Pulmonary Thromboembolism Management

Evaluation

Clinically unstable patients may have massive pulmonary embolism. Thrombolytic therapy should be considered.  

Evaluate for Venous Thromboembolism (VTE) Risk Factors  

The presence of risk factors for venous thromboembolism in hypotensive patients should raise the possibility of pulmonary embolism. The probability of pulmonary embolism increases with the number of risk factors present. Pulmonary embolism can also occur in individuals without risk factors.  

Please see Risk Factors for further information.   

Assessment of Massive Pulmonary Embolism  

In patients who are too unstable for lung imaging, right ventricular dysfunction can usually be found at the bedside. Patients may present with left parasternal heave, distended jugular veins, and systolic murmur of tricuspid regurgitations that increase with inspiration. ECG may show a new right bundle branch block, right ventricular failure, or other evidence of right ventricular strain (eg inverted T waves in leads V1 to V4).  

The most useful initial test in massive pulmonary embolism is echocardiography which can show indirect signs of acute pulmonary hypertension and right ventricular overload if acute pulmonary embolism is the cause of hemodynamic compromise. When the patient has already been stabilized by supportive treatment, a definite diagnosis should be determined. CTPA may be used to confirm diagnosis (≥50% decreased perfusion).  

Please see Laboratory Tests and Ancillaries and Imaging for further information.  

Evaluation of Contraindication to Thrombolysis 

The absolute contraindications to thrombolysis in a life-threatening situation are rarely a factor for treatment.  

Absolute Contraindications to Thrombolysis  

The following are absolute contraindications to thrombolysis: 

• Hemorrhagic stroke or stroke of unknown origin within the last 3 months
• Ischemic stroke within the last 3 months
• Presence of benign or malignant tumor or damage within the central nervous system (CNS)
• Major surgery, trauma, or injury within the past 3 months
• Gastrointestinal bleeding within the last 30 days
• Known bleeding risk or current active bleeding
• Allergy to compounds
• Bleeding diathesis

Relative Contraindications to Thrombolysis

The following are relative contraindications to thrombolysis: 

• Transient ischemic attack within the past 6 months
• On oral anticoagulants 
• Uncontrolled severe hypertension (systolic blood pressure of >180 mmHg, diastolic blood pressure of >100 mmHg)
• Pregnancy or within 1 week postpartum
• Recent traumatic CPR
• Infective endocarditis 
• Advanced liver disease
• Active peptic ulcer
• Puncture of a non-compressible vessel
• Older age (>75 years old)

Principles of Therapy

Inpatient versus Outpatient Management  

Intermediate- to high-risk patients with the following features should be managed in a hospital setting: 

• Hemodynamic instability
• Oxygen saturation (O₂ sat) <90%
• Active bleeding or at risk for major bleeding
• Currently on full-dose anticoagulants during assessment
• Severe pain 
• With comorbidities requiring hospital confinement
• With chronic kidney disease stage 4 or 5 or severe hepatic disease
• Socioeconomic reasons (eg unfavorable living conditions, concern over treatment compliance)

Low-risk pulmonary embolism patients without the abovementioned criteria should be considered for home treatment or early discharge. The patient should also be ambulatory and in stable condition with normal vital signs and low bleeding risk.  

Patients with symptomatic pulmonary embolism should initially be treated in the hospital because of decreased cardiorespiratory reserve, possible complications, and monitoring of international normalized ratio (INR) to guide Warfarin therapy. 

Parenteral Anticoagulation  

Heparin should be administered in patients with intermediate or high clinical probability of pulmonary embolism before imaging studies are performed and in low probability patients once pulmonary embolism is confirmed. If pulmonary embolism occurs postoperatively, Heparin therapy should not be started until 12-24 hours after major surgery and after consultation with the surgeon. Treatment could be delayed even longer if there is any evidence of bleeding from the surgical site. Both subcutaneous Low-molecular-weight Heparin (LMWH) or intravenous Unfractionated Heparin (UH) short-course treatments are recommended for objectively confirmed non-massive pulmonary embolism. Either LMWH or UFH is appropriate for the initial treatment of pulmonary embolism.  

Thrombolytics  

Studies have shown that there is a more rapid improvement in radiographic and hemodynamic abnormalities in acute massive pulmonary embolism patients who received thrombolytic agents and anticoagulant agents over conventional anticoagulant agents alone. There were no clinically relevant outcomes for the death rate or for the resolution of symptoms.  

Massive Pulmonary Embolism  

The use of thrombolytic therapy in pulmonary embolism should be individualized. Patients with hemodynamically unstable pulmonary embolism who are at low risk of bleeding are the most appropriate candidates. Thrombolytic therapy is recommended in high-risk pulmonary embolism patients presenting with cardiogenic shock and/or persistent arterial hypotension.  

Thrombolytic therapy may also be considered in patients with compromised oxygenation; free-floating right ventricular thrombus or patent foramen ovale documented by echocardiography; or massive hemodynamically significant pulmonary embolism without systemic hypotension or profound hypoxemia.  

Non-massive Pulmonary Embolism  

The use of thrombolytic therapy in non-high-risk patients (hemodynamically stable patients with echocardio­graphic evidence of right ventricular dysfunction) is controversial. Further studies are needed to show a clinically relevant improvement in the benefit-risk ratio of thrombolytic treatment over traditional anticoagulant therapy in these patients. Thrombolytic therapy should not be used in patients with low-risk pulmonary embolism.  

Management of Clinical Instability  

A considerable number of deaths occur within the first few hours after massive pulmonary embolism and therefore appropriate supportive therapy could have a major role in pulmonary embolism with circulatory failure. 

Oxygen (O₂) Supplementation  

Oxygen supplementation may be necessary in patients with hypoxemia. Consider monitoring oxygen saturation and give supplementary oxygen if necessary.    

Mechanical Ventilation  

Mechanical ventilation may be needed temporarily in patients who appear toxic and hypoxic. Care should be taken to limit its hemodynamic adverse effects. Positive intrathoracic pressures induced by mechanical ventilation may reduce venous return and worsen right ventricular failure.  

Hemodynamic Support  

Intravenous Fluid  

Fluids may be administered initially and cautiously, but other vasoactive therapies should promptly follow if adequate perfusion is not achieved. Aggressive fluid challenge is not recommended as it may worsen right ventricular function by causing ventricular overstretch, leading to decreased contractility.  

Adrenergic Agonists  

Adrenergic agonists should be considered for patients with low cardiac index and normal blood pressure or with impending hypotension.  

Dobutamine is considered a first-line agent to treat right-sided heart failure and cardiogenic shock. It affects vasodilatation of both systemic and pulmonary vascular beds and increases myocardial contractility while decreasing right-sided filling pressures. Norepinephrine is initially given with Dobutamine to mitigate its vasodilatory effect which may worsen hypotension.  

Dopamine has also been used for hemodynamic support in pulmonary embolism patients. Its use may be limited by the development of tachycardia.  

Epinephrine may be effective when shock complicates acute pulmonary embolism. The vasoconstrictor effect is similar to Norepinephrine and its inotropic effect is more due to potent beta₁ stimulation rather than the beta₂ effect, accounting for the improved pulmonary vascular resistance.  

Norepinephrine may be appropriate in acute massive pulmonary embolism when there is profound hypotension. It stimulates both alpha-adrenergic (inducing vasoconstriction) and beta₁-adrenergic receptors (augmenting cardiac contractility) resulting in improved systemic blood pressure, cardiac output, pulmonary vascular resistance, and right ventricular pressure. The combination with other vasoactive agents such as Dobutamine needs further evaluation.  

Nitric Oxide Inhalation  

Nitric oxide inhalation may be indicated in patients with pulmonary hypertension and a patent foramen ovale. Based on clinical studies, it may improve the hemodynamic status and gas exchange in patients with pulmonary embolism.

Pharmacological therapy

Parenteral Anticoagulants  

Unfractionated Heparin (UFH)  

Intravenous UFH treatment in pulmonary embolism is well-established. UFH should be given as a first dose bolus and when rapid reversal of effect may be required, as in patients with a high risk of bleeding. It should be given as initial anticoagulation for patients with pulmonary embolism presenting with shock or hypotension, also referred to as high-risk pulmonary embolism or clinically massive pulmonary embolism. It is preferred over LMWH in patients with severe renal failure. Heparin-induced thrombocytopenia is a rare but serious complication.  

Intravenous UFH has been proven effective in the therapy of pulmonary embolism. Studies have shown a reduced mortality rate when UFH has been used to treat venous thromboembolism disease. The recurrence of venous thromboembolism is unusual when UFH is infused at a rate that prolongs the activated partial thromboplastin time (aPTT) by >1.5 times the control value and when adequate levels are reached within 24 hours.  

Intravenous UFH requires hospitalization with frequent monitoring and dose adjustment. Measurement of aPTT should be done 4-6 hours after bolus injection, then 3 hours after each dose adjustment, or once daily when the target therapeutic dose has been attained.  

Low-Molecular Weight Heparin (LMWH)

Example drugs: Dalteparin, Enoxaparin, Nadroparin, Tinzaparin  

LMWH is now preferred over UFH in patients with acute non-massive pulmonary embolism. A number of studies have shown that LMWH has equal efficacy to UFH in patients with non-massive pulmonary embolism. The use of LMWH is safe and effective and may shorten hospital stay and improve the quality of life for patients. Monitoring of platelet count is necessary before treatment initiation and on the fifth day, then every 2-3 days if LMWH treatment is continued.  

Fondaparinux  

Fondaparinux is also a preferred initial treatment for pulmonary embolism. Heparin assay (anti-factor Xa) has been used to monitor the effects of Fondaparinux. A platelet count should be obtained prior to the start of therapy and periodically to check for any bleeding. It is not recommended for high-risk pulmonary embolism with hemodynamic instability and those with severe renal impairment. It is recommended for patients with a known history of heparin-induced thrombocytopenia.  

Duration of Therapy  

Acute-phase treatment with UFH, LMWH, or Fondaparinux should be continued for at least 5-7 days after the initiation of Warfarin and until therapeutic INR is stable and ≥2 (range: 2.0-3.0) for 2 consecutive days.  

Non-Vitamin K Oral Anticoagulants (NOACs)  

Example drugs: Apixaban, Dabigatran etexilate, Edoxaban, Rivaroxaban  

Long-term anticoagulant treatment of pulmonary embolism is used for the prevention of fatal and non-fatal recurrent venous thromboembolic events and complications. They are not recommended for the treatment of hemodynamically unstable pulmonary embolism.  

Apixaban  

Apixaban is a direct factor Xa inhibitor that effectively prevents thrombin generation. It is approved for use as monotherapy for pulmonary embolism without pretreatment with Heparin.  It has a significantly lower bleeding risk compared to Warfarin and other vitamin K antagonists.  

Dabigatran etexilate  

Dabigatran etexilate is a direct thrombin inhibitor that effectively prevents thrombin generation. It is approved for the management of pulmonary embolism in patients who have been treated with parenteral anticoagulant for 5-10 days, and to reduce the risk of recurrent pulmonary embolism in patients who have been previously treated.  

Edoxaban  

Edoxaban is a direct factor Xa inhibitor that effectively prevents thrombin generation. It may be used for the treatment of pulmonary embolism in patients treated with parenteral anticoagulant for 5-10 days.  

Rivaroxaban  

Rivaroxaban is a direct factor Xa inhibitor that effectively prevents thrombin generation. It is an alternative treatment for parenteral anticoagulants in the initial treatment of patients with high clinical pretest probability. Studies have shown that Rivaroxaban is comparable to Warfarin for the prevention of pulmonary embolism.  

Warfarin  

Warfarin should be started only when venous thromboembolism has been reliably confirmed and not given as initial monotherapy. Start on day 1 of Heparin therapy, except in patients with suspected hypercoagulable state (Protein C or Protein S deficiency) wherein adequate anticoagulation with Heparin is needed before the start of treatment to prevent Warfarin-induced skin necrosis or other transient hypercoagulable complications.  

A bolus dose is not effective; therefore it requires at least 5 days to achieve its full effect. Thus, it is recommended that Warfarin therapy overlaps with Heparin for at least 5 days until therapeutic INR is stable and ≥2 x 2 consecutive days.  

Therapy with Warfarin remains unsatisfactory and high rates of major bleeding are reported despite optimal attempts at dose adjustment by INR.  

Thrombolysis  

Antithrombotics  

Example drugs: Alteplase (r-tPA), Streptokinase, Urokinase  

Alteplase (r-tPA) has a comparable thrombolytic capacity to Streptokinase and Urokinase but can be administered for a shorter duration (2 hours). It is the preferred thrombolytic agent because of its shorter administration time.  

Streptokinase or Urokinase have similar thrombolytic effects in pulmonary embolism and have been shown to resolve pulmonary embolism comparatively at 24 hours and 3 times that as seen with Heparin alone. A duration of 12 hours of Urokinase has equivalent thrombolytic efficacy to 24 hours of Streptokinase.  

Pulmonary Thromboembolism_Management 1

Nonpharmacological

Invasive Procedures  

The main purpose of invasive procedures is to remove the obstructing thrombi from the main pulmonary arteries. It is preferred in patients with contraindications to systemic thrombolysis.  

Catheter Extraction  

Catheter extraction involves suction extraction of pulmonary embolism under fluoroscopy with ECG monitoring. It is reserved for highly compromised patients who cannot receive thrombolytic therapy due to contraindications, as an adjunct when thrombolytic therapy fails to improve circulation, or as an alternative to surgery if immediate access to cardiopulmonary bypass is not available.  

Inferior Vena Cava (IVC) Filter Placement  

IVC filter placement is recommended for patients unresponsive and/or intolerant to anticoagulant or thrombolytic therapy, patients with active bleeding complications, and those with recurrent acute pulmonary embolism with underlying pulmonary hypertension. Studies show a decreased incidence of pulmonary embolism in patients with proximal deep vein thrombosis on anticoagulant therapy.  

Pulmonary Thromboembolism_Management 2