whom eventually died. The association of right ventricle dysfunction with a BNP level in the upper tertile (>527 pg/ml) shows incremental prognostic value over right ventricle dysfunction alone (in-hospital death and progression to shock are 55% and 31%, respectively). Therefore, BNP is a predictor of in-hospital clinical deterioration, with substantial incremental prognostic value over echocardiography alone. In a similar study on 50 consecutive patients with confirmed pulmonary embolism, BNP levels are significantly C. Becattini, G. Agnelli: Acute pulmonary embolism lower in patients without right ventricle dysfunction at echocardiography compared to those with right ventricle dysfunction (55±69 vs. 340±362 pg/ml, p<0.001) [63]. A significant correlation is observed between right ventricle end-diastolic diameter and BNP levels (r=0.43, p<0.05). However, in this study BNP levels are not predictive of mortality or in-hospital complications. The predictive value of BNP levels was also evaluated with respect to early recurrences of pulmonary embolism in haemodynamically stable patients. In a large randomised controlled trial, including 2213 haemodynamically stable patients with pulmonary embolism, 90 patients died for or had non-fatal recurrent venous thromboembolism during the first 3 months after inclusion [64]. These 90 patients and a further 297 patients with uneventful follow-up had blood sampling for central BNP determination. Significantly higher mean baseline BNP levels are found in the 90 patients who experienced a recurrence with respect to controls (p=0.0002). The BNP cut-off level of 1.25 pmol/l is associated with sensitivity and specificity of 60% and 62% respectively, as assessed by the ROC curve. In order to improve prognostic stratification in patients with acute pulmonary embolism, Kostrubiec and colleagues developed a biomarker-based risk stratification in 100 consecutive patients, all normotensive on admission [65]. Serum probnp and troponin levels were assessed and echocardiography was performed in all patients at admission. All-cause 40- day mortality is 15% and mortality due to pulmonary embolism is 8%. In univariablete analysis, troponin >0.07 mg/l predicts all-cause mortality (HR 9.2; 95% CI: ), and mortality due to pulmonary embolism (HR 18.1; 95% CI: ); similarly, probnp >7600 ng/l predicts all-cause and pulmonary embolism-related death (HR 6.7; 95% CI: , and HR 7.3; 95% CI: ). A BNP <600 ng/l is associated with an uncomplicated outcome. Multivariablete analysis reveals that troponin wais the most significant independent predictor, whereas BNP and systemic systolic blood pressure measured on admission and echocardiographic parameters are not significant. Mortality due to pulmonary embolism in patients with elevated BNP and troponin T wais 33%, while no deaths were observedoccur in patients with BNP <600 ng/l. Mortality due to pulmonary embolism in patients with an elevated BNP and a normal troponin wais 3.7%. Addition of echocardiographic data does not improve group selection, while simultaneous measurement of serum troponin T and BNP allowed for a more precise prediction of prognosis in patients with acute pulmonary embolism. Patients with normal blood pressure on admission, troponin 0.07 mg/l and a BNP 600 ng/l are at a higher risk of mortality due to acute pulmonary embolism, whereas a BNP <600 ng/l wais an indicator of excellent prognosis. In a small prospective study, high serum levels of myoglobin predicted short-term adverse outcomes in 46 patients with pulmonary embolism more efficiently than serum troponin levels [66]. Further evidence is needed to establish the

9 C. Becattini, G. Agnelli: Acute pulmonary embolism 127 effective role of serum myoglobin as a prognostic predictor in pulmonary embolism. In conclusion, both cardiac troponins and BNP have high negative predictive values, which are in a range between 97% and 99%. Thus, dosing biomarkers appear to be extremely useful for risk stratification and treatment allocation. In fact, patients with negative biomarkers have extremely low risks for death or in-hospital complications such as: haemodynamic deterioration, mechanical ventilation or need for inotropic support. These patients will not benefit from any therapy other than anticoagulation. Conversely, when examined alone, the relatively low positive predictive values of biomarker results do not justify exposing patients to the risk of intracranial or other major bleedings whichthat are associated with thrombolytic therapy and interventional approaches. As a new predictor of prognosis, plasma heart-type fatty acid binding protein (H-FABP) has been recently evaluated for the prognostic stratification in a study in 77 patients with pulmonary embolism [67]. The overall 30-day mortality is 19.5% and the incidence of adverse clinical outcome (death, thrombolysis, cardiopulmonary resuscitation, intravenous vasopressors) 31.2%. Among H-FABP, myoglobin, troponin and BNP, only H-FABP is a 30-day predictor of mortality at multivariate analysis (HR 1.02; 95% CI ). Proposal for management of acute pulmonary embolism in the emergency department In patients with suspected pulmonary embolism and haemodynamic instability, the opportunity to start specific treatment while waiting for objective diagnosis has to be promptly evaluated. In patients with pulmonary embolism and normal blood pressure, echocardiography and troponin levels should be obtained as soon as possible, and at least within 24 h from admission. Patients without signs of right ventricle dysfunction at echocardiography and with normal troponin levels could are candidates for out-of-hospital management. Patients with both elevated troponin and right ventricle dysfunction at echocardiography should be admitted to intensive care units. Conclusions Mortality due to acute pulmonary embolism is estimated to range between 2% and 15% in the first two weeks after the index event. Mortality seems to be higher in patients with acute right ventricular overload. Presently, both echocardiography and biomarkers can be relied upon to detect right ventricular load. However, no consensus exists on which the markers is the most reliable and thus the best indicator of prognosis. A rapidly available and simple method for diagnosis and prognostic stratification of patients with pulmonary embolism is currently still needed, primarily in the emergency setting. 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