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Pulmonary EmbolismReview and An Update
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%
Pathophysiology of Cardiac Compensatory Mechanisms In APE
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
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
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
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
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
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
APE = Acute Cardiopulmonary Syndrome
Risk Stratification of APE
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)
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
CLINICAL CRITERIA
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
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)
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
ECHOCARDIOGRAPHY IN APE
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
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
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
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
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
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
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
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
Cardiospecific Troponins in APE
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
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
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
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
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
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
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
• 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
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%)
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
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
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
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
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.
DDx of A PEMust Rule Out Other Potentially Life-Threatening Disorders
• A MI
• Pericardial Tamponade
• Aortic Dissection
• Fulminant Pneumonia
• H & P
• CXR
• ECG
• Echocardiogram
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)
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
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
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
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
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
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
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.
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
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
Oligemia
Oligemia
Massive PE: Saddle emboli
Oligemia
Massive PE: Saddle emboli
L lung: 12 hrs after of lytic Rx
R lung: 12 hrs after lytic Rx
R lung: 24 hrs after UK (via SG catheter)
R lung: 36 hrs after UK (via SG catheter)