This document discusses the pathophysiology and treatment of acute pulmonary embolism (PE). It covers: - The pathophysiological effects of PE on right ventricular function and hemodynamics. - Clinical prediction rules and diagnostic strategies for PE including D-dimer testing and imaging modalities like CT, VQ scan, and angiography. - Treatment options for PE including anticoagulants like heparin, low molecular weight heparin, fondaparinux, and newer oral agents; as well as thrombolytics, vena cava filters, and embolectomy. LMWH is recommended as first-line treatment due to superior safety compared to unfractionated heparin

1. Acute Pulmonary Embolism By Medhat A. Soliman Prof. of Pulmonary & Critical Care Medicine Cairo University [email_address]

2. Severity of acute obstruction pre-existing chronic cor pulmonale Co-morbidity Adverse outcome Pathophysiology of Pulmonary Embolism

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. * 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

6. 2006 2007 Clinical probability Guidelines

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. 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. 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. 2006 2007 Guidelines Diagnostic strategies

12. 2006 2007 D-dimer Diagnostic strategies

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. 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, %

16. 2006 2007 Guidelines Diagnostic strategies

17. Imaging – Modalities until ~1992 ~1998 ~2000 Scinti CT MSCT MIPS , Perfusion-Imaging MRI Angio SPECT

18. Spiral CT

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. 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. LR Goodman, University of Wisconsin CT angiography Pulmonary embolism

22. LR Goodman, University of Wisconsin CT angiography Pulmonary embolism

23. LR Goodman, University of Wisconsin CT angiography Pulmonary embolism

24. Multidetector-Row CT: Superior Resolution and Sensitivity

25. CT angiography Pulmonary embolism

26. Chest radiography Pulmonary embolism Miniati et al. AJRCCM 1999

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. 2006 2007 Guidelines Diagnostic strategies

30. Chest radiography Pulmonary embolism

31. Chest radiography Pulmonary embolism

32. Q scan Chest radiography Pulmonary embolism

33. Comparison between MD-CTPA and perfusion lung scan

34. PE ruled out PE ruled out Comparison between MD-CTPA and perfusion lung scan

35. PE ruled out PE ruled out PE confirmed PE confirmed Comparison between MD-CTPA and perfusion lung scan

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 ?

43. Hirsh, J. et al. Chest 2008;133:141S-159S Inactivation of clotting enzymes by heparin

47. Hirsh, J. et al. Chest 2008;133:141S-159S Molecular weight distributions of LMWHs and heparin

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

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

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

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

64. Severity of pulmonary embolism Clinical Massive Non-massive Different management strategies Thrombolysis Heparins

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

66. NP Fam. N Engl J Med 2002; Vol. 347, No. 15 Massive PE With Haemodynamic Instability Rationale For Thrombolysis

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

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

70. Severity of pulmonary embolism RV hypokinesis (Echo) Hemodynamic Clinical Massive Non-massive submassive ESC Task Force 2000

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

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

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

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%

77. Massive PE With Haemodynamic Instability Surgical Embolectomy L Aklog. In: Management of Pulmonary Embolism. Humana Press 2007

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

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