Venous Thromboembolism:

Diagnosis & Management of Pulmonary Embolism Week 2.10

Learning Objectives
Review pathophysiology, diagnosis, prognosis & treatment of PE Review unresolved issues in the management of VTE.

Introduction
Pulmonary embolism (PE) affects 0.51 per 1000 people in the general population each year & is one of the commonest preventable causes of death among hospital inpatients.

Introduction
Although anticoagulant therapy is highly effective at preventing death, it is frequently either not administered, or administered too late, because the diagnosis of PE has not been considered.

Incidence
In prospective studies, 33% of medical ICU patients had DVTs; 18% of trauma patients had proximal DVTs. In retrospective series of respiratory ICU patients, 27% had PE on autopsy.

Pathophysiology
Virchows triad - venous stasis, hypercoagulability, injury to venous walls. DVT may predate malignancy. In one study, 7.6% patients with idiopathic DVT were diagnosed with a malignancy in next 18 months. Recurrent venous thrombosis, incidence of malignancy rose to 17%. Most malignancies were adenocarcinomas.

Pathophysiology
Most episodes of PE result from embolisation of thrombi in the leg or pelvic veins. Very large emboli may lodge at the bifurcation of the pulmonary arteries (saddle embolus), leading to rapid circulatory failure or sudden death. However, most lodge in lower-order pulmonary vessels.

Pathophysiology
Because the lung has no pain fibres, PE only causes chest pain if there is involvement of parietal pleura. Fever is common.

Types
1. Acute massive occlusion - > 50% of segmental vasculature or an equivalent amount of central clot 2. Pulmonary infarction - occurs in 10% of acute PE 3. Pulmonary embolism without infarction most common

Clinical Manifestations
Symptoms depend on severity of emboli. Acute massive occlusion - hypotension +/syncope, severe refractory hypoxaemia. Pulmonary infarction - pleuritic chest pain, tachypnoea +/- haemoptysis. PE without infarction - tachypnoea, dypsnoea, tachycardia

Clinical Manifestations
Acute onset of tachypnoea, tachycardia, unexplained agitation or anxiety, CXR changes (e.g. atelectasis, basilar infiltrate, elevated hemidiaphragm), hypotension, nonspecific back or side pain, unexplained hypoxia, respiratory alkalosis, pulmonary hypertension, asymmetric leg swelling, unilateral leg pain, increase in difference between PADP & PCWP

Massive PE
Massive PE is defined by: systemic hypotension with evidence of organ hypoperfusion & hypoxia, syncope, >50% vascular bed obstruction, or a mean pulmonary artery pressure > 20 mmHg on right heart catheterisation in addition to echocardiographic evidence of right ventricular obstruction.

Clinical diagnosis
A common approach to patients with cardiopulmonary symptoms is the following thought sequence:
Dyspnoea chest pain cough haemoptysis can occur in PE. PE can be fatal. If there is any doubt, it is negligent not to investigate for PE.

Clinical diagnosis
This fear of missing PE may account for clinicians being better at excluding PE (incorrect in only 10% of cases) than in diagnosing it (correct in 30% of cases) on clinical grounds.

Clinical diagnosis
The clinical diagnosis of PE is unreliable, because the clinical features are poorly sensitive & poorly specific for the diagnosis. < 50% of patients have classic findings (leg swelling, pain to deep pressure over calf, Homans sign, or palpable deep thrombi)

Clinical diagnosis
False-negative diagnoses may arise because PE symptoms may mimic those of other common cardiopulmonary conditions or they may be attributed to other coexisting cardiopulmonary diseases, such as congestive cardiac failure & pneumonia.

Clinical diagnosis
Because there are no diagnostic clinical features of PE, the role of the clinical assessment is to formulate the patients presenting symptoms & signs into an estimate of the pretest probability of PE. This serves to define the strategy for special investigations. Experienced clinicians can use clinical judgement (gestalt) to assign a clinical pretest probability for the diagnosis of PE with reasonable accuracy.

Clinical diagnosis
Structured clinical prediction rules perform equally well, & have the advantage that they can be used by less experienced clinicians. The Simplified Wells Scoring System is the most widely used, because it is simple and rapid, & classifies patients into low, intermediate, or high risk for PE

Wells Clinical Probability Score

Clinical History/Sign
Signs/Symptoms of DVT Pulse > 100/min
Bedrest > 3 days (except BR) OR Surgery in previous 4 weeks Must have been objectively diagnosed

Criteria
Leg swelling objectively measured AND Pain with palpation - deep vein region

Score 3.0 1.5 1.5 1.5 1.0

Immobilization Previous DVT or PE Haemoptysis Malignancy

Receiving active treatment for malignancy OR Have received active treatment for malignancy in previous 6 months OR Receiving palliative treatment for malignancy No specific criteria use History, Presentation, CXR, ECG etc. to decide

1.0

PE as likely or more likely than alternative diagnosis

3.0

TOTAL

Wells Clinical Probability Score

Clinical Probability Score LR Positive Pred Value

Low

<2

0.12

3%

Moderate

26

1.9

28%

High

>6

6.0

55%

Clinical approach to the diagnosis of PE

Cindy H Lee, Graeme J Hankey, Wai Khoon Ho, John W Eikelboom. Venous thromboembolism: diagnosis and management of pulmonary embolism. MJA 2005; 182 (11): 569-574

Laboratory investigation
Laboratory tests alone cannot reliably confirm or exclude PE, but may be useful in conjunction with the clinical pretest probability to exclude the diagnosis, to establish an alternative diagnosis, or for risk stratification. D-dimer testing in patients with suspected PE is to exclude the diagnosis; normal concentrations of D-dimer have a high negative predictive value for PE, particularly in patients with a low clinical pretest probability.

Laboratory investigation
Laboratory tests alone cannot reliably confirm or exclude PE, but may be useful in conjunction with the clinical pretest probability to exclude the diagnosis, to establish an alternative diagnosis, or for risk stratification. D-dimer testing in patients with suspected PE is to exclude the diagnosis; normal concentrations of D-dimer have a high negative predictive value for PE, particularly in patients with a low clinical pretest probability.

Laboratory investigation
The main role of the ECG & CXR in patients with suspected PE is to exclude alternative diagnoses (eg, myocardial infarction, pneumothorax). More commonly, ECG demonstrates sinus tachycardia, minor non-specific ST segment or T wave changes (especially V1, V2). Classical ECG changes (S1, Q3, T3 occur in <15% pts)) for PE are:
S wave in lead I, Q wave & T wave inversion in lead III T wave inversion in leads V1 to V4.

Laboratory investigation
The postero-anterior erect CXR may be normal or show enlarged pulmonary arteries, atelectasis, Fleischer lines - linear streaks that run parallel above an elevated hemidiaphragm, vascular oligaemia (Westermark sign - area of relatively underperfused lung), or, rarely, a wedge-shaped density indicating pulmonary infarction (Hampton Hump).

Westermark sign - area of lung which is relatively underperfused.

CXR may show decreased pulmonary vasculature & atelectasis, or Hamptons Hump. Hampton's Hump classic configuration is a zone of homogeneous wedge-shaped consolidation in the lung periphery with its base contiguous to a visceral pleural surface & its rounded convex apex directed toward the hilum

Laboratory investigation
Arterial blood gas (ABG) measurements are still widely used in the initial laboratory evaluation of suspected PE, but are of very little value to establish or exclude the diagnosis. ABGs are normal in 20% of patients with proven PE.

Diagnostic imaging
If a patient with suspected PE has concurrent, clinically apparent DVT, leg ultrasound is usually diagnostic, making lung imaging unnecessary to establish the diagnosis of PE. Otherwise, specific lung imaging studies are required to diagnose PE.

Diagnostic imaging
1st step is V/Q scan (PIOPED 1990, McMaster 1985): Normal/Near-normal - excludes PE. Only 14% had normal/near-normal scan. High probability - > 85% chance of PE, but only 13% had a high probability scan. Also, 15% of patients treated on the basis of a high probability scan would be anticoagulated, or even thrombosed unnecessarily. Low/Intermediate - low had 15-30% chance of PE, intermediate had > 30% chance of PE

Diagnostic imaging
Predictive value greatly refined by combining clinical & scanning probabilities. Unfortunately, > 50% of the scans will be nondiagnostic (intermediate/low probability). Recommended that critically ill patients with nondiagnostic scans undergo compression U/S or impedance plethysmography. If studies are abnormal - DVT can be diagnosed & anticoagulation started. If lower limb studies normal & patient does not have good cardiopulmonary reserve - pulmonary angiography (gold standard).

Diagnostic imaging
Contrast pulmonary angiography is the traditional reference standard test for the diagnosis of PE, but is rarely used: it is invasive, requires a high level of expertise, & is not widely available.

Diagnostic imaging
Ventilation perfusion (V/Q) isotope scanning reliably establishes the diagnosis of PE if the V/Q features suggest a high probability of PE,& excludes the diagnosis if the scan is normal. However, > 50% patients with suspected PE have a non-diagnostic scan (low or intermediate probability), & 25% of these have PE.

Diagnostic imaging
These indeterminate patients require further evaluation with serial compression leg vein ultrasound, computed tomography pulmonary angiography (CTPA), magnetic resonance angiography, or conventional pulmonary angiography. Improvements in the methods of ventilation perfusion scanning using tomographic imaging (SPECT) may overcome the problem of non-diagnostic scans in the future.

Diagnostic imaging
The advantages of newer multi-slice CTPA are that it is rapid, convenient, non-diagnostic in < 10% of cases, and can be used to establish alternative diagnoses. The major disadvantage of CTPA is the high radiation dose. Contrast-enhanced magnetic resonance angiography may replace multi-slice CTPA because it does not involve ionising radiation & contrast agents are safer.

Diagnostic imaging
Spiral CT angiography - very sensitive for central clot, less useful for peripheral emboli. MRI - > 90% sensitivity for central clot with high specificity. TOE - not sensitive for peripheral emboli

Saddle Pulmonary Embolus

Echo Diagnosis of Acute PE: How good is it?

Sensitivity 51%, Specificity 87% among 117 consecutive patients (Grifoni, Am J Cardiology, 1988) Sensitivity 54%, PPV 93% in case-control study (Rudoni, J Emergency Medicine, 1988) Sensitivity 67%, specificity 94% among 50 consecutive ICU patients (Perrier, Int J of Cardiology, 1988)

Echocardiography in the Diagnosis & Management of Acute PE

Echo may make or exclude alternative diagnoses
tamponade aortic dissection acute myocardial infarction

Clinical approach to the diagnosis of PE

Patients with a low clinical pretest probability of PE (probability 3.6% based on a score of < 2) should have a D-dimer assay. If the D-dimer result is negative, diagnostic imaging is not required & it is safe to withhold treatment, as the 3month cumulative incidence of subsequent VTE in untreated patients is very low (0.5%). If the D-dimer level is raised, then the algorithm for a moderate or high pretest probability should be followed.

Clinical approach to the diagnosis of PE

Patients with a moderate clinical pretest probability of PE (probability 20.5%, based on a score of 26) or high clinical pretest probability (probability 67%, based on a score of > 6) should proceed straight to V/Q scan or CTPA, because a negative D-dimer result cannot reliably exclude the diagnosis. Even with a moderate clinical probability, a negative Ddimer result may be associated with an unacceptably high (3.4%) 3-month incidence of VTE.

Clinical approach to the diagnosis of PE

A normal V/Q scan excludes the diagnosis & a high probability V/Q scan or positive CTPA confirms the diagnosis of PE. A low or intermediate probability V/Q scan or a normal or subsegmental defect on a first-generation CTPA are non-diagnostic, & should be followed by compression ultrasound of the legs, because these patients have an unacceptably high risk of PE. The presence of DVT on ultrasonography confirms the diagnosis of PE; patients with a negative ultrasound require repeat ultrasonography in 1 week.

Clinical approach to the diagnosis of PE

Repeat diagnostic imaging at the completion of anticoagulant therapy serves as a baseline reference for patients who may require evaluation for suspected recurrent VTE in the future. Residual thrombus persists in about 50% of patients for many years, & may be misdiagnosed as recurrent VTE in patients who do not have a baseline scan for comparison.

Treatment of pulmonary embolism

The aim of treatment for PE is to:
relieve symptoms, prevent death, reduce the risk of developing chronic pulmonary hypertension, prevent further clot formation promote resolution of existing clot prevent recurrence.

Treatment of pulmonary embolism

The initial treatment of PE is low-molecular-weight heparin or unfractionated heparin for at least 5 days, followed by warfarin (target international normalised ratio [INR], 2.03.0) for at least 36 months. Patients with a high clinical pretest probability of PE should commence treatment immediately while awaiting the results of the diagnostic work-up.

Treatment of pulmonary embolism

Fluids should be given with caution
RV overdistension & ischaemia Ventricular interdependence compromises LV function

Vasopressors may be necessary

Noradrenaline, dopamine.

Treatment of pulmonary embolism

Thrombolysis is indicated for patients with objectively confirmed PE who are haemodynamically unstable. Percutaneous transcatheter or surgical embolectomy may be life-saving in patients ineligible for, or unresponsive to, thrombolytic therapy.

Indications for Inferior Vena Caval Filter

Documented recurrent PE on adequate anticoagulation contraindication to anticoagulation documented free floating thrombus poor respiratory reserve/chronic pulmonary hypertension any PE in patients with cancer with hypercoagulable state

Prognosis
10% of patients with symptomatic PE die < 1 hour of onset of symptoms. Among patients who are diagnosed with PE, the mortality rate is about 10% at 2 weeks & 25% at 1 year. Only 20% of deaths during the first year after PE are a direct consequence of PE; most are due to cancer & underlying cardiopulmonary pathology.

Prognosis
The most important determinants of the clinical outcome of PE are:
presence or absence & severity of haemodynamic compromise, reduction in cardiac output, increase in pulmonary vascular resistance, right ventricular dysfunction.

Prognosis
5-10% of patients with acute PE are haemodynamically unstable at presentation. These patients have a mortality rate of 25%, compared with 4% for patients who are haemodynamically stable. Half of the haemodynamically stable patients have echocardiographic evidence of right ventricular dysfunction, which is associated with a 15% risk of death in hospital & 8% risk of death at 1 year. This compares with no risk of death in patients who do not have echocardiographic evidence of right ventricular dysfunction at presentation.

Summary
PE affects 0.51 per 1000 people/yr, & is one of the most common preventable causes of death among hospitalized patients. Clinical diagnosis is unreliable & must be confirmed objectively with V/Q scanning or CTPA. Diagnosis can be reliably excluded, without need for diagnostic imaging, if clinical pretest probability for PE is low & D-dimer assay result is negative. Initial treatment is LMWH or unfractionated heparin for 5 days, followed by warfarin (target INR = 2.03.0) for 36 months. Patients with a high clinical pretest probability of PE should commence treatment immediately while awaiting diagnostic work-up results. Thrombolysis is indicated for haemodynamically unstable patients with confirmed PE. Percutaneous transcatheter or surgical embolectomy may be lifesaving in patients ineligible for, or unresponsive to, thrombolytic therapy.

References
Cindy H Lee, Graeme J Hankey, Wai Khoon Ho, John W Eikelboom. Venous thromboembolism: diagnosis and management of pulmonary embolism. MJA 2005; 182 (11): 569-574