≥90% of participants will know how to evaluate patients effectively with suspected PE so that patients can be diagnosed and appropriate therapy administered quickly to reduce the associated morbidity and mortality.
After completing this course, the participant will be able to meet the following 13 objectives:
Acute pulmonary embolism (PE) is a form of venous thromboembolism (VTE) that is common and sometimes fatal. The clinical presentation of PE is variable and often nonspecific, making the diagnosis challenging. The evaluation of patients with suspected PE should be efficient so that patients can be diagnosed and therapy administered quickly to reduce the associated morbidity and mortality.
PE refers to obstruction of the pulmonary artery or one of its branches by material that originated elsewhere in the body. PE can be caused by thrombus, tumor, air or fat emboli, but this topic will focus upon PE due to thrombus.
PE can be classified by the following:
The following special populations see an increased incidence of deep vein thrombosis (DVT) and PE:
The pathogenesis of PE is similar to that which underlies the generation of thrombus (i.e., Virchow's triad). Virchow’s triad is a major theory delineating the pathogenesis of VTE which proposes that VTE occurs as a result of2:
A risk factor for thrombosis can now be identified in over 80% of patients with venous thrombosis. Furthermore, there is often more than one factor at play in a given patient. For examples:
Accordingly, many patients with VTE fulfill most or all of Virchow's triad of stasis, endothelial injury, and hypercoagulability.2
The few studies that have specifically examined risk factors for PE alone confirm that they are similar to those for VTE in general.1
Most emboli are thought to arise from lower extremity proximal veins (iliac, femoral, and popliteal) and more than 50% of patients with proximal vein DVT have concurrent PE at presentation.1
Calf vein DVT rarely embolizes to the lung, and two-thirds of calf vein thrombi resolve spontaneously after detection.1 However, if untreated, one-third of calf vein DVT extend into the proximal veins, where they have greater potential to embolize.
PE can also arise from DVT in non-lower-extremity veins, including renal and upper extremity veins, although embolization from these veins is less common.
Most thrombi develop at sites of decreased flow in the lower extremity veins, such as valve cusps or bifurcations. However, they may also originate in veins with higher venous flow including the inferior vena cava, or the pelvic veins, and in non-lower-extremity veins, including renal and upper extremity veins.
PE are typically multiple, with the lower lobes being involved in the majority of cases.1 Once a thrombus lodges in the lung, a series of pathophysiologic responses can occur:
The most common symptoms in patients with PE were identified in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) group.3 These symptoms include:
Less common presentations include3:
Some patients have a delayed presentation over weeks or days. One prospective study reported that patients with a delayed presentation beyond one week tended to have larger, more centrally located PE compared with patients who presented within seven days (41% versus 26%).3
Signs and symptoms of PE may also evolve over time such that patients who initially present with mild symptoms may become increasingly symptomatic or hemodynamically unstable, sometimes very quickly (minutes to hours). This may be secondary to recurrent embolization or progressive pulmonary hypertension secondary to vasoconstriction. Similarly, as a pulmonary infarct evolves, patients may develop progressive dyspnea, hypoxemia, pleuritic pain, and hemoptysis.
Importantly, symptoms may be mild or absent, even in large PE.3 Although the true incidence of asymptomatic PE is unknown, one systematic review of 28 studies found that, among the 5,233 patients who had a DVT, one-third also had asymptomatic PE.3
Common presenting signs on physical examination include3:
Although upper extremity DVT (UEDVT) embolize less commonly than lower extremity DVT (LEDVT), symptoms of UEDVT (e.g., arm pain or tightness) should also raise the suspicion of PE.
PE is a common cause of sudden cardiac arrest or circulatory collapse (8%), especially among patients younger than 65 years old.3
Laboratory tests are not diagnostic but alter the clinical suspicion for PE, confirm the presence or absence of alternative diagnoses, and provide prognostic information in the event that PE is diagnosed:
ECG abnormalities, although common in patients with suspected PE, are nonspecific.3 The most common findings are3:
Abnormalities historically considered to be suggestive of PE (S1Q3T3 pattern, RV strain, new incomplete right bundle branch block) are uncommon (less than 10%).3
ECG abnormalities that are associated with a poor prognosis in patients diagnosed with PE include3:
Nonspecific abnormalities on CXR are common (e.g., atelectasis, effusion) in PE, but a normal CXR can be seen in 12% to 22% of patients.3
A Hampton's hump and Westermark's sign are rare but, when present, should raise the suspicion for PE.3
Whenever PE is suspected, the PTP for PE should be estimated by clinical gestalt assessment or calculated using a validated PTP score (e.g., Wells score, Modified Wells score, or Modified Geneva score).3 Although gestalt estimates and calculating probability scores have comparable sensitivity when combined with D-dimer testing, meta-analyses suggest that probability scores may have higher specificity3 and increase the diagnostic yield of CTPA.3
Although the use of Wells, Modified Wells, or Modified Geneva score is acceptable, based upon extensive validation and clinical experience, the Wells criteria should be applied and the score calculated to determine the probability of having a PE into a three-tiered system of:
Wells criteria and the corresponding points for each include the following:
Despite validation of the Wells criteria, for unclear reasons, clinicians do not use them or misuse them in 50% of patients.3 In addition, they may not be as accurate in older patients.3 Wells criteria have been best validated in outpatients presenting with suspected PE. However, one study of hospitalized patients reported a sensitivity and specificity of 72% and 62%, respectively.3 The addition of D-dimer improved the sensitivity and specificity to 99% and 11%, respectively.
The Wells criteria can also be used to classify patients into a two-tiered system of clinical probability of having a PE:
Although it has been validated and is equally as useful, the three-tiered classification of low, intermediate, and high probability is preferred since this classification can be used with PE rule-out criteria (PERC) to reduce the need for unnecessary testing further, and it can also be used to interpret results of V/Q scans more accurately.
PERC was designed to identify patients with a low clinical probability of PE in whom the risk of unnecessary testing outweighs the risk of PE.3 For patients with a low probability of PE (e.g., PTP <15%, Wells score <2), the PERC is applied to determine whether or not diagnostic evaluation with D-dimer is indicated. While some experts measure D-dimer in all low-risk patients, the preference to use PERC is based upon the validity of this approach in this population, and the likely reduction (approximately 20%) of unnecessary testing (i.e., D-dimer and imaging) associated with its use.3
The pulmonary embolism rule-out criteria (PERC rule)3:
When the PERC rule is chosen, the following applies:
In low-risk patients where PERC cannot be applied (e.g., inpatients, critically-ill patients) or PERC is positive, D-dimer testing is indicated, and the following applies:
PERC is only valid in clinical settings (typically the ED) with a low prevalence of PE (<15%).3 In clinical settings with a higher prevalence of PE (>15%), the PERC-based approach has been shown to have a substantially weaker predictive value.3 Thus, it should not be used in patients with an intermediate or high suspicion for PE or for inpatients suspected as having PE.
An elevated D-dimer alone is insufficient to make a diagnosis of PE but can be used to rule out PE. D-dimer testing is best used in conjunction with clinical probability assessment:
"Sensitive D-dimer" testing is preferred that uses quantitative or semiquantitative newer generation immunoturbidimetric, latex-agglutination-based, or rapid enzyme-linked immunosorbent assays (ELISA). These assays are preferred because of their high sensitivity, and the fact that accurate results are available quickly (10 to 30 minutes), so prompt decisions regarding imaging can be made. For these assays, a level ≥500 ng/mL is usually considered positive, and <500 ng/mL is considered negative.3
In contrast, early generation D-dimer assays (e.g., qualitative rapid ELISA, first-generation latex, and erythrocyte agglutination) are less accurate. In a meta-analysis of 108 studies, when compared with other assays for D-dimer testing, the preferred assays (e.g., semiquantitative rapid ELISAs) were associated with a higher sensitivity (96% versus 90%) and negative predictive value (98 versus 95%).3
The sensitivity of D-dimer is lower in patients with subsegmental PE compared with patients who have large main, lobar, or segmental PE (53% versus 93%).3 While D-dimer assays are highly sensitive, their specificity is low, usually between 40% and 60%. D-dimer results are often falsely positive, and the proportion of false-positive results increases with certain clinical conditions and any acute or inflammatory process (e.g., age >50 years, recent surgery or trauma, acute illness, pregnancy or postpartum state, rheumatologic disease, renal dysfunction [eGFR <60 mL/min/1.73 m2]) and sickle cell disease.3
Adjusted D-dimer levels based on certain criteria have been proposed. D-dimer levels rise with age such that using the traditional cut off value of <500 ng/mL results in reduced specificity of D-dimer testing in older patients (>50 years), a population in whom PE is common. Several studies report its use with the most commonly used formula for age adjustment as3:
However, because many conditions that increase the D-dimer also increase the risk of PE, age-adjustment should be used with caution, particularly in patients with non-low probability for PE, until further data become available.
Alternate D-dimer cut-offs have also been used. In one prospective multicenter study, 3,465 patients with suspected PE from an outpatient setting underwent D-dimer testing and an assessment for the presence and absence of YEARS items.3 YEARS items include three items (that are also in the Wells score) all scored as yes or no:
PE was excluded in patients with zero YEARS items and a D-dimer level <1000 ng/mL, and patients with ≥1 YEARS item and a D-dimer <500 ng/mL. All other patients underwent CTPA. Using this algorithm, 13% of patients were diagnosed with PE. Among those in whom PE was excluded, 0.6% had symptomatic PE confirmed at three month follow-up, a rate that was similar to that reported in studies that utilize fixed D-dimer level testing <500 ng/mL.3 It was estimated that this algorithm would result in a 14% reduction in the number of CT scans performed, compared with using the Wells rule and a fixed D-dimer level <500 ng/mL. Using age-adjusted D-dimer had no additional value to this algorithm.3
A similar multicenter prospective observational study of 1,134 ED patients suspected as having PE and referred for imaging per the treating clinicians discretion, reported a potential 14% reduction in those imaged using YEARS criteria and a negative D-dimer (<1000 ng/mL for YEARS negative patients and <500 ng/mL for YEARS positive patients).3 The sensitivity and specificity of this strategy were 93% and 55%, respectively. This algorithm requires further validation and needs to be directly compared with algorithms that include PERC, as well as fixed D-dimer level cutoffs before it can be routinely used in practice.
For most patients in whom the suspicion for PE is intermediate, a sensitive D-dimer level should be measured.
For most patients in whom the probability of PE is high or in whom the suspicion is low or moderate, and the D-dimer level is elevated (≥500 ng/mL), CTPA should be performed.
When imaging is indicated, CTPA is the imaging modality of choice. A V/Q scan is reserved for patients in whom CTPA is contraindicated including:
V/Q scanning may also be indicated when CTPA is inconclusive, or when additional testing is needed, such as when the clinical suspicion of PE remains high despite negative imaging.
PE is stratified into massive, submassive, and low-risk based upon the presence or absence of hypotension and RV dysfunction or dilation. This stratification is associated with mortality risk.3
A small percentage of patients with PE present with hemodynamic instability or shock (see nomenclature above).
In patients with PE who are hemodynamically unstable or who become unstable due to recurrence despite anticoagulation, more aggressive therapies than anticoagulation are suggested. These include:
Initial therapies for hemodynamically unstable patients consist of:
For patients with a high clinical suspicion for PE who are hemodynamically unstable and unsafe to transfer to radiology for a CTPA, a portable perfusion scan can be done at some medical centers.
When portable perfusion scanning or CTPA is not available or is unsafe, bedside echocardiography (transthoracic or transesophageal) is preferred to obtain a presumptive diagnosis of PE:
If bedside echocardiography is delayed or not available, the use of thrombolytic therapy as a life-saving measure should be individualized. If not used, the patient should receive empiric anticoagulation. The initiation of anticoagulation should not be delayed while considering other, more aggressive interventional therapies. A similar approach for select patients with known PE is suggested whose course becomes complicated by hypotension during anticoagulation in whom the suspicion for recurrent PE despite anticoagulation is high.
For patients with suspected PE who remain hemodynamically unstable and the clinical suspicion is low or moderate, the approach to empiric anticoagulation should be the same as for patients who are hemodynamically stable. Empiric thrombolysis is not justified in this population.
The decision to administer thrombolysis is strongly influenced by additional clinical factors. For example, while a patient with proven PE-induced shock who is unconscious requiring very high doses of pressors is a candidate for immediate intravenous (IV) thrombolytic therapy, a patient who has low blood pressure for 20 minutes but who is awake, alert, and comfortable, with a low oxygenation requirement might be considered for anticoagulation alone or an interventional procedure. Thus, when feasible, it is prudent to adopt a multidisciplinary approach to facilitate the management of hemodynamically unstable patients with PE. Some centers have incorporated a PERT to facilitate the process.4
For patients in whom hemodynamic stability is restored following brief resuscitation (e.g., for 15 minutes), the following approach is suggested:
For patients who remain hemodynamically unstable (e.g., systolic pressure <90 mmHg for 15 minutes or longer or clear evidence of shock) despite adequate resuscitation, definitive testing is typically considered unsafe. In these circumstances, bedside lower extremity ultrasonography and transthoracic echocardiography may be used to obtain a presumptive diagnosis of PE. In this population of unstable patients, a presumptive diagnosis of PE may justify the administration of potentially life-saving therapies (e.g., thrombolysis).
In many academic medical centers, the initial evaluation and resuscitation of hemodynamically unstable patients suspected as having PE are often performed in conjunction with PERTs. These teams are comprised of cardiothoracic surgeons, pulmonary and intensive care unit clinicians, cardiologists, emergency clinicians, and interventional radiologists.3 In medical centers with limited resources (e.g., without PERT or without bedside ultrasonography), the responding clinician must rely upon clinical judgment to assess the risk-benefit ratio of empiric anticoagulation and/or thrombolysis in the absence of definitive testing.
The majority of patients with PE are hemodynamically stable on presentation.3 In this population of patients, sufficient time is available to adopt a systematic approach for the diagnosis of PE.
Patients in this group are heterogeneous and have a wide range of presentations, as well as variable risk of recurrence and decompensation. This group includes those with submassive PE (moderate/intermediate risk), and minor PE (low risk).
Several diagnostic algorithms for hemodynamically stable nonpregnant adult patients with suspected PE have been proposed.3 Their purpose is to efficiently diagnose all clinically important PE while simultaneously avoiding the risks of unnecessary testing. An approach is preferred that selectively integrates clinical evaluation, three-tiered PTP assessment, PERC, D-dimer testing, and imaging. CTPA is the imaging modality of choice. However, algorithms that use a V/Q scan are appropriate when CTPA is contraindicated, not feasible, or inconclusive.
The following approach is suggested for most hemodynamically stable (i.e., normotensive) patients with minor/low-risk PE:
Hemodynamically stable (i.e., normotensive) patients with intermediate-risk/submassive PE who are anticoagulated, should be continuously monitored for deterioration. Thrombolysis and/or catheter-based therapies may be considered on a case-by-case basis when the benefits are assessed by the clinician to outweigh the risk of hemorrhage. Examples of such patients include those who have a large clot burden, severe RV enlargement/dysfunction, high oxygen requirement, and/or are severely tachycardic.
Anticoagulant therapy is indicated for patients with PE in whom the risk of bleeding is low (see below):
Empiric anticoagulation while waiting for test results should be individualized according to the clinical suspicion for PE, the anticipated timing of definitive testing, and the risk of bleeding.
For most patients with acute PE who do not have hemodynamic compromise, thrombolytic therapy is not warranted. Under occasional circumstances, thrombolysis may be considered on a case-by-case basis when the benefits are assessed by the clinician to outweigh the risk of hemorrhage and the patient’s values and preferences have been taken into consideration.5
Situations where clinicians typically contemplate thrombolysis, particularly when patients develop signs of deterioration (e.g., increasing tachycardia, clinical signs of shock, worsening right heart dysfunction, worsening blood pressure, significant hypoxemia) despite maintaining a systolic blood pressure >90 mmHg are5:
Although most patients listed in the situations described above may not be initially treated with thrombolysis, they should be anticoagulated and carefully monitored since they are at risk of deterioration, and a decision to administer thrombolytics may need to be made promptly.
The most controversial situation in which thrombolytic therapy is often considered is RV dilation or hypokinesis without systemic hypotension (also known as "submassive" or "intermediate-risk" PE). The rationale for thrombolysis in this population is based upon the observation that severe RV dysfunction is associated with a worse prognosis than mild or no RV dysfunction.5 However, randomized trials have not shown a convincing mortality benefit in these patients. This may be because clinical trials of thrombolytic therapy have not stratified this population based upon the degree of RV enlargement or the severity of RV dysfunction. For example:
Several studies have shown improved RV function in association with the administration of thrombolytic agents (systemic and catheter-directed), and one meta-analysis has suggested a possible mortality benefit.5
Further randomized trials are needed to identify subpopulations of patients with RV dysfunction where the benefits in mortality clearly outweigh the risk of hemorrhage before it can be routinely used to treat hemodynamically stable acute PE with RV dysfunction. Specifically, more data further stratifying intermediate-risk PE based on severity of RV dysfunction, biomarkers (troponin/BNP), oxygen requirement, residual DVT, and simple vital sign parameters such as heart and respiratory rate are necessary.
Case reports and series have reported some success from systemic thrombolytic therapy during CPR when the cardiac arrest is due to suspected or confirmed acute PE.5
One retrospective study reported a 5% incidence of PE (diagnosed by autopsy, clinically, or echocardiography) in 1,246 cardiac arrest victims.5
Another retrospective study of 23 patients with pulseless electrical activity (PEA) due to confirmed massive PE reported the return of spontaneous circulation within two to 15 minutes after the administration of a tissue plasminogen activator at a reduced dose of 50 mg IV push.5
In contrast, another randomized study of 233 patients who presented with PEA arrest of unknown etiology reported that compared to placebo, thrombolysis did not improve survival or return of spontaneous circulation.5
There remains insufficient data to argue for or against the routine use of thrombolytic therapy during cardiac arrest. However, the decision to administer treatment as a potentially lifesaving maneuver for suspected PE-induced cardiac arrest can be considered on a case-by-case basis.
A large clot burden may elevate pulmonary arterial pressure without causing significant RV dysfunction or hemodynamic collapse. A large retrospective study suggested that an obstruction index by CTPA in acute PE >40% was associated with an 11-fold increase in mortality.5 However, there remains no proof that systemic thrombolysis would reduce this mortality with an acceptable bleeding rate.
Although there is no clear indication for thrombolytic therapy in patients with severe hypoxemia, a free-floating right atrial or RV thrombus (with or without a patent foramen ovale (PFO), the administration of thrombolytic therapy in such rare circumstances may be considered on an individual basis.
In every patient in whom thrombolysis is contemplated, the risk of bleeding should always be considered. The importance of the contraindication should depend on the strength of the indication.5 For example, a contraindication is of more concern if the indication for systemic thrombolytic therapy is RV dyskinesis than if the indication is shock.
Absolute or major contraindications to systemic thrombolytic therapy in acute PE include:
Relative contraindications include5:
Thrombolytic therapy may cause moderate bleeding in menstruating women, but it has rarely been associated with major hemorrhage. Therefore, menstruation is not a contraindication to thrombolytic therapy.
As an alternative to thrombolytic therapy, catheter or surgical embolectomy may be warranted if the necessary resources and expertise are available. The decision of whether to pursue one of these approaches should be based on local expertise.
|Tissue Plasminogen Activators (abbreviated tPA) is a protein involved in the breakdown of blood clots. It is a serine protease found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown. tPA can be manufactured using recombinant biotechnology techniques. tPA produced by such means are referred to as recombinant tissue plasminogen activator (rtPA).|
|Generic Name||Brand Name||Route(s) of Administration||Notes|
|rtPA (alteplase)||Activase®, Actilyse®||IV bolus followed by 100mg IV infusion over two hours (with or without UFH)||Alteplase has a short half-life (~5 min) and therefore is usually administered as an intravenous bolus followed by an infusion.|
|Tenecteplase (TNK-tPA)||TNKase®||IV push over 5 to 10 seconds (with or without UFH)||TNK-tPA has a longer half-life and greater binding affinity for fibrin than rtPA. Because of its longer half-life, it can be administered by IV bolus. Off-label use only in the treatment of acute PE if alteplase unavailable.|
*Only thrombolytic agents approved by the FDA for the treatment of PE are discussed here.
Once the decision to administer thrombolytic therapy has been made, the thrombolytic agent is typically administered via a peripheral IV infusion.5 Although bolus and catheter-directed routes of administration have been studied, there are less available data.
Unnecessary invasive procedures (particularly arterial punctures) should be minimized while thrombolytic therapy is being administered, and extreme caution should be taken with patients who have had PE-induced syncope with resultant head trauma even if the brain CT is negative.
Anticoagulant therapy is generally discontinued during the thrombolytic infusion. Discontinuing anticoagulants during thrombolysis is consistent with most commonly performed trials done in the United States. However, in other trials, particularly in Europe, this has not been the case. The potential risk of bleeding with continued anticoagulation and the risk of recurrent embolism while anticoagulation is discontinued is unknown. Full anticoagulation (usually heparin followed by an oral anticoagulant) following clot lysis is typically undertaken. The optimal duration of IV heparin following thrombolysis is unknown. Similarly, the duration of long term anticoagulation, once the patient is stabilized depends on a number of factors primarily focused on perceived risk for recurrence with an absolute minimum of three months being required.5
In hemodynamically unstable patients, systemic thrombolysis is preferred because of more widespread availability and clinical experience with these agents, as well as the rapidity with which they can be administered in life-threatening situations. Although thrombolytic therapy is rarely administered to hemodynamically stable patients, the optimal method of administration is unknown. Clinical experience suggests that if thrombolytic therapy is to be administered in, for example, intermediate-risk PE, catheter-based therapy rather than systemic therapy may be preferred, provided the expertise is available. This preference is based upon clinical experience and the likelihood of a lower risk of bleeding with this method of administration. Systemic thrombolytic therapy is a suitable alternative if local expertise is not available for catheter-directed techniques. While several catheter-based techniques are available, only one ultrasound-assisted device has been approved by the FDA.
Intravenous thrombolytic infusion regimens are the most common method of administering thrombolytics. Common regimens that are approved by the FDA for PE include:
Although rtPA (alteplase) is the most commonly used thrombolytic, the superiority of any agent or regimen over another has not been established. The evidence from small randomized trials suggests that shorter infusions (i.e., ≤2 hours) achieve more rapid clot lysis and are associated with lower rates of bleeding than longer infusions (i.e., ≥12 hours).5 The FDA-approved infusion duration for rtPA of two hours has been the main reason why this drug is commonly chosen and is the only thrombolytic agent that is FDA-approved for acute PE.
An activated partial thromboplastin time (aPTT) can be measured when the infusion of thrombolytic therapy is complete. Heparin should be resumed without a loading dose when the aPTT is less than twice its upper limit of normal. If the aPTT exceeds this value, the test should be repeated every four hours until it is less than twice its upper limit of normal, at which time heparin should be resumed. Another option is to simply restart the heparin infusion without a bolus when the thrombolytic infusion has been infused.
Coagulation assays are unnecessary during infusion of the thrombolytic agent since thrombolytic agents are administered as fixed doses.
The question of whether a lower dose of thrombolytic therapy could expedite resolution of pulmonary hypertension due to a "moderate" acute PE without significant adverse effects was examined in the Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial.5
A retrospective propensity-matched study reported that compared with patients treated with full-dose rtPA (100 mg), patients treated with half-dose rtPA (50 mg) required vasopressor therapy and invasive ventilation less often but needed escalation of therapy more often.5 Hospital mortality and rates of significant bleeding were similar.
One retrospective analysis compared reduced-dose (half-dose) thrombolysis with catheter-directed thrombolysis and found that both therapies led to similar reductions in the pulmonary artery systolic pressure and RV/LV ratio, but half-dose thrombolysis reduced the duration and cost of hospitalization.5 Further studies are required before firm conclusions can be drawn from this retrospective study.
Based on this limited evidence, a recommendation cannot be made to implement this lower-dose regimen of rtPA for "moderate" PE. Further prospective studies are needed to validate its efficacy in a larger population of patients with moderate acute PE.
Bolus infusion of thrombolytics may be effective without excess bleeding complications.5 However, this has not been directly compared to a two-hour infusion of rtPA. More trials comparing the regimens are necessary before routine bolus infusion replace the more conventional two hour regimen.
An exception is that bolus infusion of thrombolytic therapy is indicated for patients with imminent or actual PE-related cardiac arrest5:
If rtPA is unavailable, but tenecteplase is available, a single IV dose of tenecteplase given over five seconds can be given for PE-related cardiac arrest, based upon patient weight as per pharmacy protocol.5
Thrombolytics for PE-related arrest are given with systemic anticoagulation (e.g., UFH infusion).5
Thrombolytic agents can be infused directly into the pulmonary artery via a pulmonary arterial catheter.5 Guidelines suggest that catheter-directed thrombolysis may be considered for patients5:
It should be kept in mind that in spite of this guideline recommendation, catheter-based therapy can, in fact, almost never be performed faster than systemic lysis. CDT should be reserved for use in centers with appropriate expertise. The potential advantage of catheter-administered thrombolytics is that lower doses of a lytic agent can be administered, thereby reducing the risk of bleeding when compared with systemic therapy. In addition, other mechanical interventions can be simultaneously performed to aid clot dissolution (e.g., ultrasound) or mechanical removal (e.g., embolectomy).5
Data regarding this approach come from small prospective trials with mixed results. As examples:
Further randomized studies will be needed to clarify the population that would benefit from this approach before CDT can be routinely used for patients with acute PE.
VTE is comprised of two entities, DVT and PE. VTE has significant morbidity and mortality for both the inpatient and outpatient populations. The risk of recurrent thrombosis and embolization is highest in the first few days and weeks following diagnosis. Thus, initial anticoagulation during the first few days (i.e., 0 to 10 days) is critical in the prevention of recurrence and VTE-related death.
Most patients with ultrasound-proven proximal DVT (i.e., popliteal, femoral, or iliac vein DVT) and most cases of symptomatic distal DVT (below the knee and in the calf veins, i.e., peroneal, posterior, and anterior tibial DVT) should be anticoagulated. Similarly, patients with symptomatic PE and most patients with subsegmental PE should be anticoagulated. For each patient, the decision to anticoagulate must weigh the risk of morbidity and mortality without anticoagulation against the risk of bleeding on anticoagulation.
In all patients, the decision to anticoagulate should be individualized, and the benefits of VTE prevention carefully weighed against the risk of bleeding. Most clinicians agree that patients with a three-month bleeding risk of less than 2% (low risk) should be anticoagulated and that those with a bleeding risk of more than 13% (high risk) should not be anticoagulated.6 For patients with a bleeding risk between these values (moderate risk), there is no agreement regarding the preferred approach such that the decision to anticoagulate in this population must be individualized according to the values and preferences of the patient, as well as, the risk-benefit ratio.
|Heparin and LMW Heparins|
|Mechanism of Action: Heparin and LMWHs prevent a blood clot from forming by blocking the action of two of the 12 clot-promoting proteins in the blood (factors II and X) whose action is necessary for blood to clot. LMWHs are produced by chemically breaking heparin into smaller-sized molecules.|
|Generic Name||Brand Name||Route(s) of Administration||Labs to Monitor|
|Unfractionated Heparin (UFH)||IV infusion; SQ||aPTT|
|Vitamins K Antagonists|
|Mechanism of Action: Warfarin prevents the formation of blood clots by reducing the production of factors II, VII, IX and X, and the anticoagulant proteins C and S by the liver. The production of these factors by the liver is dependent on adequate amounts of vitamin K. Warfarin reduces the production of the factors because it antagonizes vitamin K.|
|Warfarin||Coumadin®; Jantoven®||PO||INR, PT|
|Direct Thrombin Inhibitors|
|Mechanism of Action: Thrombin inhibitors work by blocking the action of thrombin, a protein that is necessary for the coagulation of blood and formation of a blood clot.|
|Factor Xa Inhibitors|
|Mechanism of Action: Factor Xa inhibitors block the action of factor Xa, which is an important protein in the coagulation cascade that causes blood to clot. Reducing the action of factor Xa reduces the ability of blood to clot.|
With the exception of patients who are pregnant, have active cancer, or have severely impaired renal function (e.g., creatinine clearance [CrCl] <30mL/minute) the following approach is suggested6:
Warfarin cannot be administered as the only initial anticoagulant for the treatment of patients with VTE. However, when chosen as the long term anticoagulant, it must be co-administered with heparin so that full anticoagulation is assured.
When choosing an initial anticoagulant, the following patient populations deserve special consideration:
Initial anticoagulation refers to systemic anticoagulation administered immediately following the diagnosis of DVT or PE typically the first 0 to 10 days. It is often administered while a decision regarding long-term anticoagulation is being made. When the decision is made to administer anticoagulant therapy, it should be started immediately since a delay may potentially increase the risk of life-threatening embolization.6
The initial duration of heparin therapy varies depending upon the oral agent chosen and whether or not thrombolysis is anticipated:
A diagnosis of PE is made radiographically by one of the following modalities using the following criteria:
The approach to patients with suspected recurrent PE (days to years) should be the same as for a first suspected event with some minor differences:
For patients who present with signs and symptoms of PE, the differential diagnosis of common conditions that mimic PE include the following:
The differential diagnosis of PE depends upon the presenting signs and symptoms such as:
CTPA may identify many of these alternative diagnoses.
Once the diagnosis is made, the mainstay of therapy for patients with confirmed PE is anticoagulation, depending upon the risk of bleeding. When the PTP of PE is high or diagnostic imaging will be delayed, anticoagulation is sometimes started before a diagnosis of PE is confirmed.
Patients with life-threatening PE may require additional treatment beyond anticoagulation, including thrombolysis, IVC filters, and embolectomy. Special populations that require specific anticoagulation or alternative treatment strategies include:
In patients with PE who are hemodynamically unstable or who become unstable due to recurrence despite anticoagulation, more aggressive therapies than anticoagulation are suggested. These include:
Patients in this group are heterogeneous and have a wide range of presentations, as well as variable risk of recurrence and decompensation. This group includes those with submassive PE (moderate/intermediate risk), and minor PE (low risk).
The following approach is suggested for most hemodynamically stable (i.e., normotensive) patients with minor/low-risk PE:
Hemodynamically stable (i.e., normotensive) patients with intermediate-risk/submassive PE who are anticoagulated, close monitoring for deterioration should be ongoing. Thrombolysis and/or catheter-based therapies may be considered on a case-by-case basis when the benefits are assessed by the clinician to outweigh the risk of hemorrhage. Examples of such patients include those who have:
Anticoagulant therapy is indicated for patients with PE in whom the risk of bleeding is low:
Therapies that can be added as an adjunct to anticoagulation in patients with PE include:
The effects of thrombolytic therapy followed by anticoagulant therapy have been compared to those of anticoagulant therapy alone. The evidence consistently indicates that thrombolytic therapy leads to early hemodynamic improvement, but at the cost of increased major bleeding. Although thrombolytic therapy has been shown in one meta-analysis to improve mortality, methodologic flaws limited the analysis such that the specific population that may potentially derive benefit, as well as, the optimal agent, dose, and delivery system (catheter-directed or systemic) remain unknown.5
The prognosis from PE is variable. Accurate estimates have been limited by data that are mostly derived from earlier studies, registries, and hospital discharge records collected from heterogeneous populations of patients. For example:
Early outcomes are considered as those occurring within the first three months after the diagnosis of PE. The highest risk for events occurs within the first seven days. Death and morbidity during this period are most commonly due to shock and recurrent PE.
The incidence of late events, at three months or later following a diagnosis of PE, ranges from 9% to 32%, with increased mortality reported for as long as 30 years.4 Late mortality is mostly due to predisposing comorbidities, and less commonly due to recurrent thromboembolism or chronic thromboembolic pulmonary hypertension. As examples:
Poor prognostic factors in patients diagnosed with PE include:
Patients with PE should be monitored following diagnosis for the following:
Inadequate anticoagulation is the most common reason for recurrent VTE (PE and/or DVT) while on therapy. Explanations for subtherapeutic anticoagulation, as well as, several additional etiologies for recurrence that should be considered are:
Subtherapeutic anticoagulation is the most common reason for recurrence. A detailed history and examination should be performed to identify factors that contribute to subtherapeutic anticoagulation. These include:
Consulting a coagulation specialist may be warranted, especially when abnormal pharmacokinetics or noncompliance for medications that cannot be monitored easily (e.g., target-specific oral anticoagulants, LMW heparin) are suspected.
For those subtherapeutic on UFH, the dose should be increased to achieve therapeutic levels rapidly. For patients who are on LMW heparin or factor Xa and direct thrombin inhibitors in whom subtherapeutic anticoagulation is suspected but unconfirmed, or for those subtherapeutic on warfarin, switching to a rapid-acting anticoagulant that can be followed (e.g., UFH) may be prudent while investigations are ongoing.
Because new direct thrombin and Xa inhibitors do not require monitoring, it is yet to be determined whether challenges will emerge with monitoring for therapeutic levels.
Therapeutic anticoagulation is the optimal therapy for VTE. Suboptimal therapies, including IVC filters and embolectomy or thrombolysis not followed by anticoagulation, should be apparent to the investigating clinician. Resumption of therapeutic anticoagulation should be considered in such cases, when feasible.
In patients who develop recurrence despite therapeutic anticoagulation, a search for conditions associated with high recurrence rates is recommended. These include:
In this population, therapeutic options are limited. An approach is suggested that is similar to that performed in patients with recurrent thrombosis who have an underlying malignancy. These options include:
Recurrence may also be associated with conditions that promote thrombus propagation (e.g., mechanical obstruction of venous flow from pelvic masses or IVC filter), or thrombus dissociation (e.g., large RV4 or valvular thrombus). In such patients, treating the underlying cause or removing mobile thrombus may be appropriate, when feasible.
Occasionally, tumor or fat emboli may radiographically mimic PE due to thrombus.
Mr. Williams, a 79-year-old Caucasian male, is transported to the Emergency Room via EMS on August 5, 2019, at 0700 accompanied by his wife. She states that he has been experiencing midsternal chest pain, non-radiating with progressive difficulty breathing and intermittent coughing since 0500 this a.m. Cough non-productive.
Current Medical History:
Past Medical History:
Past Surgical History:
IV access (left forearm): 1000ml 0.9 NS hung at 50 ml/hr.
12-lead ECG done
Emergency physician obtained an initial neurologic examination:
ECG showed atrial fibrillation with ST depression.
CT of brain ordered stat.
Cardiology consult ordered stat.
Awaiting results of laboratory tests.
Mr. Williams was monitored in the ED, awaiting brain CT results, cardiology recommendations and laboratory results.
Diagnoses: COPD, atrial fibrillation, CHF
Tentative diagnoses: r/o MI, r/o pulmonary embolism, r/o brain bleed.
Mr. Williams’s health history and physical examination were performed quickly with appropriate orders written. Appropriate interventions initiated.
PE is a common and sometimes fatal disease. It is due to obstruction of a pulmonary artery or one of its branches by material (e.g., thrombus, tumor, air, or fat) that originated elsewhere in the body.
PE can be classified according to the presence or absence of hemodynamic stability (hemodynamically unstable or stable), the temporal pattern of presentation (acute, subacute, or chronic), the anatomic location (saddle, lobar, segmental, subsegmental), and the presence or absence of symptoms (symptomatic or asymptomatic).
Patients with hemodynamically unstable PE, defined as a systolic blood pressure <90 mmHg or a drop in systolic blood pressure of ≥40 mmHg from baseline for >15 minutes, should be distinguished from patients with hemodynamically stable PE because the hemodynamically unstable PE patient are more likely to die from obstructive shock in the first two hours of presentation and may, therefore, benefit from more aggressive treatment.
The overall incidence of PE is approximately 112 cases per 100,000. PE is slightly more common in males than females, and the incidence increases with age. Deaths from PE account for approximately 100,000 deaths per year in the United States.
The pathogenesis of PE is similar to that of DVT. Most emboli arise from lower extremity proximal veins (iliac, femoral, and popliteal). However, they may also originate in the right heart, inferior vena cava or the pelvic veins, and in the renal and upper extremity veins.
There is often more than one risk factor at play in any given patient, which may include both hereditary and acquired factors. The most frequent hereditary causes of VTE are the factor V Leiden and prothrombin gene mutations, which account for 50% to 60% of cases. The major acquired risk factors for VTE include prior thromboembolism, recent major surgery, trauma, immobilization, antiphospholipid antibodies, malignancy, pregnancy, oral contraceptives, and myeloproliferative disorders.
PE has a wide variety of presenting features, ranging from no symptoms to shock or sudden death. The most common presenting symptom is dyspnea, followed by CP (classically but not always pleuritic) and cough and symptoms of DVT. However, many patients, including those with large PE, have mild symptoms or are asymptomatic.
For most patients with suspected PE, an approach is suggested which combines clinical and PTP assessment and tests, including ECG, CXR, BNP and troponin levels, ABGs, and D-dimer testing. However, these tests are neither sensitive nor specific for the diagnosis of PE and are most useful for confirming the presence of alternative diagnoses or providing prognostic information in the event that PE is diagnosed. Definitive diagnostic imaging, usually CTPA and, less commonly, V/Q scanning should be performed.
The initial approach to patients with suspected PE should focus upon stabilizing the patient while clinical evaluation and definitive diagnostic testing are ongoing. Supplemental oxygen should be administered to target an oxygen saturation of ≥90%. Severe hypoxemia, hemodynamic collapse, or respiratory failure should prompt consideration of mechanical ventilation. When mechanical ventilation is necessary, an expert in cardiovascular anesthesia should be consulted, when feasible, to avoid catastrophic hypotension due to sedation and positive pressure ventilation. For those who require hemodynamic support, cautious infusions of IVF (500 to 1000 mL of normal saline) is suggested rather than larger volumes. Vasopressor therapy should be initiated if perfusion fails to respond to IVF.
Once the diagnosis is made, the mainstay of therapy for patients with confirmed PE is anticoagulation, depending upon the risk of bleeding. Alternative treatments include thrombolysis, IVC filters, and embolectomy.
For patients with a high clinical suspicion for PE who are hemodynamically unstable and successfully resuscitated, immediate anticoagulation and definitive diagnostic imaging are preferred. For patients with a low or moderate suspicion of PE who are successfully resuscitated, the same approach to diagnosis and empiric anticoagulation should be used for patients who are hemodynamically stable. For patients who remain unstable despite resuscitation, bedside echocardiography and lower extremity US with Doppler of the leg veins can be used to obtain a rapid or presumptive diagnosis of PE (visualization of thrombus or new right heart strain) to justify the administration of potentially life-saving therapies, including thrombolytic agents.
For patients with suspected PE who are hemodynamically stable, an approach that selectively integrates clinical evaluation, three-tiered PTP testing, Wells criteria, PERC, D-dimer, and imaging is advocated. CTPA, also called chest CT angiogram with contrast, is the preferred imaging exam.
Thrombolytic therapy for acute PE accelerates clot lysis and leads to early hemodynamic improvement (e.g., improved pulmonary arterial blood pressure, RV function, and pulmonary perfusion). However, it also increases major bleeding and has not been convincingly shown to improve mortality or reduce the frequency of recurrent thromboembolism.
In most cases, thrombolytic therapy should be considered only after acute PE has been confirmed because the adverse effects of thrombolytic therapy can be severe. Patient values and preferences should be taken into consideration when discussing the risk and benefits of thrombolytic therapy.
In hemodynamically unstable patients, the following applies:
In hemodynamically stable patients, the following applies:
Initial anticoagulation refers to anticoagulant therapy that is administered immediately following a diagnosis of acute VTE. It is often given over the first few days (typically from 0 to 10 days) while planning for long term anticoagulation. Anticoagulation should be started immediately as a delay increases the risk of embolization and death.
Every patient with acute VTE should be assessed for the risk of bleeding prior to anticoagulation. Most clinicians agree that anticoagulation should be administered to patients with a low risk of bleeding and avoided in those at high risk. For patients with a moderate risk of bleeding, the decision to anticoagulate must be individualized according to the values and preferences of the patient, as well as, the risk-benefit ratio as assessed by the clinician.
For most patients with acute VTE, LMW heparin SQ, fondaparinux SQ, or the factor Xa inhibitors, rivaroxaban PO or apixaban PO are preferred rather than UFH IV. A decision between these agents is usually made based upon clinician experience, as well as the risks of bleeding, patient comorbidities, preferences, cost, and convenience. Dosing for each agent is individualized.
Other populations require special consideration:
The decision to empirically anticoagulate while waiting for diagnostic test results depends upon the clinical suspicion for VTE, the expected timing of diagnostic tests, and the bleeding risk.
Full anticoagulation should be ensured during the transition from initial to long-term (maintenance) therapy when switching agents.
In patients with a low clinical probability of PE (e.g., <15%, Wells score <2), the PERC criteria should be applied. Patients who fulfill all eight criteria do not need additional testing. For patients who do not meet PERC criteria or in whom PERC cannot be applied (e.g., critically-ill patients), further testing with sensitive D-dimer measurement is indicated. No imaging is required when the D-dimer level is normal (<500 ng/mL), while imaging is indicated in those with a positive D-dimer (≥500 ng/mL).
In patients with an intermediate clinical probability of PE (e.g., Wells score 2 to 6), sensitive D-dimer testing is preferred to determine whether or not diagnostic imaging is indicated. Patients with a negative D-dimer do not need imaging, while those with a positive D-dimer should have chest imaging. However, some experts proceed directly to diagnostic imaging in select patients (e.g., those with limited cardiopulmonary reserve or those in the upper zone of the intermediate range such as a Wells score of 4 to 6).
In patients with a high clinical probability of PE (e.g., Wells score >6), diagnostic imaging with CTPA is preferred. A positive result confirms the diagnosis of PE, while a negative result excludes it in nearly all cases.
CTPA acquires thin (≤2.5 mm) section volumetric images of the chest after a bolus administration of IV contrast that is timed precisely for maximal enhancement of the pulmonary arteries. A multidetector row (≥16 detectors rows) CT scanner is required to achieve sufficient diagnostic performance. A chest CT with contrast not performed as a CTPA but for other indications is not an adequate exam to exclude suspected PE.
For patients with suspected PE in whom CTPA is contraindicated, unavailable, or inconclusive, V/Q scanning is the alternative imaging exam. V/Q scan results reported as high-, intermediate- or low-probability for PE, or normal, should be interpreted in conjunction with clinical suspicion. A high-probability V/Q scan and high clinical probability is sufficient to confirm PE. A normal scan or a low-probability scan in the setting of low clinical probability of PE can also be used to rule out PE. All other combinations of V/Q results and clinical probability are nondiagnostic.
For patients in whom both CTPA and V/Q scanning are contraindicated, unavailable, or inconclusive, noninvasive testing with lower extremity compression ultrasonography with Doppler is preferred (although not diagnostic of PE).
A diagnosis of PE is made radiographically based upon CTPA, MRPA, or catheter-based pulmonary angiography by the demonstration of a filling defect in any branch of the pulmonary artery.
The differential diagnosis of PE includes many other entities that present similarly with dyspnea, CP, hypoxemia, leg pain and swelling, tachycardia, syncope, and shock. Other competing diagnoses including heart failure, myocardial ischemia, pneumothorax, pneumonia, and pericarditis, which may be distinguished on ECG, echocardiographic, laboratory, and CXR testing. However, PE can coexist with these conditions and, therefore, the presence of an alternate diagnosis does not entirely exclude the diagnosis of PE.
For patients with suspected PE who are hemodynamically stable or hemodynamically unstable and successfully resuscitated, the administration of empiric anticoagulation depends upon the risk of bleeding, the clinical suspicion for PE, and the expected timing of diagnostic tests.
For patients with a low risk of bleeding and a high clinical suspicion for PE, empiric anticoagulation is suggested rather than waiting until definitive diagnostic tests are completed. A similar approach is used in those with moderate or low clinical suspicion for PE in whom the diagnostic evaluation is expected to take longer than four hours and 24 hours, respectively.
It is not suggested that anticoagulation therapy be initiated in patients with absolute contraindications to anticoagulant therapy or those who have an unacceptably high risk of bleeding.
For patients with a moderate risk of bleeding, empiric anticoagulant therapy may be administered on a case-by-case basis according to the assessed risk-benefit ratio.
The optimal agent for empiric anticoagulation depends upon hemodynamic instability, the anticipated need for procedures or thrombolysis, and the presence of risk factors and comorbidities.
In patients with a high clinical suspicion for PE who are hemodynamically unstable and who have a definitive diagnosis by portable perfusion scanning or a presumptive diagnosis of PE by bedside echocardiography (because definitive diagnostic testing is unsafe or not feasible), systemic thrombolytic therapy is suggested rather than empiric anticoagulation or no therapy. If bedside testing is delayed or unavailable, the use of thrombolytic therapy as a life-saving measure should be individualized. If not used, the patient should receive empiric anticoagulation.
For patients who are hemodynamically unstable and the clinical suspicion is low or moderate, empiric anticoagulation similar to that suggested for patients who are hemodynamically stable is indicated. Empiric thrombolysis is not justified in this population.
For patients in whom definitive diagnostic testing excludes PE, anticoagulant therapy should be discontinued if it was initiated empirically, and alternative causes of the patient’s signs and symptoms should be sought.
For patients in whom the diagnostic evaluation confirms PE, an approach that is stratified according to whether or not the patient is hemodynamically stable or unstable is suggested. At any time, the strategy may need to be redirected as complications of PE or therapy arise.
For most hemodynamically stable patients with PE (i.e., low risk/nonmassive), the following applies:
For most patients with hemodynamically unstable PE, the following applies:
In patients with PE who are fully anticoagulated, early ambulation is suggested rather than bed rest, when feasible. Although IVC filters are not routinely used adjunctively in patients who are therapeutically anticoagulated, they are used in rare circumstances by some experts (e.g., those with poor cardiorespiratory reserve), although this strategy is largely unproven.
PE, left untreated, has a mortality of up to 30%, which is significantly reduced with anticoagulation. The highest risk occurs within the first seven days, with death most commonly due to shock. Prognostic models that incorporate clinical findings (e.g., Pulmonary Embolism Severity Index [PESI] and the simplified PESI [sPESI] and/or biochemical markers that indicate right ventricle strain (natriuretic peptides, troponin) can predict early death and/or, recurrence.
Patients treated with UFH and/or warfarin should be monitored for laboratory evidence of therapeutic efficacy. Patients should also be monitored for early (e.g., recurrence) and late (e.g., CTEPH) complications of PE, as well as, for the complications of anticoagulation and other definitive therapies. In addition, patients should be investigated for the underlying cause of PE.
Inadequate anticoagulation is the most common reason for recurrent VTE while on therapy. The clinician should test for therapeutic levels of anticoagulants when relevant, as well as considering additional etiologies of recurrence (e.g., suboptimal therapy, ongoing prothrombotic stimuli, and alternate diagnoses).
PE can be complicated by recurrent thrombosis, CTEPH, and death.