Pulmonary embolism

Pulmonary Embolism
Acute PE can be classified as massive or submassive:
  • Massive PE causes hypotension, defined as a systolic blood pressure <90 mmHg or a drop in systolic blood pressure of ≥40 mmHg from baseline for a period >15 minutes. It should be suspected anytime there is hypotension accompanied by an elevated central venous pressure (or neck vein distension), which is not otherwise explained by acute myocardial infarction, tension pneumothorax, pericardial tamponade, or a new arrhythmia.  The physiological effect of massive pulmonary embolism is such that resulting right ventricular failure may lead to compromised left ventricular preload, which may be life-threatening
  • Sub massive PE is all acute PE not meeting the definition of massive PE, usually with RV dysfunction or myocardial necrosis. If none are present, it is usually a low risk PE.
  • Saddle PE is a PE that lodges at the bifurcation of the main pulmonary artery into the right and left pulmonary arteries.
Prognosis:
  • Patients with RV dysfunction have increased mortality.
  • An elevated brain natriuretic peptide (BNP) predicts RV dysfunction and mortality
  • Elevated serum troponin levels are associated with an increased risk of death in patients with PE
  • An elevated lactate level at presentation is associated with increased mortality.
  • A simplified PESI ( pulmonary embolism severity index) assigns one point for each of the following variables: age >80 years, a history of cancer, chronic cardiopulmonary disease, a heart rate ≥110 beats per minute, a systolic blood pressure <100 mmHg, and an arterial oxyhemoglobin saturation <90 percent. A total point score of zero indicates a low risk for mortality, while a score of one or more indicates a high risk.
  • When obstruction of the vascular bed approaches 75 percent, the right ventricle must generate a systolic pressure in excess of 50 mmHg and a mean pulmonary artery pressure approximating 40 mmHg to preserve pulmonary perfusion. The normal right ventricle is unable to accomplish this and may eventually fail.
Etiology:
Risk factors include immobilization, surgery within the last three months, stroke, paralysis, central venous instrumentation within the last three months, malignancy, OC pills, Cirrhosis, inherited thrombophilia, chronic heart disease, autoimmune diseases, and a history of venous thromboembolism. Additional risk factors identified in women include obesity (BMI ≥29 kg/m2), heavy cigarette smoking (>25 cigarettes per day), and hypertension.
 
Pathophysiology:
With pulmonary vascular bed obstruction, there is decreased oxugenation with resultant hypoxia and pulmonary vasoconstriction. There is increased pulmonary vascular resistance leading to right heart failure and possibly obstructive shock. There can also be an increased dead space with a resultant pulmonary vasocontriction to optimise gas exchange. 
 
Clinical presentation:
  • The most common symptoms were sudden onset dyspnea, pleuritic pain, cough, >2-pillow orthopnea, calf or thigh pain, calf or thigh swelling, and wheezing.
  • The most common signs were tachypnea, tachycardia, rales, decreased breath sounds, an accentuated pulmonic component of the second heart sound, and jugular venous distension.
Diagnosis:
  1. Modified Wells Criteria include the following :
    1. Clinical symptoms of DVT (3 points)
    2. Other diagnoses less likely than PE (3 points)
    3. Heart rate >100 (1.5 points)
    4. Immobilization ≥3 days or surgery in previous four weeks (1.5 points)
    5. Previous DVT/PE (1.5 points)
    6. Hemoptysis (1 point)
    7. Malignancy (1 point)
  • Modified wells score of >4 indicates that PE is likely and <4 indicates that PE is unlikely.
  • Patients classified as PE unlikely should undergo D-dimer testing and PE can be excluded if the D-dimer level is <500 ng/mL or negative.
  • Patients classified as PE likely and patients classified as PE unlikely but have a D-dimer level >500 ng/mL should undergo CT-PA.
  1. Lab abnormalities: Routine laboratory findings are nonspecific. They include leukocytosis, an increased ESR, and an elevated serum LDH or AST (SGOT) with a normal serum bilirubin.
  2. ABGs usually reveal hypoxemia, hypocapnia, and respiratory alkalosis. Typical findings of PE are not always seen.
  3. Brain natriuretic peptide (BNP) levels may be elevated.
  4. Serum troponins are elevated in 30 to 50 percent of patients who have a moderate to large pulmonary embolism.
  5. EKG may show S1Q3T3 pattern ( S wave >1.5mm, Q wave in lead III and aVF), right ventricular strain, new incomplete right bundle branch block and P-wave pulmonale
  6. D-dimer level <500 ng/mL is sufficient to exclude PE in patients with a “low pretest probability” of PE. It can be false positive in patients with cancer, infection, trauma and inflammatory diseases.
  7. V/Q Scan: A normal V/Q scan virtually excludes PE. However, it is not a reliable test if chest x ray is not normal to begin with. 
  8. Spiral (helical) CT scanning with intravenous contrast is the test of choice, if pretest probability is high. ( Not D-dimer)
PE rule out criteria (PERC) is a useful clinical decision rule to help rule-out pulmonary embolism in patients with low risk. These include
  1. age < 50 years
  2. heart rate less than 100 beats per minute. (pts on beta blockers are excluded)
  3. room air oxygen saturations 95% or greater ( Chronic hypoxia is excluded)
  4. no prior deep venous thrombosis [DVT] or PE
  5. no recent trauma or surgery (4 weeks)
  6. no hemoptysis
  7. no exogenous estrogen
  8. no clinical signs suggestive of DVT (Unilateral leg swelling on visual inspection. (Obese pts are excluded)
A complete negative on 8 of the above has less than 2% chance of PE and hence, do not order any further workup. Excluded patients include cancer and thrombophilia.
 
Investigations:
  1. Ultrasound of lower extremities is warranted in all patients with PE. Around 20-30% of distal DVT’s migrate to lungs but more than 50% of proximal DVT’s come from calf veins.
  2. ECHO is indicated to look for RV strain and pulmonary artery pressure. In acute PE, pulmonary artery pressures should be normal as it doesn’t have enough time to develop hypertrophy and thereby increasing pressures.
  3. Hypercoagulable states: The most frequent causes of an inherited hypercoagulable state are the factor V Leiden mutation, Activated protein C resistance (APC resistance) and the prothrombin gene mutation, which together account for 50 to 60 % of cases. Defects in protein S, protein C, antithrombin deficiency, lupus anticoagulant , homocystenemia or antiphopholipid antibody account for most of the remaining cases, while a rare cause is one of the dysfibrinogenemia.
Protein C and S levels are decreased in acute thrombosis and warfarin therapy. Antithrombin levels are decreased in acute thrombosis and heparin therapy. Hence, checking these in acute thrombosis may not be quite useful. However, normal levels rules out deficiency. 
 
Treatment:
  1. Respiratory support — Supplemental oxygen should be administered if hypoxemia exists. In view of high PA pressures with a failing right ventricle, avoid any positive pressure ventilation if possible, due to risk of worsening hemodynamics. Intubation should be the last resort. HFNC can be a reasonable option. 
  2. Hemodynamic support — Hypotension may be roughly defined as SBP <90 mmHg or a drop in SBP of ≥40 mmHg from baseline, but the precise thresholds that warrant hemodynamic support depend to some degree upon the patient’s baseline blood pressure and whether there is clinical evidence of hypoperfusion (eg, change in mental status, diminished urine output). Although intravenous fluids are used as the first-line therapy, they should be administered cautiously because increased right ventricular (RV) wall stress can decrease the ratio of RV oxygen supply to demand. In an already failing right ventricle, excess volume could be detrimental. Vasopressors/Inotropes should be considered if BP is not rapidly restored. Considering starting vasopressors early to maintain adequate perfusion pressures. Norepinephrine causes venoconstriction thereby increasing preload, improve inotropy, and increase mean arterial pressure.  Levophed is a good choice in RV failure. Ann Am Thorac Soc. 2014 Jun;11(5):811-22Epinephrine may be superior to norepinephrine because it has stronger inotropic activity and causes pulmonary vasodilation due to beta-2 agonist activity. Chest. 1993 Jul;104(1):300-2.
In a normotensive patient with RV dilation from acute PE, diuretics instead of fluids improved shock index, systolic blood pressure, renal function, oxygenation, and reduction in RV dilation. Circ J. 2013;77(10):2612-8. Epub 2013 Jul 13
  1. Anticoagulant therapy — Empiric anticoagulation is indicated when there is no risk for bleeding and there is a high suspicion of acute PE, a moderate suspicion for acute PE and the diagnostic evaluation is expected to take longer than four hours, or a low clinical suspicion for acute PE and the diagnostic evaluation is expected to take longer than 24 hours. Although they are not thrombolytic, these drugs allow the fibrinolytic system to function unopposed, ultimately decreasing the thromboembolic burden.
LMWH or subcutaneous fondaparinux is preferred over UFH for most hemodynamically stable patients with acute PE.  IV UFH is appropriate when there is persistent hypotension due to acute PE (i.e. massive PE), an increased risk of  bleeding, or concern about subcutaneous absorption (eg, morbid obesity), as well as when thrombolysis is being considered.
 
Long term oral anticoagulants approved for DVT/PE include warfarin, Factor Xa inhibitors like rivaroxaban (Xarelto), and direct thrombin inhibitors like Dabigatran (Pradaxa).
  1. Thrombolytic therapy — Persistent hypotension or shock (ie, a systolic blood pressure <90 mmHg or a decrease in the systolic blood pressure by ≥40 mmHg from baseline) due to acute PE is the only widely accepted indication for Thrombolysis.
The following are situations during which clinicians typically contemplate thrombolysis:
  • Severe hypoxemia
  • Right ventricular dysfunction ( RV dilation or RV systoilic dysfunction ) 
  • Extensive embolic burden on computed tomography
  • Large perfusion defect on ventilation-perfusion scans
  • Free-floating right atrial or ventricular thrombus
  • Patent foramen ovale
  • Cardiopulmonary resuscitation
Contraindications to systemic thrombolytic therapy in acute PE include an intracranial neoplasm, recent (i.e. <2 months) intracranial surgery or trauma, active or recent internal bleeding during the prior six months, history of a hemorrhagic stroke, bleeding diathesis, severe uncontrolled hypertension (i.e., systolic blood pressure >220 mmHg or diastolic blood pressure >110 mmHg), nonhemorrhagic stroke within the prior two months, surgery within the previous ten days, and thrombocytopenia (i.e. <100,000platelets/mm3).
 
Unnecessary invasive procedures (particularly arterial punctures) should be minimized while thrombolytic therapy is being considered. An activated partial thromboplastin time (aPTT) should be measured when infusion of the thrombolytic therapy is complete. Heparin should be resumed without a loading dose when the aPTT is less than twice its upper limit of normal.
  1. IVC filters — Placement of an IVC filter is generally considered in patients who have contraindications to anticoagulation, failed anticoagulation, or developed a complication due to anticoagulation. In addition, IVC filter placement is often considered when the hemodynamic or respiratory compromise is severe enough that another PE may be lethal. 
However, the only absolute indications for IVC filter are contraindication to therapeutic anticoagulation or failure of anticoagulation when there is acute proximal DVT.
 
Other situations in which the placement of an IVC filter is controversial include: a compromised pulmonary vascular bed due to an embolic event, such that another embolic event would be poorly tolerated orproximal DVT in a patient with poor cardiopulmonary reserve or DVT in a patient who has a high risk of bleeding. Routine placement of IVC filters in every PE should be strongly discouraged. 
  1. Catheter directed thrombolysis ( EKOS) : usually performed by interventioanl radiology. During catheter-assisted thrombolysis treatment, a catheter is advanced to pulmonary artery to the location of the blood clot. The catheter will deliver continuous low dose tPA @0.5 – 1mg/hr for 15-20 hours, along with a fixed low dose heparin drip. EKOS device will also simultaneously deliver ultrasound energy to mechanically dislodge clot by agitating fibrin fibres inside the clot and loosen up the clot. Mainly considered in patients with high risk of bleeding. However, in patients who do not have any contraindications to systemic tPA, there is no significant benefit to catheter guided thrombolysis. 
ULTIMA Study: When compared with heparin alone in PE with RV dysfunction, catheter directed thrombolysis was superior in reversing RV dilation at 24 hours. Circulation. 2014 Jan 28;129(4):479-86
 
SEATTLE II Study: Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis of 1mg/hr for 24 hrs decreased RV dilation, reduced pulmonary hypertension, decreased anatomic thrombus burden, and minimized intracranial hemorrhage in patients with acute massive and submassive PE. JACCCardiovasc Interv. 2015 Aug 24;8(10):1382-92  
    
In studies comparing catheter directed thrombolysis with and without ultrasound, there were no differences in the resolution of clot, rasing questions about the utility of ultrasound in EKOS guided therapy. However, these studies did show the benefit of localized tPA though.Circ Cardiovasc Interv. 2015;8(1) Vascular and Endovascular Surgery 2016, 50 (6): 405-10 ,  Chest. 2015 Sep;148(3):667-73.
 
  1. Embolectomy — Embolectomy should be considered when a patient's presentation is severe enough to warrant thrombolysis (eg, persistent hypotension due to acute PE), but thrombolytic therapy either fails or is contraindicated. 
  2. Inhaled NO: Much of the elevation in pulmonary vascular resistance (PVR) is actually be due to pulmonary vasoconstriction due to vasoactive mediators (i.e., thromboxane and serotonin) rather than mechanical obstruction. Inhaled nitric oxygen is short-acting and doesn’t cause systemic vasodilation. So it is a safe and reasonable option, if other interventions are failing. Respir Care. 2012 Mar;57(3):444-8.
Complications:
  1. Early — the presence of shock or hypotension remains the principal prognostic clinical marker which clearly indicates high risk of death, prompting the treating clinician to consider a more aggressive therapy than heparin, such as thrombolytics.
  2. Late — Pulmonary hypertension is a consequence of acute PE. Some patients have persistent or worsened elevation of their right ventricular systolic pressure six months after their acute PE, suggesting pulmonary hypertension. This was frequently accompanied by dyspnea at rest and/or exercise intolerance.
Clinical Trials:
  1. Thrombolytics in sub acute PE (MOPPETT trial): It mainly assessed the PH and recurrent PE after 28 months. This randomized trial suggests that “safe dose” thrombolysis is safe and effective in the treatment of moderate PE, with a significant reduction in the pulmonary artery pressure and recurrent PE that was maintained at 28 months.  Moderate PE is defined as pulmonary angiographic involvement of >70% involvement of thrombus in >2 lobar or left or right main pulmonary arteries. 
In this study, initially unfractionated heparin was given at 70 U/kg as a bolus but not to exceed 6,000 U, with subsequent dose adjustment to keep the activated partial thromboplastin time at 1.5 to 2 times the baseline value. Although tPA was infused, the maintenance dose of unfractionated heparin was kept at 10 U/kg/hour and not to exceed 1,000 U/hour. At 3 hours after termination of thrombolysis, the dose of unfractionated heparin was increased to 18 U/kg/hour.
 
In the present study, dose of tPA is 50mg, which was given as a 10-mg bolus by an intravenous push within 1 minute followed by infusion of the remaining 40 mg within 2 hours. For those weighing <50 kg, the total dose was calculated as 0.5 mg/kg, which was given as a 10-mg initial bolus followed by the remainder within 2 hours.
 
This study demonstrated that half-dose thrombolytics (50 mg tPA) might safely reduce the rate of recurrent PE and late-onset pulmonary hypertension in intermediate risk pulmonary embolism.  (Am J Cardiol. 2013 Jan 15;111(2):273-7)
 
  1. Thrombolytics in sub acute PE (PEITHO study):
This study assessed the mortality benefit and complications of tPA in sub massive PE. Even though fibrinolytic therapy prevented hemodynamic decompensation, it increased the risk of major hemorrhage and stroke.
 
Submassive PE is defined as patients who were normotensive, but had right ventricular dysfunction on echocardiogram and elevated troponin. Patients with intermediate-risk (“submassive”) pulmonary embolism received a single bolus of 30-50 mg of tenecteplase along with heparin infusion. (This dose should be considered a full dose of tPA: 50 mg of tenecteplase is the standard dose in the package insert. The half-dose in MOPPETT was 50 mg of alteplase, whose standard dose is 100 mg).
 
At 7 days, patients receiving tenecteplase had lower composite end point of  death or shock vs. those treated with heparin alone (~3% vs. ~6%). Most of this difference was in the rate of shock, not death. Patients getting tenecteplase also had half the rate of mechanical ventilation. However, after one month, mortality was similar (2.4% vs. 3.2%, nonsignificantly favoring tPA).
 
Please note that extra cranial bleeding occurred in 6.3% in the tenecteplase group vs. 1.2% in the placebo group. Stroke occurred in 2.4% in the tenecteplase group vs. 0.2% in the placebo group. (N Engl J Med 2014; 370:1402-1411)
  1. MAPPETT Study: In patients with sub massive PE, treatment with heparin plus placebo was associated with almost three times the risk of death when compared to heparin with 100mg of tPA. 35% of PE patients survived to discharge when given 100mg tPA with heparin.  MAPPETT study
  2. TOPCOAT Trial In patients with submassive PE, the use of tenecteplase resulted in a reduction in adverse outcomes based on a complicated composite outcome. The composite outcomes include mortality, vasopressor use, intubation, major bleeding, functional capacity, RV function and many other things. This trial was prematurely terminated. 
  3. Wang Study: Compared with the 100 mg/2 h regimen, the 50 mg/2 h rt-PA regimen exhibits similar efficacy and perhaps better safety in patients with acute PTE. These findings support the notion that optimizing rt-PA dosing is worthwhile when treating patients with PTE. Chest. 2010;137(2):254-262
 
Pearls:
  • An increased PaCO2-EtCO2 gradient in PE is suggestive of increased dead space.
  • Start heparin straightaway after tPA, but usually at low doses around 1000units/hr. 
  • For tPA bleed, give FFP/ PCC, cryoprecipitate and antifibrinolytics. Serial fibrinogen levels may measure a patient’s fibrinolytic balance. 
  • In sub-massive PE, giving half the dose of tPA has long term benefits in reducing the incidence of pulmonary hypertension and recurrent PE.
  • ACLS dose tPA for PE is 0.6mg/kg as a push over 2 mins. 
  • 25% of Lethal PE and 33% of Massive PE arose from isolated calf DVT in a huge autopsy study (Acta Chir Scand Suppl 478:1, 1977). They propagate to deep veins 80% of time (Arch Intern Med 153:2777, 1993). so the myth about not having to worry about calf emboli is not completely true.
  • Platelets coating a fresh emboli can release potent vasoconstrictors causing pulmonary hemodynamic consequences not expected from the size of the emboli alone. Acute PE also increases pulmonary vascular resistance by hypoxic pulmonary vasoconstriction, physical obstruction of blood flow, and release of humoral factors, such as serotonin, thrombin, and histamine 
  • Elevated WBCs are often seen with PE, as high as 20,000.
  • If you see new anterioseptal and inferior lead t-wave inversions, think very strongly about PE 
  • D-dimer concentration increases with age and its specificity for embolism decreases, which makes the test less useful to exclude pulmonary embolism in older patients
  • UFH can be given SQ at dose of 333 U/kg initial dose and then 250 U/kg BID both in and outpatient (JAMA 2006;296(8):935)
  • Warfarin initiated at 10mg daily doses for the first two days produced therapeutic INRs more rapidly than use of 5mg initial doses.
  • IVC filter placement with anticoagulation was associated with a slight reduction in symptomatic PE as compared with anticoagulation alone but filters were associated with a significant increase in recurrent DVT.
  • Pregnancy: V/Q lung scanning delivers a higher fetal dose of radiation than does CTPA; perfusion scanning alone will reduce the radiation exposure. However, the radiation dose delivered to mothers is higher with CTPA than with scintigraphy.
  • An improvement in pulmonary vascular resistance by even 10% with tPA can unload the RV to a reasonable degree. 
  • Thrombolysis can be performed as late as 14 days after the onset of the first symptoms. 
  • In patients who are getting thrombolysis for submassive PE, consider stopping tPA when fibrinogen levels are less than 150. Some investigators have used TEG to determine the balance of thrombolysis and titrate thrombolytic medications.
  •  

1 thought on “Pulmonary embolism

  1. Your workup for PE management is extremely helpful and educational as a fellow RN. Reading through your rationales, I now understand why you ordered 100+ labs for a PE patient. Your extensive workup for PE management was concise and impressive. Thank you for all you do.

Leave a Comment