Pulmonary embolism resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Rim Halaby; Pratik Bahekar, MBBS [2]; Chetan Lokhande, M.B.B.S [3]

Pulmonary embolism Resident Survival Guide Microchapters
Overview
Causes
FIRE
Diagnosis
Treatment
Do's
Don'ts

Overview

Pulmonary embolism (PE) is the acute obstruction of the pulmonary artery or one of its branches. The obstruction in the pulmonary artery can be due to thrombus, air, tumor, or fat. Most often, PE is due to a venous thrombosis which has been dislodged from its site of formation in the deep veins of the lower extremities, a process referred to as 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 syncope (22-26% of the cases). In severe cases, hypotension and/or shock can occur.

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
• Air bubble
• Fragment of a tumor
• Fragment of fat (secondary to bone fracture)

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, and either lasting for at least 15 minutes or necessitating the administration of inotropic support

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 (RV) dysfunction OR myocardial necrosis

AND

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

Right Ventricular Dysfunction

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

• Echocardiography findings:
  • RV dilation (apical 4-chamber RV diameter divided by LV diameter > 0.9)
  • RV systolic dysfunction
• CT findings: RV dilation (4-chamber RV diameter divided by 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.

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

Is a CT available immediately?

What is the pretest probability of PE? Assess the pretest probability of PE by using one of the risk score: - Wells score - Geneva score - PERC

No

Yes

Order echocardiography

Does the patient have RV overload?

Low pretest probability

Intermediate pretest probability

High pretest probability OR PE is likely

Administer 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

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 for 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 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

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 ❑ Bolus 80 U/kg ❑ Infusion 18 U/kg/hour ❑ 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 ❑ Bolus 80 U/kg ❑ Infusion 18 U/kg/hour ❑ Adjust the dosages according to the aPTT OR SC ❑ 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 ❑ Bolus 80 U/kg ❑ Infusion 18 U/kg/hour ❑ Adjust the dosages according to the aPTT ❑ SC unfractionated heparin ❑ 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

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

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:

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
Identify predisposing factors: ❑ Bone fracture (hip or leg) ❑ Orthopedic surgery ❑ Major general surgery ❑ Significant trauma ❑ Spinal cord injury ❑ Central venous lines ❑ Chemotherapy ❑ Chronic heart failure ❑ Respiratory failure ❑ Hormone replacement therapy ❑ Cancer ❑ Oral contraceptive pills ❑ Stroke ❑ Pregnancy ❑ Postpartum ❑ Prior history of VTE ❑ Thrombophilia ❑ Bed rest for more than 3 days ❑ Prolonged car or air travel ❑ Advanced age ❑ Laparoscopic surgery ❑ Prepartum ❑ Obesity ❑ Varicose veins Obtain a detailed history: ❑ Autoimmune diseases ❑ Hyperviscosity syndrome ❑ Deficiencies of antithrombin, protein C, and protein S ❑ Polycythemia vera ❑ Leukemias ❑ Hyperhomocysteinemia ❑ Myeloproliferative neoplasms ❑ Paroxysomal nocturnal hemoglobinuria ❑ Waldenstrom macroglobulinemia ❑ Multiple myeloma ❑ Family history (suggestive of inherited thrombophilia) ❑ Deep vein thrombosis ❑ Pulmonary embolism ❑ Recurrent miscarriage ❑ Social history (increased risk in females) ❑ Heavy cigarette smoking (>25 cigarettes per day) ❑ Intravenous drug use (if injected directly in femoral vein) ❑ Alcohol ❑ Medications ❑ Hormone replacement therapy ❑ Tamoxifen ❑ Bevacizumab ❑ Glucocorticoids
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 ❑ JVD suggestive of right heart failure Lungs ❑ Rales ❑ Crackles ❑ Pleural friction rub

Long Term Management

The long term management of PE depends on whether the episode is the first episode or not, whether it is provoked or unprovoked and 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 or second episode of PE?

First episode

Second episode

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

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).
• Consider stent placement in the iliac vein to manage obstructive lesions after CDT, PCDT, or surgical venous thrombectomy. (Class IIa; Level of Evidence C)
• Consider a trial of percutaneous transluminal angioplasty without stenting to manage isolated obstructive lesions in the common femoral vein.(Class IIa; Level of Evidence C).
• Consider an iliac vein stent in patients with advanced PTS and iliac vein obstruction to reduce PTS symptoms and heal venous ulcers. (Class IIa; Level of Evidence C).
• Consider same regiment of anticoagulation for IFDVT patients without stents as recommended for venous stent placement. (Class IIa; Level of Evidence C).
• Consider an antiplatelet therapy with concomitant anticoagulation after venous stent placement, if the patient is at high risk of rethrombosis. (Class IIb; Level of Evidence C).
• Administer 30 - 40 mm Hg knee-high graduated ECS everyday for a minimum of 2 years in IFDVT. (Class I; Level of Evidence B).
• Administer of 30 - 40 mm Hg knee-high graduated ECS if prior IFDVT and a symptomatic PTS.(Class IIa; Level of Evidence C).
• Consider an intermittent sequential pneumatic compression followed by daily use of 30 - 40 mm Hg knee-high graduated ECS, in IFDVT and severe edema.(Class IIb; Level of Evidence B).
• Administer either intravenous UFH(Class I; Level of Evidence A), UFH by subcutaneous injection(Class I; Level of Evidence B), an LMWH (Class I; Level of Evidence A), or fondaparinux (Class I; Level of Evidence A) in the absence of suspected or proven heparin induced thrombocytopenia,in the patients suffering from IFDVT.
• Administer a direct thrombin inhibitor(Class I; Level of Evidence B) for IFDVT who have suspected or proven heparin-induced thrombocytopenia.
• Administer IVC filter if acute proximal DVT (or acute PE) with contraindications to anticoagulation or if there is a presence of active bleeding complication (Class I; Level of Evidence B).
• Administer anticoagulation if contraindications to anticoagulation or active bleeding complications are resolved in the patient with IVC filter.(Class I; Level of Evidence B).
• Evaluate periodically for the filter retrieval according to the specific filter’s retrieval window, if retrievable IVC filter is administered. (Class I; Level of Evidence C).
• Consider to administer an IVC filter, in recurrent DVT (without PE) despite therapeutic anticoagulation(Class IIb; Level of Evidence C).
• Consider an IVC filter if PE occurs in spite of therapeutic anticoagulation. (Class IIa; Level of Evidence C).
• Consider a permanent nonretrievable IVC filter, in IFDVT patients who are likely to require permanent IVC filtration like, long-term contraindication to anticoagulation. (Class IIa; Level of Evidence C).
• If there is a short-term contraindication to anticoagulant therapy or a time-limited indication for an IVC filter, consider placement of a retrievable IVC filter for the IFDVT patients.(Class IIa; Level of Evidence C).
• Evaluate for chronic thromboembolic pulmonary hypertension if the patient presents with unexplained dyspnea, exercise intolerance, or clinical evidence of right-sided heart failure, irrespective of prior history of symptomatic VTE(Class I; Level of Evidence C).
• Do EKG 6 weeks after an acute PE to screen for persistent pulmonary hypertension which can predict the development of chronic thromboembolic pulmonary hypertension. (Class IIa; Level of Evidence C).
• Use subcutaneous lowmolecular-weight heparin (LMWH), intravenous or subcutaneous unfractionated heparin (UFH) with monitoring, unmonitored weight-based subcutaneous UFH, or subcutaneous fondaparinux, if the patient is objectively confirmed to have PE and have no contraindications for anticoagulation.
• Use lepirudin, argatroban, or bivalirudin(a non– heparin-based anticoagulant), if the patient is suspected or diagnosed with heparin-induced thrombocytopenia(Class I; Level of Evidence A).
• Fibrinolytics are proven to be beneficial if there is an evidence of present or developing circulatory or respiratory insufficiency; or an evidence of moderate to severe RV injury.
• Evaluate chronic thromboembolic pulmonary hypertension for pulmonary endarterectomy, irrespective of the symptos severity. (Class I; Level of Evidence B)
• Administer anticoagulants indefinitely when chronic thromboembolic pulmonary hypertension is diagnosed, and the contraindications for anticoagulation are absent. (Class I; Level of Evidence C)

Don'ts

• Do not administer IVC filter routinely in the treatment of IFDVT(Class III; Level of Evidence B).

References