50 year old woman with hypoxia and syncope

Mary Pak, MDPrimary Care Conference

August 25, 2004

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

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.

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

Case Presentation (con’t)

• PMH: Recurrent clear cell CA ovary (s/p TAH-BSO, carboplatin/taxol)(s/p partial omentectomy 5/04)

RosaceaHypertensionRheumatic fever as a childReactive Airway DiseaseDJD

• Allergies: AmoxicillinIbuprofen

Case Presentation (con’t)

• Medications: Losartan 50 mg dailyHCTZ 50 mg twice dailyhydrocortisone 50 mg po bidspironolactone 50 mg po bidibuprofen 600 mg po q6hglucosamineTopical metronidazoleomeprazolezolpidem PRN

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 HTNBrother ?blood disorderNo other cancers

Case Presentation (con’t)• Physical Examination:

Temp 36.4, BP 118/84, pulse 116, resp 20O2 sat 98% 4L O2

Lungs: bibasilar crackles, no wheezesCV: Regular rhythm, tachycardic, 2/6 systolic murmur enhanced by respirations, no rubs or gallopsAbdomen: soft, obese, NT, well-healed midline

scar with minimal serosanguinous drainage.Ext: no edema, good pulses, no Homan’s signNeuro: nonfocal

Patient Data

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 8.9D-Dimer 8.9

CK 30, troponin 0.3

ABG: 7.45/29/80 on 4L OABG: 7.45/29/80 on 4L O22

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 AngioMultiple filling defects including central left and right main pulmonary arteries, left subclavian thrombus, markedly dilated right ventricle. “Extensive and multiple acute and chronic PE”

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.

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 PEGoldhaber SZ Lancet 2004; 363: 1295-1305

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

1. Anderson et al Arch Intern Med 1991

2. AHA. 2001 Heart and Stroke Statistical Update. 2000

3. ACS. Breast cancer facts and figures.2001

4. NHTSA. 2001

* For the year 1998

# Estimated for the year 2001

+ For the year 2000

Incidence of PE

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0--9 10--19 20--29 30--39 40--49 50--59 60--69 70--79 80--89

Incidence of acute PE as admitting diagnosis(%)

Age (years)

Stein PD. et al. Chest 1999; 116: 909-913.

Pathophysiology of Hemodynamic Instability in PE

Wood KE Chest 2002; 121: 877-905.

Outcomes in Pulmonary Embolism

Wood KE Chest 2002; 121: 877-905

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.

Thrombolysis in PE StudyInclusion 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 RBBBb) S waves in Lead I combined with Q waves in lead III

or inverted T waves in V1 – V3Konstantinides S N Engl J Med 2002; 347: 1143-50

Thrombolysis in PE Study (con’t)Exclusion Criteria:

1) age > 802) 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.

Konstantinides S N Engl J Med 2002; 347: 1143-50

Study Findings

Konstantinides S N Engl J Med 2002; 347: 1143-50

Study Findings (con’t)

P=0.005

Konstantinides S N Engl J Med 2002; 347: 1143-50

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.

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.

Wan S Circulation 2004; 110: 744-749.

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

Approach to the Patient With Major Pulmonary Embolism

Wood KE Chest 2002; 121: 877-905

Conclusions

1) Pulmonary embolism is a common disease with significant potential morbidity and mortality.

2) Syncope can be an indicator of hemodynamically significant pulmonary embolism

3) Thrombolytic therapy in hemodynamically significant PE has a mortality benefit with a number needed to treat of 10.

References

1) Stein PD, et al. Incidence of Acute Pulmonary Embolism in a General Hospital. Chest 1999; 116: 909 – 913.

2) 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.

3) 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.

4) 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.

5) Goldhaber SZ, Pulmonary Embolism. Lancet 2004; 363: 1295 – 1305.

References6) Wood KE. Major Pulmonary Embolism: Review of a

Pathophysiologic Approach to the Golden Hour of Hemodynamically Significant Pulmonary Embolism. Chest 2002; 121: 877-905 .

7) 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.

8) 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.