Pulmonary Embolism


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  • Pulmonary Embolism

    1. 1. Acute Pulmonary Embolism By Medhat A. Soliman Prof. of Pulmonary & Critical Care Medicine Cairo University [email_address]
    2. 2. Severity of acute obstruction pre-existing chronic cor pulmonale Co-morbidity Adverse outcome Pathophysiology of Pulmonary Embolism
    3. 3. Venous Thromboembolism Importance of Right Ventricular Dysfunction PA pressure  RV afterload  RV wall stress  O 2 demand  RV dilation RV dysfunction RV ischemia RV perfusion  RV ejection  Septal shift LV preload  LV ejection  Hypotension / Shock
    4. 4. * RVPO: right ventricular pressure overload In-Hospital Mortality Venous Thromboembolism Continuum of RV Dysfunction W Kasper. J Am Coll Cardiol 1997;30:1165-1171 Massive PE
    5. 5. Respiratory Effects <ul><li>Lung volume reduction </li></ul><ul><ul><li>Low chest wall distension ( pain ) </li></ul></ul><ul><ul><li>Decreased alveolar surfactant </li></ul></ul><ul><li>Hypoxemia </li></ul><ul><ul><li>V/Q mismatch </li></ul></ul><ul><ul><li>R-L shunt </li></ul></ul><ul><ul><li>Decreased O2 in mixed venous blood </li></ul></ul><ul><ul><li>Decreased oxyHB affinity for O2 </li></ul></ul><ul><li>hypercapnia </li></ul>
    6. 6. 2006 2007 Clinical probability Guidelines
    7. 7. State-of-the-art Three scoring systems have been tested prospectively and validated in large scale clinical trials: <ul><li>Wells’ score (Ann Intern Med 1998) </li></ul><ul><li>Geneva score (Arch Intern Med 2001; Ann Intern Med 2006) </li></ul><ul><li>Pisa score (Am J Respir Crit Care Med 1999; Am J Med 2003) </li></ul>Clinical probability
    8. 8. n=1239, mostly outpatients Wells’ score 28% intermediate high low 78% 3% 28% 78% 3% State-of-the-art Clinical probability Low < 2 Intermediate 2 to 6 High > 6 Signs and symptoms of DVT 3.0 Heart rate > 100 1.5 Immobilization or surgery 1.5 Previous DVT or PE 1.5 Hemoptysis 1.5 Malignancy 1.5 PE as or more likely than an alternative diagnosis 3.0
    9. 9. low Geneva score n=986, only outpatients intermediate high 10% 81% 38% State-of-the-art Clinical probability Recent surgery 2 Previous PE or DVT 2 Older age 2 Hypocapnia 2 Hypoxemia 2 Tachycardia 2 Platelike atelectasis 2 Hemidiaphragm elevation 2 Low ≤ 4 Intermediate 5 to 8 High ≥ 9
    10. 10. Pisa score n=750, mostly inpatients 3% 97% 41% intermediate high low State-of-the-art Clinical probability High One or more of three symptoms (sudden onset dyspnea, chest pain, fainting) , not explained, and one or more of three chest x-ray findings (amputation of hilar artery, focal oligemia, pleural-based consolidation) Interme-diate One or more of the above symptoms, alone or with EKG findings of acute right ventricular overload Low None of the above symptoms is present or an alternative diagnosis that may account for their presence is identified
    11. 11. 2006 2007 Guidelines Diagnostic strategies
    12. 12. 2006 2007 D-dimer Diagnostic strategies
    13. 13. D-dimer in suspected PE di Nisio et al, JTH 2007;5: 296-304 SimpliRed (40) Whole-blood assay VIDAS (40) ELFA STA-lia test (25) Tinaquant (12) Latex quantitative Nycocard (23) Instantia (13) Membrane ELISA Asserachrome (24) Microplate ELISA (number of studies) Type of D-dimer 82 (59-93) 96 (93-98) 94 (83-98) 92 (75-98) 88 (68-96) 86 (59-96) 94 (83-98) Sn, % Deep vein thrombosis 72 (56-84) 44 (36-52) 46 (28-64) 53 (32-73) 50 (31-68) 65 (43-81) 47 (29-65) Sp, % 86 (43-97) 97 (91-99) 96 (80-99) 94 (71-99) 91 (64-98) 89 (54-98) 96 (80-99) Sn, % Pulmonary embolism 70 (44-87) 41 (26-57) 43 (20-68) 50 (23-76) 47 (23-72) 62 (33-84) 44 (21-69) Sp, %
    14. 14. D-dimer in suspected PE di Nisio et al, JTH 2007;5: 296-304 100 90 80 70 60 50 40 30 20 10 0 100 90 80 70 60 50 40 30 20 10 0 ELFA Latex quantitative Microplate ELISA Membrane ELISA Latex semiquantitative Whole-blood Latex qualitative Sensitivity, % Specificity, %
    15. 15. D-dimer in suspected PE <ul><li>D-dimer rules out PE in around 30% of patients in the emergency department </li></ul><ul><li>Highly sensitive D-dimer assays rule out PE in patients with a low or intermediate probability </li></ul><ul><li>Less sensitive D-dimer assays should be restricted to patients with a low clinical probability </li></ul><ul><li>D-dimer is not useful nor validated in high probability patients </li></ul><ul><li>The diagnostic yield of D-dimer is lower in cancer patients, the elderly, inpatients and during pregnancy </li></ul>
    16. 16. 2006 2007 Guidelines Diagnostic strategies
    17. 17. Imaging – Modalities until ~1992 ~1998 ~2000 Scinti CT MSCT MIPS , Perfusion-Imaging MRI Angio SPECT
    18. 18. Spiral CT
    19. 19. CT in suspected PE: a story of evolution 2-slice CT 199 2 2 x 2.7 mm 25 sec Courtesy of Emmanuel Coche 4-slice CT 1998 4 x 1 mm 25 sec 64 - slice 2004 64 x 0.625 mm 4 sec 16-slice CT 2002 16 x 0.75 mm 10 sec
    20. 20. MDCT: visualization of peripheral arteries Coche E et al. Eur Radiol 2003;13:815-22. Ghaye et al. Radiology 2001;219:629-36. 96% of subsegmental arteries and 54% of sub-subsegmental arteries are identified on multislice CT (4 rows of detectors) Courtesy of Emmanuel Coche
    21. 21. LR Goodman, University of Wisconsin CT angiography Pulmonary embolism
    22. 22. LR Goodman, University of Wisconsin CT angiography Pulmonary embolism
    23. 23. LR Goodman, University of Wisconsin CT angiography Pulmonary embolism
    24. 24. Multidetector-Row CT: Superior Resolution and Sensitivity
    25. 25. CT angiography Pulmonary embolism
    26. 26. Chest radiography Pulmonary embolism Miniati et al. AJRCCM 1999
    27. 27. Westermark’s sign (1938) Fleischner’s sign (1962) Hampton’s sign (1940) At least one of these findings was identified in 75% of 202 patients with proven PE PISA-PED Am J Respir Crit Care Med 1999 chest radiography Clinical probability
    28. 28. 2006 2007 Guidelines Diagnostic strategies
    29. 30. Chest radiography Pulmonary embolism
    30. 31. Chest radiography Pulmonary embolism
    31. 32. Q scan Chest radiography Pulmonary embolism
    32. 33. Comparison between MD-CTPA and perfusion lung scan
    33. 34. PE ruled out PE ruled out Comparison between MD-CTPA and perfusion lung scan
    34. 35. PE ruled out PE ruled out PE confirmed PE confirmed Comparison between MD-CTPA and perfusion lung scan
    35. 36. Role of V/Q scan in PE diagnosis <ul><li>Contraindications to CT scan: </li></ul><ul><ul><li>Allergy to iodine contrast agents </li></ul></ul><ul><ul><li>Renal failure </li></ul></ul><ul><ul><li>Pregnancy? </li></ul></ul><ul><li>High diagnostic yield and avoidance of unnecessary irradiation </li></ul><ul><ul><li>Pregnant patients </li></ul></ul><ul><ul><li>Young patients with normal chest X-ray </li></ul></ul><ul><li>Local logistics </li></ul>
    36. 37. Advantages of CT for PE: summary <ul><li>Multidetector CT is widely available and accurate for ruling in and ruling out PE </li></ul><ul><li>It is also somewhat useful for differential diagnosis purposes </li></ul><ul><li>A strategy combining clinical assessment, D-dimer and CT is valid and cost-effective </li></ul><ul><li>If V/Q scanning is available, it should be considered in younger patients or in presence of contraindications to CT </li></ul>
    37. 38. Clinical probability of PE assessment Implicit or prediction rule Validated algorithm for diagnosing PE based on CT < 500 µg/L No Rx Low or intermediate ELISA D-dimer No PE V/Q scan? CT venography? Angiography? Lower limb US? Helical CT PE Rx High No PE No Rx PE Rx > 500 µg/L Helical CT ?
    38. 39. Conclusions <ul><li>Clinical probability assessment (implicit or by a score) should be incorporated in diagnostic algorithms for PE </li></ul><ul><li>Highly sensitive D-dimer assays are safe first-line tests to rule out PE in patients with a low-intermediate clinical probability </li></ul><ul><li>Multidetector CT is safe to rule out PE in outpatients with low/intermediate clinical probability </li></ul><ul><li>V/Q lung scan is still useful in patients with no preexisting lung disease and those with conraindications to CT </li></ul><ul><li>Algorithms should be adapted to local logistics and regularly updated </li></ul>
    39. 40. Initial Therapy for APE <ul><li>Anticoagulant therapy </li></ul><ul><li>Vena caval filter </li></ul><ul><li>Thrombolytics </li></ul><ul><li>Embolectomy </li></ul>
    40. 43. Hirsh, J. et al. Chest 2008;133:141S-159S Inactivation of clotting enzymes by heparin
    41. 46. Subcutaneous UFH <ul><li>Monitored SC UFH: initial dose of 17,500 U/12h , or a weight –adjusted dose of approximately 250U/kg/12h with dose adjustment depending on APTT </li></ul><ul><li>Fixed unmonitored SC UFH : initial dose of 333 U/kg followed by a twice daily dose of 250 U/kg /12 h </li></ul>
    42. 47. Hirsh, J. et al. Chest 2008;133:141S-159S Molecular weight distributions of LMWHs and heparin
    43. 48. LMWH Prepared from animal gut mucosa; contains heparin sulfate (84%), dermatan sulfate (12%), and chondroitin sulfate (4%) NV Organon/Oss, Netherlands Danaparoid sodium (Orgaran) Nitrous acid depolymerization Knoll/Markham, Ont Reviparin (Clivarine) Enzymatic depolymerization with heparinaze Leo Laboratories/Dublin, Ireland Tinzaparin (Innohep) Peroxidative depolymerization Wyeth-Ayerst/Philadelphia, PA Ardeparin (Normiflo) Nitrous acid depolymerization Pharmacia/Peakack, NJ Dalteparin (Fragmin) Benzylation followed by alkaline depolymerization Aventis/Collegeville, PA Enoxaparin sodium (Lovenox/Clexane) Nitrous acid depolymerization Sanofi/Gentilly, France Nadroparin calcium (Fraxiparin) Method of Preparation Manufacturer/Location Agents
    44. 49. 4.1Initial anticoagulation in VTE <ul><li>For patients with objectively confirmed non-massive PE, we recommend acute treatment with subcutaneous LMWH, or intravenous UFH (both Grade 1A) </li></ul><ul><li>For patients with a high clinical suspicion of PE, we recommend treatment with anticoagulants while awaiting the outcome of diagnostic tests (Grade 1C+) </li></ul><ul><li>In patients with acute non-massive PE, we recommend LMWH over UFH (Grade 1A) </li></ul><ul><li>In acute non-massive PE, we recommend initial treatment with LMWH or UFH for at least 5 days (Grade 1C) </li></ul>Item 1 Item 2 Item 3 Item 4 Item 5 Item 6 Item 7 Item 8 Item 9 598,1,2,1,0,1,1,1,1,1,1,1,1,0 HR Büller 7th ACCP Conference Chest 2004; 126: 401S-428S
    45. 50. <ul><li>Total 29 comparative studies </li></ul><ul><li>15 excluded: dose finding; duplicate reports; inability to extract clinical data; adjusted dose LMWH </li></ul><ul><li>14 studies analyzed for incidence recurrent VTE, major bleeding and mortality (n=4754 ) </li></ul><ul><ul><ul><li>van Den Belt AG, Prins MH, Lensing AW, et al. Fixed dose subcutaneous LMWH versus adjusted dose unfractionated heparin for venous thromboembolism. The Cochrane Library, issue 4, 2002. </li></ul></ul></ul>LMWH versus UFH in the treatment of acute venous thromboembolism
    46. 51. <ul><li>LMWH UFH OR 95% CI </li></ul><ul><li>Recurrent VTE 86/1998 113/2021 0.75 0.55-1.01 </li></ul><ul><li>3.8% 2.6% </li></ul><ul><li>Major hemorrhage 30/2353 51/2401 0.60 0.39-0.93 </li></ul><ul><li>1.3% 2.1% </li></ul><ul><li>Mortality 135/2108 172/2137 0.78 0.62-0.99 </li></ul><ul><li>6.4% 8.0% </li></ul>LMWH versus UFH
    47. 52. Similar efficacy Superior safety Out of hospital Cost-effective Easier to use Less thrombocytopenia No laboratory monitoring LMWH drug of choice in the treatment of venous thromboembolism
    48. 53. <ul><li>Synthetic pentasaccharides </li></ul><ul><li>FONDAPARINUX </li></ul><ul><li>IDRAPARINUX </li></ul><ul><li>O ral Direct Thrombin Inhibitor </li></ul><ul><li>XIMELAGATRAN </li></ul>New drugs for the Treatment of DVT and PE
    49. 54. Pentasaccharides tailor made OCH 3 OCH 3 Fondaparinux ( Arixtra ® ) MOST LIKE NATURAL Once-a-day (1987) Org31550 MORE POTENT A new binding site discovered Idraparinux, SanOrg34006 SIMPLIFIED (1992) Once-a-week
    50. 55. Specific inhibition of factor Xa via ATIII Fondaparinux Idraparinux DX9065a BAY59-7939 LY-51,7717 BMS-562247 Mechanism of Action: 1 AT pentasacharides 3 AT Xa IIa II Fibrinogen Fibrin clot Extrinsic pathway Intrinsic pathway Xa AT 2
    51. 56. Fondaparinux Idraparinux <ul><li>Terminal half-life ~15 hours </li></ul><ul><li>Terminal half-life ~130 hours </li></ul><ul><li>100% bioavailability via the subcutaneous route </li></ul><ul><li>No metabolites and excreted mainly in the urine </li></ul><ul><li>Linear, dose-dependent pharmacokinetic profile </li></ul><ul><li>Peak concentration (C max ) reached in 1–3 hours </li></ul><ul><li>No significant binding to other blood, plasma or endothelial proteins </li></ul>
    52. 57. Conclusions <ul><ul><ul><li>Fondaparinux is at least as effective and equally safe as UFH for the initial treatment of PE and as LMWH for the initial treatment of DVT </li></ul></ul></ul><ul><ul><ul><li>The fondaparinux regimen is a once daily s.c. injection without body-weight adaptation and offers an uniform approach for both DVT and PE patients </li></ul></ul></ul><ul><ul><ul><li>Will allow for simplified treatment at home </li></ul></ul></ul>
    53. 58. Anticoagulation for Treatment of PE ACCP Guidelines 8 th Ed; 2008 <ul><li>For patients with objectively confirmed PE , we recommend short- term treatment with SC LMWH (Grade 1A) , IV UFH (Grade 1A) , monitored SC UFH (Grade 1A) , fixed –dose SC UFH (Grade 1A) ,or SC fondaparinux(Grade1A). </li></ul><ul><li>For patients in whom there is a high clinical suspicion of PE , we recommend treatment with anticoagulants while awaiting the outcome of diagnostic tests( Grade 1C) </li></ul><ul><li>In patients with acute PE , we recommend initial treatment with LMWH, UFH or fondaparinux for at least 5 days and until the INR is > 2.0 for at least 24h (Grade 1C) </li></ul><ul><li>In patients with acute PE , we recommend initiation of oral anticoagulants together with LMWH, UFH , or fondaparinux on the first treatment day (Grade 1A) </li></ul>
    54. 59. Anticoagulation for Treatment of VT and PE (cont.) <ul><li>In patients with acute nonmassive PE , we recommend initial treatment with LMWH over IV UFH (Grade 1A) </li></ul><ul><li>If there is concern about SC absorption , or in patients for who throbomlytic therapy is being considered or planned , we suggest IV UFH over SC LMWH, SC fondaparinux , or SC UFH (Grade 2C) </li></ul><ul><li>In patients with acute PE treated with LMWH , we recommend against routine monitoring with anti- factor Xa level measurements( Grade 1A) . </li></ul><ul><li>In patients with acute PE and severe renal failure , we suggest UFH over LMWH ( Grade 2C) </li></ul>
    55. 61. Initial therapy for APE <ul><li>Anticoagulant therapy </li></ul><ul><li>Vena caval filter </li></ul><ul><li>Thrombolytics </li></ul><ul><li>Embolectomy </li></ul>
    56. 62. Retrievable Vena cavafilter(ALN ) for secondary prevention of VTE Mismetti et al Chest 2007; 131: 223-9 <ul><li>Prospective cohorte study of 220 retrivable filters (1999-2005) 18 months follow-up </li></ul><ul><li>All patients had an acute or past of VTE </li></ul><ul><li>Indications for filter placement: </li></ul><ul><ul><li>Recurreces vte 10.9% </li></ul></ul><ul><ul><li>Transient bleeding event 21.8% </li></ul></ul><ul><ul><li>Definitive CI to A C2 26.8% </li></ul></ul><ul><ul><li>Obligation to stop AC for surgery,major trauma </li></ul></ul><ul><ul><li>or invasive procedure 37.7% </li></ul></ul><ul><ul><li>Filter retrievable was attempted in 25.3%after a median of 51 Days(range 6 to 352 days ) and succesfull in 92% </li></ul></ul><ul><li>For most patients with PE , we recommend against the routine </li></ul><ul><li>use of a vena caval filter in addition to anticoagulants (Grade 1A) </li></ul><ul><li>In patients with acute PE , if anticoagulant therapy is not possible </li></ul><ul><li>Because of risk of bleeding , we recommend placement of an IVC </li></ul><ul><li>Filter ( Grade 1C) </li></ul><ul><li>For patients with acute PE who have an IVC filter inserted as an </li></ul><ul><li>alternative to anticoagulants , we recommend that they should </li></ul><ul><li>Subsequently receive a conventional course of anticoagulant therapy </li></ul><ul><li>If their risk of bleeding resolves ( Grade 1C ) </li></ul><ul><li>ACCP Guidelines 8 th Ed ; (2008) </li></ul>
    57. 63. Initial therapy for APE <ul><li>Anticoagulant therapy </li></ul><ul><li>Vena caval filter </li></ul><ul><li>Thrombolytics </li></ul><ul><li>Embolectomy </li></ul>
    58. 64. Severity of pulmonary embolism Clinical Massive Non-massive Different management strategies Thrombolysis Heparins
    59. 65. Shock SBP<90 mmHg : Miller index/angio/sCT/autopsy : Swan-Ganz, Echo-Doppler Anatomic Hemodynamic Clinical Massive Non-massive Classification of severity of pulmonary embolism ESC Task Force 2000 Syncope HR/SBP > 1
    60. 66. NP Fam. N Engl J Med 2002; Vol. 347, No. 15 Massive PE With Haemodynamic Instability Rationale For Thrombolysis
    61. 67. Size/morphology of PE thrombi Saddle PE – no influence on outcome Pruszczyk et al., Heart 2002 Mobile PE – better outcome on th-lysis Podbregar et al., Chest 2002
    62. 68. Acute PE: Approved thrombolytic regimens Accelerated regimen: 0.6 mg/kg over 15 min 100 mg over 2 h rtPA Accelerated regimen: 3 million IU over 2 h 4,400 IU/kg as a loading dose over 10 min, followed by 4,400 IU/Kg/h over 12-24 h Urokinase Accelerated regimen: 1.5 million IU over 2 h 250,000 IU as a loading dose over 30 min, followed by 100,000 IU/h over 12-24 h Streptokinas e
    63. 69. THROMBOLYTIC THERAPY in the treatment of acute PE <ul><li>For most patients with PE,we recommend clinicians do not use thrombolytic therapy (1A) </li></ul><ul><li>For patients who are hemodynamically unstable, we suggest use of thrombylitic therapy (2B) </li></ul>7th ACCP Conference on Antithrombotic and Thrombolytic therapy( CHEST 2004,)
    64. 70. Severity of pulmonary embolism RV hypokinesis (Echo) Hemodynamic Clinical Massive Non-massive submassive ESC Task Force 2000
    65. 71. submassive TH-lysis ? SBP<90mmHg Shock, ECHO/CT High PASP ? RV dilatation ? RV domination ? IVC distension ? RV hypokinesis ? pressure overload reversible (?) RV failure subjective assessment
    66. 72. RV RV D /LV D < 0.9: good prognosis RV D /LV D >0.9 : high death risk 4 retrospective studies; 692 patients Venous Thromboembolism Risk Stratification: Multidetector-CT
    67. 73. Risk Stratification of PE Contemporary Algorithm for PE Severity PE confirmed, stable patient Troponin (or BNP) testing Imaging of RV (Echo, CT) Low risk (non-massive PE) Intermediate risk (submassive PE) Biomarker test negative AND RV normal Either biomarker positive OR RV abnormal Biomarker test positive AND RV abnormal
    68. 74. Risk Stratification of PE Therapeutic Implications High-Risk PE Shock, CPR Low Risk Patient normotensive Anticoagulation LMWH►VKA Thrombolysis Surgery / Intervention Intermediate Risk normotensive, echo+, biomarker+ ? 5% 85% 10%
    69. 75. <ul><li>Thrombolysis in Submassive PE </li></ul><ul><li>PE confirmed by lung scan, Spiral CT , or pulmonary angiography </li></ul><ul><li>2.CT ; RV/LV > 0,9 </li></ul><ul><li>3. Systolic blood pressure on admission  90 mm Hg </li></ul><ul><li>4. RV dysfunction on echocardiography </li></ul><ul><li>5. Positive Troponin T test and NT- proBNP </li></ul>
    70. 76. Initial therapy for PE <ul><li>Anticoagulant therapy </li></ul><ul><li>Thrombolytics </li></ul><ul><li>Embolectomy </li></ul>
    71. 77. Massive PE With Haemodynamic Instability Surgical Embolectomy L Aklog. In: Management of Pulmonary Embolism. Humana Press 2007
    72. 78. Massive PE With Haemodynamic Instability Catheter-Based Procedures N Kucher. In: Management of Pulmonary Embolism. Humana Press 2007 AngioJet Xpeedior, Possis, MN Aspirex, Straub, CH
    73. 79. <ul><li>For most patients with PE, we recommend against pulmonary embolectomy ( Grade 1C ) </li></ul><ul><li>In selected highly compromised patients who are unable to receive thrombolytic therapy or whose critical status does not allow sufficient time to infuse thrombolytic therapy, we suggest use of mechanical approaches ( Grade 2C ) </li></ul><ul><li>ACCP recommendations for antithrombotic therapy </li></ul><ul><li>Chest 2004 </li></ul>Pulmonary embolectomy for the initial treatment of PE
    74. 80. 488 patients underwent thrombolysis 40 (8.2%) did not respond within 36 h (persistent “clinical instability” + RV dysfunction) Repeat Thrombolysis (n=26) Uneventful in-hospital course in 31% (mortality, 38%) A prospective single-centre registry N Meneveau. Chest 2006;129:1043-1050 Surgical Embolectomy (n=14) Uneventful in-hospital course in 79% (mortality, 7%) P=0.004 Massive PE With Haemodynamic Instability Embolectomy After Failed Thrombolysis
    75. 82. Prognostic Parameters for Acute PE <ul><li>Age > 70 years </li></ul><ul><li>Hemodynamic status at presentation </li></ul><ul><li>- Shock </li></ul><ul><li>- Hypotension (SBP < 90 mmHg) </li></ul><ul><li>- Syncope </li></ul><ul><li>Comorbidities (CHF, COPD, Cancer, Renal Failure) </li></ul><ul><li>Physical findings of RV dysfunction </li></ul><ul><li>ECG signs of RV strain </li></ul><ul><li>ECHO: - RV dilatation and dyskinesis </li></ul><ul><li>- Free-floating right heart thrombi </li></ul><ul><li>- PA systolic pressure > 50 mmHg </li></ul><ul><li>- Patent foramen ovale </li></ul><ul><li>CT: RV/LV ratio > 0,9 </li></ul><ul><li>Elevated troponin /FABP level </li></ul><ul><li>Elevated BNP level </li></ul>