pe management

8/18/2019 PE Management

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Management of pulmonary embolism John A Strange

David Pilcher

Abstract Pulmonary embolism (PE) is a common condition with significant mortal-

ity and morbidity. Its occurrence frequently triggers referral to critical care

services. Patients within critical care environments are also at elevated

risk of developing venous thrombo-embolism and PE. This highlights

the need for critical care clinicians to be confident in their approach to

the patient with PE. Furthermore, the co-morbid conditions in this patient

group may present additional challenges both in diagnosis (e.g. safe ac-

cess to radiology) and management (e.g. relative contraindication to anti-

coagulation/thrombolysis in trauma or intracranial haemorrhage). This

brief review summarizes the contemporary evidence base regarding

both diagnosis and treatment strategies and draws upon this to suggest

a simple algorithm for investigation, risk stratification and management,

particularly tailored to patients within a critical care setting.

Keywords Anticoagulation; computed tomography pulmonary angio-

gram (CTPA); embolectomy; IVC filter; massive pulmonary embolism;

pulmonary embolism; submassive pulmonary embolism; thrombolysis;

venous thrombo-embolism

Royal College of Anaesthetists CPD matrix: 2C01, 2C03, 2C04, 1B00, 2C00

Definitions

The term pulmonary embolism (PE) encompasses the movement

of abnormal material to the pulmonary arteries and through the

pulmonary vasculature such that it obstructs blood flow; exam-

ples include embolism of air/gas, fat and thrombus. The most

common cause of PE is the migration of thrombus from veins (or

right heart) to the pulmonary arterial tree. Other forms of PE are

beyond the scope of this article.

Diagnostic considerations

PE is a commonly considered but relatively infrequently

diagnosed condition in hospitalized patients. This is unsur-

prising when one considers that the clinical presentation of PE

varies from breathlessness in isolation to sudden death, mak-

ing clinical assessments insensitive and highly unspecific

(Table 1, signs, symptoms and differential diagnosis of PE).

Consideration of risk factors contributing to the development

of venous thrombo-embolism (VTE) and PE (Table 2, Virch-

ow’s triad, primary and secondary hypercoagulable states) mayimprove diagnostic rates, but a missed diagnosis, or the

inappropriate application of treatment both carry considerable

risks. The use of biomarkers and choice of imaging modalities

can be guided by clinical decision rule (CDR) systems of which

the most widely reported are the Well’s score and the Geneva

score. These aim to stratify risk and focus resources on those

most likely to benefit. The evolution of these tests and scoring

systems has resulted in various approaches to investigating

and treating possible PE; a suggested scheme geared more

particularly to the critical care environment is outlined in

Figure 1.

Investigation/severity assessment

Bedside investigations

An arterial blood gas analysis (ABG) demonstrating hypoxia

(with widened alveolarearterial oxygen gradient e Aea

gradient) and hypocapnia with a concomitant increase in end-

tidal CO2 gradient is suggestive of PE but lacks specificity,

equally a normal blood gas does not exclude PE. A normal ECG is

found in one-third of cases, other findings include sinus tachy-

cardia, T-wave inversion, right bundle branch block, p-pulmo-

nale and other features suggestive of right ventricular strain. The

classically described deep S wave in lead I, with a Q-wave and

inverted T-wave in lead III (so called S1Q3T3) is rare and sug-

gests more significant disease. The ECG is also important inscreening for differential diagnoses. The chest X-ray may help to

exclude common differentials such as pneumothorax, pneu-

monia or pleural effusion. Identifying more specific abnormal-

ities such as oligaemia and abnormal pulmonary artery contours

is generally the preserve of radiologists.

Biomarkers

D-dimers are cross-linked fibrin degradation products. Serum

levels are elevated in VTE and therefore PE. They have poor

specificity and poor positive predictive value for PE. The most

useful D-dimer result is a negative, which makes the diagnosis of

Learning objectives

After reading this article you should be able to:

C describe the disease entity of venous thrombo-embolism/pul-

monary embolism (VTE/PE) and outline risk factors for its

development, recognizing the varied spectrum of presentation

in PEC outline an appropriate diagnostic strategy for the evaluation of

possible PE, risk stratifying according to clinical presentation

and investigations

C understand the various treatment options for PE and how they

should be utilized in light of the risk stratification and diag-

nostic findings

John A Strange MB BCh FFARCSI DIBICM is a Senior Registrar in Intensive

Care Medicine at The Alfred Hospital, Melbourne, Australia. Conflicts of

interest: none declared.

David Pilcher MB BS FRACP MRCP FCICM is a Consultant Specialist in

Intensive Care Medicine at The Alfred Hospital, Melbourne, Australia.

Conflicts of interest: none declared.

INTENSIVE CARE

ANAESTHESIA AND INTENSIVE CARE MEDICINE 15:2 72 2014 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.mpaic.2013.12.009




PE unlikely, although a high D-dimer concentration is an inde-

pendent predictive factor associated with mortality.1

Measurements of troponin, brain natriuretic peptide (BNP) or

NT-terminal pro-BNP (NT-pro-BNP) although not useful in

diagnosing PE may stratify risk and determine prognosis in

confirmed PE.2

Raised troponin predicts haemodynamic insta-bility in non-massive PE and increased risk of death regardless of

PE size. In proven PE, low levels of BNP and NT-pro-BNP

correlate with good outcomes,2 the latter is likely a superior

predictor of outcome than troponin.3

Imaging

There is no ideal imaging modality in PE, studies show that

confidence in any result can be improved by first assessing the

pre-test probability of there being a PE. Unfortunately these

studies are not representative of the critical care population,

where a majority of patients have high pre-test probability of PE,

in each scoring system.

Computed tomography

Computed tomography pulmonary angiography (CTPA) scan-

ning, especially the multi-detector scanner (MD-CTPA), has now

largely replaced lung ventilationeperfusion (V/Q) scanning as

the cost-effective and reliable imaging procedure of choice in

patients with suspected PE.4 The CTPA scan has the advantage of

greater diagnostic accuracy, being readily available at most

hospitals, more rapid image-acquisition time, and the possibilityof making an alternative diagnosis (Figure 2). High-resolution

images to the level of segmental and in some cases sub-

segmental pulmonary arteries can be obtained in a short time-

period (often a single breath-hold). When compared to conven-

tional angiography it appears reliable, with excellent sensitivity,

specificity and accuracy.5 The CTPA scan can also be used to

assess the severity of PE. An increased right ventricular/left

ventricular (RV/LV) ratio6 and clot in the proximal branches of

the pulmonary artery correlate with the clinical severity of PE. It

is therefore recommended that the CTPA scan should be the

principal imaging test for patients with high and moderate

probability of PE.

Although inconclusive CTPA scans occur in around 10%, anegative CTPA result means that withholding anticoagulant

therapy is safe. An emerging problem of CTPA scanning,

however, is the increased detection (around 10%) of small

peripheral emboli in subsegmental pulmonary arteries due to

better visualization of these arteries. The clinical significance of

these findings in critically ill patients is unknown, however

these are usually unlikely to lead to a bad outcome if left

untreated.

Ventilation/perfusion scans

Lung ventilation/perfusion scanning demonstrates regional

abnormalities in the distribution of inhaled radioactive gas,

and injected radioactive contrast agent respectively. Matchedor mismatched defects are interpreted, and reported as low,

intermediate or high probability for PE. This technique is still

widely and effectively employed where CTPA is unavailable or

contraindicated (such as intravenous contrast allergy) but is

limited by the large proportion of patients with intermediate or

low probability results e leaving clinical uncertainty as to

who to treat (as many as 40% of these patients will have had

a PE).

Echocardiography

Echocardiograms have poor negative predictive value (up to 50%

of clots missed) but can show pathognomonic patterns for PE,

and may identify clot in the right ventricle or proximal pulmo-nary arteries (generally only on trans-oesophageal studies). It is

of greatest utility in the most severe cases, where haemodynamic

instability may prevent safe transport to CT. In these patients

trans-thoracic echocardiography (TTE) can be employed at the

bedside to investigate the cause of haemodynamic instability, to

exclude other diagnoses (tamponade, myocardial infarction,

aortic dissection) and assess severity of known PE (the presence

of RV dysfunction in any patient implies a more grave prog-

nosis). In a selected group of patients, where there is a high index

of clinical suspicion for PE, findings on TTE may be sufficiently

compelling to allow the rapid institution of potentially life-saving

treatments such as thrombolysis.

Clinical assessments aiding in the diagnosis of PE

History

Previous DVT/PE

Family history of DVT/PE/sudden death

History/family history of thrombophilia

Secondary hypercoagulability ( Table 2 )

SignsIncreasing risk of massive pulmonary embolism

None

Tachycardia

Moderate fever

RV dysfunction (raised JVP, parasternal heave, loud P2)

Hypotension

Skin mottling

Peripheral cyanosis

Central cyanosis

Cardiovascular collapse/arrest

NB also important to examine for signs of DVT in limbs

Differential diagnoses

Acute myocardial infarctionAcute pulmonary oedema

Asthma/exacerbations of COPD

Pericardial tamponade

Pleural effusion

Fat embolism

Pneumothorax

Aortic dissection

Rib fracture

Anxiety

Symptoms

Dyspnoea (most common)

Pleuritic chest pain

Haemoptysis (late sign, lung infarction)Syncope

COPD, chronic obstructive pulmonary disease; DVT, deep vein thrombosis;

JVP, jugular venous pressure; PE, pulmonary embolism; RV, right ventricular.

Table 1

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Disease spectrum

Massive pulmonary embolism

This is defined as PE causing sustained (>15 minutes) hypo-

tension (systolic BP <90 mmHg) or a sustained significant drop

in systolic blood pressure (>40 mmHg). Even when treated this

condition has mortality exceeding 25% (65% if cardiopulmonary

resuscitation is required). Acute RV failure is a very common

feature. There may only be a brief window of opportunity to

identify and address the condition. Patients remain at significant

risk of death for several days after an event.

Submassive PE

Submassive PE typically describes other acute PEs, where pa-

tients have evidence of RV dysfunction (best confirmed with

echocardiography, but also possibly shown on CT) but have a

normal blood pressure. This subgroup has up to four times the

mortality risk and increased rates of recurrence, they may also go

on to develop shock or RV thrombus.7

Prevention of recurrenceis a priority but therapies to remove clot such as thrombolysis

may have a role in this group. All other patients with PE are

haemodynamically stable and have normal RV function, the

majority tend to follow an uneventful course (<2% mortality)

unless further PE occurs.

Treatment

The major principles of management are aimed at either prevention

of further embolization and thrombosis (anticoagulation and

inferior vena caval filters), removal of established clot (thrombol-

ysis and embolectomy) and concurrent haemodynamic support.

Anticoagulation

Anticoagulation decreases mortality in patientswith PE. The riskof

a major bleeding event secondary to anticoagulation is lower

(<3%)8 than the risk of death from undiagnosed PE (30%). This

suggests that all confirmed cases and those with high clinicalprobability of PE should be anticoagulated e unless there is a

compelling contraindication. Low-molecular-weight heparins

(LMWH) are as effective and safe as unfractionated heparin and

offer several advantages, including a longer half-life, increased

bioavailability, a more predictable doseeresponse and fewer re-

quirements for monitoring and dose adjustments. They should be

readily used in the stable patient with PE. Unfractionated heparin

offers rapid therapeutic dosing when weight based protocols are

employed (Table 3 e suggested dosing, complications and con-

traindications of heparin therapy), and can be easily therapeuti-

cally monitored and reversed with protamine if significant bleeding

occurs. The predominant complication of both unfractionated

heparin and LMWHs is bleeding. Both bleeding complications andheparin-induced thrombotic thrombocytopenia syndrome (HITTS)

appear to be less common when LMWH is used.

Oral anticoagulants should be commenced when possible to

allow LMWH or unfractionated heparin to cease. For warfarin,

which has an initial procoagulant effect, this is when the inter-

national normalized ratio (INR) is greater than 2.0. New oral

anticoagulants, including rivaroxaban (competitively binds acti-

vated factor X) and dabigatran (direct inhibitor of thrombin)

have been developed. These drugs have more rapid onset of

action and more predictable anticoagulant effects potentially

allowing fixed dosing without routine laboratory coagulation

Pathophysiology and risk factors for VTE

Virchow’s triad epathophysiology of intravenous clot formation

Alterations in blood flow (stasis)

Vascular endothelial injury (vein wall damage)

Alterations in blood constituents (inherited and acquired hypercoagulable states)

Primary hypercoagulable states (inherited thrombophilias) Secondary (acquired) hypercoagulable states

Factor V Leiden mutation (activated protein C resistance) found in >20% of

patients with confirmed VTE

Prothrombin gene mutation (probably at least as common as Factor V Leiden)

Protein S deficiency

Protein C deficiency

The lupus anticoagulant (antiphospholipid antibody)

Antithrombin III deficiency

Dysfibrinogenaemias (rare)

Inherited vena cava abnormalities (rare)

Hyperhomocystinaemia (rare)

Immobility

Recent or current hospitalization

Surgery within past 3 months

Malignancy

Infection within past 3 months

Pregnancy and puerperium

Trauma (especially with limb paralysis)

Burns

Oestrogens (OCP/HRT), tamoxifen

Cardiovascular risk factors (smoking, obesity, hypertension,

diabetes etc)

IV drug abuse, central venous devices

Increasing ageChronic renal failure or nephrotic syndrome

Hyperviscosity syndromes (myeloma etc)

Initially after commencement of warfarin without

heparin/LMWH cover

HRT, hormone replacement therapy; LMWH, low-molecular-weight heparin; OCP. oral contraceptive pill; VTE, venous thrombo-embolism.

Table 2

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monitoring, however their place in critically ill patients remains

to be established.

Inferior vena caval (IVC) filters

IVC filters are mechanical devices percutaneously inserted into

the distal vena cava with the intention of physically entrapping

clot as it embolizes from leg or pelvic veins (the most common

sites of deep vein thrombosis (DVT)). They may be used toprevent further embolization or as primary prevention, although

safety and efficacy have not been firmly established. An IVC filter

is indicated for patients where anticoagulation is contraindicated

and those who experience recurrent PE despite adequate anti-

coagulation.9 They may have a role in patients with massive or

submassive PE who have undergone open surgical embolectomy

or thrombolysis. Insertion is usually performed percutaneously

in a radiology department, but it can be done at the bedside.

They lower early recurrence but increase long-term DVT recur-

rence rates. Newer retrievable designs may be more efficacious

and safer if removed at the appropriate time (Table 4 suggested

role of IVC filters in PE).

Thrombolysis

There is a general consensus advocating the use of thrombolytics

in massive PE with significant or ongoing haemodynamic insta-

bility. Their use may result in dramatic improvements in hae-

modynamics and oxygenation. However when compared to IV

heparin therapy, clot resolution is similar after only a few days.

Patient registry data suggest that mortality and recurrence of PE

is lower when thrombolytics are used rather than heparin alone,however no head-to-head randomized trial has demonstrated a

mortality difference. A meta-analysis of studies comparing

thrombolysis with heparin showed a trend toward superiority

with thrombolytics, this trend became a significant reduction in

mortality when studies not including massive PE were excluded

from the analysis. Thrombolysis of patients with submassive PE

significantly reduces their chance of deteriorating to a degree that

requires ICU admission.10

No study has shown a significant difference in the efficacy of

different thrombolytic agents e a suggested protocol of two 10-

unit doses of reteplase, separated by 30 minutes, is effective and

simple to implement. There is no evidence that using a central

INITIAL CLINICAL ASSESSMENT

Intermediate or high clinical probability of PE(using Clinical Decision Rule system)

Haemodynamically stable Haemodynamically unstable

INITIAL DIAGNOSTIC TESTMulti-detector CTPA scan

(V/Q if CTPA contraindicated)Echocardiograph

SEVERITY ASSESSMENTFOR STRATIFICATIONOF TREATMENT

PE confirmed if thrombus in RV or PA

PE likely if RV dysfunction

If PE confirmed, stratify risk usingCTPA, blood tests and echocardiograph

RV/LV ratioproximal clot in main PA,

Segmental orsub-segmental PE and

CONFIRMATORY TESTSCTPA scan

raised troponin, BNP

or NT pro-BNP

normal troponin, BNP

or NT pro-BNP

Echocardiograph CTPA scanif safe

Echocardiographto assess RV function

TREATMENT Anticoagulant therapy

Thrombolytic therapy / Embolectomy if RV dysfunction Anticoagulant therapy only

↑

BNP, brain natriuretic peptide; CTPA, computed tomography pulmonary angiography; LV, left ventricular; NT, NT-terminal; PA, pulmonary artery;

PE, pulmonary embolism; RV, right ventricular.

Figure 1 Algorithm for severity stratification assessment and treatment of patient with pulmonary embolus.

INTENSIVE CARE






venous or PA catheter for administering thrombolytics confers a

treatment advantage or any reduction in bleeding complications.

Delaying therapy in an unstable patient to gain central access

cannot be justified and may result in arterial injury or pneumo-

thorax (relative contraindications to thrombolysis).Concerns around haemorrhagic complications are justified as

major bleeding occurs in 10% of patients thrombolysed for PE

(versus <3% with heparin infusion alone), though intracerebral

haemorrhage is less common than might be feared (0.9%).

Massive PE and submassive PE with RV dysfunction both carry

significant mortality risk, employing thrombolytics in their

treatment can often be justified in the face of relative contrain-

dication (such as recent surgery), the challenge is to balance an

individual patient’s risks from acute PE with those from fibri-

nolytic treatment itself.

Embolectomy

Mortality from surgical embolectomy for PE ranges from 25% to

50%. There remains a role for surgery but this is probably

limited to patients with massive PE, treated within cardio-

thoracic centres or where thrombolytic therapy is contra-

indicated. Surgery has been advocated for removal of free

floating RV thrombus.

Alternative approaches include, percutaneous embolectomy,

catheter direct therapy with targeted thrombolysis or rheolysis

(physical disruption of clot), or a combination of the above.

These are emerging techniques without a large body of research

to characterize their usefulness, mortality with these techniques

remains above 20%.

Concurrent haemodynamic support

Shocked patients (massive PE) need urgent supportive care in

parallel to definitive and preventative treatment. Insertion of a

PA catheter may guide therapy with vasoactive agents and

monitor response to thrombolysis but should not delay definitive

treatment.

Initially volume loading with IV fluids may improve haemo-

dynamics, however excessive intervention may overload an

already stressed or injured right ventricle, leading to further

decline and risking left ventricular failure e treatment should be

titrated against clinical response.

Figure 2 Three images from a single computed tomography pulmonary angiography (CTPA) study performed with a high clinical suspicion of pulmonary

embolism (PE). Image 1 demonstrates large PEs in the proximal right and inferior left pulmonary artery. Image 2 shows a significant concurrent pneu-

mothorax. Image 3 demonstrates a right ventricular/left ventricular (RV/LV) ratio >1 signifying significant RV dysfunction. Together these images show the

high utility of CTPA in diagnosis/exclusion of PE, diagnosis/exclusion of differential diagnoses, and in risk stratifying a patient so as to guide therapy.

Suggested dosing, heparin therapy

Heparin loading dose Initial maintenance infusion

80 units/kg (caution in

obesity/anasarca)

18 units/kg/hour

Six-hourly monitoring of activated partial thromboplastin time

(APTT) e suggested dosing adjustments:

APTT Dose change

(units/kg/hour)

Heparin re-bolus Repeat APTT

<35 þ4 80 units/kg At 6 hours

35e45 þ2 40 units/kg At 6 hours

46e70 No change None At 6 hours

71e90 2 None At 6 hours

>90 3 Stop infusion 1 hour At 6 hours

Table 3

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In massive PE blood supply to the RV can become compro-

mised, clot causes increased pulmonary vascular resistance

(increased PAPs) with right ventricular overload (increased

central venous pressure) leading to increased mean right ven-

tricular pressure (RVPm) this is compounded by possible LVF

causing decreased mean arterial pressure (MAP) (right heart

output ¼ left heart output), the result is a drop in right ventric-ular coronary perfusion pressure (RVCPP ¼ MAP RVPm).

Values below 30 mmHg lead to significant cardiac ischaemia,

worsening RV failure, shock and possibly death.

The pathogenesis outlined above suggests that therapy be

aimed at increasing MAP (i.e. filling and pressor support) and at

reducing RVPm (i.e. reducing PAPs/pulmonary vascular resis-

tance). The latter can be achieved with selective pulmonary va-

sodilators (e.g. nitric oxide or inhaled prostacyclin) though these

may result in systemic hypotension. Noradrenaline can coun-

teract these concerns to a degree and is also the preferred ino-

trope for its concomitant beneficial a- and b-adrenergic effects on

MAP and cardiac output respectively. Caution should be exer-

cised when using inotropes that have systemic vasodilatory ef-fects (such as milrinone or dobutamine), which may increase

cardiac output without increasing MAP and therefore not

significantly improve RVCPP.

Extracorporeal membrane oxygenation (ECMO) is an alter-

native form of mechanical assistance, which may be available in

specialized institutions. It should be considered for patients with

PE who have had cardiopulmonary arrest or have very severe

shock.

VTE prophylaxis

For inpatients (and a selected group of patients at home) pro-

phylaxis of VTE is the most important aspect of PE management.

Multiple studies have robustly demonstrated the need for, andeffectiveness of prophylactic strategies in preventing DVT and PE

across patient groups.9 Local protocols will vary but good

evidence exists for pharmacological prophylaxis with SC heparin,

LMWHs or fondaparinux. IVC filters prevent recurrent PE over

the long term, but at the cost of increased DVT risk. Mechanical

approaches with graduated compression stockings and inter-

mittent pneumatic compression devices are also options to be

combined with anticoagulants or in their place if they are

contraindicated. A

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Suggested indications for insertion of inferior venacaval filter

Absolute indications

New or recurrent pulmonary embolism despite anticoagulation

Contraindications to anticoagulation

Complications resulting from anticoagulation

Other recommended indications

Following thrombolytic therapy

Post-surgical embolectomy

Extensive deep vein thrombosis

Table 4

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