Download ESC GuideLine 2008: Acute Pulmonary Embolism

Guidelines on the diagnosis and management
of acute pulmonary embolism
The Task Force for the Diagnosis and Management of
Acute Pulmonary Embolism of the
European Society of Cardiology (ESC)
2008
Caso Clinico
Uomo di 62 anni si presenta con una storia di dispnea ingravescente
che dura da 5 giorni, con ortopnea, dopo un viaggio di lavoro di 3
giorni.
Esame fisico: Fc 102 bpm.PA 110/60 mmHg
Sat. O2 86% in aria
Distensione delle giugulari
Non soffi cardiaci
Estremità normali .Polmoni : ndn
D-dimero elevato ( 5,13 mg/L-V.N.< 0,5).Troponina T < 0,01 mcg/L.
TC : trombosi multipla delle aa polmonari e dilatazione del Vdx
Come trattare questo paziente ?
ESC GuideLine 2008: Acute Pulmonary Embolism
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
EPIDEMIOLOGY
•PE and DVT are two clinical presentations of venous thromboembolism
(VTE) and share the same predisposing factors
•In most cases PE is a consequence of DVT
•Among patients with proximal DVT , about 50% have an associated
usually clinically asymptomatic PE at lung scan
•In about 70% of patients with PE, DVT can be found in the lower limbs
if sensitive diagnostic methods are used
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
EPIDEMIOLOGY
•According to prospective cohort studies, the acute case fatality
rate for PE ranges from 7 to 11%
•Also, recurrent episodes are about three times more likely to be PE
after an initial PE than after an initial DVT (about 60% after PE vs. 20% after DVT)
•The prevalence of PE among hospitalized patients in the United States,
according to data collected between 1979 and 1999, was 0.4%( annual incidence
in USA was estimated as 600 000 cases)
•342 000 inhabitants in Brittany, France, the incidences of VTE and PE were
18.3 and 6.0/10 000/year respectively.
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
Predisposing factors for venous thromboembolism
VTE is currently regarded as the result of
the interaction between patient- related
and setting -related risk factors.
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
Additional risk markers.Clinical and routine laboratory tests
European Heart Journal (2008) 29, 2276–2315
A recent survey performed in 358 hospitals across 32 countries
shows that only 58,5 and 39,5% patients at risk of VTE due to
medical or surgical causes, respectively, received adequate
prophilaxis ( 1 )
Reports of a high risk of PE among obese people,smokers and
patients affected by systemic hypertension or metabolic
syndrome have renewed interest in the link between arterial
thomboembolism and VTE( 2 )
( 1 )Endorse Study-Lancet 2008;371:387-394
( 2 )Lancet 2007;370:1773-1779
Natural Hystory
The evidence suggests that DVT develops less frequently in general
than in orthopaedic surgery
The risk of VTE after surgery is highest during the first two weeks but
remains elevated for 2-3 months
Antithrombotic prophylaxis significantly reduces the risk of periopera
tive VTE
The longer the duration of antithrombotic prophylaxis,the lower the
incidence of VTE
Most patients with symptomatic DVT have proximal clots, and PE in 4050% of cases ( often asymptomatic )
PE occurs 3-7 days after the onset of DVT, and may be fatal within
1 h after the onset of symptoms in 10% of cases
PE presents with shock or hypotension in 5-10% of cases
Natural Hystory
-In up to 50% of cases without shock but with lab. signs of RVD and /or
injury indicates a poorer prognosis
-After PE , complete risolution of perfusion defects occurs in about two
thirds of all patients
-Most deaths ( > 90% ) seems to occur in untreated patients , because of
unricognized PE
-Fever than 10% of all deaths were thought to occur in treated patients
-CTETH was found in 0,5-5 % of patients with treated PE
-The frequency of VTE recurrence is higher in patients with idiopatic VTE
-The risk of fatal PE is higher after a previous episode of isolate DVT
-Without anticoagulation about 50% of patients with symptomatic prox.
DVT or PE have a recurrence of thombosis within 3 months
-In patients with previous VTE who have finished their course of at least
3 – 12 months of VKI the risk of fatal PE was 0,19-0,49 events/pat/year
Pathophysiology
• The consequences of acute PE are primarily haemodinamic and
become apparent when > 30-50% of the pulmonary arterial bed is occluded
by thromboemboli
• Large e/o multiple emboli might abruptly increase vascular resistence
to a level of afterload which cannot be matched by the right ventricle.
• Sudden death may occur ,usually in the form of electromechanical
dissociation
• Alternatively , the patient presents with syncope and /or systemic
hypotension, wich might progress to shock and death due to acute RV
failure
• Rightward bulging of the interventricular septum may further
compromise cardiac output as a result of diastolic left ventricle ( LV)
disfunction
• Decrease of aortic pressure may affect RV coronary perfusion and the
function of RV
• However, a non preconditioned , thin walled Rv is not expected to
generate mea pulmonary pressures exceding 40 mm Hg
• Secondary haemodinamic destabilization may occur , usually within
24 – 48 hour,as a result of recurrent emboly and /or deterioration of RV
function.
• This may be caused by early recurrences, which are common in
undiagnosed or inadequately treated VTE
• Alternatively , compensatory inotropic and chronotropic stimulation
may not suffice to mantain RV function , with increased RV myocardial
oxygen demand and decreased RV coronary perfusion gradient
• Both elements contribute to RV ischaemia and dysfuncion, and may
initiate a vicious circle leading to a fatal outcome
• Pre-existing cardiovascular disease ………………
• Respiratory insufficience in PE is predominantly a consequence of
haemodinamic disturbance
• Several factors may contribute to hypoxia during a episode of PE:
-Low cardiac output results in desaturation of mixed venous blood
- Ventilation / perfusion mismatch
- 1/3 right to left shunt trough a patent foramen ovale ( ipoxaemia , risk
of paradoxycal embolization)
ESC GuideLine 2008: Acute Pulmonary Embolism
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
European Heart Journal (2008) 29, 2276–2315
Severity of Pulmonary Embolism
Severity of Pulmonary Embolism
Severity of Pulmonary Embolism
Risk-Adjusted Treatment Strategy
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
Diagnosis: Clinical Presentation
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
D-dimer levels
are elevated in plasma in the presence of an acute clot because
of simultaneous activation of coagulation and fibrinolysis.
Hence, a normal D-dimer level renders acute PE or DVT unlikely, i.e.
the negative predictive value (NPV) of D-dimer is high
On the other hand, although D-dimer is very specific for fibrin,
the specificity of fibrin for VTE is poor because fibrin is produced in a wide variety of
conditions, such as cancer, inflammation, infection, necrosis, dissection of the aorta,
and the positive predictive value (PPV) of D-dimer is low
European Heart Journal (2008) 29, 2276–2315
A negative D-dimer result in higly sensitive assay safely excludes
PE in patients with a low or moderate clinical probability, while
a moderately sensitive assay excludes PE only in patients with
a low clinical probability
When using a recently introduced two level clinical probability
assessment scheme , a negative D-dimer result excludes PE
safely in PE – unlikely patients either by a higly sensitive or
moderately sensitive assay
In the emergency department , a negative ELISA D-dimer test can
exlude PE without further testing in approximately 30% of
patients
ESC GuideLine 2008: Acute Pulmonary Embolism
Compression ultrasonography and
computed tomographic venography
•Searching for a proximal DVT in patients with PE by CUS yields a positive result in
around
20% of patients.
•CUS can be used either as a backup procedure to reduce the
overall false-negative rate when using single-detector CT
•It can be performed to avoid CT when positive in patients with
contraindications to contrast dye and/or irradiation.
•Combining CT venography with CT angiography adds a significant amount of radiation
and is not useful when using MDCT
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
Ventilation–perfusion scintigraphy
•A normal perfusion scan is very safe for excluding PE
•Although less well validated, the combination of a nondiagnostic V/Q scan
in a patient with a low clinical probability of PE is an acceptable criterion
for excluding PE.
•A high-probability ventilation–perfusion scan establishes the diagnosis
of PE with a high degree of probability, but further tests may be considered
in selected patients with a low clinical probability due to the lower PPV
of a high-probability V/Q scan result in such patients.
•In all other combinations of V/Q scan result and clinical probability,
further tests should be performed.
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
Computed tomography
• A SDCT or MDCT showing a thrombus up to the segmental level can be taken as
adequate evidence of PE in most instances, whereas the necessity to treat isolated
subsegmental thrombi in a patient without a DVT is unclear.
• In patients with a non-high clinical probability, a negative SDCT must be combined
with negative CUS to safely exclude PE, whereas MDCT
may be used as a stand-alone test.
•Whether further testing is mandatory in the rare patients who have a negative MDCT
despite a high clinical probability is not settled.
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
Pulmonary angiography
• Pulmonary angiography is a reliable but invasive test and is currently useful
when the results of non-invasive imaging are equivocal.
•Whenever angiography is performed,
direct haemodynamic measurements should be performed.
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
Echocardiography
• In a patient with suspected PE who is in a critical condition,
bedside echocardiography is particularly helpful
in emergency management decisions.
•In a patient with shock or hypotension, the absence of echocardiographic signs
of RV overload or dysfunction practically excludes PE as a cause of
haemodynamic compromise.
•The main role of echocardiography in non-high-risk PE is further prognostic
stratification to the intermediate or low-risk category.
European Heart Journal (2008) 29, 2276–2315
Echocardiographic Parameters
• Estimates from postmortem data suggests that 30-50% of PE are never
diagnosed, and misdiagnosis is also common
• This results in large part from signs and symptoms that frequently
overlap with other cardiopulmonary disorders
• Consequently , the initial diagnostic test obtained in patients with
symptoms suggestive of PE is frequently something other than the
modern gold standard of PE protocol CT scan
• Many echocardiographic abnormalities in patients with PE has been
described
• Most lack sufficient sensibility and specificity as a stand alone test
• However ,Echo , is easily obtained , safe, portable , frequently
obtained prior the definitive diagnosi of PE .
• Understanding the utility of Echo findings is critical because they may
increase the clinician’s suspicion for PE
RV and LV EDD and Area from apical four chamber
view
Mc Connell Sign ,from apical four chamber view
“Free wall ipokinesis or akinesis coupled with normoor hyperkinesia of the RV apex”
“ D “ – sign or systolic flattening or shifting of the
interventricular septum as seen from the parasternal
short axis view
• Qualitative indices: Mc Connell Sign-” D “ sign
• Quantitative Indices:
- Pulmonary artery diameter
- RV EED
- LV EDD
- Ratio RV EDD/ LV EDD
- RV area
- LV area
- Rv / LV area ratio
- PA AcT
-TR velocity
- “60/ 60 “ sign
ESC GuideLine 2008: Acute Pulmonary Embolism
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
Diagnostic strategies
European Heart Journal (2008) 29, 2276–2315
ESC Guideline 2008: Acute Pulmonary Embolism
Diagnostic strategies
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
European Heart Journal (2008) 29, 2276–2315
ESC Guideline 2008: Acute Pulmonary Embolism
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
European Heart Journal (2008) 29, 2276–2315
ESC Guideline 2008: Acute Pulmonary Embolism
Treatment: Haemodynamic and respiratory support
•Haemodynamic and respiratory support is necessary in patients with suspected or
confirmed PE presenting with shock or hypotension.
•Isoproterenol is an inotropic drug which also induces pulmonary vasodilatation,
but these favourable effects are often outweighed by peripheral vasodilatation.
•Norepinephrine appears to improve RV function via a direct positive inotropic effect
while also improving RV coronary perfusion by peripheral vascular
alpha receptor stimulation and the increase in systemic blood pressure.
No clinical data are available on the effects of norepinephrine in PE,
and its use should probably be limited to hypotensive patients
•The use of dobutamine and/or dopamine can be considered for patients with PE, low
cardiac index and normal blood pressure.
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
Treatment: Haemodynamic and respiratory support
•There are few data with respect to inhaled aerosolized prostacyclin in the treatment
of pulmonary hypertension secondary to PE
•Preliminary experimental data suggest that levosimendan may restore right ventricular–pulmonary
arterial coupling in acute PE as a result of combined pulmonary vasodilation
and increased RV contractility
•There is increasing interest in the use of endothelin antagonists and phosphodiesterase-5 inhibitors
in PE. In experimental studies, antagonism of endothelin receptors attenuated the severity of
pulmonary hypertension caused by massive P
•Sildenafil infusion also attenuated the increase in pulmonary artery pressure in experimental PE
be taken to limit its adverse haemodynamic effects.
•When mechanical ventilation is required, care should positive intrathoracic pressure
induced by mechanical ventilation may reduce venous return and worsen RV failure in patients
with massive PE. Therefore, positive end-expiratory pressure should be applied with caution.
Low tidal volumes (approximately 6 ml/kg lean body weight) should be used in an attempt to keep
the end-inspiratory plateau pressure below 30 cm H2O
European Heart Journal (2008) 29, 2276–2315
Thrombolytic Agents and Regimens and Contraindications to
Thrombolysis
Konstantinides S. N Engl J Med 2008;359:2804-2813
ESC Guideline 2008: Acute Pulmonary Embolism
Treatment: Surgical pulmonary embolectomy
Treatment: Percutaneous catheter embolectomy
and fragmentation
Catheter embolectomy or fragmentation of proximal pulmonary
arterial clots
may be considered as an alternative to surgical treatment in high-risk
PE patients
When thrombolysis is absolutely contraindicated or has failed.
European Heart Journal (2008) 29, 2276–2315
Anticoagulant Drugs for Initial Treatment of Pulmonary Embolism
Konstantinides S. N Engl J Med 2008;359:2804-2813
ESC Guideline 2008: Acute Pulmonary Embolism
Treatment: Initial anticoagulation
European Heart Journal (2008) 29, 2276–2315
ESC Guideline 2008: Acute Pulmonary Embolism
Treatment: Initial anticoagulation
European Heart Journal (2008) 29, 2276–2315
ESC Guideline 2008: Acute Pulmonary Embolism
Treatment: Therapeutic strategies
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
Treatment: Long-term anticoagulation and secondary prophylaxis
•The long-term anticoagulant treatment of patients with PE is aimed at preventing
fatal and non-fatal recurrent VTE events.
•VKAs are used in the vast majority of patients, while LMWH may be an effective and safe
alternative to VKAs in cancer patients.
•VKAs should be given at doses adjusted to maintain a target INR of 2.5 (range 2.0–3.0).
•Most of the studies focusing on long-term anticoagulation for VTE included patients with
DVT, and only one study specifically focused on patients with PE
•However, the implications for treatment of proximal DVT or PE are very similar,
the main difference being that recurrent episodes are about three times more likely
to be PE after an initial PE than after an initial DVT
European Heart Journal (2008) 29, 2276–2315
ESC Guideline 2008: Acute Pulmonary Embolism
Treatment: Long-term anticoagulation and secondary prophylaxis
European Heart Journal (2008) 29, 2276–2315
ESC GuideLine 2008: Acute Pulmonary Embolism
Treatment: Venous filters
•Interruption of the inferior vena cava as a method or preventing PE was first suggested by
Trousseau in 1868.
•Venous filters became available in the late 1960s and percutaneous deployment
was made possible almost 30 years ago.
•Filters are usually placed in the infrarenal portion of the inferior vena cava (IVC).
•If thrombus is identified in the IVC below the renal veins, more superior placement may
be indicated.
•Permanent IVC filters may provide lifelong protection against PE;
•However, they are associated with complications and late sequelae, including recurrent
DVT episodes and development of the post-thrombotic syndrome.
•Complications of permanent IVC filters are common, although they are infrequently fatal
European Heart Journal (2008) 29, 2276–2315
Discussione del Caso Clinico
• In un paziente con EP sospetta l’iter diagnostico
dovrebbe comprendere la valutazione della
probabilità basata su scores validati.
• Se la probabilità è intermedia / bassa , un D-dimero
basso esclude sostanzialmente la diagnosi, mentre
un D-dimero aumentato impone l’esecuzione di una
MDCT
Contrast-Enhanced CT Angiograms Showing Acute Pulmonary Embolism
Tapson V. N Engl J Med 2008;358:1037-1052
• Il nostro paziente ha una probabilità clinica Intermedia , un Ddimero positivo , emboli in rami delle aa polmonari
• Deve iniziare immediatamente terapia anticoagulante ( EBPM /
Fondaparinux)
• MDCT mostra disfunzione del VDx : si tratta dunque di EP a
rischio intermedio.
• Si può considerare la terapia trombolitica che però in questo
caso ha un ruolo incerto perche’ la troponina è negativa
• Si inizia TAO al II° - III° giorno di ospedalizzazione ( per
assicurarsi che la disfunzione del vdx non progredisca verso
l’instabilità emodinamica ,che richiederebbe la trombolisi)
• Si sospende l’eparina quando INR ( 2-3 ) si è stabilizzato per 2
giorni consecutivi
Take home messages
• PE is a common disease wich may lead to a life threatening
right ventricular failure.Even an apparently mild episode of
PE should be promptly diagnosed and treated to prevent early
and potentially life threatening recurrences
• Because of non specific clinical presentations PE should be
always considere in the differential diagnosis of dyspnoea,
chest pain , syncope and many other clinical symptoms and
signs.Of note , 20-30% patients with PE have no predisposing
factors
• Only appropriately validated diagnostic strategies should be
used to justify specific PE treatment as witholding
anticoagulation despite clinical suspicion of acute PE
• Diagnostic and management strategy should be chosen
according to the severity of a ( suspected or confirmed) PE
episode,understood as the level of risk of early PE – related
death
• Pat. with shock or hypotension are suspected to have “ High
risk PE “ ( early mortality > 15%) and requires immediate
diagnostic work –up to decide whether or not emergency
thrombolysis and / or embolectomy is justified. MDTC or ECHO
are most useful tools in such emergency
• Remaining patients are suspected to have “Non –high –risk
PE”.In this case diagnostic evaluation should be stratified
according to the level of clinical probability of PE-It can be
assessed with validated scores or by clinical judgement
• Negative D-dimer result obtained with a high sensitive test can
help to select patients with a low to intermediate clinical
probability of PE in whom anticoagulation may be safely
withold without further diagnostic evaluation
• In all other patients more estensive algorithms should be
followed,based on MDCT evaluation.In specific clinical
conditions and in cases with discordant results of clinical
evaluation and CT angiography, alternative validated diagnostic
strategies/test should be used for therapeutic decision making
• Unfractionated i.v. heparin should be used in pat. With “High –
risk-PE, severe renal dysfunction or at high bleeding risk.In all
other case s.c. LMWH or Fondaparinux are recommended as
initial treatment and should be followed by long term oral
anticoagulation
• Thrombolysis or ( if contraindicated or failed) embolectomy is
recommended in “ High –risk –PE”
• “ Non – high- risk PE” may furher risk stratified.The presence
of objective signs of RVD e/o myocardial injury identify
“ Intermediate-risk PE” in wich thrombolysis is not routinely
recommend but may be considered in selected patients
• “Low risk PE” can be diagnosed if no signs of right ventricular
dysfunction or myocardial injury can be detected.If free from
precedent co-morbidities,such patients may be considered for
early discharge and ambulatory treatment
• Percutaneous interventions , such as thrombus
fragmentation/aspiration and venous filter implantation may be
considered in selected clinical situations
• The duration of the long term oral anticoagulant therapy should
be decided based on the presence and reversibility of factors
predisposing to recurrent venous thromboembolic disease
Major gaps in evidence
Diagnosis
• Whether negative MDCT angiography alone permits to
whithold anticoagulation treatment despite high clinical
probability of PE remains unclear
• Diagnostic signifiance of sub-segmental pulmonary clots
documented at MDCT angiography is unclear
• The respective value of three levels versus –two levels
stratification of clinical probability of PE remains unclear
Prognostic assessment
• The optimal cut- of values of ECHO, CT and Biomarckers –
derived criteria of RV overload remains to be defined
• The optimal cut- off levels of troponin and new biomarkers of
myocardial injury remain to be defined
• The prognostic signifiance of concomitant presence of signs of
right ventricular dysfunction and myocardial injury needs to be
defined
Pharmacological therapy
• Whether ( and how to identified ) a subgroup of patients with “
intermediate-risk PE “ would benefit more from thrombolytic
threatment than heparin- lone therapy is unclear
• The safely and efficacy of new generation of oral anticolagulant
in initiak and long term treatment of PE needs to be defined
Intervention
The safety and efficacy of retrievable venous filters needs further
assessment.
The safety and efficacy of percutaneous intervention (fragm/
aspir) in acute PE needs further assessment