Pulmonary embolism resident survival guide

For pulmonary embolism prevention resident survival guide click here.

Editor(s)-In-Chief: The APEX Trial Investigators, C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]; Pratik Bahekar, MBBS [3]; Chetan Lokhande, M.B.B.S [4]

Pulmonary embolism Resident Survival Guide Microchapters
Overview
Causes
FIRE
Diagnosis
Long term treatment
Do's

Overview

Pulmonary embolism (PE) is the acute obstruction of the pulmonary artery or one of its branches by a thrombus, air, tumor, or fat. Most often, PE is due to a venous thrombus which has been dislodged from its site of formation in the deep veins of the lower extremities, a process referred to as venous thromboembolism. PE is a potentially lethal condition. The patient can present with a range of signs and symptoms; however, the typical presentation is characterized by dyspnea (78-81% of the cases), pleuritic chest pain (39-56% of the cases), and/or syncope (22-26% of the cases). The diagnostic approach of PE depends on whether the patient is a high-risk patient due to the presence of hypotension and/or shock or a non-high risk patient, as well as on the pre-test probability of this disease. While fibrinolytic therapy is the treatment of choice for patients with massive PE, patients with non-massive PE are treated with anticoagulation therapy.

Causes

Life Threatening Causes

Pulmonary embolism is a life-threatening condition and must be treated as such irrespective of the underlying cause.

Common Causes

• Blood clot (most common cause)
• Air bubble
• Fragment of a tumor
• Fragment of fat (secondary to bone fracture)
• Amniotic fluid

Classification

Massive Pulmonary Embolism

Massive pulmonary embolism falls under the category "high risk patients" in the European guidelines. High risk PE patients have a risk of PE-related early mortality of > 15%.
Massive PE is characterized by the presence of:

• Sustained hypotension (systolic blood pressure <90 mm Hg) not due to arrhythmia, hypovolemia, sepsis, or left ventricular dysfunction, that is either lasting for at least 15 minutes or necessitating the administration of inotropes

OR

• Pulselessness

OR

• Persistent profound bradycardia (heart rate < 40 bpm) plus findings of shock

Submassive Pulmonary Embolism

Submassive pulmonary embolism falls under the category "intermediate risk patients" in the European guidelines. Intermediate risk PE patients have a risk of PE-related early mortality ranging between 3 and 15%.
Submassive PE is characterized by:

• Right ventricular dysfunction OR myocardial necrosis

AND

• Absence of systemic hypotension (systolic blood pressure >90 mm Hg)

Right Ventricular Dysfunction

Right ventricular (RV) dysfunction is characterized by the presence of AT LEAST ONE of the following:

• Echocardiography findings:
  • RV dilation (ratio of apical 4-chamber RV diameter to left ventricle (LV) diameter > 0.9)
  • RV systolic dysfunction
• CT findings: RV dilation (ratio of 4-chamber RV diameter to LV diameter > 0.9)
• BNP > 90 pg/mL
• N-terminal pro-BNP >500 pg/mL
• EKG findings:
  • New complete or incomplete right bundle-branch block
  • Anteroseptal ST elevation or ST depression
  • Anteroseptal T-wave inversion

Myocardial Necrosis

Myocardial necrosisis defined as the presence of:

• Elevation of troponin I (>0.4 ng/mL)

OR

• Elevation of troponin T (>0.1 ng/mL)

Low-Risk Pulmonary Embolism

Low risk PE patients have a risk of PE-related early mortality of <1%. Low risk PE is characterized by the absence of hypotension, shock, RV dysfunction, and myocardial necrosis.

FIRE: Focused Initial Rapid Evaluation

A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.

Abbreviations: CT: Computed tomography; IV: Intravenous; IVC: Inferior vena cava; PE: Pulmonary embolism; PERC: PE Rule-Out Criteria; RV: Right ventricle; SC: Subcutaneous; VKA: Vitamin K antagonist

Step 1: Confirm PE

Identify cardinal findings that increase the pretest probability of PE ❑ Dyspnea ❑ Pleuritic chest pain ❑ Syncope ❑ Tachycardia ❑ Tachypnea

Does the patient who is suspected to have PE have hypotension or shock?

Yes

No

Suspected high-risk PE

Suspected non-high risk PE

❑ Administer parenteral anticoagulation (in case there are no contraindications) during the diagnostic workup

Is a CT available immediately?

What is the pretest probability of PE?

No

Yes

❑ Order Echocardiography

Does the patient have RV overload?

Low pretest probability

Intermediate pretest probability

High pretest probability OR PE is likely

❑ Administer parenteral anticoagulation (in case there are no contraindications) during the diagnostic workup

❑ Administer anticoagulation (in case there are no contraindications) during the diagnostic workup

No

Yes

❑ Order CT

❑ Order D-dimer

Positive

Negative

Positive

Negative

Is the patient unstable OR no other tests are available?

Is the patient stabilized AND CT is now available?

❑ Order CT

PE is excluded

❑ Order CT

Positive

Negative

Positive

Negative

PE is excluded

❑ Consider thrombolytic therapy OR ❑ Embolectomy

❑ Order CT

PE is confirmed

PE is excluded

PE is confirmed

PE is excluded

PE is confirmed

PE is excluded

Positive for PE

Negative for PE

Click here for the initial treatment

Click here for the initial treatment

Click here for the initial treatment

PE is confirmed

PE is excluded

Click here for the initial treatment

Assessment of the Pretest Probability of PE

The assessment of the pretest probability of PE can be achieved through scoring systems. The most commonly used score is the Wells score. Other scores, such as Geneva score and PERC can also be used.

Wells Score

The Wells score is a simple, commonly used clinical risk prediction tool to evaluate the need for further testing in patients suspected to have pulmonary embolism.

Calculation of Wells Score

Pulmonary embolism Wells Score Calculator

Variable	Wells Score
Clinically suspected DVT (leg swelling, pain with palpation)	3.0
Alternative diagnosis is less likely than PE	3.0
Immobilization/surgery in previous four weeks	1.5
Previous history of DVT or PE	1.5
Tachycardia (heart rate more than 100 bpm)	1.5
Malignancy (treatment for within 6 months, palliative)	1.0
Hemoptysis	1.0

Interpretation of Wells Score

Wells Criteria

Shown below is the pretest probability of PE according to Wells criteria.

• Score >6.0: High probability (Rate of PE: ~66.7%)
• Score 2.0 to 6.0: Moderate probability (Rate of PE: ~20.5%)
• Score <2.0: Low probability (Rate of PE: ~3.6%)

Modified Wells Criteria

Shown below is the pretest probability of PE according to the modified Wells Criteria.

• Score > 4: PE likely (Rate of PE: ~40.7%)
• Score 4 or less: PE unlikely (Rate of PE: ~7.8%)

Step 2: Initial Treatment

Assess the severity of pulmonary embolism

Massive PE (also known as high-risk PE) Cardiogenic shock OR Persistent hypotension (≤90mmHg) OR Drop of the blood pressure by ≥ 40mmHg for > 15 min OR Pulselessness OR Profound bradycardia (<40 bpm) with findings of shock

Submassive PE (also know as intermediate-risk PE) Right ventricular dysfunction AND/OR Myocardial injury (Troponin +)

Low-risk PE No cardiogenic shock AND No hypotension AND No right ventricular dysfunction AND No myocardial injury (Troponin -)

Provide hemodynamic and respiratory support ❑ Begin high dose unfractionated heparin ❑ Bolus 10.000 U ❑ Continuous infusion of at least 1250 U/hour for a targeted aPTT of at least 80 s ❑ Administer rapidly 500-1000 mL of normal saline (caution with fluid overload) ❑ Have a low threshold for ionotropes (dopamine or dobutamine) ❑ Administer oxygen for hypoxemic patients

Is there any contraindication to fibrinolytic therapy?

Is there any contraindication for anticoagulation therapy?

Is there any contraindication for anticoagulation therapy?

NO

YES

NO

YES

NO

YES

❑ Discontinue unfractionated heparin AND ❑ Begin fibrinolytic therapy

❑ Surgical pulmonary embolectomy OR ❑ Percutaneous catheter embolectomy

❑ Anticoagulation therapy AND ❑ Hospital admission

❑ IVC filter AND ❑ Hospital admission

❑ Anticoagulation therapy AND ❑ Early discharge/home treatment

❑ IVC filter AND ❑ Early discharge/home treatment

Does the patient fail to improve OR Develop cardiogenic shock OR Develop hypotension?

Does the patient fail to improve OR Develop cardiogenic shock OR Develop hypotension (<90 mmHg) OR Develop respiratory distress (SaO2<95% with Borg score>8 or altered mental status) OR Have moderate to severe RV dysfunction (RV hypokinesis or estimated RVSP>40 mmHg) OR Have elevated biomarkers (troponin> upper limit of normal, BNP>100 pg/mL, or pro-BNP>900 pg/mL)?

YES

NO

YES

NO

❑ Surgical pulmonary embolectomy OR ❑ Percutaneous catheter embolectomy

❑ Continue with the same treatment

Is there any contraindication for fibrinolytic therapy?

❑ Continue with the same treatment

NO

YES

❑ Hold anticoagulation and give thrombolytics

❑ Surgical pulmonary embolectomy OR ❑ Percutaneous catheter embolectomy

Does the patient fail to improve?

YES

NO

❑ Surgical pulmonary embolectomy OR ❑ Percutaneous catheter embolectomy

❑ Continue with the same treatment

Dosage of Fibrinolytic Therapy

Shown below is the dosage schedule for the thrombolytic agents:

• Streptokinase (FDA-approved)
  • Loading dose: 250 000 IU over 30 min
  • Maintenance dose: 100 000 IU/h over 12–24 hr
  • Accelerated regimen: 1.5 million IU over 2 hr
• Urokinase (FDA-approved)
  • Loading dose: 4400 IU/kg over 10 min
  • Maintenance dose: 4400 IU/kg/h over 12–24 hr
  • Accelerated regimen: 3 million IU over 2 hr
• Recombinant tissue plasminogen activator (rtPA)
  • Alteplase (FDA-approved): 10-mg IV bolus followed by 90 mg IV infusion over 2 hours
  • Reteplase: 10-U IV bolus followed in 30 mins by another 10-U IV bolus
  • Tenecteplase: 0.5-mg/kg IV bolus (max 50mg)

Contraindications to Fibrinolytic Therapy

Shown below is a table summarizing the absolute and relative contraindications to fibrinolytic therapy among pulmonary embolism patients.

Absolute contraindications	Relative contraindications
❑ Previous hemorrhagic stroke or stroke of unknown origin ❑ Ischemic stroke within the last 6 months ❑ Central nervous system tumor or damage ❑ Major trauma, head injury, or surgery within the last 3 weeks ❑ Gastrointestinal bleed within the last month ❑ Known bleeding	❑ Transient ischemic attack within the last 6 months ❑ Oral anticoagulant therapy intake ❑ Advanced liver disease ❑ Infective endocarditis ❑ Peptic ulcer disease that is currently active ❑ Pregnancy or within 1 week post partum ❑ Punctures that are non-compressible ❑ Traumatic resuscitation ❑ Systolic blood pressure >180 mmHg refractory to treatment

Choice of Initial Anticoagulation Therapy

Begin initial anticoagulation therapy in: ❑ Confirmed PE OR ❑ High or intermediate probability of PE while awaiting the diagnostic tests

Is the patient high risk or non-high risk?

High risk

Non-high risk

❑ Administer IV unfractionated heparin ❑ 80 U/kg as bolus, followed by 18 U/kg/h, OR ❑ 70 U/kg as bolus, followed by 15 U/kg/h for stroke or cardiac patients ❑ Adjust the dosages according to the aPTT

Does the patient have: ❑ High risk of bleeding OR ❑ Severe renal failure?

Yes

No

❑ Administer unfractionated heparin: IV injection ❑ 80 U/kg as bolus, followed by 18 U/kg/h, OR ❑ 70 U/kg as bolus, followed by 15 U/kg/h for stroke or cardiac patients ❑ Adjust the dosages according to the aPTT OR SC injection ❑ 333 U/kg as bolus, followed by 250 U/kg ❑ Administer VKA as an overlap anticoagulation if VKA is planned for long term treatment

❑ Administer ONE of the following: ❑ SC low molecular weight heparin (1st line) ❑ Enoxaparin 1.0 mg/kg every 12 hours OR 1.5 mg/kg once daily ❑ Tinzaparin 175 U/kg once daily ❑ SC fondaparinux (1st line) ❑ 5 mg once daily (if body weight <50 kg) ❑ 7.5 mg once daily (if body weight <50-100 kg) ❑ 10 mg once daily (if body weight >100 kg) ❑ IV unfractionated heparin ❑ 80 U/kg as bolus, followed by 18 U/kg/h, OR ❑ 70 U/kg as bolus, followed by 15 U/kg/h for stroke or cardiac patients ❑ Adjust the dosages according to the aPTT ❑ SC unfractionated heparin ❑ 333 U/kg as bolus, followed by 250 U/kg ❑ Administer VKA as an overlap anticoagulation if VKA is planned for long term treatment

Adjustment of Heparin Dosage According to aPTT

aPTT	Variation in the dosage
< 1.2 x control (<35 s)	Bolus: 80 U/kg Infusion rate: increase by 4 U/kg/h
1.2-1.5 x control (35-45 s)	Bolus: 40 U/kg Infusion rate: increase by 2 U/kg/h
1.5-2.3 x control (46-70 s)	Continue the same dosage
2.3-3.0 x control (71-90 s)	Infusion rate: decrease by 2 U/kg/h
> 3.0 x control (>90s)	Stop infusion for a period of 1 hour, then Infusion rate: decrease by 3 U/kg/h

Contraindications to Anticoagulation

• Disorders predisposing to bleeding
• Gastrointestinal bleeding
• Genitourinary tract bleeding
• Prior history of peptic ulcer disease
• Severe thrombocytopenia
• Surgery within the prior 14 days
• Thrombotic stroke within the prior 14 days

Complete Diagnostic Approach

A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.

Abbreviations: DVT: Deep venous thrombosis; JVD: Jugular venous distention; P2: Second heart sound; RV: right ventricle; S3: Third heart sound ; S4: Fourth heart sound

Characterize the symptoms: ❑ Dyspnea (78–81%) ❑ Pleuritic chest pain (39–56%) ❑ Fainting (22–26%) ❑ Cough (20%) ❑ Substernal chest pain (12%) ❑ Hemoptysis (11%) ❑ Wheezing ❑ Cyanosis (11%) ❑ Fever (7%) ❑ Asymptomatic ❑ Findings suggestive of DVT (15%) ❑ Calf or thigh pain and swelling ❑ Edema, erythema, tenderness, or a palpable cord in the calf or thigh ❑ Symptoms suggestive of shock (in case of massive PE) ❑ Altered mental status ❑ Cold extremities ❑ Cyanosis ❑ Oliguria
Elicit a detailed history: ❑ Risk factors ❑ Chemotherapy ❑ Chronic heart failure ❑ Respiratory failure ❑ Hormone replacement therapy ❑ Cancer ❑ Oral contraceptive pills ❑ Stroke ❑ Pregnancy ❑ Postpartum ❑ Prior history of VTE ❑ Thrombophilia ❑ Advanced age ❑ Laparoscopic surgery ❑ Prepartum ❑ Obesity ❑ Varicose veins ❑ Triggers ❑ Bone fracture (hip or leg) ❑ Hip replacement surgery ❑ Knee replacement surgery ❑ Major general surgery ❑ Significant trauma ❑ Spinal cord injury ❑ Athroscopic knee surgery ❑ Central venous lines ❑ Chemotherapy ❑ Bed rest for more than 3 days ❑ Prolonged car or air travel ❑ Laparoscopic surgery ❑ Prepartum ❑ Previous episode of VTE ❑ Age ❑ Location ❑ Past medical history of diseases associated with hyperviscosity ❑ Atherosclerosis ❑ Collagen vascular disease ❑ Heart failure ❑ Myeloproliferative disease ❑ Nephrotic syndrome ❑ Autoimmune diseases ❑Polycythemia vera ❑ Hyperhomocysteinemia ❑ Paroxysmal nocturnal hemoglobinuria ❑ Waldenstrom macroglobulinemia ❑ Multiple myeloma ❑ History of thrombophilia ❑ Factor V Leiden mutation ❑ Prothrombin gene mutation G20210A ❑ Protein C or Protein S deficiency ❑ Antithrombin (AT) deficiency ❑ Antiphospholipid syndrome (APS) ❑ Abortion ❑ Abortion at second or third trimester of pregnancy (suggestive of an inherited thrombophilia or APS) ❑ Drugs that may increase the risk of VTE ❑ Hydralazine ❑ Phenothiazine ❑ Procainamide ❑ Tamoxifen ❑ Bevacizumab ❑ Glucocorticoids ❑ Family history (suggestive of inherited thrombophilia) ❑ Deep vein thrombosis ❑ Pulmonary embolism ❑ Recurrent miscarriage ❑ Social history ❑ Heavy cigarette smoking (>25 cigarettes per day) ❑ Intravenous drug use (if injected directly in femoral vein) ❑ Alcohol
Examine the patient: Vital signs ❑ Blood pressure ❑ Blood pressure lower than baseline, suggestive of cardiogenic shock (associated with tachycardia and end organ hypoperfusion) ❑ Tachycardia (26%) ❑ Tachypnea (70%) ❑ Low grade fever Skin ❑ Lower extremity swelling, erythema, and/or tenderness suggestive of DVT ❑ Edema (suggestive of right heart failure) ❑ Cyanotic and cold skin, lips, nail bed (suggestive of cardiogenic shock) Heart ❑ Cardiac murmur ❑ Graham-Steell murmur (suggestive of pulmonary regurgitation) ❑ Accentuated P2 ❑ S3 or S4 gallop (suggestive of RV dysfunction) ❑ JVD (suggestive of right heart failure) Lungs ❑ Rales ❑ Crackles ❑ Pleural friction rub
Order tests: ❑ CBC ❑ Electrolytes ❑ ABG ❑ Hypoxemia ❑ Hypocapnea ❑ Respiratory alkalosis ❑ EKG ❑ Sinus tachycardia ❑ Stress on the right ventricle ❑ Right axis deviation ❑ Right bundle branch block ❑ S1Q3T3 ❑ Deep S in lead I ❑ Q wave in lead III ❑ Inverted T wave in lead III ❑ Chest X ray ❑ Atelectasis (most common) ❑ Fleishner sign: enlarged pulmonary artery ❑ Hampton hump: peripheral wedge-shaped density above the diaphragm that implies lung infarction ❑ Westermark's sign: vasoconstriction distal to the pulmonary embolus ❑ Pleural effusion ❑ Elevated diaphragm ❑ Enlarged hilum ❑ Normal (in 12%)

Long Term Treatment

The long term treatment of PE depends on whether the episode is the first one or not, whether it is provoked or unprovoked, and on the risk of bleeding of the patient. Among non cancer patients, the first line therapy for long term management of PE is vitamin K antagonists (VKA); whereas the first line treatment among cancer patients is low molecular weight heparin. If long term treatment with VKA is decided, VKA should be started at the same day with heparin allowing for at least 5 days of overlap until the INR is ≥2 for at least 24 hours. Among patients on extended anticoagulation therapy, the risk vs benefits of the anticoagulation therapy should be assessed regularly (for example annually).

Is this the first episode of PE?

YES

NO

Is PE provoked?

What is the risk of bleeding?

Yes, transient reversible risk factor

Yes, cancer

No (unprovoked)

Low or moderate

High

Therapy for 3 months ❑ VKA (first line) OR ❑ LMWH OR ❑ Dabigatran OR ❑ Rivaroxaban

Extended therapy or until cancer is cured ❑ LMWH (first line) OR ❑ VKA OR ❑ Dabigatran OR ❑ Rivaroxaban

Therapy for ≥ 3 months ❑ VKA (first line) OR ❑ LMWH OR ❑ Dabigatran OR ❑ Rivaroxaban

Extended therapy ❑ VKA (first line) OR ❑ LMWH OR ❑ Dabigatran OR ❑ Rivaroxaban

Therapy for 3 months ❑ VKA (first line) OR ❑ LMWH OR ❑ Dabigatran OR ❑ Rivaroxaban

Re-assess the risk of bleeding

Low or moderate

High

Extended therapy

Do not extend the therapy beyond the initial 3 months

Note that edoxaban has been evaluated for the treatment of VTE and is currently seeking approval for this indication.

Vitamin K Antagonist

• Begin with 5 mg warfarin for 2 days followed by dosing based on the INR.
• Start at the 1st or 2nd day of the initial parenteral therapy.
• Target INR is 2-3.
• Monitor INR monthly.
  • If the INR is stable but there is one value 0.5 below or above the target range, continue the same dose and repeat INR within 1-2 weeks.
• Avoid NSAIDs, COX2 selective NSAIDs and some antibiotics

Assessment of Risk of Bleeding

The risk factors of bleeding with anticoagulation therapy are:

• Age > 75 years
• Alcohol abuse
• Anemia
• Antiplatelet therapy
• Cancer
• Comorbidity and reduced functional capacity
• Diabetes
• Frequent falls
• Liver failure
• Metastatic cancer
• Poor anticoagulant control
• Previous bleeding
• Prior stroke
• Recent surgery
• Renal failure
• Thrombocytopenia

Shown below is a table summarizing the risk of bleed based on the number of risk factors. Note that, although the presence of one risk factor signify moderate risk of bleeding, if the single risk factor is severe (such as severe thrombocytopenia or recent major surgery) then the patient is at high risk of bleeding despite the presence of a single risk factor.

Risk of bleeding	Number of risk factors
Low Risk	0
Moderate Risk	1
High Risk	≥2

Do's

• When indicated, administer fibrinolytic therapy for a short infusion time (for 2 hours) rather than over prolonged perfusion (for 24 hours).

• When indicated, administer fibrinolytic therapy via a peripheral vein rather than pulmonary artery catheter.

• Begin anticoagulation therapy among high-risk patients suspected to have pulmonary embolism and those with high or intermediate pre-test probability of pulmonary embolism during the diagnostic workup while awaiting confirmatory tests.
• If long term anticoagulation is extended for a longer period beyond 3 months, the same drug initially started should be continued.
• Among patients started on heparin, if the risk of heparin induced thrombocytopenia is more than 1%, monitor platelet count every 2 to 3 days from the 4th until the 14th day of treatment or until the discontinuation of heparin.
• Screen for thrombophilia if this is a first episode of VTE in a patient less than 50 years of age.

References