• Pulmonary embolism (PE) refers to exogenous or endogenous material that travels to the lungs through the pulmonary circulation, causing a potential spectrum of consequences.

• Thrombus from the deep veins of the lower extremities is by far the most common material to embolize to the lungs

• Tumor cells, air bubbles, carbon dioxide, intravenous catheters, fat droplets, and talc in intravenous drug abusers are also potential sources of emboli.

• Genetic and acquired factors contribute to the likelihood of VTE.

• The two most common autosomal dominant genetic mutations are the factor V Leiden and the prothrombin gene mutations

• However, only a minority of patients with VTE have identifiable predisposing genetic factors. The majority of patients with predisposing genetic factors will not develop clinical evidence of clotting

Major Acquired Risk Factors
Advancing age Arterial disease including carotid and coronary disease Obesity Cigarette smoking Chronic obstructive pulmonary disease Personal or family history of venous thromboembolism Recent surgery, trauma, or immobility including stroke Acute infection Long-haul air travel Cancer Pregnancy, oral contraceptive pills, or hormone replacement therapy • Pacemaker, implantable cardiac defibrillator leads, or indwelling central venous catheters • • • • • • • • • •

Major Thrombophilias Associated with VTE

• Inherited Factor V Leiden resulting in activated protein C resistance • Prothrombin gene mutation 20210 • Antithrombin III deficiency • Protein C deficiency • Protein S deficiency • Acquired Antiphospholipid antibody syndrome • Hyperhomocysteinemia

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Embolization :

• About half of patients with pelvic vein thrombosis or proximal leg DVT develop PE, which is usually asymptomatic.

• Isolated calf vein thrombi pose a much lower risk of PE, but they are the most common source of paradoxical embolism.

• With increased use of chronic indwelling central venous catheters, permanent pacemakers and internal cardiac defibrillators, upper extremity venous thrombosis is becoming a more common problem. These thrombi rarely embolize and cause PE. •


• The most common gas exchange abnormalities are hypoxemia (decreased arterial PO2 ) and an increased alveolar-arterial O2 tension gradient.

• Anatomic dead space increases because breathed gas does not enter gas exchange units of the lung.

• Physiologic dead space increases because ventilation to gas exchange units exceeds venous blood flow through the pulmonary capillaries.

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Other pathophysiological abnormalities include:

• Increased pulmonary vascular resistance due to vascular obstruction or  platelet secretion of vasoconstricting neurohumoral agents such as serotonin.

• Impaired gas exchange due to increased alveolar dead space

• Alveolar hyperventilation due to reflex stimulation of irritant receptors

• Increased airway resistance due to constriction of airways distal to the bronchi

• Decreased pulmonary compliance due to lung edema, lung hemorrhage, or loss of surfactant

Right Ventricular Dysfunction


 Clinical Decision Rule
• >4 score points = high probability    ≤4 score points = non–high probability    

• • • • • • •

Score Points DVT symptoms or signs An alternative diagnosis is less likely than PE HR > 100/min 1.5 Immobilization or surgery within 4 wk Prior DVT or PE Hemoptysis Cancer treated within 6 mo or metastatic

3 3

1.5 1.5 1 1


Myocardial infarction Pericarditis Heart failure Pneumonia Asthma Chronic obstructive pulmonary disease Pneumothorax Pleurodynia Pleuritis from connective tissue disease Thoracic herpes zoster (“shingles”) Rib fracture Musculoskeletal pain Primary or metastatic intra thoracic cancer Infra diaphragmatic processes (e.g., acute cholecystitis, splenic infarction) Hyperventilation syndrome

Clinical Syndromes of Pulmonary Embolism
• Classification of Acute Pulmonary Embolism : Classification Presentation Therapy Massive PE Systolic BP ≤ 90 mm Hg Thrombolysis  or poor tissue perfusion embolectomy  or multisystem organ failure IVC filter  plus plus  rt or ltPA thrombus anticoagulation  or “high clot burden” SubmassivePE Hemodynamically stablebut Addition of thrombolysis,  mod. or sev.RVdysfunction

or or

Clinical Syndromes of Pulmonary Embolism
• PULMONARY INFARCTION.  Caused by a tiny peripheral pulmonary embolism  Tissue infarction usually occurs 3 to 7 days after embolism.  Pleuritic chest pain, often not responsive to narcotics  Low-grade fever  Pleural rub  Occasional scant hemoptysis  Leukocytosis • PARADOXICAL EMBOLISM.  small DVT that embolizes to the arterial system, usually through a

patent foramen ovale.

Clinical Syndromes of Pulmonary Embolism
NONTHROMBOTIC PULMONARY EMBOLISM:  include fat, tumor, air, and amniotic fluid
  

-Fat embolism syndrome is most often observed after blunt trauma complicated by longbone fractures. -Air embolus can occur during placement or removal of CVC - Amniotic fluid embolism may be catastrophic and is characterized by respiratory failure, cardiogenic shock, and DIC.

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Nonimaging Diagnostic Modalities

PLASMA d-DIMER ASSAY: • Quantitative plasma D-dimerenzyme-linked immunosorbent assay (ELISA) rises in the presence of DVT or PE . • The sensitivity of the D-dimer is greater than 95% for PE. • The D-dimer is a useful "rule out" test. It is normal (<500 ng/mL) in more than 95% of patients without PE. • In patients with low clinical suspicion of DVT, it is normal in more than 90% without DVT. • The D-dimer assay is not specific. • Levels increase in pts with MI, pneumonia, sepsis, cancer, the postoperative state, and 2nd or 3rd trimester of pregnancy. • Therefore, it rarely has a useful role among hospitalized patients because their D-dimers are frequently elevated due to some systemic illness

Nonimaging Diagnostic Modalities

• Elevated Cardiac Biomarkers :  -Serum troponin levels increase in RV microinfarction.
 

-Myocardial stretch often results in elevation of BNP or NT-pro- BNP -Elevated cardiac biomarkers predict an increase in major complications and mortality from PE

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  

-Sinus tachycardia - Incomplete orcompleteRBBB - Right axis deviation -T wave inversions in leads III and aVF or in leads V1-V4 -S wave in lead I and a Q wave and T wave inversion in lead III (S1Q3T3) -QRS axis >90 degrees or an indeterminate

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Noninvasive Imaging Modalities
CHEST RADIOGRAPHY :  -A normal or near-normal CXR in a dyspneic patient often occurs in PE.  -Well-established abnormalities include
    

focal oligemia( Westermark's sign), a peripheral wedged-shaped density above the diaphragm (Hampton's hump), or

 

an enlarged right descending pulmonary artery ( Palla's sign).

Chest CT
• CT of the chest with IV contrast is the principal imaging test for the diagnosis of PE.

• Multi detector-row spiral CT acquires all chest images with 1 mm .This CT scanners can image small peripheral emboli.

• The CT scan also obtains excellent images of the RV and LV and can be used for a risk stratification as well as a diagnostic tool.

• In patients without PE, the lung parenchymal images may establish alternative diagnoses not apparent on chest xray that explain the presenting symptoms and signs, such as pneumonia, emphysema, pulmonary fibrosis, pulmonary mass, or aortic pathology.

Lung Scanning
• Lung scanning is now a second-line diagnostic test for PE. • It is mostly used for patients who cannot tolerate intravenous contrast. • Small particulate aggregates of albumin labeled with a gamma-emitting radionuclide are injected IV and are trapped in the pulmonary capillary bed.

• The perfusion scan defect indicates absent or decreased blood flow, possibly due to PE.

• Ventilation scans, obtained with radiolabeled inhaled gases such as xenon or krypton, improve the specificity of the perfusion scan.

• Abnormal ventilation scans indicate abnormal non ventilated lung, thereby providing possible explanations for perfusion defects other than acute PE, such as asthma or COPD.

Lung Scanning

• A high probability scan for PE is defined as having two or more segmental perfusion defects in the presence of normal ventilation.

• The diagnosis of PE is very unlikely in patients with normal and near-normal scans but is about 90% certain in patients with high-probability scans.

• As many as 40% of patients with high clinical suspicion for PE and "low-probability" scans do, in fact, have PE at angiography.

Magnetic Resonance (MR)
• MR utilizes gadolinium contrast agent, which, unlike iodinated contrast agents used in venography or CT angiography, is not nephrotoxic.

• MR imaging should be considered for suspected DVT or PE patients with renal insufficiency or contrast dye allergy.

• MR pulmonary angiography detects large proximal PE but is not reliable for smaller segmental and sub segmental PE.

• Echocardiography is not a reliable diagnostic imaging tool for acute PE.

• Transthoracic echo. rarely images thrombus directly.  The best-known indirect sign of PE on transthoracic echo. is  McConnell's sign, hypokinesis of the RV free wall with normal  motion of the RV apex.

• Transesophagealecho should be considered when CT scanning facilities are not available or when a patient has renal failure or severe contrast allergy.  This imaging modality can directly visualize large proximal PE.

• The primary diagnostic criterion for DVT is loss of vein compressibility. Normally, the vein collapses completely when gentle pressure is applied to the skin overlying it.

• When PE is suspected, venous ultrasonography is useful if it demonstrates DVT because DVT can be considered a surrogate for PE.

• However, at least half of patients with PE have no imaging evidence of DVT.

• Therefore if clinical suspicion of PE is moderate or high, patients without evidence of DVT should undergo further investigation for PE.

Invasive Diagnostic Modalities
Pulmonary Angiography :  -Chest CT with contrast has virtually replaced invasive pulmonary angiography as a diagnostic test.
  

- reserved for patients with technically unsatisfactory chest CTs or for those in whom an interventional procedure such as catheter-directed thrombolysis or embolectomy is planned. - A definitive diagnosis of PE depends upon visualization of an intraluminal filling defect in more than one projection. -Secondary signs of PE include abrupt occlusion ("cut-off") of vessels, segmental oligemiaor avascularity, a prolonged arterial phase with slow filling, or tortuous, tapering peripheral vessels

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Invasive Diagnostic Modalities
• Contrast Phlebography
 

Venous ultrasonography has virtually replaced contrast phlebography as the diagnostic test for suspected DVT.

Integrated diagnostic approach


Risk Stratification

Predictors of Increased Mortality
• Clinical  Systolic blood pressure less than or equal to 100 mm Hg  Age older than 70 years  Heart rate higher than 100 beats/min  Congestive heart failure ,Chronic lung disease ,Cancer

• Cardiac Biomarkers and Imaging  Elevated troponin I or troponin T  Elevated BNP or pro-BNP  Right ventricular hypokinesis on echocardiogram  Right ventricular enlargement on chest CT

Unfractionated heparin (UFH) prevents additional thrombus formation and permitting endogenous fibrinolytic mechanisms to lyse clot that has already formed. • UFH is dosed to achieve a target (aPTT) that is 2–3 times the upper limit of the laboratory normal. This is usually equivalent to an aPTT of 60–80 s. • For UFH, a typical IVbolus is 5000–10,000 units followed by a continuous infusion of 1000–1500 units/h. • The most popular nomogram utilizes an initial bolus of 80 units/kg, followed by an initial infusion rate of 18 units/kg per hour.
 

• The major advantage of UFH is that it has a short half-life.

• The major disadvantage of UFH is that achieving the target aPTT can be difficult and may require repeated blood sampling and heparin dose adjustment every 4–6 h.

Raschke Nomogram

Variable Action Initial IV heparin bolus then 18 U/kg/hr aPTT <35 seconds (<1.2 × control) then increase by 80 U/kg bolus,

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80 U/kg bolus,

4 U/kg/hr aPTT 35 - 45 seconds (1.2 -1.5 c) by 2 U/kg/hr
   

40 U/kg bolus, then

aPTT 46 - 70 seconds (1.5 to 2.3 c) aPTT 71 - 90 seconds (2.3 to 3 c )

No change infusion rate

• Low Molecular Weight Heparins: •  exhibit less binding to plasma proteins and endothelial cells and consequently have greater bioavailability, a more predictable dose response, and a longer half-life than UFH.
 

-No monitoring or dose adjustment is needed unless the patient is markedly obese or has renal insufficiency.

• Enoxaparin 1 mg/kg twice daily and tinzaparin 175 units/kg once daily have received FDA approval for treatment of patients who present with DVT.

• The weight-adjusted doses must be adjusted downward in renal insufficiency because the kidneys excrete LMWH

• Fondaparinux:  -Fondaparinux, an anti-Xa pentasaccharide, is administered by once-daily subcutaneous injection and has been approved by the FDA to treat DVT and PE.
       

-No laboratory monitoring is required. -Patients weighing <50 kg receive 5 mg, 50–100 kg receive 7.5 mg, and >100 kg receive 10 mg. -The dose must be adjusted downward for patients with renal dysfunction because the drug is excreted by the kidneys.

• This vitamin K antagonist prevents carboxylation activation of coagulation factors II, VII, IX, and X.

• The full effect of warfarin requires at least 5 days.

• If warfarin is initiated as monotherapy a paradoxical exacerbation of hypercoagulability can increase the likelihood of thrombosis rather than prevent it.

• Overlapping UFH, LMWH, or fondaparinux with warfarin for at least 5 days can counteract the early procoagulant effect of unopposed warfarin.

• Dosing  - In an average-sized adult, warfarin is usually initiated in a dose of 5 mg.
 

-Doses of 7.5 or 10 mg can be used in obese or largeframed young patients who are otherwise healthy. - Patients who are malnourished or who have received prolonged courses of antibiotics are probably deficient in vitamin K and should receive smaller initial doses of warfarin, such as 2.5 mg. -The prothrombin time is standardized with the INR. -The target INR is usually 2.5, with a range of 2.0–3.0

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Optimal Duration of Anticoagulation
• Clinical Setting Recommendation  1ST provoked PE/proximal leg DVT mo
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6 3

  

First provoked upper extremity DVT mo or isolated calf DVT Second provoked VTE 12 mo indefinite duration


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Third VTE Indefinite duration

Inferior Vena Caval Filters
• The indications for insertion of an IVC filter are  (1) active bleeding that precludes anticoagulation, and  (2) recurrent venous thrombosis despite intensive anticoagulation

• Prevention of recurrent PE in patients with Rt. heart failure who are not candidates for fibrinolysis or prophylaxis of extremely high-risk patients are "softer" indications for filter placement.

• The filter itself may fail by permitting the passage of small to medium-sized clots. • Large thrombi may embolize to the pulmonary arteries via collateral veins that develop. • A more common complication is caval thrombosis with marked bilateral leg swelling

Inferior Vena Caval Filters
• Retrievable filters can now be placed for patients with  -an anticipated temporary bleeding disorder or  -for patients at temporary high risk of PE

• The filters can be retrieved up to several months following insertion, unless thrombus forms and is trapped within the filter.

• The retrievable filter becomes permanent if it remains in place or if, for technical reasons such as rapid endothelialization, it cannot be removed

Maintaining Adequate Circulation
• For patients with massive PE and hypotension, the most common initial approach is administration of 500–1,000 ml of normal saline.

• However, fluids should be used with extreme caution.

• Excessive fluid administration exacerbates RV wall stress, causes more profound RV ischemia, and worsens LV compliance and filling by causing further IVS shift toward the LV.

• Dopamine and dobutamine are first-line inotropic agents for treatment of PE-related shock.


• Thrombolysis usually  (1) dissolves much of the obstructing pulmonary arterial thrombus  (2) prevents the continued release of serotonin and other neurohumoral  factors that exacerbate pulmonary hypertension and  (3) dissolves much of the source of the thrombus in the pelvic or  deep leg veins, thereby decreasing the likelihood of recurrent PE.

• The preferred fibrinolytic regimen is 100 mg of recombinant tissue plasminogen activator (tPA) administered as a continuous peripheral IV infusion over 2 h.

• Patients appear to respond to fibrinolysis for up to 14 days

• Contraindications to fibrinolysis include intracranial disease, recent surgery, or trauma.

• The overall major bleeding rate is about 10%, including a 1– 3% risk of intracranial hemorrhage.

• Indication for PE fibrinolysis is massive PE.

• For patients with preserved systolic blood pressure and submassive PE, guidelines recommend individual patient risk assessment of the thrombotic burden versus bleeding risk

• Pulmonary Embolectomy
 

-The risk of intracranial hemorrhage with fibrinolysis has prompted the renaissance of surgical embolectomy for acute PE - At Brigham and Women's Hospital, 47 patients with massive PE underwent emergency surgery in 53 months, with a 94% survival rate

• Alternative to open surgical embolectomy is catheter embolectomy

Pulmonary Thrombo endarterectomy
• Chronic thromboembolic pulmonary hypertension is caused by vascular obstruction at the capillary level, not direct thromboembolic occlusion

• Patients severely impaired with dyspnea due to chronic thromboembolic PHTN should be considered for pulmonary thromboendarterectomy, which, if successful, can markedly reduce and at times even cure PHTN.

• The two most common complications are
 

(1) "pulmonary steal," where blood rushes from previously perfused areas to newly revascularized areas of the lung; and

Prevention of Postphlebitic Syndrome
• The only therapy to prevent postphlebitic syndrome is daily use of below-knee 30–40 mmHg vascular compression stockings.

• They halve the rate of developing postphlebitic syndrome.

• These vascular compression stockings should be prescribed as soon as DVT  is diagnosed, and the stockings should be fitted carefully to maximize  their benefit.

Prevention of VTE

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Harrison's Internal Medicine ,17th e Braunwald’s Heart Disease ,8th e Cecil Medicine, 23rd ed.