50 year old woman with hypoxia and syncope

1. 50 year old woman with hypoxia and syncope Mary Pak, MD Primary Care Conference August 25, 2004

2. Objectives Clinical presentation of a patient with pulmonary embolism Pathophysiology of hemodynamically significant pulmonary embolism Discussion of the evidence-based role of thrombolytic therapy in pulmonary embolism Disclosure No financial support was provided for this presentation

3. Case Presentation 50 year old woman was brought to the ER by her husband after he witnessed her �passing out�. Starting at 10AM of the morning of admission, the patient and her husband report at least 3 episodes of �passing out�, twice where the patient woke up on the floor. No seizure activity noted. No bowel or bladder incontinence. Episodes usually activity related like walking to the bathroom.

4. Case Presentation (con�t) Review of Systems: Low grade fevers 99.6 to 100.2, ? Chills, weight loss 10 lbs. Dyspnea, worsening x 2 weeks ? Chest tightness ? Worse with respirations No lightheadedness or dizziness No palpitations

5. Case Presentation (con�t) PMH: Recurrent clear cell CA ovary (s/p TAH-BSO, carboplatin/taxol) (s/p partial omentectomy 5/04) Rosacea Hypertension Rheumatic fever as a child Reactive Airway Disease DJD Allergies: Amoxicillin Ibuprofen

6. Case Presentation (con�t) Medications: Losartan 50 mg daily HCTZ 50 mg twice daily hydrocortisone 50 mg po bid spironolactone 50 mg po bid ibuprofen 600 mg po q6h glucosamine Topical metronidazole omeprazole zolpidem PRN

7. Case Presentation (con�t) Social History: Married, former insurance claims examiner, denies any smoking, alcohol or drug use. Family History: Father died at age 72, hx HTN Brother ?blood disorder No other cancers

8. Case Presentation (con�t) Physical Examination: Temp 36.4, BP 118/84, pulse 116, resp 20 O2 sat 98% 4L O2 Lungs: bibasilar crackles, no wheezes CV: Regular rhythm, tachycardic, 2/6 systolic murmur enhanced by respirations, no rubs or gallops Abdomen: soft, obese, NT, well-healed midline scar with minimal serosanguinous drainage. Ext: no edema, good pulses, no Homan�s sign Neuro: nonfocal

9. Patient Data CXR read out as prominent pulmonary vascularity, no air space diseaseCXR read out as prominent pulmonary vascularity, no air space disease

10. Patient Data (con�t) Labs: Creatinine 0.8, K 4.6, CO2 22 WBC 9.2, Hgb 9.8, hct 29 plt 336, INR 1.2 D-Dimer 8.9 CK 30, troponin 0.3 ABG: 7.45/29/80 on 4L O2

11. Patient Data (con�t) EKG sinus tachycardia ~120, S wave in lead I, small Q wave in lead III,  T wave inversions in lead III, and V1 � V3. CT Angio Multiple filling defects including central left and right main pulmonary arteries, left subclavian thrombus, markedly dilated right ventricle. �Extensive and multiple acute and chronic PE�

12. Patient Data (con�t) Echocardiogram: RV findings c/w massive acute PE with markedly dilated RV and severely reduced systolic function. Findings also notable for large multilobulated, non-mobile RV thrombus along the apical wall. Normal LV systolic function.

13. Pulmonary Embolism PE is a common and often life-threatening disease. Mortality rates reported 28% 30-day mortality in Olmsted County 17.4% 3-month mortality in the International Cooperative Pulmonary Embolism Registry (52 institutions in 7 countries) 14% in-hospital mortality in a Japanese registry On average, 200,000 deaths a year due to PE

14. Causes of Death in the US Pulmonary Embolism1 ~200,000 Coronary Heart Disease2 ~460,000 AIDS 2* 13,426 Breast Cancer 3# 40,200 Highway fatalities 4+ 41,800 Accidents 2* 97,835

15. Incidence of PE Difficult to diagnose so estimates range from 55,000 � 94,000 new cases in US annually to >600,000 in US by autopsy studies.Difficult to diagnose so estimates range from 55,000 � 94,000 new cases in US annually to >600,000 in US by autopsy studies.

16. Pathophysiology of Hemodynamic Instability in PE RV volume refers to the volume of muscle mass!!RV volume refers to the volume of muscle mass!!

17. Outcomes in Pulmonary Embolism

18. Thrombolysis in Major Pulmonary Embolism Few randomized studies looking at thrombolysis in PE Most trials excluded hemodynamically comprised patients Largest randomized trial is out of Germany and enrolled 256 patients. Prospective, randomized double-blind, placebo-controlled trial using 100 mg alteplase as study drug 118 patients in the study drug + heparin group, 138 patient in the placebo + heparin group. 10 mg Alteplase bolus followed by 90 mg infusion over 2 hours All patients received usual care with unfractionated heparin All patients were transitioned to warfarin with target INR 2.5 � 3.5.10 mg Alteplase bolus followed by 90 mg infusion over 2 hours All patients received usual care with unfractionated heparin All patients were transitioned to warfarin with target INR 2.5 � 3.5.

19. Thrombolysis in PE Study Inclusion Criteria (at least 1 of the following): 1) echocardiographically detected RV dysfunction (RVE + loss of collapse of IVC without LV or mitral valvular disease) ; 2) Echocardiographically detected pulmonary artery hypertension defined as tricuspid regurgitant jet > 2.8 m/sec + confirmation of PE by V/Q, CT angio or PAgram; 3) Precapillary pulmonary hypertension by right heart cath with PAP > 20 mmHg and PCWP <18 mmHG (to exclude CHF) + confirmation of PE by V/Q, CT angio or PAgram; 4) New ECG signs of RV strain + confirmation of PE by V/Q, CT angio or PAgram a) complete or incomplete RBBB b) S waves in Lead I combined with Q waves in lead III or inverted T waves in V1 � V3

20. Thrombolysis in PE Study (con�t) Exclusion Criteria: 1) age > 80 2) Hemodynamic instability (SBP < 90 mmHg) with or without shock; 3) onset of symptoms > 96 hours prior to diagnosis; 4) Thrombolytic treatment, major surgery, or biopsy within the previous 7 days; 5) Major trauma within the preceding 10 days; 6) Stroke, TIA, craniocerebral trauma or neurologic surgery within the preceding 6 months; 7) GI bleeding within the previous 3 months; 8) Uncontrolled hypertension; 9) A known bleeding disorder; 10) Current anticoagulation therapy; 11) Inability to tolerate alteplase; 12) pregnancy or lactation; 13) life-expectancy < 6 months due to underlying disease; 14) Known diabetic retinopathy; 15) Planned use of thrombolytics for extensive DVT.

21. Study Findings Primary endpoints: death escalation of treatment 9 patients in the alteplase group required additional thrombolysis because of arterial hypotension (1), worsening symptoms (8). Secondary (rescue) thrombolysis performed roughly three times higher in the placebo group. Indications for secondary thrombolysis included cardiogenic shock (4), arterial hypotension requiring pressors (4), worsening symptoms including respiratory failure (24 including 3 who needed mechanical ventilation)Primary endpoints: death escalation of treatment 9 patients in the alteplase group required additional thrombolysis because of arterial hypotension (1), worsening symptoms (8). Secondary (rescue) thrombolysis performed roughly three times higher in the placebo group. Indications for secondary thrombolysis included cardiogenic shock (4), arterial hypotension requiring pressors (4), worsening symptoms including respiratory failure (24 including 3 who needed mechanical ventilation)

22. Study Findings (con�t)

23. Study Findings (con�t) Probability of event-free survival during hospital stay was significantly lower in the placebo + heparin group. Alteplase + heparin may improve the clinical course of patients with acute submassive PE (ie, hemodynamically stable patients) with RV dysfunction/pressure overload.

24. Meta-Analysis: Thrombolysis vs Heparin in PE 11 randomized trials identified Only 5 trials included patients with major pulmonary embolism (involving hemodynamic instability) No benefit of thrombolytic therapy compared with heparin for initial treatment of unselected patients with acute PE. Subgroup analysis indicates a benefit of thrombolysis in those patients with major pulmonary embolism.

25. Meta-Analysis (con�t) Subgroup analysis: In patients with major PE with hemodynamic instability (including syncope), thrombolytic therapy was associated with significant reduction in recurrent PE or death (19% in thrombolytic + heparin vs 9.4% in heparin alone). Number needed to treat? 10. Nonmajor bleeding was significantly higher in the thrombolysis group (22.7%) when compared with heparin alone (10%). Number needed to harm? 8 Major bleeding: fatal bleeding hemorrhagic stroke drop in hgb by 4 g/dL (with or without the need for PRBC transfusions) Major bleeding: fatal bleeding hemorrhagic stroke drop in hgb by 4 g/dL (with or without the need for PRBC transfusions)

26. Approach to the Patient With Major Pulmonary Embolism

27. Conclusions Pulmonary embolism is a common disease with significant potential morbidity and mortality. Syncope can be an indicator of hemodynamically significant pulmonary embolism Thrombolytic therapy in hemodynamically significant PE has a mortality benefit with a number needed to treat of 10.

28. References Stein PD, et al. Incidence of Acute Pulmonary Embolism in a General Hospital. Chest 1999; 116: 909 � 913. Wan S, et al. Thrombolysis Compared With Heparin for the Initial Treatment of Pulmonary Embolism: A Meta-Analysis of the Randomized Controlled Trials. Circulation 2004; 110: 744-749. Agnelli G, Becattini C, Kirschstein T. Thrombolysis vs Heparin in the Treatment of Pulmonary Embolism: A Clinical Outcome-Based Meta-Analysis. Arch Intern Med 2002; 162: 2537-2541. Konstantinides S, et al. Heparin Plus Alteplase Compared With Heparin Alone in Patients With Submassive Pulmonary Embolism. N Engl J Med 2002; 347: 1143 � 50. Goldhaber SZ, Pulmonary Embolism. Lancet 2004; 363: 1295 � 1305.

29. References Wood KE. Major Pulmonary Embolism: Review of a Pathophysiologic Approach to the Golden Hour of Hemodynamically Significant Pulmonary Embolism. Chest 2002; 121: 877-905 . Wood KE. The presence of Shock Defines the Threshold to Initiate Thrombolytic Therapy in Patients with Pulmonary Embolism. Intensive Care Med 2002; 28: 1537 � 1546. Anderson FA, Wheeler HB, Goldberg RJ. A Population Based Perspective of the Hospital Incidence and Case Fatality Rates of Deep Venous Thrombosis and Pulmonary Embolism: the Worchester DVT Study. Arch Intern Med 1991; 151: 933-938.