RECAPEM

Acute Pulmonary Embolism: Management of Massive and Submassive Pulmonary Embolism

October 24, 2020, by Shahriar Lahouti

CONTENTS

Preface

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Venous thromboembolism (VTE), clinically presenting as DVT or pulmonary embolism(PE), is globally the third most frequent acute cardiovascular syndrome behind myocardial infarction and stroke.1 PE is a life-threatening condition and a leading cause of morbidity and mortality. It is a heterogeneous disease. Some patients look great while others are profoundly ill. Even among the latter group, the clinical manifestation, and outcome significantly vary among the patients.

Not to mention the fact that patients can evolve rapidly in one direction or the other. Studies have shown that patients with hemodynamic instability from PE are more likely to die within the first two hours and the risk remains high for up to 72 hours after presentation, which implies the necessity for employing emergent appropriate diagnostic and therapeutic measures.

There has been many advances in the field of PE in recent years and the therapeutic options can range from anticoagulation alone, catheter-directed thrombolysis, systemic thrombolysis, catheter embolectomy, surgical embolectomy, and/or mechanical circulatory support such as extracor-poreal membrane oxygenation (ECMO).

In response to increasing patient complexity and increasing therapeutic alternatives, there has been a rise in the development of multidisciplinary groups of clinicians with expertise in the diagnosis and medical, surgical, and interventional management of PE who collaborate in a novel way to improve patient care. This multidisciplinary team approach is termed the PERT (Pulmonary Embolism Response Team).

In the following discussion, the approach to management of PE is explored (which is for the most part consistent with the PERT consortium consensus practices 2and the recommendation from the Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology3).

Nomenclature

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PE can be classified by the several parameters including; hemodynamic status of the patient, anatomic location of the thrombus and the temporal pattern of presentation.

The hemodynamic status (unstable or stable): This classification is the ground for risk stratifying PE into high, intermediate and low risk (more on this below).

  • Hemodynamically unstable PE is the one which causes “Hypotension”; traditionally defined as systolic blood pressure (SBP) <90 mmHg or a drop in SBP of ≥40 mmHg from baseline for a period >15 minutes or hypotension that requires vasopressor support and is not explained by other etiologies such as hypovolemia, sepsis,etc.3
    • This heterogenous group of patients are at high risk of adverse cardiovascular events and the term ‘Massive” PE (MPE) is applied accordingly. The word ‘massive’ may seem to you a PE with a large clot, as the word massive may imply; however it has been shown that among patients with a large clot (e.g. saddle PE) only 22% are hemodynamically unstable, with an associated mortality of 5%.45 Size Does Not Matter! 6In fact there are several other parameters in addition to the degree of mechanical obstruction, i.e. size of the clot; that may contribute to hemodynamic instability as well such as individual physiologic reserve and degree of pulmonary vasoconstriction mediated by platelet activation (more on this here).
    • The spectrum of severity and risk of death varies among individuals as some patients are dependent on high dose vasopressor with symptoms and signs of end-organ hypoperfusion (obstructive shock ≈ crashing MPE)7 8 9 vs. those with low dose pressor requirement to keep their SBP above 90mmHg (non-crashing MPE).3
  • Hemodynamically stable PE is defined as PE that does not meet the definition of hemodynamically unstable PE. This is a heterogenous group with some patients presenting with right ventricle dysfunction and mild or borderline hypotension that stabilizes in response to fluid therapy (a.ka. “submassive” or “intermediate-risk” PE)10 vs. those patients presenting with small, mildly symptomatic or asymptomatic PE (also known as “low-risk PE”).

The anatomic location: Defines the location of the clot within the pulmonary artery (saddle, lobar, segmental or subsegmental).

  • Saddle PE: Refers to the clots at the bifurcation of the main pulmonary artery, often extending into the right and left main pulmonary arteries. Traditionally saddle PE was believed to be associated with hemodynamic instability and death, while as explained earlier, several retrospective studies show that this is not true.45
  • Central PE: Refers to the thrombus in the right or left main pulmonary arteries.In patients with stable hemodynamic, presence of central clot correlates with RV dysfunction11 and predicts a higher rate clinical deterioration and 30-day mortality.12 13 14
  • Lobar, segmental and subsegmental PE: Refers to embolism that is lodged at lobar, segmental, or subsegmental branches of a pulmonary artery.
  • Clot in transit (CIT): Clot that is “In Transit” through the right heart is often classified as a form of PE 15, even though the thrombus may have not yet lodged in a pulmonary artery.

The temporal pattern of presentation: Patients with PE can present acutely, subacutely, or chronically.

  • Acute: Patients with acute PE typically develop rapid onset of symptoms and signs immediately after obstruction of pulmonary vessels. Acute onset or accelerating symptoms are worrisome.
  • Subacute: Some patients with PE may also present with stable symptoms for several days or weeks following the initial event. Subacute presentation reduces the risk of sudden deterioration.
  • Chronic: Some patients are symptomatic for > 10-14 days; suggesting a more chronic thrombus (over time, clots organize and become less responsive to thrombolysis).

Clinical presentation

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The clinical signs and symptoms of acute PE are non-specific and highly variable from asymptomatic to full blown cardiac arrest among the patients. Given this nonspecificity, knowledge of predisposing factors to VTE, is important to determine the clinical probability of the disease. However, in 40% of patients with PE, no predisposing factors are found.16

Most common presenting symptoms and signs include17:

  • Dyspnea (73%): It may be acute and severe in central and extensive PE; but mild and transient in small peripheral PE.
  • Syncope, presyncope (10%)
  • Chest pain
    • In small peripheral PE, chest pain often is pleuritic caused by irritation of pleura following pulmonary infarction
    • In extensive, central PE; chest pain may have a typical angina character, possibly reflecting RV ischemia, and requiring differential diagnosis from an acute coronary syndrome or aortic dissection.
  • Hemoptysis (13%)
    • In the context of PE, hemoptysis is a result of pulmonary infarction often seen with small, peripheral PE, or typically later in the course of PE with central clot, when it breaks down and the fragments migrate distally. Since bleeding reflects necrosis of lung tissue, it originates from the small pulmonary capillaries and veins, hence it is often minor; unless the patient has preexisting conditions such as lung cancer,aspergilloma, cystic fibrosis or vascular malformations.18 Keep in mind that presence of minor hemoptysis is not a barrier to PE management (i.e. anticoagulation can be continued), unless the hemoptysis is unusually brisk.
  • Silent PE: one systematic review found that, among the 5233 patients who had a DVT, one-third also had asymptomatic PE. 19
  • Sudden cardiac arrest or circulatory collapse (8%)20 2122
  • Hypoxemia: is a frequent finding but <40% of patients have normal arterial oxygen saturation.23 A normal arterial SO2 does not rule out the presence of PE.
  • Tachypnea (54%)
  • Tachycardia: Generally sinus tachycardia reflects activation of neurohormonal mechanisms (increased sympathetic discharge) in the face of increased RV afterload. Sinus tachycardia is present in < 40% of patients.Atrial arrhythmias, most frequently atrial fibrillation, may be associated with acute PE.
  • DVT (70%): Calf or thigh swelling, erythema, edema, tenderness, palpable cords.

Diagnosis

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Definitive imaging includes computed tomographic pulmonary angiography (CTPA) and less commonly, ventilation perfusion scanning or other imaging modalities. For patients who are hemodynamically unstable and in whom definitive imaging is unsafe, bedside echocardiography or venous compression ultrasound may be used to obtain a presumptive diagnosis of PE to justify the administration of potentially life-saving therapies.3 The diagnostic approach to PE will be discussed in detail separately.

DDx of symptoms and signs

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For patients who present with symptoms and signs of PE, the differential diagnosis depends upon the presenting signs and symptoms (e.g. dyspnea, chest pain, syncope, etc). By enlarge, the major competing diagnoses may include(not comprehensive list):

  • Critical DDx of chest pain: Acute coronary syndrome, Acute aortic syndrome, Pericarditis, PE
  • Critical DDx of dyspnea: Heart failure, PE, Pneumothorax, Acute exacerbations of chronic lung disease, Pneumonia, Metabolic e.g. diabetic ketoacidosis
  • Critical DDx of syncope: In appropriate clinical context, the critical conditions associated with syncope may include: PE, Tamponade, Malignant arrhythmia, Acute aortic syndromes(e.g. aortic dissection), Left ventricle outflow tract obstruction (e.g. HCM, Severe aortic stenosis), Subarachnoid hemorrhage, Severe volume loss (e.g. GI bleeding, Ruptured ectopic pregnancy).

DDx and other considerations in unstable PE:

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n unstable patients suspected of PE, sometimes performing CTPA is not feasible. In this situation, presence of following findings could be helpful in making presumptive diagnosis of PE in appropriate clinical context:3

  • Presence of predisposing risk factors
  • POCUS for DVT: In the majority of cases (70%) PE originates from DVT mostly in the lower limbs, and only rarely from upper limb (mostly following venous catheterization).
  • Echo: Presence of “clot in the right heart”
  • Echo: Presence of RV dysfunction and dilated IVC (especially in the absence of other obvious causes for RV pressure overload such as pulmonary hypertension).
  • Clear lung fields on auscultation or absence of B-lines on ultrasound (especially in patients without a history of cardiopulmonary disease).

More importantly, many unstable patients with PE often have multifactorial instability (e.g. PE plus sepsis). Since thrombolysis is only beneficial when PE is driving the patient’s instability, it is crucially important to consider “Whether This PE Is Causing The Patient’s instability”? (figure 1)

Factors that should be considered are:

  • Global hemodynamic assessment by ultrasound
    • If PE is driving the instability, there should be at least a dilated IVC and dilated RV (especially in those patients without preexisting cardiopulmonary conditions). Otherwise consider whether another process is causing the patient’s instability (e.g. hypovolemic shock plus small PE). In the absence of clear clinical evidence of volume loss (watery diarrhea!, GI bleeding), a virtual IVC is against diagnosis of MPE.3
  • Clot burden on CT
    • The precise thrombus burden (as measured by percentage or semi-quantitative indexes such as Mastora or Qanadli) have been shown that does not correlate well with the adverse outcomes. 24 25 26
    • However in order to blame the patient’s instability on PE, there should be a moderate to large clot burden on the CT scan.If there is only a small amount of clot, PE probably isnot causing the instability. For example, a patient with right ventricular dilation and small clot burden may have chronic pulmonary hypertension.

PE in cardiac arrest: The differential diagnosis

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PE has been reported to be associated with 5 to 13% of unexplained cardiac arrest.27 Mortality related to cardiac arrest caused by PE is high (≈95%).28 Approximately 90% of episodes of cardiac arrest following PE have been reported to occur within 1-2 hours of symptoms onset. The diagnosis of PE as a possible cause of unexplained cardiac arrest would be more likely in the presence of following factors:

  • Symptom before the arrest: In a study, most common reported symptoms before the cardiac arrest was reported as syncope and acute onset of dyspnea. This is in contrast to cardiac arrest following coronary events or aortic dissection where the acute onset of chest pain is reported to be the most common symptom before the cardiac arrest.29
  • Presence of predisposing conditions: Presence of underlying risk factors (e.g. major surgery and immobilization, or history of VTE, etc) will increase the probability of PE; although up to 30% of patients presenting with PE have no underlying risk factors.30
  • Pulseless electrical activity: PE has been reported in up to 63% of patients presented with PEA as the initial cardiac rhythm, whereas asystole and ventricular fibrillation were responsible for 32% and 5% of the cases respectively.29
  • Presence of a clot in the right-sided heart chamber
  • DVT: Ultrasonographic evidence for DVT will increase the possibility of PE, although absence of DVT does not rule out PE.31

What does Not indicate PE as a cause of unexplained cardiac arrest?

  • While it was believed that RV enlargement during cardiac arrest on echo suggests PE, several recent studies have disproved this belief. In fact RV enlargement can be seen with other possible causes of cardiac arrest such as hyperkalemia, primary arrhythmia (VF) and this finding should Not be translated to the presence of PE.32 33 34 35

DDx of true PEA(a.k.a PRES; pulseless with a rhythm and echocardiographic standstill):36

  • Tamponade,Tension pneumothorax or hemothorax, PE
  • Acute myocardial infarction,Hyperkalemia,Sodium channel blocker intoxication
  • Hypovolemia (catastrophic bleeding such as aortic dissection, massive GI bleeding, etc)

Initial evaluation and risk stratification: primary factors

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When a patient with suspected PE presents with hemodynamic instability, physiological-based resuscitation is started promptly (more on this below) while decision is being contemplated for definitive therapy. This could range from full dose systemic thrombolytic (ST), reduced dose ST, catheter directed thrombolysis (CDL), catheter embolectomy, surgical embolectomy.

To determine the line of appropriate treatment, one should assess the risk of early cardiovascular death (PE severity). The principle of risk stratification is based on the fact that “whether the hemodynamic burden of the clot is severe enough to cause RV failure and obstructive shock.

As shown below (figure 2), risk stratification is performed by evaluating the parameters which can guide us to learn more about the hemodynamic impact of the clot.

History:

  • Syncope or near-syncope: It has been shown that patients with acute PE who presented with syncope have a higher prevalence of hemodynamic instability and RV dysfunction at presentation, and an elevated risk for early PE-related adverse outcomes.37 38

General appearance: Are there features of poor organ perfusion (shock state)?

The worrisome finding include:

  • A sense of impending doom: If the patient volunteers a sensation that they are dying, they’re often right.
  • Confusion, agitation, diaphoresis
  • Mottling
  • Cool extremities

Vital signs: Are there findings of shock (obstructive) or impending to arrest?

  • Hypotension: Traditionally, it is the pivotal parameter that defines the massive pulmonary embolism (MPE).
    • SBP < 90 mmHg for 15 minutes
    • Fall in SBP by >40 mmHg for 15 minutes
    • Requirement for vasopressors to keep SBP > 90 mmHg
  • Tachycardia (HR>120/min) and shock index (SI) >1: suggest a poor hemodynamic reserve and a worse prognosis.39 40
  • Bradycardia is the most worrisome, and may be a harbinger of impending brady-asystolic arrest (often how these patients die).3
  • Tachypnea: severely elevated RR (e.g > 30 breaths/minute)41 42

Imaging: For a clot to cause hemodynamic instability, some degree of RV dysfunction should be present. Is there evidence of right ventricle dysfunction”?

  1. Echocardiography: It provides crucially important information to risk stratify presumptive PE. In the presence of MPE; there would almost always be some evidence for right ventricular dysfunction. These parameters are graphically presented below (figure 3). Of these, an RV/LV diameter ratio ≧ 1.0 and a TAPSE <16 mm are the findings for which an association with unfavourable prognosis has most frequently been reported.3 In addition to RV dysfunction, echo can identify the presence of a clot in the right heart (CIT, clot in transit) and patent foramen ovale (PFO) and a right-to-left shunt through PFO.
    • Clot that is “in transit” through the heart is often classified as a form of PE, even though the thrombus has not yet lodged in a pulmonary artery.43 44 45 A large clot puts pulmonary circulation at danger as it is likely to break off at some point in future. It has been reported to be associated with high mortality (odds ratio of 3 for all-cause related morality and 4.8 for PE-related mortality). Generally presence of a large clot in transit moves the patient’s severity classification up by one class (e.g. a patient with an otherwise low-risk submassive PE who is found to have a large CIT would be reclassified as having a high-risk submassive PE).
    • In patients with major pulmonary embolism, echocardiographic detection of a PFO signifies a particularly high risk of death and arterial thromboembolic complications.46 A PFO also increase the risk of ischemic stroke due to paradoxical embolism in patient with acute PE and RV dysfunction.47

Diagnostic consideration(Echo):

Bedside echo is extremely useful in unstable patients with suspected high risk PE,in which the absence of echocardiographic signs of RV overload or dysfunction practically excludes PE as the cause of hemodynamic instability (Figure 1). In the latter cases, echocardiography may be of further help in the differential diagnosis of the cause of shock, by detecting pericardial tamponade, acute valvular dysfunction, severe global or regional LV dysfunction, aortic dissection, or hypovolemia.

Conversely, in an unstable patient with suspected PE, presence of a large clot-in-transit or unequivocal signs of RV pressure overload (figure 3) especially those findings which are more specific for PE (more on this here) , justify emergency reperfusion treatment for PE if immediate CTPA is not feasible in a patient with high clinical probability and no other obvious causes for RV pressure overload.

Chronic RV dysfunction may be seen in pulmonary hypertension and this should not be misinterpreted as evidence of a massive or submissive PE. Echocardiographic signs which are more suggestive for a chronic RV pressure overload may include:

  • Increased RV wall thickness (>5mm in subxiphoid view)
  • A very high tricuspid regurgitant jet velocity (>3.8 m/s or a PAP of >60mmHg)
  • Presence of pericardial effusion

In these cases, chronic thromboembolic (or other) pulmonary hypertension should be included in the differential diagnosis and if clinical suspicion for PE is high, a more comprehensive work up and imaging (CTPA, V/Q scan) is warranted.

2.Computed Tomographic Pulmonary Angiography (CTPA):

  • RV dilation
    • RV/LV ratio of ≧1.0 on CT is associated with a 2.5 fold increased risk for all-cause mortality, and with a five-fold risk for PE-related mortality.48
    • Mild RV dilation (RV/LV slightly above 0.9) on CT is a frequent finding (>50% of hemodynamically stable PE patients), and it probably has minor prognostic significance.49
      • Therefore If RV dilation on CT is equivocal, additional signs of RV dysfunction should be sought either on CT scan or echocardiography.
  • Bowing of the RV into the LV: This may be best observed in a coronal CT projection (as with echocardiography, evaluation of the heart in multiple planes may improve diagnostic accuracy).3
  • Contrast reflux into the inferior vena cava and hepatic vein: 50 51Presence of contrast reflux into IVC (figure below) is associated with increased all-cause mortality (odds ratio of 2.2).3

Diagnostic consideration (CTPA):

  • The diagnostic imaging findings in CTPA for PE is discussed separately. For the purpose of this discussion, CTPA is considered diagnostic of PE if it shows PE at the segmental or more proximal level (figure 14).
    • If there’s a high clinical suspicion for major PE in a patient with renal insufficiency, failing to get a CTPA for the fear of “contrast nephropathy” is a common mistake as such an entity probably does not exist! 52 53 (more on this here)
  • Pleural effusion in PE: In appropriate clinical context (predisposing risk factors for VTE, pleuritic chest pain), presence of pleural effusion should raise clinical suspicion for PE.54 55Nearly all pleural effusions due to pulmonary embolism are exudates, frequently hemorrhagic. The presence of bloody pleural fluid is not a contraindication for the administration of anticoagulant therapy.56

Laboratory:

  • Troponin: Elevated troponin is associated with increased mortality risk (odds ratio of 5)57 The cutoff values might be Troponin I >0.1 ng/ml or Troponin T >0.03 ng/ml.58 On their own, increased circulating levels of cardiac troponins have relatively low specificity and positive predictive value for early mortality in normotensive patients with acute PE. However, when interpreted in combination with clinical and imaging findings, they may improve the identification of an elevated PE-related risk and the further prognostic stratification of such patients.Age-adjusted high-sensitivity troponin T cut-off values (≧14 pg/mL for patients aged <75 years and ≧45 pg/mL for those ≧75 years) may further improve the negative predictive value of this biomarker.59
  • Lactate: Elevated lactate (arterial plasma levels ≧2mmol/L) reflects increased sympathetic tone and is a marker of hemodynamic stress. It predict PE-related complications, both in unselected60 and in initially normotensive PE patients.61

EKG: As the clot is lodged in the pulmonary artery, there will be a resistance to blood flow from the right ventricle. This causes strain on the right ventricle. Changes indicative of RV strain such as inversion of T waves in leads V1-V4, a QR pattern in V1, a S1Q3T3 pattern, and incomplete or complete right bundle branch block are usually found in more severe cases of PE 62and can put a patient in the submassive category.10

Impairment of RV coronary perfusion (due to the high afterload and low systemic blood pressure) can cause RV injury pattern with ST elevation in V1-V3 and/or ST depression in V4-V6.63 Another EKG finding of RV injury pattern which is reported to be associated with high in-hospital mortality rate is ST elevation in aVR and ST depression in lead I.64 65These patterns can be frequently mistaken for acute myocardial infarction.In cases of diagnostic uncertainty regarding ST elevation MI vs. PE, perform immediate bedside echocardiography.

  • ST elevation MI should cause regional wall motion abnormalities involving the left ventricle and dysfunction of the left ventricle.
  • Massive PE will cause RV dilation and usually an under-filled left ventricle (which is vigorously contracting).

Risk stratification: Overview

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Acute PE walks through a spectrum of disease severity. It can be classified into high, intermediate and low risk groups. Given the disease heterogeneity, sometimes patients do not perfectly fit into any of the following categories.

High risk PE (massive PE): The characteristic feature of MPE which distinguishes this group from the others is hemodynamic instability in the presence of RV dysfunction. Lack of RV dysfunction argues against diagnosis of acute MPE, and suggests that hemodynamic instability may be caused by another problem. It has been shown that high risk PE is associated with a mortality rate of 25-65%.66

  • A subgroup of patients with MPE are at higher risk of impending cardiovascular collapse; i.e ‘Crashing MPE’. These patients presents with typical features of impending to arrest including:
    • Requirement for a higher dose of vasopressor (e.g. norepinephrine >>8mcg/min) to keep their SBP above 90mmHg.
    • Persistent bradycardia (e.g. HR<40) with features of shock
    • Altered, mottled, cold/clammy extremities, sensing of dying
    • Patients with PE who has survived cardiac arrest (status post cardiac arrest)

Intermediate risk PE (Submassive PE): Is characterised clinically by hemodynamic stability, despite the fact that the clot burden on RV performance is significant enough to cause some degree of RV dysfunction.3 Patients with submassive PE (SMPE) can be further classified into two subgroups:

  • High risk SMPE: characterized by worrisome clinical or laboratory features such as:
    • Troponin rise, or
    • Elevated lactate, or
    • Shock index (HR/SBP)>1, or
    • Diaphoresis, Severe tachypnea (e.g. RR>30), or
    • Large CIT
  • Low risk SMPE: Other than evidence for RV dysfunction, they do not have worrisome findings.

Low risk PE: Patients with clinically stable hemodynamic profile and No evidence of RV dysfunction (on echo/CT). 3

The definition of massive and submassive PE is based on their impact on hemodynamic and RV performance. The size of the clot is irrelevant.67 However absence of large clot burden on CT is against diagnosis of massive and submassive PE. If performing CT is not possible, presence of proximal DVT, or a large clot within the right heart poses risk of further embolization and is associated with increased risk of mortality.68

Other prognostic factors (which are less useful)

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Brain natriuretic peptide (BNP) or NT-BNP:

Pressure overload on the heart is associated with increased myocardial stretch and leads to release of BNP and NT-proBNP. However it does not distinguish between right heart vs. left heart failure which makes it nonspecific test for acute RV failure. Similar to cardiac troponins, elevated BNP or NT-proBNP concentrations possess low specificity and positive predictive value (for early mortality) in normotensive patients with PE69, but low levels of BNP or NT-proBNP are capable of excluding an unfavourable early clinical outcome, with high sensitivity and a negative predictive value.70

Elevated WBC count (>12.6 x 109/L)

In a retrospective study including 14228 patients with PE, the association between the admission WBC count and 30‐day mortality and hospital readmission was examined.For patients with PE and an admission WBC count of > 12.6 ×109/L, the adjusted odds ratio for all-cause mortality was reported 2.2.71

Neutrophil / lymphocyte ratio (NLR)

Recently the neutrophil to lymphocyte ratio (NLR) has been gaining attention in many fields of medicine. This ratio reflects occult physiologic stress, because endogenous cortisol will increase the neutrophil count and reduce the lymphocyte count, thereby increasing the ratio.The NLR combines both of these changes, making it more sensitive than either alone. NLR may be elevated by any cause of physiologic stress. Therefore, this test will be predictive of PE-related mortality only in patients with isolated PE (no other active medical problems). Several meta-analysis suggest that elevated NLR may be an even stronger prognostic indicator than troponin.72 73 74 Studies used a different cutoffs, but based on available data, NLR may be interpreted in the context of acute PE as follow:

  • NLR <5.5 suggests low mortality risk (~2.7%)
  • NLR >9.2 suggests high mortality risk (~26%)
  • NLR in the range of 5.5-9.2 remains in the grey zone.

DVT:

The diagnosis of concomitant DVT has been identified as an adverse prognostic factor, being independently associated with death within the first 3 months after acute PE.75 In a meta-analysis investigating 8859 patients with PE, the presence of concomitant DVT was confirmed as a predictor of 30 day all-cause mortality (odds ratio of 1.9), although it did not predict PE-related adverse outcomes at 90 days.76Thus, concomitant DVT can be regarded as an indicator of significant comorbidity in acute PE.

Clot burden on CT:

  • At first, high clot burden is poorly defined in literature. In one study, an obstruction index on CTPA >40% was defined as a large clot burden and reported to be associated with high mortality.77The MOPPETT trial defined large clot burden as >70% involvement of the pulmonary vascular bed with embolism in ≥2 lobar arteries or main pulmonary arteries on CTPA or by a high probability ventilation/perfusion scan showing ventilation/perfusion mismatch in ≥2 lobes.78
  • However as explained earlier, the precise thrombus burden has not been shown to correlate well with the adverse outcomes. 24 25 26
  • Bottom line: Clot burden on CT can have diagnostic value in patients with hemodynamic instability, i.e. in unstable PE with small clot burden, one should consider other etiologies for hemodynamic instability such as hypovolemia and sepsis. From the standpoint of therapeutic decision making (thrombolysis vs. anticoagulation alone) clot burden on CT per se is not useful, unless other high risk features for death from PE (e.g. hemodynamic instability, worsening clinical situation, worrisome laboratory markers) were present.

Comorbidities: Patients with decreased physiologic reserve and pre-existing cardiovascular and pulmonary conditions are barely tolerant to thromboemboli. Such patients can deteriorate and become hemodynamically unstable with even smaller clots. Keep in mind that the term “massive” PE does not necessarily describe the size of the PE as much as its hemodynamic effect.79

Prediction model for assessing severity of PE: useful or not?

There are several prognostication tools (PESI80, sPESI 81Bova82 )developed for risk stratification in patients with pulmonary embolism who are hemodynamically stable. As none of these factors or scores definitively determines prognosis, clinician gestalt also plays an important role.2One study of 11 clinical prognostic models reported that although the sensitivity of some models, including PESI and sPESI, were >89%, none had a specificity greater than 48%.83 At this time, only a combination of RV dysfunction on an echocardiogram (or CTPA) with a positive cardiac troponin test has directly been tested as a guide for early therapeutic decisions (anticoagulation plus reperfusion treatment vs. anticoagulation alone) in a large randomized controlled trial (RCT) of PE patients presenting without hemodynamic instability.84

  • PESI (Pulmonary Embolism Severity Index) score& Simplified PESI score (sPESI score): PESI is currently the one that has been most extensively validated among the other clinical scores integrating PE severity and comorbidity to predict all-cause 30-day mortality. However what is most deserved in management of a patient with PE is the short term risk of PE-related hemodynamic collapse for risk stratification and appropriate decision making for treatment. Moreover, problem arises as it emphasizes more on baseline epidemiological features of the patient rather than the patient’s acute hemodynamic status, therefore an elderly with many comorbidities but a small subsegmental PE may get a high score; while a younger adult with few comorbidities but a high risk submissive PE incorrectly get a low score. According to the 2019 ESC guidelines, “Signs of RV dysfunction or elevated cardiac biomarker levels may be present, despite a calculated PESI of I-II or an sPESi of 0. Until the implications of such discrepancies for the management of PE are fully understood, these patients should be classified into the intermediate-risk category.”

Pathophysiology and determinant of outcome

(PE spiral of death)

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The primary cause of death in massive PE is cardiovascular collapse (but not the respiratory failure).85 Following hemodynamically significant PE, pulmonary arterial pressure (PAP)is increased which is attributed to predominantly two factors:

  1. Mechanical obstruction (Clot size): PAP increases if >30-50% of the total cross-sectional area of the pulmonary arterial bed is occluded by thromboembolism.86
  2. Pulmonary arterial vasoconstriction: PE-induced vasoconstriction, is mediated by the platelet activation and release of thromboxane A2 and serotonin, which contributes to the initial (first 10-30 minutes) increase in pulmonary vascular resistance (PVR) after PE.87 88This finding explains why hemodynamic manifestation of PE does not depends on the size of the clot alone (figure 6)
  3. Hypoxic vasoconstriction: Hypoxemia causes vasoconstriction in the affected lung area.89

The right ventricle is not well-adapted to this new set of high-pressure system, and therefore despite compensatory mechanisms, it fails to provide left ventricle preload and consequently systemic arterial pressure drops (figure 7).90 91

The key point to understand the PE viscous cycle is RV perfusion. The right ventricle is perfused by the right coronary artery during both ventricular systole and diastole. Perfusion pressure within the right coronary artery is equal to (aortic pressure minus pulmonary arterial pressure). The rising pulmonary arterial pressure initially impairs RV perfusion during diastole (causing RV ischemic injury). Later on as systemic blood pressure falls below critical level, RV perfusion is further insulted during ventricular systole as well (more on this here).

The respiratory failure in PE is predominantly a consequence of hemodynamic disturbances.3 92Understanding the pathophysiology of gas exchange interference in PE is helpful for rationalizing the respiratory therapeutic measures which will be explored later.

Massive PE: Due to the obstructed flow, blood cannot reach to the well-ventilated alveoli. This will create units with dead space ventilation (wasted ventilation). The direct consequence of wasted ventilation is increased PCO2 in pulmonary capillaries.

Clinical pearls:

  • In MPE, the respiratory acidosis (hypercapnia) is not corrected by measures such as increasing the respiratory rate or tidal volume, since blood flow does not even reach to alveoli for gas-exchange.
  • In MPE, the pulmonary artery CO2 goes up, while the alveolar CO2 goes down. If one can measure end-tidal CO2 it will show a low reading.93
    • End-tidal CO2 gradient is calculated as {arterial CO2 minus end-tidal CO2}.A high gradient (although nonspecific) can be suggestive for pulmonary embolism during cardiopulmonary resuscitation.94

Subsegmental, peripheral PE: As explained above, PE causes units with dead space ventilation. The body intuitively redirects the blood flow from non-perfused units (dead space units) into well perfused areas.These areas are flooded with blood flow resulting in overall (↓V/Q) and hypoxemia. In this situation, hypoxemia responds to 100% FiO2.95

How unresponsive hypoxemia in PE can be explained? Severe unresponsive hypoxemia always reflects some sort of shunts.

In MPE, shunt physiology can happen via the following mechanisms (100% FiO2 cannot ideally correct low arterial oxygen saturation):

  • PFO: Skyrocketing right-side heart pressure can lead to open foramen ovale and thereby creating right-to-left shunt.3
  • Atelectasia: When a saddle PE breaks off, the smaller clot fragments move distally. Such distal micro-emboli evokes inflammation which causes localized bronchoconstriction, and if severe enough, will cause atelectasia (shunt units). 96
  • Alveolar edema: As unobstructed pulmonary vascular beds receive the redirected blood from poorly perfused units, the pulmonary capillaries (and endothelial cells) within these overperfused areas are injured, and therefore alveolar edema will develop (shunt units).

In subsegmental, peripheral PE: development of atelectasis or pulmonary edema (as explained) can create shunt units (though uncommon).

Initial resuscitation of high risk PE

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Acute RV failure with resulting low systemic output is the leading cause of death in patients with high-risk PE. Arguably definitive treatment of thromboembolic disease involves pharmacological or mechanical removal of the clot, however institution of such treatment often takes time. Meanwhile the focus of resuscitation should be on hemodynamic support, and oxygenation.The principles of acute right heart failure management have been explored previously (more on this here). In the following discussion the key points are reviewed.97 98

  • Avoid unnecessary lines, and ABG:
    • Patients with massive PE will often require thrombolysis. Minor vascular trauma that occurs when placing an arterial or venous line may become a real problem after giving thrombolytics. Thus, unnecessary lines or ABG sticks should be avoided. Peripheral lines are fine for short-term use of most vasopressors. An ABG or VBG is exceedingly unlikely to change management.
    • If lines do need to be placed, they should be inserted with extreme care by the most experienced operator with extreme care.For example, a central line should ideally be placed on the first entry into the vessel.
  • Avoid Intubation:
    • Patients with RV failure are frequently hypotensive or are highly susceptible to the development of severe hypotension during induction of anaesthesia, intubation, and positive-pressure ventilation (as positive pressure within the chest reduces the preload).3 97 Accordingly Intubation often precipitates cardiac arrest.
    • If you can’t avoid intubation, the following measures are taken to reduce the risk of cardiac arrest:
      • Correct hypotension. Try to target for a higher SBP in the range of 130-140mmHg usually with push dose pressor. This will provide a safe margin, if the pressure falls following intubation.
      • Preoxygenate: hypoxemia causes pulmonary vasoconstriction, further worsening the RV afterload.
      • Correct acidosis and hypercarbia: The hypercarbia and respiratory acidosis in patients with MPE is due to the dead space ventilation. Therefore efforts to over-vigorous bag ventilation or increasing the respiratory rate and tidal volume on mechanical ventilator are futile. Inhaled pulmonary vasodilator can improve the underlying pathophysiology. Consider getting inhaled pulmonary vasopressors at the bedside and ready to be given.
      • Use cardiostable sedatives (e.g. ketamine)
      • Intubation: Let it be done by the most experienced operator. Employ apneic oxygenation.
      • After the intubation: Avoid over-vigorous bag ventilation, set for the lowest PEEP on mechanical ventilator, use tidal volume of <6ml/kg lean body weight used in an attempt to keep the end-inspiratory plateau pressure <30 cm H2O. Pay attention to hemodynamic and oxygenation especially within 10-15 minutes after intubation.
      • More comprehensive lecture (here)
  • Employ fluid-conservative strategy: ‘By enlarge MPE isn’t a fluid-depleted state”
    • In the presence of RV outflow tract obstruction (e.g. MPE), volume loading has the potential to over-distending the RV and ultimately cause a reduction in systemic cardiac output.98 Avoid fluid boluses unless the patient has frank clinical evidence of volume loss (e.g. watery diarrhea! GI bleeding) or a small IVC with respiratory collapsibility of > 70% is seen.
      • Note that small IVC almost never occurs in the presence of MPE, unless the patient is volume depleted otherwise the diagnosis of MPE is under question.
  • Pressor-aggressive strategy: “Protect right heart perfusion pressure”
    • Patients with right heart failure are extremely intolerant to low systemic blood pressure.Right heart coronary perfusion occurs during both ventricular systole and diastole. The diastolic phase of perfusion is already impaired due to the high pulmonary arterial pressure, hence making the right heart perfusion more contingent upon the systolic phase.
    • Keep MAP reasonably above 60-65mmHg. The agent of choice would be the one with optimal systemic vasopressor activity while having the least pulmonary vasoconstriction effect (↓PVR/SVR). Norepinephrine, epinephrine99 and vasopressin100 administration are recommended.
  • Optimize oxygenation, correct hypercarbia and acidosis
    • Hypoxemia has a vasospastic effect on the pulmonary vessel. Administration of supplemental oxygen is indicated in patients with PE and SO2<90%. Oxygenation technique includue high-flow oxygen (i.e. a high-flow nasal cannula) and mechanical ventilation (non-invasive or invasive) in cases of extreme instability (i.e. cardiac arrest).
    • Although hypoxemia is one of the features of massive PE, a severe hypoxemia/respiratory failure that is refractory to conventional oxygen supplementation should make one to consider one of the following possibilities:
      • Right-to-left shunting of blood through a patent foramen ovale (PFO) or atrial septal defect. Massive PE can cause elevation of right-sided pressures contributing to right-to-left shunting of deoxygenated blood.101
      • Another coexistent pulmonary process (e.g. pneumonia, pneumothorax).
    • Hypercarbia and acidosis cause pulmonary vasoconstriction. Strategies that decrease pulmonary vascular resistance may include inhaled nitric oxide, epoprostenol, nitroglycerine, and milrinone. Suggested dosage include:
      • Epoprostenol at 0.05mcg/kg/min
      • Nitric Oxide at 20ppm102
      • Milrinone (1mg/ml), inhale 5mg over 15 minutes103
      • Nitroglycerin (1mg/ml), inhale 5mg over 15 minutes.See more on this here: PULMCrit: Nebulized nitroglycerin

Anticoagulation

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The benefit of early therapeutic anticoagulation to improve mortality and decrease recurrence in acute PE is well proven.104Anticoagulation should be initiated even prior to the confirmed diagnosis when there is high clinical suspicion of acute PE and the bleeding risk is low, particularly if results of diagnostic tests are expected to be delayed.3 Keep in mind that anticoagulant prevents additional clot from forming, but it doesn’t break down the existing clot.

Selection of the initial anticoagulation agent is dependent on many factors, including risk stratification, patient clinical factors (eg, hepatic and renal function and bleeding risk), and clinician judgment.

  • Intermediate and high-risk PE:2 Most of these patients require advanced therapies (e.g. thrombolysis) and therefore unfractionated heparin (UFH) may be the preferred agent since it can be stopped if the patient begins bleeding, and also can be down-titrated in anticipation of thrombolysis or procedures.It is also recommended for patients with serious renal impairment [creatinine clearance (CrCl) ≦ 30 mL/min] or severe obesity.The dosing of UFH is adjusted based on the activated partial thromboplastin time (figure 10).105
  • Low risk PE: The low molecular weight heparins (LMWH) is preferred as it has been shown to be associated with a lower risk of major bleeding106 and heparin-induced thrombocytopenia.107It does not require routine monitoring of anti-Xa levels.If LMWH is prescribed in patients with CrCl 15-30 mL/min, an adapted dosing scheme should be used (figure 9).

Systemic thrombolysis: Background

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Mechanism of action: Thrombolytic agents activate plasminogen to form plasmin, which accelerates lysis of thromboemboli (figure 11).Generally the clinical improvement is noted within the first hour of infusion.Despite the short half life of most thrombolytic agents, fibrinolytic activity persists for approximately 1hr after infusion is terminated.

Side effects: Systemic thrombolytics challenge the hemostatic balance in the patients. Bleeding is the major complication with variable rate among individuals, depending on the pharmacologic properties of the thrombolytic agent used, the administration protocol and patients susceptibility to bleeding. The small fragments generated from fibrin degradation have anticoagulant activity108 and these will circulate for several hours in plasma, making patients susceptible to bleeding for several hours.

Variability in response to thrombolytics: The balance between fibrin generation and fibrinolysis is complex, dynamic and unique for every patient. That is to say, some patients are highly sensitive to thrombolysis whereas other patients are resistant.109 110

Thrombolytic in PE: Thrombolytics were primarily and more extensively used for ischemic stroke and acute myocardial infarction, with relatively far less evidence for its application in patients with PE. It seems that the contraindication for the lytics as well as its dosage are borrowed from thrombolysis for stroke and myocardial infarction.

Why trials on systemic thrombolytic therapy in PE show conflicting data? The limitation on these trials comes from the following:

  • Small sample size and patient crossover between the groups.
  • Including variable populations of patients (heterogeneous groups, and age) with variable severity of PE (stable and unstable).
  • Variable methods of administration and dosing of thrombolytic agents will limit generalizability between studies.
  • Studies often overlap thrombolysis and anticoagulants (e.g. heparin) in a dangerous fashion, with subsequent attribution of bleeding events to the thrombolytic agent!!

What is consistent finding among the studies?

  • Lytic in MPE is life saving: Thrombolytic therapy in unstable PE results in early hemodynamic improvement. It speeds up clot resolution and improvement in pulmonary obstruction, pulmonary arterial pressure, pulmonary vascular resistance, right ventricle and pulmonary perfusion.These improvements are accompanied by a reduction in RV dilation on echocardiography. The use of thrombolysis for massive PE is widely accepted as the standard of care. This has been shown to reduce mortality and PE recurrence compared to anticoagulation alone.111 112 113
  • Lytic does not cut down development of long-term complication: Traditionally it was believed that thrombolysis would reduce the risk of chronic thromboembolic pulmonary hypertension and thereby improve long-term functional endpoints (e.g dyspnea), however the long-term results of the PEITHO trial convincingly disproved this.114 At this time, the primary reason to use thrombolysis is to reduce the risk of cardiac arrest.

Where is the most controversial area in PE management?

  • There is still controversy regarding the optimal management strategy for intermediate high risk PE.

Decision making on institution of thrombolytic

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Decisions should be made following thorough evaluation of risk of death from PE vs. risk of bleeding from thrombolytics (figure 12). For example in a patient who is actively dying from PE and has absolute contraindication for thrombolysis, err on the side of systemic thrombolytic administration if other methods are not immediately available for clot resolution. On the other hand, in patients with low intermediate risk of PE with relative contraindication of bleeding and in the absence of worrisome clinical findings, it might be reasonable to postpone thrombolytic therapy, pending the clinical deterioration of the patient. Because the decision to administer thrombolysis is difficult, most experts consider early involvement of PERT (Pulmonary embolism response team); if available. It involves a multidisciplinary approach that comprises a team of experts including pulmonologists, cardiologists, thoracic surgeons, interventional radiologists, emergency department physicians, and pharmacists.2

Once decision has been made for administration of thrombolytic, the method of administration (e.g. catheter-directed versus systemic) and dosing (full or reduced-dose; infusion versus bolus) depends on a delicate balance between the patient’s clinical and hemodynamic status and individualized risks of bleeding, available expertise, and extent of the emboli (figure 14).

Other treatment modalities such as interventional radiology (catheter directed thrombolysis, percutaneous mechanical thrombectomy) and surgical embolectomy will be discussed separately.

Calculation of risk-benefit:

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Although the exact numbers are debatable, in the following discussion the calculation of risk-benefit is explained more. If we approximate the risk of intracranial hemorrhage 1% in a patient with PE whose short-term risk of cardiac arrest and death is > 5%, then patient should benefit from thrombolysis as:

  • Risk of ICH 1%
  • Reduction in the rate of cardiac arrest via thrombolytic is 50% (odds ratio = 0.45, number needed to treat = 10)112 116
  • Therefore in our patient with 5% risk of cardiac arrest, thrombolysis will reduce the risk of cardiac arrest to < 2.5%

Monitoring and coordinating thrombolytic and anticoagulants

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During thrombolytic infusion, patients should be monitored closely for stability, clinical signs of improvement, development of neurological signs, and for hemodynamic or clinical signs of bleeding.

  • Avoid unnecessary lines and ABGs if administration of thrombolytic is contemplated.
  • Preferentially stop all anticoagulants (e.g UFH) before institution of thrombolytic especially in non-crashing patients.
  • Complication during thrombolytic infusion:
    • Minor bleeding during thrombolytic therapy is common and is not generally an indication to stop therapy. Minor bleeding may include bleeding at compressible sites (epistaxis or wound) or bleeding that is not hemodynamically significant (minor GI bleeding, or minor genitourinary tract bleeding) and is not at critical sites. Thrombolytic therapy may cause moderate bleeding in menstruating women, but it has been rarely associated with major hemorrhage. Therefore, menstruation is neither a contraindication to thrombolytic therapy nor to stop the infusion.
    • Major bleeding is an indication for immediate discontinuation of infusion and treatment of bleeding. Bleeding is considered major if it occurs at a critical site (e.g. ICH); is not easily accessible, and/or hemodynamically significant one which requires PRBC transfusion.117
  • UFH can be reinstituted (Without a Bolus) after infusion of thrombolytic is completed, once aPTT results came back and is below 1.5-2.0 times the normal and ideally fibrinogen level is above 100-150 mg/dL.

Thrombolytic for MPE (first or recurrent event):

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The decision to administer systemic thrombolytic in patients with unstable PE is relatively straightforward. Hemodynamic instability is the only widely accepted indication for full dose systemic thrombolytic in the absence of absolute contraindications. In the presence of absolute contraindications, other therapeutic methods such as catheter directed therapies (with/without thrombolysis or suction) or surgical embolectomy may be considered if available. However if the patient is actively dying, and none of the alternative options are available, one may choose low dose systemic thrombolysis as “Alteplase 50mg IV over 2hr” (Wang,Chest, 2010)118

Thrombolysis for High Risk Submassive PE:

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Several reports have suggested that systemic thrombolysis reduces the risk of clinical decompensation compared to anticoagulation alone.119 120 121 At this time most experts contemplate thrombolysis for ‘high risk SMPE’ following a thorough risk stratification and weighting benefit to risk of treatment in addition to patient’s preferences and values.

  • Reduced dose systemic thrombolysis: There’re bodies of evidence that shows reduced dose systemic thrombolysis works! the trend in management of high risk submassive PE is shown below:
  • A randomized trial comparing full-dose to reduced-dose systemic thrombolytic in patients with intermediate or high-risk PE demonstrated similar improvements in a host of surrogate end points including metrics of RV dysfunction or PA pressure change with small differences in bleeding, favoring the reduced-dose strategy.122
  • Reduced dose systemic thrombolytic may be considered in select patients with intermediate-high risk PE and who have low risk of bleeding.2 123

Low risk PE: Systemic thrombolysis is not recommended for clinically stable patients with minor RV dysfunction or minor myocardial necrosis (figure 14).2

Integrated risk-adapted diagnostic and management algorithm for pulmonary embolism (in adult, non-pregnant patients)

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Special situations

Right-heart thrombus (RHT) or clot-in-transit (CIT)

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There are several discrete muscular ridges or bands in the right heart, which sometimes are mistaken for tumor or thrombi (more on this here). However a large clot in transit is fairly unmistakable (figure 15). Clot in transit defined as a large, mobile (i.e unattached to any intracardiac structure), serpentine echogenicity trapped in the right heart chambers. It has been shown that large CIT is associated with increased mortality124 and will move the patient’s severity classification up by one class.

Figure 15. Large,mobile,snake-like clot in the right atrium. Courtesy of M.Chardoli, MD

In the absence of a patent foramen ovale (PFO) treatment is similar to PE (with the increased severity classification taking into account) 2

  • In the absence of contraindication for thrombolysis, systemic thrombolysis has been shown to improve the patient’s survival. 125 126
  • In the presence of contraindication, patients might benefit from IR clot extraction.

In the presence of PFO and clot-in-transit (figure 16), there’s a significant risk of paradoxical embolization into arterial circulation with risk of stroke.In this situation,thrombolysis is relatively contraindicated as it may breaks off the clot and precipitate arterial embolization.127 These patients are better suited to surgical removal of the clot. 128

PE in cardiac arrest

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Thrombolytics therapy has been reported to increase the rate of return of spontaneous circulation (ROSC) and survival (with survival >50%).129 130 131however a few consideration shall be made here:

  • Avoid measures that increase intrathoracic pressure: avoid over-aggressive bagging (explained earlier).
  • Epinephrine: Patients with PE in cardiac arrest frequently gain pulse and then re-arrest. If the patient regains a pulse after an epinephrine bolus, promptly consider to start a high-dose epinephrine infusion (e.g. 20 mcg/min, then titrate based on blood pressure). These patients often seem to re-arrest after the epinephrine bolus wears off.
  • Thrombolysis: Patients should receive thrombolysis regardless of their contraindications unless immediate VA-ECMO is available. The coding dose of alteplase is 50mg IV push over 60 seconds (from the “PEAPETT” Study)129, which may repeat after 15 minutes if ROSC is not established.
  • Extended CPR: Consider extended CPR (e.g. 60-90 minutes) to provide time for thrombolytic to circulate.132
  • Inhaled pulmonary vasodilator: Consider administration of any pulmonary vasodilator available via the endotracheal tube (e.g. nitric oxide, epoprostenol, or milrinone) to reduce RV afterload.

Refractory hypoxemia

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Severe refractory hypoxemia may rarely occur in the absence of hypotension and while such cases do not neatly fit in intermediate or high-risk PE categories, a few points should be considered here:

  • Refractory hypoxemia (explained earlier) oftentimes reflects some degree of shunt. The differential diagnosis may include:
    • Right-to-left shunt via PFO (PE increases right-sided pressure and contributes to right-to-left shunting)133
    • Coexistent pulmonary disease such as pneumonia
  • TTE with injection of agitated saline is the method of choice for determining the right-to-left shunting. Chest CT may be helpful to identify other coexistent etiologies.
  • Treatment of PE-related right-to-left shunting:
    • Oxygenation: High flow nasal cannula with 100% FiO2 is the first line for improving oxygenation. Keep in mind that intubation with positive pressure ventilation will not improve the condition and may make it worse (by increasing right-sided heart pressure, it may increase the shunt fraction).
    • Inhalational pulmonary vasodilators: Improve both hemodynamic and oxygenation via decreasing RV afterload and improving shunt fraction.
    • Thrombolytic treatment: in the absence of absolute contraindication, systemic thrombolytic treatment is potentially considered. Other methods such as catheter directed thrombolysis or embolism extraction by interventional radiology are suitable options in patients with risk of bleeding.

Going further

Post Peer Reviewed By: Mojtaba ChardoliMD, Darab Zohri. MD

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Shahriar Lahouti

Founder, Chief Editor
I am Shahriar Lahouti and RECAP EM is my primary FOAMed project. The philosophy of RECAP EM is to promote critical thinking and enlightening the mindsets with most rational, current evidence towards a safer practice.

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