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Pulmonary Embolism Review and An Update

Pulmonary Embolism Review and An Update . Pulmonary Embolism: A Major Cause of Hospital Death. Accounts for 10% of all in hospital deaths. Major contributing factor in a further 10%. Overall mortality rate of approximately 14%.

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Pulmonary Embolism Review and An Update

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  1. Pulmonary Embolism Review and An Update

  2. Pulmonary Embolism: A Major Cause of Hospital Death Accounts for 10% of all in hospital deaths Major contributing factor in a further 10% Overall mortality rate of approximately 14% Linblad B. Br Med J 1991;302:709-711 Wessler S. NIH 1986 Consensus Development Conference on Prevention of PE

  3. Pathophysiology of Cardiac Compensatory Mechanisms In APE

  4. Important Variables • Pt’s baseline characteristics/comorbidities • Embolus size: anatomic vs. physiologic • Adequacy of cardiopulmonary compensatory mechanisms • Time to presentation, diagnosis,and initiation of proper therapy

  5. Magnitude of the Problem: PE CHF Via Venous Stasis Existing pts w CHF • Mechanisms of Heart Failure Post-PE • Pressure Effects • Volume Effects • Neurohormonal changes • Remodeling • Coronary Ischemia Increased incidence of PE Via Recurrent PE PE pts developing CHF

  6. Pathophysiology of Right Ventricular Dysfunction After Acute Pulmonary Embolism Pulmonary Embolism PA Pressure RV Afterload RV Wall Tension RV Ischemia/ Infarction RV O2 Demand RV Dilatation/ Dysfunction RV O2 Supply RV Cardiac Output IV Septal Shift Toward the LV Coronary Perfusion LV Preload IDENTIFY PTS BEFORE THEY CROSS THIS BRIDGE LV Output Hypotension Lualdi and Goldhaber. Am Heart J. 1995;130:1276-1282.

  7. Post-thrombotic Syndrome 800,000 Silent PE 1 Million Pulmonary Hypertension 30,000 Venous Thromboembolic DiseaseMagnitude of the Problem DVT 2-6 Million Recurrence Clinical PE + 600,000 Internal Medicine Consensus Reports, July, 2002.

  8. Incidence of Symptomatic CTPH after a First, Symptomatic, Properly Treated PE VTE is a CHRONIC disease Pengo, V. et al. N Engl J Med 2004;350:2257-2264

  9. Only those who developed “unexplained persistent dyspnea” had echo S PA pressure > 40 mmHg and mean PA pressure > 25 mmHg We know: 5 yr survival when S PA pressure > 40 is 30%, 10% w S PA pressure > 50 mmHg Incidence of Symptomatic CTPH after a First, Symptomatic, Properly Treated PE Pengo, V. et al. N Engl J Med 2004;350:2257-2264

  10. Risk Stratification of APE APE = Acute Cardiopulmonary Syndrome

  11. Important Aspects in Risk Stratification in APE • Time is survival: The golden hours/days • Minor APE, vs. Major APE, vs. Massive APE • Do not forget the surgical option • Aggressive? (vs. PROACTIVE)

  12. Risk Stratification of PE • The Traditional: Clinical Criteria • The Sophisticated But Old: Radiographic Criteria, Echocardiographic Criteria • The New and Evolving: The Physiologic Criteria, I.e., Cardiospecific Biomarkers

  13. CLINICAL CRITERIA

  14. The Bounameaux PE Point Score (The Geneva Risk Score) Cancer +2 SBP < 90mmHg +1 Score of > 2 predicts death recurrent VTE, or major bleed at 3 months Vicki J et.al Thromb Haemost 2000; 84: 548-552

  15. Risk Factors for Mortality after PE in the ICOPER:a Multivariate Analysis of 815 patients Variable Hazard Ratio (95% CI) Age > 70 yrs 1.6 (1.1-2.3) COPD 1.8 (1.2-2.7) RR > 20 breath/min 2.0 (1.2-3.2) RV Hypokinesis 2.0 (1.3-2.9) Cancer 2.3 (1.5-3.5) Clinical CHF 2.4 (1.5-3.7) SBP < 90mmHg 2.9 (1.7-5) Goldhaber SZ et.al Lancet 1999;353: 1386-1389

  16. History of congestive heart failure is associated with a worse long - term survival following acute PE • Less reserve allows small emboli to have significant effects • Pre-existing RV dysfunction decreases cardiac output • Unpredictable clinical response to emboli • Increased risk for recurrent emboli 29 months follow up Factors affecting outcome % Mortality Paraskos et al. NEJM 1973;289:55-8

  17. ECHOCARDIOGRAPHY IN APE

  18. Echocardiography in the diagnosis of PE • Cannot use as a single diagnostic tool • RV hypokinesis present in only 40% of patients with APE with normal systemic pressure • Useful tool to risk stratify in patients diagnosed with PE • Larger perfusion defect on V/Q scan are associated with RV dysfunction • Transesophageal echo useful in assessing thrombus in pulmonary artery

  19. Physical signs Systemic hypotension Right-sided S3 Increased jugular venous pressure Cyanosis Tricuspid regurgitation Parasternal lift Palpable impulse at LUSB Clinical Manifestations of RV Dysfunction • Symptoms • Dyspnea • Lightheadedness • Syncope

  20. RV dysfunction in APE • Echo findings in acute PE • RV dilatation • RV hypokinesis • IV septal flattening • Dec. inspiratory collapse of IVC • Right PA dilatation • Tricuspid regurgitation Outcomes with RV Dysfunction • 2-fold increased 14-day mortality rate • 3-fold increase in 1-year mortality rate • Increased risk of recurrent PE • ?Increased risk of in situ thrombosis in RV and RA

  21. Potential Mechanisms Acute  afterload  RV more spherical shape to distribute pressure Localized ischemia of the RV free wall Tethering of RV apex to hyperdynamic LV Regional Pattern Akinesia of the mid-RV free wall Normal RV apex and base Sensitivity=77% Specificity=94% PPV=71% NPV=96% McConnell’s Sign in the Diagnosis of PE McConnell et al. Am J Card 1996;78:469-73

  22. The Incidence of PE in unexplained sudden cardiac arrest with PEA Emergency TEE for Sudden Cardiac Arrest (n = 36) V Fib, VT, Asystole (n = 11) PEA (n = 25) No isolated RV enlargement (n = 11) RV enlargement w/o LV enlargement (n = 14) No PE (n = 5) PE (n = 9) PE seen at autopsy (n = 1) PE seen on TEE (n = 8) Contusion (n = 1) RV infarct (n = 1) Cor Pulmonale (n = 1) Ventricular Hypertrophy (n = 2) 2 survived hospitaliz. Comess KA, et al. Am J Med 2000;109:351-356

  23. Problems with Echocardiography • Findings are operator-dependent • Only able to visualize thrombus in PA (0 -19%) • Left PA distal to left main bronchus not examined • Specificity of isolated RV dilatation is low (COPD, RV infarct, Cardiomyopathy, Valvular heart disease, cardiac sarcoidosis, technical error) • Low utility for TTE in critically-ill patients Gossage JR. Chest 1997;112:1158-1159

  24. X 4 X 1.5 ICOPER Mortality Rates in 2454 patients (52 hospitals, 7 countries) Hospital 2 weeks 3 months Total mortality Hemodynamically unstable (103; 4.2%) Hemodynamically stable (2182; 88.9%) No RV dysfunction(n= 263) RV dysfunction (n= 428) N/A N/A N/A 10% 19% 11.4% N/A N/A 11% 21% 17.4% 58.3% 15.1% 15.0% 23.0% Goldhaber et al. Lancet. 1999;353:1386—1389.

  25. M/S RVD and Other Benefits of Echo in APE • Diagnostic tool (Hemo- dynamically unstable pts w unexplained dyspnea, syncope, or RVD) • PFO: 35% prevalence in pts w APE and RVD, mortality 33% (vs 14% w/o PFO) • RAT: Double mortality at 14 days (21% vs 11%) compared to those w/o RAT • 15%, mortality independent of BP • Predicts complicated in-hospital course • Predicts recurrence (mortality 50%) • Predicts persistent pulmonary HTN (initial RVSP > 50 mmHg, persistance >38 days) Circulation. 1998 May 19;97(19):1946-51. J Am Coll Cardiol. 2003 Jun 18;41(12):2245-51 Goldhaber, Lancet, 1993 & 1999. Grifoni, Circ 2000. Kasper, Heart 1997. Ribeiro Am Heart J 1997 & J Intern Med 1999.

  26. Cardiospecific Troponins in APE

  27. + Tn - Tn Cardiac Troponins (I & T) and Other Findings at Presentation 100 P<0.05 80 60 P<0.001 Patient (%) 40 20 0  BP ECG Echo CPK

  28. 60 50 40 30 20 10 0 Mortality Complications Recurrence In-Hospital Course Based on cTn at Presentation Normal Tn Moderately  Tn High Tn Patient (%)

  29. < 0.07 40 0.07 – 0.6 > 0.6 30 20 10 0 Relation Between cTnI Concentrations on Admission and Mortality (%). 36 % 4.8 0 Mortality La Vecchia: Heart, Volume 90(6).June 2004.633-637

  30. Cardiac Troponins as Determinants of Outcome in APE

  31. Prediction of In-Hospital Mortality La Vecchia: Heart, Volume 90(6).June 2004.633-637

  32. Proposed cTnT Curve Release Characteristics MC MC MC Time Time Time

  33. Elevated Cardiac Tn in the Absence of Acute MI • Acute PE • Acute pericarditis • Acute or severe heart failure • Myocarditis • Sepsis and/or shock • Renal failure • False positive troponin

  34. BNP in APE • low median BNP levels predict benign clinical outcome in APE • No correlation between RV systolic pressure and BNP • NPV for proBNP < 500 pg/mL to predict adverse outcome was 97% • proBNP independent predictor of adverse clinical outcome: OR 14.6 (1.5-139), P 0.02, even after adjustment for: Submassive or massive Tulevski et al November 2001Kucher et al, April 2003

  35. ten Wolde et alApril 2003 • Higher median BNP levels were associated with: - death within 3 months, P <0.001 - all cause death (adjusted for age and cancer) OR 9.4 (1.8-49.2) - death related to PE: OR 14.1 (1.5-131.1) • NPV for uneventful outcome of a BNP value <21.7 pmol/L is 99% (93%-100%)

  36. Kucher et alMay 2003 • Median BNP higher in patients with adverse events than in patents with benign course: - 194.2 pg/mL (3.7-1201.1) vs 39.1 (1.0-1560.0) • A cut-off of < 50 pg/mL (lower than that used as the cut-off value for CHF, <90 pg/mL) identified 95% of patients with a benign clinical course

  37. Reasons to Consider Thrombolysis in Pulmonary Embolism • Treat acute hemodynamic instability • Reverse abnormal hemodynamics • Lower mortality • Reverse acute and subacute RV dysfunction • Prevent chronic thromboembolic-induced pulmonary hypertension

  38. Randomized trial intending to enroll 40 patients Massive PE, hypotension, and heart failure Stopped after 8 patients Results Group Outcome SK+Heparin 0 of 4 died Heparin 4 of 4 died Autopsy in 3 of 4 revealed evidence of RV infarct and no significant CAD 1,500,000 U/1 Hour streptokinase with heparin is more effective than heparin alone in PE with heart failure Jerjes-Sanchez et al. J Thromb Thrombolysis 1995;2:227-9

  39. Kaplan-Meier Estimates of the Probability of Event-free Survival among Patients with Acute Submassive Pulmonary Embolism, According to Treatment with Heparin plus Alteplase or Heparin plus Placebo P = 0.006 256 normotensive pts w PE and pulm. HTN or RV dysfunction RCDB Trial: 100 mg Alteplase over 2 hrs (118 pts) vs. UFH and placebo End points: in hospital mortality or escalation of Rx (pressors, secondary lysis, intubation, CPR, thrombectomy) Konstantinides, S. et al. N Engl J Med 2002;347:1143-1150

  40. In-HospitalEvent Thrombolysis(n = 169) Heparin(n = 550) P Value Death 4.7% 11.0% .016 Death from PE 4.1% 10.0% Recurrent PE 7.7% 19.0% <.001 Major bleeding 22.0% 7.8% <.001 Intracranial bleed 1.2% 0.4% The MAPPET Registry 1001 patints from 204 prticipating German venters 9/1993-12/1994. PE with RV dysfunction and/or Pulmonary HTN The Management and Prognosis of Pulmonary Embolism Registry (MAPPET) Konstantinides et al. Circulation. 1997;96:882–888.

  41. A MI Pericardial Tamponade Aortic Dissection Fulminant Pneumonia H & P CXR ECG Echocardiogram DDx of A PEMust Rule Out Other Potentially Life-Threatening Disorders

  42. Thrombolysis (n = 12) Heparin (n = 11) Rest Exercise Rest Exercise Pulmonary artery pressure Pulmonary vascular resistance 17 171 19 179 22* 351** 32 437 Long-Term Hemodynamic Benefit of lytic Rx in Patients With PE *P <. 05 **P < .02 Sharma et al. Vasc Med. 2000;5:91–95.

  43. Contraindications to Fibrinolytic Therapy • Recent major trauma or surgery (within 10 days) • Recent CVA, intracranial, intraspinal trauma or surgery (within 2 months) • Bleeding diathesis • Active internal bleeding • Uncontrolled hypertension (SBP >200 or DBP >110 mmHg) • Cardiopulmonary resuscitation (prolonged) • Pregnancy • Infective endocarditis • Diabetic proliferative retinopathy

  44. Thrombolytic Regiments: T-PA 50-90 mg 47 pts T-PA 100 mg 138 pts T-PA 0.6 mg/kg bolus 59 pts UK 2000u/lb/hr x 24 hrs 23 pts UK 3 million U/2 hrs 45 pts Risk Factors for Bleeding Age >70 y led to x 4 bleeding risk compared to those < 50 y/o Increased BMI > 30 leads to x 2 increased bleeding risk compared to <25 Catheterization leads to x 5 bleeding risk compared to no catheterization Analysis of 312 patients who received lytic Rx in 5 clinical trials (t-PA and UK) Mikkola KM, et al. Am Heart J1997;134:69-72

  45. Treatment of Acute PE: Old Algorithm Massive PE (>50% perfusion defect) Moderate to large PE (>30% perfusion defect) Small PE Hemodynamic instability Hemodynamically stable; normal RV Hemodynamically stable; normal RV Impaired cardio- pulmonary reserve RV dysfunction on echocardiogram Young, low- risk patient Hemodynamic instability and/or RV dysfunction Thrombolysis (unless contraindicated) Heparin Long-term anticoagulation Thrombolysis Modified from Olin in: Stoller JK et al. Cleveland Clinic Intensive Rev Internal Med. 2nd ed;2000: 413–427. Wolfe et al. Curr Prob Cardiol. 1993;18:587–633. Lualdi and Goldhaber. Am Heart J. 1995;130:1276–1282.

  46. PE NO SHOCK SHOCK BNP  TROPONIN  BNP  OR TROPONIN  ECOCARDIOGRAPHY NO RV DYSFUNCTION RV DYSFUNCTION ANTICOAGULATION, ONGOING EVALUATION THROMBOLYSIS OR EMBOLECTOMY Treatment of Acute PE: Proposed Algorithm Kucher and Goldhaber, Circ 11/2003

  47. FDA-Approved Lytic Regimens for PE • Streptokinase • 250,000 IU load over 30 minutes • 100,000 IU/hr for 24 hours • Urokinase • 4400 IU/kg load over 10 minutes • 4400 IU/kg/h for 12-24 hours • rt-PA • 100 mg IV over 2 hours

  48. Thrombolytic Therapy in Pulmonary Embolism • rt-PA 100 mg over 2 hours was superior to a low-dose regimen of UK (4400 /kg/h) at 2 hours, but there was no difference at 24 hours1 • rt-PA 100 mg over 2 hours is equal in efficacy to UK 3 million units over 2 hours2 1. Goldhaber et al. Lancet. 1988;1:293-298. 2. Goldhaber et al. J Am Coll Cardiol. 1992;20:24-30.

  49. Surgical Results of Pulmonary Thromboendarterectomy (1997-2000) Fedullo PF et al. New Engl J Med. 2001.345:1465-72.

  50. Incidence of Intracranial Hemorrhage Withrt-PA Treatment for Pulmonary Embolism Dose of rt-PA, mg Incidence of ICH Source (Year) Goldhaber (1987) Goldhaber (1988) Verstraete (1988) PIOPED (1990) Levine (1990) Goldhaber (1992) Dalla-Volta (1992) Meyer (1992) Diehl (1992) Goldhaber (1993) Goldhaber (1994) Sors (1994) Gulba (1994) Gisselbrecht (1996) Total Fatal ICH 0/47 0/22 0/34 0/9 0/33 2/44 1/20 0/34 2/54 1/46 3/87 0/53 1/22 2/54 12/559 (2.1%) 9/559 (1.6%) 50—90 100 50—100 40—80 ~50 100 100 100 ~67 100 50 or 100 50 or 100 120 50—100

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