Prise en charge initiale de

l’Embolie Pulmonaire
Grave
Olivier Sanchez
Université Paris Descartes, Sorbonne Paris Cité
Service de Pneumologie et Soins Intensifs, HEGP
INSERM UMR-S 1140

4ème Congrès
Urgences Cardiologiques
St-Gilles les Bains – 1er juin 2018
Stratification du risque - ESC 2014
Examen Hypotension
clinique Choc

Stratification
Elevé
du risque
IVD aiguë sur VD antérieurement sain:
le cas de l’embolie pulmonaire grave
 Post-charge VD

Dilatation VD Pré-charge VD
 FC, Effet Starling

Dysfonction VD
Interdépendance VD/VG Ischémie VD
Syst et diast
Contraintes péricardiques

FEVD Débit coronaire

Pré-charge VG HypoPA
Traitement symptomatique de l’EP
grave

 Oxygénothérapie nasale

 Ventilation mécanique
 Indications rares: tr de conscience et arrêt cardiaque
 Faible Vt, pas de PEP
 Intubation oro-trachéale

 Attention aux KT ! +++

 Repos strict au lit

Traitement symptomatique de l’EP
grave: expansion volémique
 Loi de Starling sur VD, mais
 Risque de  pré-charge VG par interdépendance VD/VG
  ischémie VD

 Mercat et al Crit Care Med 1999;27:540-4

 13 patients EPAM + I Circulatoire aiguë

Base FL 250 FL 500

POD, mmHg 9±1 14 ± 1* 17 ± 1*

PAPm, mmHg 31 ± 2 34 ± 2* 35 ± 2*

IC, L/mn/m2 1,6 ± 0,1 1,7 ± 0,1* 2 ± 0,1*

PAom,mmHg 101 ± 4 103 ± 4 103 ± 4

Traitement symptomatique de l’EP
grave: inotropes
 Dopamine et dobutamine
 Effets comparables chez l’animal
  IC sous dobu chez l’homme (Jardin et al Crit Care Med 1985)

 Levosimendan
  the sensibilité des myofilaments cardiaques au Ca2+ pendant la systole sans affecter la diastole
 Vasodilatation des circulations pulmonaires, systémiques et coronaires
 Amélioration fonction VD (Morelli Crit Care Med 2006)

 Noradrénaline
  contractilité myocardique (ß1 +)
 Vasoconstriction périphérique (1 +) :  PA systémique  débit coronaire droit
 Si hypotension artérielle systémique
 Traitement anticoagulant

 Dès que le diagnostic est suspecté +++

 Héparine non fractionnée

 Si choc

 Héparine de bas poids moléculaire – fondaparinux

 Si EP de gravité intermédiaire
Amélioration hémodynamique et fibrinolyse
100
UFH
tPA 100 mg/2h
90
TPR (% of the initial value)

SK 100 000 UI/h, 12h

SK 1.500 000 UI/2h
80 UK 4400 UI/kg/h, 12h
tPA 0.6 mg/kg, 15 min

70

60

50

40
0 1 2 3 4 5 6 7 8 9 10 11 12
hours
Meyer 92, Sors 94, Meneveau 97, Meneveau 98
Fibrinolyse et réduction de
l’obstruction vasculaire pulmonaire
% de résolution de l’obstruction vasculaire
(scintigraphie)

Héparine (n =70) Urokinase (n = 72)

24h 7.4% (± 28.2) 23.7% (± 26.2)

J2 16.2% (± 30.2) 27.4% (± 27.3)

J7 41.9% (± 31.5) 44.9% (± 28.9)

UPET. Circulation 1973; 57: II 48-51

 Fibrinolyse dans l’EP grave
Meta-analyse, 5 études ayant inclus des malades instables
( non exclusivement)
Thrombolyse Héparine Odds Ratio
(n = 128) (n = 126)
Récidives 3.9% 7.1% 0.61 (0.23-1.62)

Décès 6.2% 12.7% 0.47 (0.20-1.10)

Décès ou récidive 9.4% 19.0% 0.45 (0.22-0.92)

Hémorragie 21.9% 11.9% 1.98 (1.00-3.92)

Wan et al. Circulation 2004; 110: 744-9

Thrombolyse vs héparine dans l’EP
Study n Unstable Fibrinolytic drug Diagnostic
patients (n) procedure

UPET 1973 160 Yes (11) Urokinase Invasive

Tibbutt 1974 30 Yes (14) Streptokinase Invasive
Ly 1978 25 Yes (2) Streptokinase Invasive
Dotter 1979 31 Yes (2) Streptokinase Invasive
Marini 1988 30 No Urokinase Invasive
PIOPED 1990 13 No rtPA Invasive
Levine 1990 58 No rtPA Non-invasive
Dalla-Volta 1992 36 No rtPA Invasive
Goldhaber 1993 101 No rtPA Non-invasive
Jerjes Sanchez 1995 8 Yes (8) Streptokinase Non-invasive
Konstantinides 2002 256 No rtPA Non-invasive
 Stratification du risque - ESC 2014
Examen Hypotension
Pas de choc
clinique Choc

Evaluation clinique PESI I/II PESI III – V

du risque: PESI sPESI =0 sPESI ≥1

Evaluation VD non dilaté VD dilaté ET

retentissement VD ou biomarqueurs biomarqueur
TDM/Echo normaux, ou l’un élevé
BNP, cTn… des 2 anormal

Stratification
Faible Intermédiaire faible Intermédiaire fort Elevé
du risque
 Diuretics in Normotensive Patients With Acute PE
and RV Dilatation
Ternacle et al Circ J 2013;77:2612-8

 Retrospective study

 70 normotensive patients with acute PE and RV dilation

 40 patients received iv furosemide (78±42 mg) during the first 24H
 30 patients received isotonic saline solution (1,6±0,9L)

RV/LV sBP Shock index

 Fibrinolyse dans l’EP sans choc
Meta-analyse, 6 études ayant inclus des malades stables
(EP non exclusivement sub-massive)

Thrombolyse Héparine Odds Ratio

(n = 246) (n = 248)
Récidives 2.0% 2.8% 0.76 (0.28-2.08)

Décès 3.3% 2.4% 1.16 (0.44-3.05)

Hémorragie 2.4% 3.2% 0.67 (0.24-1.86)

Wan et al. Circulation 2004; 110: 744-9:

 PEITHO: Overview of study design
Confirmed acute
symptomatic PE

Primary Outcome, Secondary Outcomes

Tenecteplase
(weight-adapted bolus)

Seconray Outomes, SAE

Absence of
hemodynamic UFH, LMWH or
collapse UFH infusion Fondaparinux

DOUBLE
BLIND
Confirmed RV <2 h VKA
dysfunction + R
myocardial injury Placebo

UFH, LMWH or
UFH infusion Fondaparinux

1005 patients
included
UFH bolus VKA
i.v.
Day 2 Day 7 Day 30
ClinicalTrials.gov # NCT00639743
EudraCT # 2006-005328-18
 PEITHO: Primary efficacy outcome

Tenecteplase Placebo
(n=506) (n=499) P value
n (%) n (%)
All-cause mortality or
hemodynamic collapse within 7
13 (2.6) 28 (5.6) 0.015
days of randomization

0.23 0.44 0.88

0 1.00 2.00
Odds ratio
Thrombolysis superior

ITT population The PEITHO Investigators

PEITHO: Secondary efficacy outcomes

Placebo
Tenecteplase (n=506) (n=499) P value
n (%) n (%)
All-cause mortality within 7 6 (1.2) 9 (1.8) 0.43
days

Hemodynamic collapse 8 (1.6) 25 (5.0) 0.002

within 7 days
Need for CPR 1 5
Hypotension / blood pressure drop 8 18

Catecholamines 3 14
Resulted in death 1 6

ITT population The PEITHO Investigators

 PEITHO: Safety outcomes (within 7 days of randomization)

Placebo
Tenecteplase (n=506) (n=499) P value
n (%) n (%)
Non-intracranial bleeding
Major 32 (6.3) 6 (1.5) <0.001
Minor 165 (32.6) 43 (8.6) <0.001

Strokes by day 7 12 (2.4) 1 (0.2) 0.003

Hemorrhagic 10 1
Ischemic 2 0

ITT population The PEITHO Investigators

Risk concept & lysis rationale in 2004-2014
Focus on echo plus biomarkers

Risk parameters and scores

Early mortality risk Cardiac

PESI class III-V RV dysfunction
laboratory
or sPESI >1 (imaging)
markers

High + + (+) Primary reperfusion

Interm-high + Both positive Monitoring

Intermediate
Interm-low + One (or none) positive Hospitalize

Assessment optional; Consider early

Low −
if assessed, both negative discharge

European Heart Journal (2014):doi:10.1093/eurheartj/ehu283

Risk concept & lysis rationale in 2004-2014
Focus on echo plus biomarkers

Risk parameters and scores

Early mortality risk Cardiac Death at 30 days

PESI class III-V RV dysfunction
laboratory
or sPESI >1 (imaging)
markers

High + + (+) 23/105

22% (14-29.8%)
Interm-high + Both positive 21/272
Intermediate 7.7% (4.5-10.9%)
Interm-low + One (or none) positive 20/333
6.0% (3.4-8.6%)
Assessment optional;
Low − 1/196
if assessed, both negative
0.5% (0-1.5%)

The ESC Guidelines Task Force. Eur Heart J (2014):doi:10.1093/eurheartj/ehu283

Becattini C, et al. Eur Respir J 2016;48(3):780-786
Clinical criteria for ‘imminent decompensation’
PEITHO post hoc analysis
Placebo arm (n=499) Tenecteplase arm (n=506)
Clinical criteria of
Clinical outcome Relative risk Clinical outcome
pulmonary Prevalence in Prevalence in Relative risk
with vs without with vs without
embolism severity treatment arm (95% CI) treatment arm (95% CI)
criterion criterion
SBP ≤110 mmHg 82 (16.6%) 9 (11.0%) vs 24 1.89 (0.91-3.91) 82 (16.3%) 4 (4.9%) vs 15 1.37 (0.47-4.02)
(5.8%) (3.6%)
Respiratory rate 181 (46.2%) 21 (11.6%) vs 6 4.08 (1.68-9.89) 211 (51.3%) 8 (3.8%) vs 4 1.90 (0.58-6.20)
>20 breaths/min (2.8%) (2.0%)
Chronic heart 26 (5.3%) 6 (23.1%) vs 26 4.14 (1.87-9.16) 21 (4.2%) 1 (4.8%) vs 18 1.27 (0.18-9.07)
failure (5.6%) (3.7%)
Active cancer 32 (6.7%) 6 (18.7%) vs 6 3.22 (1.43-7.26) 41 (8.4%) 3 (7.3%) vs 14 2.33 (0.70-7.76)
(2.4%) (3.1%)
At least one 250 (50.2%) 27 (10.8%) vs 6 4.46 (1.88-10.62) 286 (56.5%) 11 (3.8%) vs 8 1.06 (0.43-2.58)
severity criterion (2.4%) (3.6%)
At least 2 criteria 64 (12.9%) 13 (20.3%) vs 20 8.40 (3.32-21.23) 66 (13.0%) 5 (7.6%) vs 14 2.08 (0.71-6.15)
(4.6%) (3.2%)
At least 3 criteria 7 (1.4%) 2 (28.6%) vs 31 11.81 (2.87- 2 (0.4%) 0 (0.0%) vs 19 -
(6.3%) 48.52) (3.8%)
Barco S et al, for The PEITHO Investigators. Eur Respir J 2018
 Clinical criteria for ‘imminent decompensation’
PEITHO post hoc analysis
 Inclusion criteria: rationale
Clinical criteria of
Placebo arm (n=499) Tenecteplase arm (n=506)
Clinical outcome Relative risk Clinical outcome
pulmonary Prevalence in Prevalence in Relative risk
with vs without with vs without
embolism severity treatment arm (95% CI) treatment arm (95% CI)
criterion criterion
SBP ≤110 mmHg 82 (16.6%) 9 (11.0%) vs 24 1.89 (0.91-3.91) 82 (16.3%) 4 (4.9%) vs 15 1.37 (0.47-4.02)
(5.8%) (3.6%)
Respiratory rate 181 (46.2%) 21 (11.6%) vs 6 4.08 (1.68-9.89) 211 (51.3%) 8 (3.8%) vs 4 1.90 (0.58-6.20)
>20 breaths/min (2.8%) (2.0%)
Chronic heart 26 (5.3%) 6 (23.1%) vs 26 4.14 (1.87-9.16) 21 (4.2%) 1 (4.8%) vs 18 1.27 (0.18-9.07)
failure (5.6%) (3.7%)
Active cancer 32 (6.7%) 6 (18.7%) vs 6 3.22 (1.43-7.26) 41 (8.4%) 3 (7.3%) vs 14 2.33 (0.70-7.76)
(2.4%) (3.1%)
At least one 250 (50.2%) 27 (10.8%) vs 6 4.5 (1.9-10.6) 286 (56.5%) 11 (3.8%) vs 8 1.1 (0.4-2.6)
severity criterion (2.4%) (3.6%)
At least 2 criteria 64 (12.9%) 13 (20.3%) vs 20 8.4 (3.3-21.2) 66 (13.0%) 5 (7.6%) vs 14 2.1 (0.7-6.2)
(4.6%) (3.2%)
At least 3 criteria 7 (1.4%) 2 (28.6%) vs 31 11.81 (2.87- 2 (0.4%) 0 (0.0%) vs 19 -
(6.3%) 48.52) (3.8%)
Barco S et al, for The PEITHO Investigators. Eur Respir J 2018
 Eur Heart J 2015;36:605-14

Efficacy
Intermediate risk PE Odds Ratio (95% CI)

Mortality 0.42 (0.17 – 1.03)

PE mortality 0.17 (0.05 – 0.67)

Death or treatment
0.37 (0.20 – 0.69)
escalation

PE recurrence 0.25 (0.06 – 1.03)

 Eur Heart J 2015;36:605-14

Safety

Odds Ratio (95% CI) P-value I2 (%)

Major bleeding 2.91 (1.95 – 4.36) < 0.001 25

Fatal/intracranial bleeding 3.18 (1.25 – 8.11) 0.008 0

« Faible » dose de thrombolyse?
• rtPA: 0.6 mg/kg sur 15 min
 Sors H. et al. Chest 1994; 106: 712-17

• rtPA: 50 mg sur 2 h
 Wang C. et al. Chest 2010; 137:254–262

• rtPA: 0.5 mg/kg max: 50 mg: 10 mg bolus + 2h infusion

 Sharifi M. et al. Am J cardiol 2013; 111: 273-77
Pleine dose vs demi dose?

• Essai randomisé en double aveugle multicentrique

• 87 patients avec EP (pas à risque intermédiaire)

• rtPA: 100 mg/2h (n = 27)

• rtPA: 0.6 mg/kg/15 min (n = 60)

Goldhaber SZ. et al. Chest 1994; 106: 718-24

Pleine dose vs demi dose?

Goldhaber SZ. et al. Chest 1994; 106: 718-24

Efficacy and Safety of Low Dose Recombinant Tissue-
Type Plasminogen Activator for the Treatment of Acute
Pulmonary Thromboembolism
Wang et al Chest 2010;137:254-62

 Randomized, multicenter controlled trial

 118 patients with acute PE

 Cardiogenic shock (31%) or RV dysfunction on cardiac imaging (69%)

 rtPA 100mg / 2h vs rtPA 50 mg / 2h

 Improvement at D1 and D14 after randomization

 RV dysfunction

 Pulmonary vascular obstruction on V/Q lung scan or CT

Efficacy and Safety of Low Dose Recombinant Tissue-
Type Plasminogen Activator for the Treatment of Acute
Pulmonary Thromboembolism
Wang et al Chest 2010;137:254-62

→ Similar efficacy

→ Trend to less bleeding

 Pleine dose vs demi dose: efficacité

Zhang Z. et al. Thromb Res 2014; 133: 357-63

 Am J Cardiol 2013;111:273-277

 121 patients with intermediate high-risk PE rtPA Control p

n = 58* n = 56*
 « safe dose » thrombolysis
PH**/recurrent PE 9 (16) 35 (63) < 0.001
 rtPA: < 50kg: 0.5 mg/kg - ≥ 50kg: 50 mg (28 months)
 LMWH or UFH
Death/recurrent 1 (1.6) 6 (10) 0.049
 Vs anticoagulant alone PE (28 months)
 LMWH or UFH Major bleeding 0 0
(hospitalisation)

**sPAP ≥ 40 mmHg
*7 patients lost to follow-up
Faible dose vs héparine: efficacité?

Zhang Z. et al. Thromb Res 2014; 133: 357-63

 Faible dose: tolérance

Faible dose vs pleine dose

Faible dose vs héparine

Zhang Z. et al. Thromb Res 2014; 133: 357-63

Traitements fibrinolytiques approuvés et
contre-indications – ESC 2014

2014 ESC guidelines on the diagnosis and management of acute PE – Eur Heart J 2014
 Les méthodes d’exception

 Assistances circulatoires
 Thrombectomie chirurgicale
 Thrombectomie par cathéter +/- fibrinolyse locale
 Persistance de l’état de choc malgré traitement symptomatique et
fibrinolyse
 Contre-indication absolue à la fibrinolyse
  3% des EP graves
 Discussion multidisciplinaire indispensable (PE Rescue Team)
 Pneumologues, cardiologues, réanimateurs, radiologues interventionnels, chirurgiens
 Assistance circulatoire

 Décharge le VD

 Améliore le débit cardiaque et la perfusion

périphérique

 Rapidement efficace

 Indiqué chez les patients en état de choc

réfractaire et/ou avec multiple dysfonctions
d’organe

 Nécessite une équipe médico-chirurgicale

entrainée +++

 Extracorporeal membrane oxygenation (ECMO)

veino-artérielle

 Système sans pompe: Novalung®

 Assistance circulatoire

• 2 stratégies d’utilisation:
• Seule jusqu’à l’amélioration clinique
• Avec ou sans thrombolyse

• En attente d’une thrombectomie chirurgicale

VA-ECMO for patients with high-risk PE

Corsi et al.
Critical Care
2017;21:76
VA-ECMO for patients with high-risk PE

Corsi et al.
Critical Care
2017;21:76
VA-ECMO for patients with high-risk PE

Corsi et al.
Critical Care
2017;21:76
Embolectomie chirurgicale

 Cohortes rétrospectives

 Avec ou sans CEC

 Mortalité élevée y compris dans les séries récentes

Période Décès n/N Décès %

1968-1989 184/526 35%
1990-1999 188/627 30%
2000-2008 41/215 19%

Samoukovic G. et al. Interactive Cardiovasc Thorac Surg 2010; 11: 265–270

 ULTIMA study

 Essai multicentrique randomisé

 59 patients
USAT Control
 EP proximale n = 30 n = 29
 VD/VG ≥ 1
 Sans choc RV/LV before 1.28 ± 0.19 1.20 ± 0.14

 Ultrasound Assisted catheter directed

RV/LV after (24h) 0.99 ± 0.17 1.17 ± 0.20
thrombolysis (USAT)
 rtPA 10 à 20 mg sur 15h
 HNF Major bleeding 0 0

 HNF
Kucher N. et al. Circulation 2014; 129:479-86
 SEATTLE II study

 Registre prospectif multicentrique

 EKOS
 rtPA 24 mg sur 12h à 24h

 150 patients EP
 Avec choc n=31
 Intermédiaire haut risque n=119

 Modification VD/VG (CT) à H48

 1 perdu de vue

Piazza JACC Intv 2015;8:1382-92

PERFECT registry

 Registre multicentrique prospectif

 101 patients EP
 Choc n=28
 « submassive » n=73

 Désobstruction par cathéter

 Mécanique
 Thrombolyse: rtPA ou UK en perfusion continue sur 24h

 Succès clinique
 Stabilisation hémodynamique, VD/VG, PAPs, survie
 24/28 (86%) EP + choc / 71/73 (97%) EP submassive

 Pas d’hémorragie

 Décès hospitalier 6%
Kuo Chest 2015;148:667-73
2014 ESC guidelines on the diagnosis and management of acute PE – Eur Heart J 2014
 HBPM curatif sauf si
insuffisance rénale

2014 ESC guidelines on the diagnosis and management of acute PE – Eur Heart J 2014
 SOS Embolie Pulmonaire Grave
 Services de Pneumologie et Soins Intensifs, Réanimations Médicale
et Chirurgicale, Radiologie Interventionnelle et Chirurgie Cardio-
Vasculaire - HEGP

01 56 09 29 92