Материал: 2019 ESC acute pulmonaryembolism

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A. Enlarged right ventricle, parasternal long axis view

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B. Dilated RV with basal RV/LV ratio >1.0, and McConnell sign (arrow), four chamber view

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Echocardiographic examination is not mandatory as part of the routine diagnostic workup in haemodynamically stable patients with suspected PE,124 although it may be useful in the differential diagnosis of acute dyspnoea. This is in contrast to suspected high-risk PE, in which the absence of echocardiographic signs of RV overload or dysfunction practically excludes PE as the cause of haemodynamic instability. In the latter case, echocardiography may be of further help in the differential diagnosis of the cause of shock, by detecting pericardial tamponade, acute valvular dysfunction, severe global or regional LV dysfunction, aortic dissection, or hypovolaemia.152 Conversely, in a haemodynamically compromised patient with suspected PE, unequivocal signs of RV pressure overload, especially with more specific echocardiographic findings (60/60 sign, McConnell sign, or rightheart thrombi), justify emergency reperfusion treatment for PE if immediate CT angiography is not feasible in a patient with high clinical probability and no other obvious causes for RV pressure overload.152

Mobile right-heart thrombi are detected by TTE or transoesophageal echocardiography (TOE), or by CT angiography, in <4% of unselected patients with PE.153 155 Their prevalence may reach 18% among PE patients in the intensive care setting.156 Mobile right-heart thrombi essentially confirm the diagnosis of PE and are associated with high early mortality, especially in patients with RV dysfunction.155,157 159

In some patients with suspected acute PE, echocardiography may detect increased RV wall thickness or tricuspid insufficiency jet velocity beyond values compatible with acute RV pressure overload (>3.8 m/s or a tricuspid valve peak systolic gradient >60 mmHg).160 In these

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cases, chronic thromboembolic (or other) pulmonary hypertension (PH) should be included in the differential diagnosis.

4.10 Compression ultrasonography

In the majority of cases, PE originates from DVT in a lower limb, and only rarely from upper-limb DVT (mostly following venous catheterization). In a study using venography, DVT was found in 70% of patients with proven PE.161 Nowadays, lower-limb CUS has largely replaced venography for diagnosing DVT. CUS has a sensitivity >90% and a specificity of

95% for proximal symptomatic DVT.162,163 CUS shows a DVT in 30 50% of patients with PE,162 164 and finding a proximal DVT in patients suspected of having PE is considered sufficient to warrant anticoagulant treatment without further testing.165 However, patients in whom PE is indirectly confirmed by the presence of a proximal DVT should undergo risk assessment for PE severity and the risk of early death.

In the setting of suspected PE, CUS can be limited to a simple fourpoint examination (bilateral groin and popliteal fossa). The only validated diagnostic criterion for DVT is incomplete compressibility of the vein, which indicates the presence of a clot, whereas flow measurements are unreliable. A positive proximal CUS result has a high positive predictive value for PE. The high diagnostic specificity (96%) along with a low sensitivity (41%) of CUS in this setting was shown by a recent meta-analysis.165,166 CUS is a useful procedure in the diagnostic strategy of patients with CT contraindications. The probability of a positive proximal CUS in suspected PE is higher in patients with signs and symptoms related to the leg veins than in asymptomatic patients.162,163

In patients admitted to the emergency department with haemodynamic instability and suspicion of PE, a combination of venous ultrasound with cardiac ultrasound may further increase specificity. Conversely, an echocardiogram without signs of RV dysfunction and a normal venous ultrasound excluded PE with a high (96%) negative predictive value in one study.167

For further details on the diagnosis and management of DVT, the reader is referred to the joint consensus document of the ESC Working Groups of Aorta and Peripheral Vascular Diseases, and Pulmonary Circulation and Right Ventricular Function.1

4.12 Computed tomography venography

When using CTPA, it is possible to image the deep veins of the legs during the same acquisition.115 However, this approach has not been widely validated and the added value of venous imaging is limited.164 Moreover, using CT venography is associated with increased radiation doses.168

5 Assessment of pulmonary embolism severity and the risk of early death

Risk stratification of patients with acute PE is mandatory for determining the appropriate therapeutic management approach. As described in section 3.3, initial risk stratification is based on clinical symptoms and signs of haemodynamic instability (Table 4), which indicate a high risk of early death. In the large remaining group of patients with PE who present without haemodynamic instability, further (advanced) risk stratification requires the assessment of two sets of prognostic criteria: (i) clinical, imaging, and laboratory indicators of PE severity, mostly related to the presence of RV dysfunction; and (ii) presence of comorbidity and any other aggravating conditions that may adversely affect early prognosis.

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5.1 Clinical parameters of pulmonary embolism severity

Acute RV failure, defined as a rapidly progressive syndrome with systemic congestion resulting from impaired RV filling and/or reduced RV flow output,68 is a critical determinant of outcome in acute PE. Tachycardia, low systolic BP, respiratory insufficiency (tachypnoea and/or low SaO2), and syncope, alone or in combination, have been associated with an unfavourable short-term prognosis in acute PE.

5.2 Imaging of right ventricular size and function

5.2.1 Echocardiography

Echocardiographic parameters used to stratify the early risk of patients with PE are graphically presented in Figure 3, and their prognostic values are summarized in Supplementary Data Table 3. Of these, an RV/LV diameter ratio >1.0 and a TAPSE <16 mm are the findings for which an association with unfavourable prognosis has most frequently been reported.148

Overall, evidence for RV dysfunction on echocardiography is found in >25% of unselected patients with acute PE.145 Systematic reviews and meta-analyses have suggested that RV dysfunction on echocardiography is associated with an elevated risk of short-term mortality in patients who appear haemodynamically stable at presentation,180,181 but its overall positive predictive value for PE-related death was low (<10%) in a metaanalysis.180 This weakness is partly related to the fact that echocardiographic parameters have proved difficult to standardize.148,180 Nevertheless, echocardiographic assessment of the morphology and function of the RV is widely recognized as a valuable tool for the prognostic assessment of normotensive patients with acute PE in clinical practice.

In addition to RV dysfunction, echocardiography can identify right- to-left shunt through a patent foramen ovale and the presence of right heart thrombi, both of which are associated with increased

mortality in patients with acute PE.67,158 A patent foramen ovale also increases the risk of ischaemic stroke due to paradoxical embolism in patients with acute PE and RV dysfunction.182,183

5.2.2 Computed tomographic pulmonary angiography

CTPA parameters used to stratify the early risk of patients with PE are summarized in Supplementary Data Table 3. Fourchamber views of the heart by CT angiography can detect RV enlargement (RV end-diastolic diameter and RV/LV ratio measured in the transverse or four-chamber view) as an indicator of RV dysfunction. The prognostic value of an enlarged RV is supported by the results of a prospective multicentre cohort study in 457 patients.184 In that study, RV enlargement (defined as an RV/LV ratio >0.9) was an independent predictor of an adverse inhospital outcome, both in the overall population with PE [hazard

ratio (HR) 3.5, 95% CI 1.6 7.7] and in haemodynamically stable patients (HR 3.8, 95% CI 1.3 10.9).184 A meta-analysis of 49

studies investigating >13 000 patients with PE confirmed that an increased RV/LV ratio of >1.0 on CT was associated with a 2.5- fold increased risk for all-cause mortality [odds ratio (OR) 2.5,

95% CI 1.8 3.5], and with a five-fold risk for PE-related mortality (OR 5.0, 95% CI 2.7 9.2).185

Mild RV dilation (RV/LV slightly above 0.9) on CT is a frequent finding (>50% of haemodynamically stable PE patients186), but it probably has minor prognostic significance. However, increasing RV/ LV diameter ratios are associated with rising prognostic specificity,187,188 even in patients considered to be at ‘low’ risk on the basis of clinical criteria.186 Thus, RV/LV ratios > 1.0 (instead of 0.9) on CT angiography may be more appropriate to indicate poor prognosis.

Apart from RV size and the RV/LV ratio, CT may provide further prognostic information based on volumetric analysis of the heart chambers189 191 and assessment of contrast reflux to the inferior vena cava (IVC).185,192,193

5.3 Laboratory biomarkers

5.3.1 Markers of myocardial injury

Elevated plasma troponin concentrations on admission may be associated with a worse prognosis in the acute phase of PE. Cardiac troponin I or T elevation are defined as concentrations above the normal limits, and thresholds depend on the assay used; an overview of the cut-off values has been provided by a meta-analysis.194 Of patients with acute PE, between 30 (using conventional assays)194,195 and 60% (using highsensitivity assays)196,197 have elevated cardiac troponin I or T concentrations. A meta-analysis showed that elevated troponin concentrations were associated with an increased risk of mortality, both in unselected patients (OR 5.2, 95% CI 3.3 8.4) and in those who were haemodynamically stable at presentation (OR 5.9, 95% CI 2.7 13.0).195

On their own, increased circulating levels of cardiac troponins have relatively low specificity and positive predictive value for early mortality in normotensive patients with acute PE. However, when interpreted in combination with clinical and imaging findings, they may improve the identification of an elevated PE-related risk and the further prognostic stratification of such patients (Supplementary Data Table 4). At the other end of the severity spectrum, high-sensitivity troponin assays possess a high negative predictive value in the setting of acute PE.197 For example, in a

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prospective multicentre cohort of 526 normotensive patients, high-sensitivity troponin T concentrations <14 pg/mL had a negative predictive value of 98% for excluding an adverse in-hospital clinical outcome.63 Age-adjusted high-sensitivity troponin T cutoff values (>14 pg/mL for patients aged <75 years and >45 pg/mL for those >75 years) may further improve the negative predictive

value of this biomarker.196

Heart-type fatty acid-binding protein (H-FABP), an early and sensitive marker of myocardial injury, provides prognostic information in acute PE, both in unselected198,199 and normotensive patients.200,201 In a meta-analysis investigating 1680 patients with PE, H-FABP concentrations >6 ng/mL were associated with an adverse short-term

outcome (OR 17.7, 95% CI 6.0 51.9) and all-cause mortality (OR 32.9, 95% CI 8.8 123.2).202

5.3.2 Markers of right ventricular dysfunction

RV pressure overload due to acute PE is associated with increased myocardial stretch, which leads to the release of B-type natriuretic peptide (BNP) and N-terminal (NT)-proBNP. Thus, the plasma levels of natriuretic peptides reflect the severity of RV dysfunction and haemodynamic compromise in acute PE.203 A meta-analysis found that 51% of 1132 unselected patients with acute PE had elevated BNP or NT-proBNP concentrations on admission; these patients had a 10% risk of early death (95% CI 8.0 13%) and a 23% (95% CI 20 26%) risk of an adverse clinical outcome.204

Similar to cardiac troponins (see above), elevated BNP or NTproBNP concentrations possess low specificity and positive predictive value (for early mortality) in normotensive patients with PE,205 but low levels of BNP or NT-proBNP are capable of excluding an unfavourable early clinical outcome, with high sensitivity and a negative predictive value.180 In this regard, an NT-proBNP cut-off value <500 pg/mL was used to select patients for home treatment in a multicentre management study.206 If emphasis is placed on increasing the prognostic specificity for an adverse early outcome, higher cut-off values >600 pg/mL might be more appropriate.207

5.3.3Other laboratory biomarkers

Lactate is a marker of imbalance between tissue oxygen supply and demand, and consequently of severe PE with overt or imminent haemodynamic compromise. Elevated arterial plasma levels >2 mmol/L

predict PE-related complications, both in unselected208 and in initially normotensive209,210 PE patients.

Elevated serum creatinine levels and a decreased (calculated) glomerular filtration rate are related to 30 day all-cause mortality in acute PE.211 Elevated neutrophil gelatinase-associated lipocalin and cystatin C, both indicating acute kidney injury, are also of prognostic value.212

A recent meta-analysis investigating 18 616 patients with acute PE

found that hyponatraemia predicted in-hospital mortality (OR 5.6, 95% CI 3.4 9.1).213

Vasopressin is released upon endogenous stress, hypotension, and low CO. Its surrogate marker, copeptin, has been reported to be useful for risk stratification of patients with acute PE.214,215 In a singlecentre derivation study investigating 268 normotensive PE patients, copeptin levels >24 pmol/L were associated with a 5.4-fold (95% CI

1.7 17.6) increased risk of an adverse outcome.216 These results

were confirmed in 843 normotensive PE patients prospectively included in three European cohorts.217

5.4 Combined parameters and scores for assessment of pulmonary embolism severity

In patients who present without haemodynamic instability, individual baseline findings may not suffice to determine and further classify PE severity and PE-related early risk when used as stand-alone parameters. As a result, various combinations of the clinical, imaging, and laboratory parameters described above have been used to build prognostic scores, which permit a (semi)quantitative assessment of early PE-related risk of death. Of these, the Bova218 221 and the H- FABP (or high-sensitivity troponin T), Syncope, Tachycardia (FAST) scores219,222,223 have been validated in cohort studies (see Supplementary Data Table 4). However, their implications for patient management remain unclear. To date, only a combination of RV dysfunction on an echocardiogram (or CTPA) with a positive cardiac troponin test has directly been tested as a guide for early therapeutic decisions (anticoagulation plus reperfusion treatment vs. anticoagulation alone) in a large randomized controlled trial (RCT) of PE patients presenting without haemodynamic instability.224

5.5 Integration of aggravating conditions and comorbidity into risk assessment of acute pulmonary embolism

In addition to the clinical, imaging, and laboratory findings, which are directly linked to PE severity and PE-related early death, baseline parameters related to aggravating conditions and comorbidity are necessary to assess a patient’s overall mortality risk and early outcome. Of the clinical scores integrating PE severity and comorbidity, the Pulmonary Embolism Severity Index (PESI) (Table 7) is the one that has been most extensively validated to date.225 228 The principal strength of the PESI lies in the reliable identification of patients at low risk for 30 day mortality (PESI classes I and II). One randomized trial employed a low PESI as the principal inclusion criterion for home treatment of acute PE.178

In view of the complexity of the original PESI, which includes 11 differently weighed variables, a simplified version (sPESI; Table 7) has been developed and validated.229 231 As with the original version of the PESI, the strength of the sPESI lies in the reliable identification of patients at low risk for 30 day mortality. The prognostic performance of the sPESI has been confirmed in observational cohort studies,227,228 although this index has not yet been prospectively used to guide therapeutic management of low-risk PE patients.

The diagnosis of concomitant DVT has been identified as an adverse prognostic factor, being independently associated with death within the first 3 months after acute PE.232 In a meta-analysis investigating 8859 patients with PE, the presence of concomitant DVT was confirmed as a predictor of 30 day all-cause mortality (OR 1.9, 95% CI 1.5 2.4), although it did not predict PE-related adverse outcomes at 90 days.233 Thus, concomitant DVT can be regarded as an indicator of significant comorbidity in acute PE.

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Table 7 Original and simplified Pulmonary Embolism Severity Index

BP = blood pressure; b.p.m. = beats per minute; CI = confidence interval. aBased on the sum of points.

5.6 Prognostic assessment strategy

The classification of PE severity and the risk of early (in-hospital or 30 day) death is summarized in Table 8. Risk assessment of acute PE begins upon suspicion of the disease and initiation of the diagnostic workup. At this early stage, it is critical to identify patients with (suspected) high-risk PE. This clinical setting necessitates an emergency