pulmonary embolism review and an update. pulmonary embolism: a major cause of hospital death linblad...
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![Page 1: Pulmonary Embolism Review and An Update. Pulmonary Embolism: A Major Cause of Hospital Death Linblad B. Br Med J 1991;302:709-711 Wessler S. NIH 1986](https://reader035.vdocuments.site/reader035/viewer/2022062518/56649e745503460f94b752e4/html5/thumbnails/1.jpg)
Pulmonary EmbolismReview and An Update
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Pulmonary Embolism: A Major Cause of Hospital Death
Linblad B. Br Med J 1991;302:709-711
Wessler S. NIH 1986 Consensus Development Conference on Prevention of PE
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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Pathophysiology of Cardiac Compensatory Mechanisms In APE
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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
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Magnitude of the Problem: PE CHF
Via Recurrent PE
Via Venous Stasis
Increased incidence of PE
Mechanisms of Heart Failure Post-PE
• Pressure Effects
• Volume Effects
• Neurohormonal changes
• Remodeling
• Coronary Ischemia
Existing pts w CHF
PE pts developing CHF
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Pathophysiology of Right Ventricular Dysfunction After Acute Pulmonary Embolism
Lualdi and Goldhaber. Am Heart J. 1995;130:1276-1282.
Pulmonary Embolism
PA Pressure RV Afterload
RV Dilatation/Dysfunction
RV Cardiac Output
LV Preload
LV Output
RV Wall Tension
RV O2 Demand
RV Ischemia/Infarction
IV Septal ShiftToward the LV
RV O2 Supply
Coronary Perfusion
HypotensionIDENTIFY PTS BEFORE THEY
CROSS THIS BRIDGE
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Venous Thromboembolic DiseaseMagnitude of the Problem
Internal Medicine Consensus Reports, July, 2002.
DVTDVT2-6 Million2-6 Million
Clinical Clinical PEPE
+ 600,000+ 600,000
Post-thrombotic Post-thrombotic SyndromeSyndrome800,000800,000
Silent PESilent PE1 Million1 Million
Pulmonary Pulmonary HypertensionHypertension
30,00030,000
Recurrence
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Pengo, V. et al. N Engl J Med 2004;350:2257-2264Pengo, V. et al. N Engl J Med 2004;350:2257-2264
Incidence of Symptomatic CTPH after a First, Symptomatic, Properly Treated PE
VTE is a CHRONIC disease
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Pengo, V. et al. N Engl J Med 2004;350:2257-2264Pengo, V. et al. N Engl J Med 2004;350:2257-2264
Incidence of Symptomatic CTPH after a First, Symptomatic, Properly Treated PE
• 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
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APE = Acute Cardiopulmonary Syndrome
Risk Stratification of APE
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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)
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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
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CLINICAL CRITERIA
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Variable Point Score
Heart Failure +1
Prior DVT +1
Hypoxaemia +1
DVT on US +1
The Bounameaux PE Point Score(The Geneva Risk Score)
Vicki J et.al Thromb Haemost 2000; 84: 548-552
SBP < 90mmHg +1
Cancer +2
Score of > 2 predicts death recurrent VTE, or major
bleed at 3 months
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Risk Factors for Mortality after PE in the ICOPER: a Multivariate Analysis of 815 patients
Goldhaber SZ et.al Lancet 1999;353: 1386-1389
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)
Clinical CHF 2.4 (1.5-3.7)
SBP < 90mmHg 2.9 (1.7-5)
Cancer 2.3 (1.5-3.5)
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History of congestive heart failure is associated with a worse long - term survival
following acute PE
0
10
20
30
40
50
60
70
80
90
No CHF CHF
• 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
% M
orta
lity
Paraskos et al. NEJM 1973;289:55-8
Factors affecting outcome29 months follow up
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ECHOCARDIOGRAPHY IN APE
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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
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Clinical Manifestations of RV Dysfunction
Physical signs• Systemic hypotension• Right-sided S3
• Increased jugular venous pressure
• Cyanosis• Tricuspid regurgitation• Parasternal lift• Palpable impulse at
LUSB
Symptoms
• Dyspnea
• Lightheadedness
• Syncope
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RV dysfunction in APE
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
Echo findings in acute PE
• RV dilatation
• RV hypokinesis
• IV septal flattening
• Dec. inspiratory collapse of IVC
• Right PA dilatation
• Tricuspid regurgitation
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McConnell’s Sign in the Diagnosis of PE
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 et al. Am J Card 1996;78:469-73
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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)
RV enlargement w/oLV enlargement (n = 14)
No isolated RV enlargement (n = 11)
No PE (n = 5) PE (n = 9)
PE seen on TEE(n = 8)
PE seen at autopsy(n = 1)
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
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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
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ICOPER
Total mortality
Hemodynamically unstable (103; 4.2%)
Hemodynamically stable (2182; 88.9%)
No RV dysfunction(n = 263)
RV dysfunction (n = 428)
Hospital
Goldhaber et al. Lancet. 1999;353:1386—1389.
2 weeks 3 months
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%
Mortality Rates in 2454 patients (52 hospitals, 7 countries)
X 4
X 1.5
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M/S RVD and Other Benefits of Echo in APE
• 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)
• 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)
Goldhaber, Lancet, 1993 & 1999. Grifoni, Circ 2000. Kasper, Heart 1997. Ribeiro Am Heart J 1997 & J Intern Med 1999.
• 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
• 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
Circulation. 1998 May 19;97(19):1946-51.J Am Coll Cardiol. 2003 Jun 18;41(12):2245-51
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Cardiospecific Troponins in APE
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80
0
20
40
60
100
Pat
ien
t (
%)
+ Tn
- Tn
CPKEchoECG BP
Cardiac Troponins (I & T) and Other Findings at Presentation
P<0.05
P<0.001
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Mortality Complications Recurrence
40
0
10
20
30
50
60
Pat
ien
t (
%)
Normal Tn
Moderately Tn
High Tn
In-Hospital Course Based on cTn at Presentation
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40
0
10
20
30
36
4.8
0
Relation Between cTnI Concentrations on Admission and Mortality (%).
La Vecchia: Heart, Volume 90(6).June 2004.633-637
< 0.07
0.07 – 0.6
> 0.6
%
Mortality
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Event Hospital Mortality Complicated Hospital Course
OR (95% CI) OR (95% CI)
cTn -I (ng/ml)
<0.07 ------- ------
0.07-1.5 7.1 (0.7-7.0) 3.16 (0.8-1.4) P=0.095 P=0.079
>1.5 16.9 (1.6-177.6) 15.4 (3.8-62.6)
P=0.019 P= <0.0001
cTn –T (ng/ml)
<0.04 ------- ------
0.04-1 2.3 (0.2-27.4) 4.4 (0.1-19.1) P=0.504 P=0.046
>1.5 6.5 (1.1-38.1) 8.71 (2.5-29.5)
P=0.038 P= <0.0005
Cardiac Troponins as Determinants of Outcome in APE
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Prediction of In-Hospital Mortality
P value (univar.)
P Value (multivar.)
OR 95% CI
Heart Rate
PAP
O2 Sat
+ cTnI on admit
cTnI concentration on admit
0.027
0.022
<0.0001
0.002
<0.0001
0.10
NS
NS
0.046
0.007
1.24
1.17
0.44
17.9
9.27
0.96-1.61
0.66-2.07
0.07-2.7
1.06-303.8
1.82-47.1
La Vecchia: Heart, Volume 90(6).June 2004.633-637
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cTnTRelease
AMI (moderate/large)
ACS (microinfarction)
APE
Peak
Shape
Timing
MC
Repetitive up/down sloping
Possible Possible Not seen
Duration of elevation
10-14 days >120 hours 40 hours p admission
MC
Time
MC
Time
MC
Time
Proposed cTnT Curve Release Characteristics
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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
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• 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
BNP in APE
Tulevski et al November 2001 Kucher et al, April 2003
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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%)
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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
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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
• Treat acute hemodynamic instability– Reverse abnormal hemodynamics– Lower mortality
• Reverse acute and subacute RV dysfunction
• Prevent chronic thromboembolic-induced pulmonary hypertension
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1,500,000 U/1 Hour streptokinase with heparin is more effective than heparin
alone in PE with heart failure
• 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
Jerjes-Sanchez et al. J Thromb Thrombolysis 1995;2:227-9
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Konstantinides, S. et al. N Engl J Med 2002;347:1143-1150
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
256 normotensive pts w PE and pulm. HTN or RV dysfunctionRCDB Trial: 100 mg Alteplase over 2 hrs (118 pts) vs.UFH and placeboEnd points: in hospital mortality or escalation of Rx (pressors,secondary lysis, intubation, CPR, thrombectomy)
P = 0.006
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The MAPPET Registry
The Management and Prognosis of Pulmonary Embolism Registry (MAPPET)Konstantinides et al. Circulation. 1997;96:882–888.
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%
In-HospitalEvent
Thrombolysis(n = 169)
Heparin(n = 550) P Value
PE with RV dysfunction and/or Pulmonary HTN
1001 patints from 204 prticipating German venters 9/1993-12/1994.
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DDx of A PEMust Rule Out Other Potentially Life-Threatening Disorders
• A MI
• Pericardial Tamponade
• Aortic Dissection
• Fulminant Pneumonia
• H & P
• CXR
• ECG
• Echocardiogram
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Long-Term Hemodynamic Benefit of lytic Rx in Patients With PE
*P <. 05**P < .02Sharma et al. Vasc Med. 2000;5:91–95.
Pulmonary artery pressure
Pulmonary vascular
resistance
17
171
19
179
22*
351**
32
437
ExerciseRest Rest Exercise
Thrombolysis (n = 12) Heparin (n = 11)
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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
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Analysis of 312 patients who received lytic Rx in 5 clinical trials (t-PA and UK)
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
Mikkola KM, et al. Am Heart J1997;134:69-72
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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.
Massive PE (>50% perfusion defect)Moderate to large PE (>30% perfusion defect)
Small PE
Hemodynamic instability
RV dysfunctionon echocardiogram
Thrombolysis(unless contraindicated)
Long-term anticoagulation
Hemodynamically stable; normal RV
Hemodynamically stable; normal RV
Impaired cardio-pulmonary reserve
Hemodynamicinstability and/orRV dysfunction
Thrombolysis
Heparin
Young, low-risk patient
Treatment of Acute PE: Old Algorithm
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BNP TROPONIN
BNP ORTROPONIN
ECOCARDIOGRAPHY
NO RV DYSFUNCTION RV DYSFUNCTION
ANTICOAGULATION, ONGOING EVALUATION
THROMBOLYSIS OR EMBOLECTOMY
NO SHOCK SHOCK
PE
Treatment of Acute PE: Proposed Algorithm
Kucher and Goldhaber, Circ 11/2003
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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
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1. Goldhaber et al. Lancet. 1988;1:293-298.
2. Goldhaber et al. J Am Coll Cardiol. 1992;20:24-30.
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
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Surgical Results of Pulmonary Thromboendarterectomy (1997-2000)
PVR (dyn/sec/cm-5)
Study Location N Pre-op Post-op % Mortality
Nakajima et al, 1997 Japan 30 937±45 299±16 13
Mayer et al, 1997 Germany 32 967±238 301±151 9
Gilbert et al, 1998 Baltimore 17 700±200 170±80 24
Miller et al, 1998 Philadelphia 25 NA NA 24
Dartevelle et al, 1999 France 68 1174±416 519±250 13
Ando et al, 1999 Japan 24 1066±250 268±141 21
Jamieson & Kapelanski, 2000
San Diego, CA 457 877±452 267±192 7
Mares et al, 2000 Austria 33 148±107 975±93 9
Mares et al, 2000 Austria 14 1334±135 759±99 21
Rubens et al, 2000 Canada 21 765±372 208±92 5
D’Armini et al, 2000 Italy 33 1056±344 196±39 9
Fedullo PF et al. New Engl J Med. 2001.345:1465-72.
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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
50—90
100
50—100
40—80
~50
100
100
100
~67
100
50 or 100
50 or 100
120
50—100
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%)
Source (Year) Dose of rt-PA, mg Incidence of ICH
Incidence of Intracranial Hemorrhage Withrt-PA Treatment for Pulmonary Embolism
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Summary• Mortality rate from PE is high and approaches 10% in
the first hour
• Thrombolysis should be considered in high-risk patients who present with hemodynamic instability, acute PE, right ventricular failure, or pulmonary hypertension
• Thrombolysis can reverse abnormal hemodynamics and reduce mortality
• Expansion of thrombolysis usein APE should be considered in light of “physiologic” risk stratification
• We may be able to identify a subgroup of APE patients who may qualify for outpatient treatment
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Oligemia
Oligemia
Massive PE: Saddle emboli
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Oligemia
Massive PE: Saddle emboli
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L lung: 12 hrs after of lytic Rx
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R lung: 12 hrs after lytic Rx
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R lung: 24 hrs after UK (via SG catheter)
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R lung: 36 hrs after UK (via SG catheter)