Pulmonary Embolism

Traditional risk factors for thromboembolic disease

• Venous thrombosis
  • Strong: trauma, fractures, major orthopedic surgery, oncological surgery, immobilization combined with other risk factors
  • Moderate: nononcological surgery, exogenous estrogen (e.g., OCPs, HRT); pregnancy and puerperium, previous VTE
  • Weak: advanced age, prolonged travel, bed rest (e.g., > 3 days) as a sole risk factor, metabolic syndrome
• Arterial thrombosis
  • Smoking
  • Obesity
  • Hyperlipidemia
  • Diabetes mellitus
  • Hypertension

RISK FACTORS FOR PE

• Major (relative risk 5-20) – SLOMMP
  • Surgery – major abdominal/pelvic, hip/knee replacements, post ICU
  • Lower limb problems – #, varicose veins
  • Obstetrics – late pregnancy, C/S, puerperium
  • Malignancy – abdominal/pelvic, advanced/metastatic
  • Mobility – hospitalization, institutional care
  • Previous VTE
• Minor (relative risk 2-4) – COM
  • Cardiovascular – congenital heart disease, CHF, HT, superficial venous thrombosis, CVL
  • Oestrogens – OCP, HRT (Increased estrogen and progestin → increase in prothrombin and fibrinogen and a decrease in protein S)
  • Miscellaneous
    • COPD
    • neurological disability
    • occult malignancy
    • thrombotic disorder
    • long distance travel
    • obesity 
    • IBD
    • nephrotic syndrome – 
    • dialysis
    • myeloproliferative disorders
    • paroxysmal nocturnal haemoglobinuria
    • Bechet’s disease
• Thrombophillias 🡪 test in those < 50years with recurrent or a strong FHx
• Factor V Leiden mutation
• Prothombin gene mutation
• Hyperhomocysteinaemia
• Antiphospholipid antibody syndrome
• Deficiency of antithrombin III, protein C or protein S
• High concentrations of factor VIII or XI
• Increased lipoprotein (a)

INVESTIGATIONS

• ECG:

• mostly normal
• sinus tachycardia
• SI, QIII, TIII 
• non specific ST changes or TWI in anterior leads (right heart strain),
• right axis deviation
• s wave (I and aVL) > 1.5mm
• Q wave in III and aVF
• p pulmonale
• RBBB

• CXR: rules out other pathology, focal oligaemia, wedge density (pulmonary infarction)
• ABG: reduced PaO2 in keeping with size of PE, metabolic acidosis with circulatory collapse, respiratory alkalosis
• D-Dimer: reassuring if negative to exclude PE, use in conjunction with clinical probability
• TNT: elevation is associated with adverse outcome even in normotensive patients, also associated with haemodynamic instability in patients with non-massive PE
• BNP and NT-terminal BNP: if low correlates well with uneventful course
• CTPA: as good as pulmonary angiography (gold standard), can calculate RV/LV ratio (>0.9) = severe
• ECHO: RV dialation, paradoxical septal motion towards the LV, TR, RVF, PHT or PA thrombus on TOE
• US: leg veins (not as accurate as initially thought -> have low threshold to re-scan)
• V/Q scan: only really used now when CT is contraindicated (normal scan, low, intermediate and high probability with various criteria)

• D-dimer testing
  • D-dimer is a degradation product of cross-linked fibrin and is elevated in plasma in the presence of clot because of the activation of coagulation and fibrinolysis. 
  • A negative D-dimer using a quantitative enzyme-linked immunoabsorbent assay (ELISA) has a sensitivity of >95% and effectively excludes PE in low- and intermediate-probability groups. 
  • Qualitative D-dimer tests are less reliable, but they have been used safely in the primary care setting with the Wells rule in excluding PE
  • D-dimer cannot be used to confirm PE as fibrin is also produced in
    • Cancer
    • Inflammation
    • Infection
    • necrosis.
  • The combination of clinical assessment and D-dimer testing misses less than 2% of VTE in a general practice population. 

• Lower limb (compression) ultrasound
  • Compression ultrasound (US) has high sensitivity for detection of proximal deep vein thrombosis (DVT), which is the source of PE in 90% of patients
  •  A positive lower limb US is present in 30–50% of patients with PE and is useful where tests using ionising radiation are less desirable, for example in pregnancy.

• Ventilation-perfusion lung scintigraphy
  • uses macro-aggregated albumin (MAA) particles labelled with technetium-99m to assess lung tissue perfusion 
  • compares it with ventilation images obtained after inspiring an aerosol of technetium-99m-labelled fine-carbon particles.
  • The test takes approximately 30 minutes and is usually well tolerated.
  • When PE occludes a pulmonary artery branch, the area supplied by this vessel will appear as a ‘cold’ defect with no activity on perfusion imaging and no corresponding defect on ventilation imaging, called a VQ ‘mismatch’. 
  • A ‘matched’ defect present on both ventilation and perfusion indicates hypoperfusion is due to vasoconstriction secondary to hypoventilation and not due to PE.
  • A normal VQ scan – excludes PE
  • Positive scan +  presence of intermediate to high pre-test probability  – confirms PE
  • indeterminate scan
    • can be up to 70% of scans 
    • further investigation is required
  • Radiation burden is very favourable (1.1–1.5 mSv) compared with CTPA and makes the VQ scan very useful in pregnancy and younger patients.

• CTPA (Computed tomographic pulmonary angiography)
  • CTPA is fast and generally well tolerated 
  • CT has superior sensitivity for the detection of small subsegmental emboli when compared with planar VQ imaging, but increased diagnosis has been associated with an increase in complications from anticoagulation without a decrease in mortality from PE
    • Small emboli are believed to be resorbed with no clinical effect. 
  • CT is relatively contraindicated in the presence of moderate-to-severe renal disease because of the risk of contrast-induced nephropathy.
  • CT also has a relatively high radiation dose of 7 mSv (or more than 5 times a VQ scan). 
  • This makes it relatively less attractive for younger patients and young women in particular, because of the relatively large dose delivered to the radiosensitive breast. 
  • Novel CT reconstruction algorithms (so-called ‘low-dose’ CT), which allow less radiation to be delivered while preserving diagnostic quality are increasingly  available, and should be used if available 

VQ or CTPA?

VQ	CTPA
Less radiation dose	detects clots in smaller vessels
	widespread availability
	contrast-induced nephropathy
In Pregnancy – PE is a leading cause of maternal mortality. D-dimer assays are of limited usefulness
Perfusion-only lung scanning using a reduced dose of 100 MBq technetium-99m yields a dose to the foetus of approximately 0.25 mSv	0.25 mSv = is identical to CTPA
The dose to the maternal breast is significantly less with VQ scans
Breastfeeding needs to be interrupted for 13 hours after VQ	Breast feeding does not need to be stopped after CT contrast

PERC Rule: 

• FACTS & FIGURES: If any criteria are positive, the PERC rule is not satisfied and cannot be used to rule out PE in this patient.

EVIDENCE APPRAISAL:

• The original article from 2004 (J Thromb Haemost . 2004 Aug;2(8):1247-55_ was a prospective study with a derivation section and a validation section.
  • 3148 patients from 10 sites were included in the derivation.
  • 21 potential variables were included for analysis, with the 8 final variables selected from these.
  • 1427 low-risk and 382 very low-risk patients from 2 sites were included in the validation section.
  • In low-risk patients there was a sensitivity of 96% and specificity of 27%.
  • In very low-risk patients there was a sensitivity of 100% and specificity of 15%.
  • The false negative rate at 90 days in low-risk patients was 1.4% which is below the 1.8% testing threshold.
• A second multicenter validation was done in 2008. This expanded upon the initial validation study and defined low pretest probability as <15%
  • 8138 patients from 13 sites were included in the study. Some of these sites were included in the initial paper.
  • Clinical gestalt for a pretest probability of <15%, 15-40% or >40% was collected from the providers.
  • 20% of the cohort was deemed low risk (<15%)
  • For patients who were PERC negative and pre-test probability was <15% the false negative rate at 45 days was 1.0% with a sensitivity of 97.4% and specificity of 21.9%.

MANAGEMENT

• Grade severity of PE
  • MASSIVE – haemodynamically unstable -> thrombolyse/embolectomy
  • SUB-MASSIVE – haemodynamically stable with evidence of RV dysfunction -> strongly consider thrombolysis/embolectomy but need to balance risk of bleeding
  • NON-MASSIVE – haemodynamically stable with normal RV function -> anticoagulation

• Management Goals
  • prevent further embolism
  • removal of emboli (massive or sub-massive)
  • haemodynamic support (massive)

• Resuscitation
  • A – may need intubation if in cardiovascular collapse or cardiac arrest
  • B – high flow O2 as a pulmonary vasodilator, ventilation to optimize V/Q mismatch, hyperventilation to clear CO2
  • C – invasive monitoring, fluid management to optimize right ventricular function, inotropic support, cautious fluid boluses, use milrinone, noradrenaline or adrenaline (rather than alpha agonists)
  • Specific Treatment

THROMBOLYSIS

• For severely compromised patients
  • systolic blood pressure is <90 mmHg
  • bradycardia <40 beats/minute
  • RV compromise
• as successful as embolectomy in massive PE (earlier the better)
• can be used up to 14 days after symptoms begin
• PE resolve more quickly than with heparin alone
• rTPA 1.5mg/kg is maximum dose (as good through peripheral IV or CVL)
• alteplase 100 mg (0.6mg/kg) as a continuous infusion over 2 hours
• follow straight away with heparin
• if bleeds -> FFP and anti-fibrinolytics 

• contraindications:
  • absolute – bleeding, recent stroke, HI, current GI bleeding, relative – PUD, surgery within 7 day, prolonged CPR

• use in submassive PEs is contentious
  • doesn’t reduce mortality but does reduce deterioration
  • ‘fibrinolysis may be considered for … submassive acute pulmonary embolism (with) … hemodynamic instability, worsening respiratory insufficiency, severe right ventricular dysfunction, or major myocardial necrosis and low risk of bleeding complications’

ANTICOAGULATION

• The goals of treatment are to :
  • reduce mortality and early recurrence for initial anticoagulation (first 5–10 days),
  • reduce late recurrences for the long term (mostly 3–6 months) and extended anticoagulation (beyond the first 3–6 months).
• start immediately when there is a suspicion (prior to imaging)
• LMWH reduces complications and thrombus size, compared with unfractionated heparin, for the initial treatment of VTE without altering mortality.
• Heaprin/dalteparin 200 U/kg, up to 18,000 U daily or
• Heaprin/dalteparin 100 U/kg, up to 9000 U twice daily

     or 

• Clexane – enoxaparin 1.5 mg/kg daily or 
• Clexane – enoxaparin  1 mg/kg twice daily.Twice-daily

• Warfarin
  • should be started on the same day as anticoagulant therapy in patients with acute PE 
  • Parenteral anticoagulation and warfarin should be continued together for a minimum of at least five days and until the INR is 2.0
  • INR maintained at 2–3. 

 > 5 days followed by Alternatives that could be considered instead of warfarin:

• Anti-Xa (rivaroxaban, apixaban and edoxaban)
• Antithrombin (dabigatran) 

• Rivaroxaban
  • 15 mg twice daily for three weeks, then 20 mg daily
  • currently approved and subsidised for use in pulmonary embolism in Australia, 
• Apixaban
  • If CrCl more than 25 mL/min- 10 mg orally, twice daily for 7 days, then decrease to 5 mg twice daily
  • Do not use apixaban if calculated creatinine clearance (CrCl) is less than 25 mL/min

• Dabigatran
  • <75 years and CrCl more than 50 mL/min: 150 mg orally, twice daily
  • <75 years and CrCl 30 to 50 mL/min, or increased risk of major bleeding: 110 mg orally, twice daily
  • >75 years or older and CrCl more than 30 mL/min: 110 mg orally, twice daily.

Treatment duration

• PE
  • is six months
  • may be three months in the presence of a transient major risk factor
  • indefinite if there are ongoing major risk factors (eg cancer, recurrent unprovoked pulmonary embolism)

• proximal DVT or PE
  • by a major provoking factor that is no longer present = anticoagulant therapy for 3 months
• isolated distal DVT
  • by a major provoking factor that is no longer present = 6 weeks of anticoagulant therapy; after 6 weeks, the risk of recurrence of an isolated distal DVT is low.

• After 3 months of therapy, decide whether to stop or to continue indefinitely with extended anticoagulant therapy 
• Assess the risk of bleeding and of recurrence of thromboembolism, and actively seek the patient’s preference.
• Factors that predict increased likelihood of bleeding include a patient having:
  • a prior bleeding episode
  • active peptic ulcer disease
  • oesophageal varices

Subsegmental pulmonary embolism

• clinical surveillance is preferred to anticoagulation for patients with
  • SSPE (no involvement of proximal pulmonary arteries)
  • no proximal DVT with low risk for recurrent VTE. 
  • ultrasound scanning of the deep veins in both legs should be performed to exclude proximal DVT
  • clinical surveillance may be supplemented by serial ultrasound scanning.
• Recommendations to not treat SSPE are weak as there are no randomised trials on the safety of anticoagulation versus no treatment in this subgroup;23 GPs may want to seek advice from specialist colleagues for this group.

Superficial thrombophlebitis

• Superficial thrombophlebitis is usually a self-limiting disorder
• but it may be complicated by deep vein thrombosis or pulmonary embolism
  • particularly if the patient has risk factors that are common to superficial thrombophlebitis and venous thromboembolism [eg malignancy, pregnancy]).
  • It may also be complicated by contiguous extension of thrombus. 
• Conditions associated with superficial thrombophlebitis
  • intravenous cannulation
  • pregnancy
  • malignancy
  • varicose veins
  • other causes of venous stasis and venous trauma.
• Antibiotics are not indicated for superficial thrombophlebitis unless the patient has sepsis

• Treatment
  • intravenous cannulation : consider treatment with a topical or oral NSAID only)
  • spontaneous superficial thrombophlebitis specially thrombus involves thigh veins
    • consider treatment LMWH for 4 to 6 weeks

SURGICAL

• embolectomy (massive PE and unresponsive to thrombolysis or is contraindicated)
• right heart catheterisation with clot destruction
• IVC filter (high risk of further embolic or recurrent PE despite adequate anticoagulation, contraindications to anticoagulation, extensive DVT, massive PE)

Prevention

• Giving anticoagulants to people at risk of clots before and after surgery and to people who have had a heart attack, stroke, or complications of cancer
• Wearing elasticated compression stockings, which squeeze the legs helping the veins and leg muscles move blood more efficiently and reduce the pooling of blood in the lower legs
• Elevating the legs when possible and during the night to help reduce blood pooling
• Physical activity, which promotes blood circulation
• Intermittent pneumatic compression, which involves using a device that massages and squeezes the veins in the legs to improve blood flow.

PE (pulmonary embolism) and fitness to fly (flying)

• The risk of blood clots developing while traveling is generally low, but the risk increases with longer duration of travel, and if you have other risk factors.
• Acute thromboembolic disease e.g. DVT/PE is an absolute contraindication to flying 
• patients with a history of pulmonary embolism or DVT should be considered for full oral anticoagulation
• Any specialised prophylaxis should be targeted at those at the highest risk and include:
  • properly fitted anti-embolism stockings giving graduated compression to the limb (if no contraindications),
  • subcut Clexane is highly effective and has a low risk of bleeding and in extremely high risk cases oral anticoagulation.
  • It is important to emphasise that the risk of side effects from the use of aspirin outweigh any potential anti-thrombotic effect and its use is not recommended
• Activities can help to prevent blood clots during travel:
  • Avoid sitting for too long. If flying, move around the airplane cabin every hour and do some deep knee bends. If driving, stop every hour and walk around
  • While sitting, flex your ankles every half hour or so
  • Wear compression stockings to help promote circulation and fluid movement in the lower legs
  • Drink plenty of water to prevent dehydration, which can contribute to the formation of blood clots.