Dott. Maurizio M. Ciammaichella

 

PULMONARY EMBOLISM

 

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CLINICALPATHOPHYSIOLOGY

History: PE is so common and so lethal that the diagnosis should be actively sought in every patient who presents with any chest symptoms that cannot be proven to be due to some other cause.

• Symptoms that should provoke a suspicion of PE must include chest pain, chest wall tenderness, back pain, shoulder pain, upper abdominal pain, syncope, hemoptysis, shortness of breath, painful respiration, new onset of wheezing, any new cardiac arrhythmia, or any other unexplained symptom referable to the thorax.

• The classic triad of signs and symptoms of PE (hemoptysis, dyspnea and chest pain) are neither sensitive nor specific. They occur in fewer than 20% of patients in whom the diagnosis is made and most patients with those symptoms will be found to have some etiology other than PE to account for them. Of patients who go on to die from massive PE, only 60% have dyspnea, 17% have chest pain and 3% have hemoptysis.

• Many patients with PE are initially completely asymptomatic, and most of those who do have symptoms have an atypical presentation.

• Patients with pulmonary embolism often present with primary or isolated complaints of seizure, syncope, abdominal pain, high fever, a productive cough, new onset of reactive airway disease ("adult-onset asthma"), hiccoughs, new onset atrial fibrillation, disseminated intravascular coagulation, or any of a host of other signs and symptoms.
  
• Pleuritic or respirophasic chest pain is a particularly worrisome symptom. PE can be proven in 21% of young, active patients who come to the ED complaining only of pleuritic chest pain. These patients usually lack any other classical signs, symptoms, or known risk factors for pulmonary thromboembolism. Such patients often are inappropriately dismissed with an inadequate workup and a non-specific diagnosis, such as musculoskeletal chest pain or pleurisy.

Physical:

• Massive PE causes hypotension due to acute cor pulmonale, but the physical examination early in submassive PE may be completely normal. Initially, physical findings are absent in most patients with PE.

• After 24-72 hours, loss of pulmonary surfactant often causes atelectasis and alveolar infiltrates that are indistinguishable from pneumonia on clinical examination and by x-ray.

• New wheezing may be appreciated. If pleural lung surfaces are affected, a pulmonary rub may be heard.

• The spontaneous onset of chest wall tenderness without a good history of trauma is always worrisome, because patients with PE may have chest wall tenderness as the only physical finding.

• In patients with massive PE, the incidence of physical signs has been reported as follows:

• 96% have tachypnea > 16/min

• 58% develop rales

• 53% have an accentuated second heart sound

• 44% have tachycardia > 100/min

• 43% have fever > 37.8 degrees C

• 36% have diaphoresis

• 34% have an S3 or S4 gallop

• 32% have clinical signs and symptoms suggesting thrombophlebitis

• 24% have lower extremity edema

• 23% have a cardiac murmur
  
• 19% have cyanosis

Causes:

• Hypercoagulable states

• Prolonged venous stasis or significant injury to the veins can provoke DVT and PE in any person, but there is increasing reason to believe that spontaneous DVT and PE are nearly always related to some underlying hypercoagulable state. Other identified "causes" most likely serve only as triggers for a system that is already out of balance.

• Hypercoagulable states may be acquired or congenital. An inborn resistance to activated protein C is the most common congenital risk factor for DVT that has been identified to date. Most patients with this syndrome have a genetic mutation in factor V known as "factor V Leyden," although there are other mechanisms that can also produce a resistance to activated protein C.

• Primary or acquired deficiencies in protein C, protein S, or antithrombin III are also common underlying causes of DVT and PE.

• Risk markers

• The most important clinically identifiable risk markers for DVT and PE are a prior history of deep vein thrombosis or pulmonary embolism, a recent surgery or pregnancy, prolonged immobilization, or an underlying malignancy. Many other recognized markers of risk for venous thromboembolic disease are listed here.
  
  AIDS (lupus anticoagulant)
  
  Antithrombin III deficiency
  
  Behcet's disease
  
  Blood type A
  
  Burns
  
  Catheters (Indwelling venous infusion catheters)
  
  Chemotherapy
  
  Congestive heart failure
  
  Drug abuse (IV drugs)
  
  Drug-induced lupus anticoagulant
  
  DVT in the past
  
  Estrogen replacements (high-dose only)
  
  Fibrinogen abnormality
  
  Fractures
  
  Hemolytic anemias
  
  Heparin-associated thrombocytopenia
  
  Homocysteinuria
  
  Hyperlipidemias
  
  Immobilization
  
  Malignancy
  
  Myocardial infarction
  
  Obesity
  
  Old age
  
  Oral contraceptives
  
  PE in the past
  
  Phenothiazines
  
  Plasminogen abnormality
  
  Plasminogen activator abnormality
  
  Polycythemia
  
  Postoperative
  
  Postpartum period
  
  Pregnancy
  
  Protein C deficiency
  
  Protein S deficiency
  
  Resistance to activated protein C
  
  SLE (lupus)
  
  Thrombocytosis
  
  Trauma
  
  Ulcerative colitis
  
  Varicose veins
  
  Venography
  
  Venous pacemakers
  
  Venous stasis
  
  Warfarin (first few days of therapy)

WORKUP

Lab Studies:

• Clinical variables alone lack sufficient power to permit a treatment decision, so patients in whom PE is suspected must undergo diagnostic tests until the diagnosis is proven or ruled out, or until some alternative diagnosis is proven.
  
  Unfortunately, no known blood or serum test can move a patient with a high clinical likelihood of pulmonary thromboembolism into a low likelihood category or vice versa.

• The arterial blood gas (ABG) PO2 has a ZERO or even a negative predictive value in a typical population of patients with a clinical suspicion of PE. This is contrary to what has been taught in many textbooks, and it seems counter-intuitive, but it is demonstrably true. The reason is as follows:

• Other etiologies that masquerade as PE are more likely to lower the PO2 than is PE. In fact, because other diseases that may masquerade as PE (e.g., COPD, pneumonia and CHF) affect oxygen exchange more than PE, the blood oxygen level often has an inverse predictive value for PE.

• In most settings, fewer than half of all patients with symptoms suggestive of PE actually turn out to have PE as their diagnosis. In such a population, if any reasonable level of PaO2 is chosen as a dividing line, the incidence of PE will be higher in the group with a PaO2 above the dividing line than in the group below the divider. This is a specific example of a general truth that may be demonstrated mathematically for any test finding with a Gaussian distribution and a population incidence of less than 50%.
  
  Conversely, in a patient population with a very high incidence of PE and a lower incidence of other respiratory ailments (such as a population of postoperative orthopedic patients with sudden onset of shortness of breath) a low PO2 has a strongly positive predictive value for PE.

• The discussion above holds true not only for the arterial PO2, but also for the alveolar-arterial oxygen gradient and for the oxygen saturation level as measured by pulse oximetry. In particular, pulse oximetry is extremely insensitive, will be normal in the majority of patients with PE, and should not be used to direct a diagnostic workup.

• The white blood cell (WBC) count may be normal or elevated. It is not uncommon to see a WBC count as high as 20,000 in patients with PE.

• Clotting studies are normal in most patients with pulmonary thromboembolism.

• Prolongation of the PT, the APTT, or the clotting time have no prognostic value in the diagnosis of PE. Recurrent DVT and PE can and often do occur in patients who are fully anticoagulated.

• New PE in the hospital occurs despite therapeutic anticoagulation in:
  
  3% of patients who have non-floating deep vein thrombus without PE at presentation.
  
  13% of those who present with a floating thrombus but no PE.
  
  11% of those who already had PE at presentation but had no floating thrombus.
  
  39% of those presenting with PE who have a floating thrombus visible at venography..

• D-dimer is a unique degradation product produced by plasmin-mediated proteolysis of cross-linked fibrin. D-dimer is measured by latex agglutination or by an enzyme-linked immunosorbent assay (ELISA) test that is considered positive if the level is greater than 500 ng/ml.

• The latex agglutination test (one trade name is "SimpliRED") is completely unreliable, with a sensitivity of only 50% - 60% for DVT and PE.

• The ELISA test is more sensitive than the latex agglutination test, but in a population with a PE prevalence of 50%, the negative predictive value of the test is still only 79%. Under the best of circumstances the D-dimer study misses 10% of the patients with positive pulmonary angiograms, while only 30% of those with a positive D-dimer will have a positive angiogram.
  
• At the present time, D-Dimer is not sensitive or specific enough to change the course of diagnostic evaluation or treatment for patients with suspected PE. Complex theoretical algorithms that attempt to combine unreliable D-dimer results with unreliable guesses at clinical likelihood are not useful in guiding the workup of a live patient with signs or symptoms suggestive of DVT and PE.

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Imaging Studies:

Other Tests:

TREATMENT

Prehospital Care:

• The most important thing that can be done in the prehospital setting is to transport the patient to a hospital. As long as there is no way to make a reliable clinical diagnosis of PE without diagnostic tests, it will remain difficult to treat PE in a meaningful way in the field.

Emergency Department Care:

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Consultations:

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MEDICATION

SUMMARY

Immediate full anticoagulation is mandatory for all patients with suspected DVT or PE, because effective anticoagulation with heparin reduces the mortality of PE from 30 percent to less than 10 percent. Heparin works by activating antithrombin III to slow or prevent the progression of deep venous thrombus and to reduce the size and frequency of pulmonary emboli. Heparin does not dissolve existing clot.

Anticoagulation is essential, but anticoagulation alone does not guarantee a successful outcome. Recurrence or extension of deep venous thrombosis and pulmonary embolism may occur despite full and effective heparin anticoagulation.

Fibrinolytic therapy is mandatory for three groups of patients: those who are hemodynamically unstable, those with right-heart strain and exhausted cardiopulmonary reserves, and those who are expected to have multiple recurrences of pulmonary thromboembolism over a period of years. Patients with a prior history of PE and those with known deficiencies of protein C, protein S, or antithrombin III should be included in this latter group.

Besides those for whom it is mandatory, fibrinolysis should be considered as a potential therapy for every patient with proven PE.

Chronic anticoagulation is essential for patients who survive an initial DVT and PE. The optimum total duration of anticoagulation has been controversial in recent years, but there is a general consensus that there is a significant reduction in recurrences and a net positive benefit associated with at least 6 months of anticoagulation.

Compression stockings (providing a 30 - 40 mm Hg compression gradient) should always be used because they are a safe and effective adjunctive treatment that can limit or prevent extension of thrombus.

True gradient compression stockings (30- 40 mm Hg or higher) are highly elastic, providing a gradient of compression that is highest at the toes and gradually decreases to the level of the thigh. This reduces capacitive venous volume by approximately 70% and increases the measured velocity of blood flow in the deep veins by a factor of five or more. Compression stockings of this type have been proven effective in the prophylaxis of thromboembolism, and are also effective in preventing progression of thrombus in patients who already have DVT and PE.

A 1994 meta-analysis calculated a DVT risk odds ratio of 0.28 for gradient compression stockings (as compared to no prophylaxis) in patients undergoing abdominal surgery, gynecologic surgery, or neurosurgery. Other studies have found that gradient compression stockings and low-molecular-weight heparin were the most effective modalities in reducing the incidence of deep vein thrombosis after hip surgery, and were more effective than subcutaneous unfractionated heparin, oral warfarin, dextran, or aspirin.

The ubiquitous white stockings known as "anti-embolic stockings" or as "Ted hose" produce a maximum compression of 18 mm HG. Ted hose rarely are fitted in such a way as to provide even that inadequate gradient compression. Because they provide such limited compression, they are of no efficacy in the treatment of DVT and PE, nor have they been proven effective as prophylaxis against a recurrence.

True 30 - 40 mm Hg gradient compression pantyhose are available in pregnant sizes. They are recommended by many specialists for all pregnant women because they not only prevent DVT, but they also reduce or prevent the development of varicose veins during pregnancy.

Drug Category: Fibrinolytics - Fibrinolysis is always indicated for hemodynamically unstable patients with PE, because there is no other medical therapy that can improve acute cor pulmonale quickly enough to save the patient's life.

Because it is less invasive and has fewer complications, fibrinolytic therapy has replaced surgical embolectomy as the primary mode of treatment for hemodynamically unstable patients with pulmonary thromboembolism. Surgical thromboembolectomy is now reserved for patients who have failed fibrinolysis or who cannot tolerate lytic therapy.

Fibrinolytic regimens currently in common use for pulmonary embolism include two forms of recombinant tissue plasminogen activator, t-PA (alteplase) and r-PA (reteplase) along with urokinase and streptokinase. Alteplase is usually given as a front-loaded infusion over 90 or 120 minutes. Urokinase and streptokinase usually are given as infusions over 24 hours or more. Reteplase is a new generation thrombolytic with a longer half-life that is given as a single bolus or as twoboluses administered 30 minutes apart.

Of the four, the faster-acting agents reteplase and alteplase are to be preferred for patients with pulmonary embolism, because the condition of patients with pulmonary embolism can deteriorate extremely rapidly.

Many comparative clinical studies have shown that administration of a 2-hour infusion of alteplase is more effective (and more rapidly effective) than urokinase or streptokinase over a 12-hour period. One prospective randomized study comparing reteplase and alteplase found that total pulmonary resistance (along with pulmonary artery pressure and cardiac index) showed a significant improvement after just 0.5 hours in the reteplase group as compared to 2 hours in the alteplase group. There do not seem to be important differences between different fibrinolytic agents with respect to safety or overall efficacy.

Streptokinase is least desirable of all the fibrinolytic agents because antigenic problems and other adverse reactions force the cessation of therapy in a large number of cases.

Empiric thrombolysis may be indicated in selected hemodynamically unstable patients, particularly when the clinical likelihood of PE is overwhelming and the patient's condition is deteriorating. The overall risk of severe complications from thrombolysis is low and the potential benefit in a deteriorating patient with PE is high. Empiric therapy is especially indicated when a patient is so severely compromised that he or she will not survive long enough to obtain a confirmatory study. Empiric thrombolysis should be reserved, however, for cases that truly meet the definitions above, as many other clinical entities (including aortic dissection) may masquerade as PE, yet may not benefit from thrombolysis in any way.

If indicated, fibrinolysis may be used in pregnancy at the same dose used for non-pregnant patients. Fear of complications should never prevent the use of fibrinolytics when a pregnant patient has significant right ventricular dysfunction from PE, as the best predictor of fetal outcome in this setting remains maternal outcome.

Drug Name	Reteplase - Reteplase is a second-generation recombinant tissue-type plasminogen activator. As a fibrinolytic agent it seems to work faster than its fore-runner, alteplase, and it may also be more effective in patients with a larger clot burden. It has also been reported to be more effective than other agents in lysis of older clot. Two major differences help explain these improvements. Compared to alteplase, reteplase does not bind fibrin so tightly, allowing the drug to diffuse more freely through the clot. Another advantage seems to be that reteplase does not compete with plasminogen for fibrin-binding sites, allowing plasminogen at the site of the clot to be transformed into clot-dissolving plasmin. The FDA has not approved reteplase for use in pulmonary embolism. Studies of reteplase for pulmonary embolism have used the same dose approved by the FDA for coronary artery fibrinolysis.
Adult Dose	Two 10-unit IV boluses, given 30 minutes apart. In the setting of cardiac arrest or impending arrest due to pulmonary embolism, a single IV bolus of 20 units has been used successfully in a small number of cases.
Pediatric Dose	Reteplase does not have a known pediatric dosing protocol.
Contraindications	All fibrinolytics are contraindicated in the following situations: Active internal bleeding History of cerebrovascular accident Recent intracranial or intraspinal surgery or trauma Intracranial neoplasm, arteriovenous malformation, or aneurysm Known bleeding diathesis Severe uncontrolled hypertension In the following conditions, the risks of fibrinolytic therapy may be increased and should be weighed against the anticipated benefits: Recent major surgery Recent puncture of noncompressible vessels Cerebrovascular disease Recent gastrointestinal or genitourinary bleeding Recent trauma Hypertension: systolic BP 180 mm Hg and/or diastolic BP 110 mm Hg High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation Acute pericarditis Subacute bacterial endocarditis Hemostatic defects including those secondary to severe hepatic or renal disease Significant hepatic dysfunction Pregnancy Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions Septic thrombophlebitis or occluded AV cannula at seriously infected site Advanced age (e.g., over 75 years old) Patients currently receiving oral anticoagulants, e.g., warfarin sodium Any other condition in which bleeding would be particularly difficult to manage because of its location As with any medication, avoid use in patients with documented hypersensitivity to this medication or related products.
Interactions	The risk of bleeding is increased when fibrinolytic agents are combined with antiplatelet agents or anticoagulants.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Combining fibrinolytic agents and heparin can be confusing. Heparin should never be given concurrently when urokinase, streptokinase, or APSAC are used to treat any condition. Instead, heparin is started when the thrombin time or the aPTT is at or below a level that is twice the normal control value. Heparin should be given concurrently with alteplase or reteplase for treatment of acute MI. Neither heparin nor aspirin should be given concurrently when tissue plasminogen activator is used for acute ischemic stroke. When tissue-type plasminogen activators are used for pulmonary embolism, heparin may be given concurrently or it may be held and restarted after the end of fibrinolytic therapy or when the thrombin time or the aPTT is at or below a level that is twice the normal control value. Coagulation studies should be performed 4 hours after the initiation of fibrinolytic therapy.

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Drug Name	Alteplase - alteplase is the drug most often used to treat Pulmonary Embolism in the emergency department. One advantage of alteplase is the fact that the FDA has approved the drug for this indication. Another advantage is the fact that most emergency department personnel are familiar with the use of alteplase because it is so widely used for treatment of patients with acute myocardial infarction.
Adult Dose	The FDA-approved regimen of alteplase for pulmonary embolism is 100 mg administered by intravenous infusion over 2 hours. An accelerated 90-minute regimen is widely used, and most authors believe it is both safer and more effective than the approved 2-hour infusion. For the accelerated regimen the recommended total dose is based upon patient weight, not to exceed 100 mg. For patients weighing more than 67 kg , the total recommended dose to be administered is 100 mg. The drug is given as a 15 mg intravenous bolus followed by 50 mg infused over the next 30 minutes and then 35 mg infused over the next 60 minutes. For patients weighing less than 67 kg , the drug is administered as a 15 mg intravenous bolus, followed by 0.75 mg/kg infused over the next 30 minutes (not to exceed 50 mg) and then 0.50 mg/kg over the next 60 minutes (not to exceed 35 mg). Heparin therapy should be instituted or reinstituted near the end of or immediately following the alteplase infusion, when the partial thromboplastin time or thrombin time returns to twice normal or less.
Pediatric Dose	Use the same weight-adjusted accelerated regimen as in adults.
Contraindications	All fibrinolytics are contraindicated in the following situations: Active internal bleeding History of cerebrovascular accident Recent intracranial or intraspinal surgery or trauma Intracranial neoplasm, arteriovenous malformation, or aneurysm Known bleeding diathesis Severe uncontrolled hypertension In the following conditions, the risks of fibrinolytic therapy may be increased and should be weighed against the anticipated benefits: Recent major surgery Recent puncture of noncompressible vessels Cerebrovascular disease Recent gastrointestinal or genitourinary bleeding Recent trauma Hypertension: systolic BP 180 mm Hg and/or diastolic BP 110 mm Hg High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation Acute pericarditis Subacute bacterial endocarditis Hemostatic defects including those secondary to severe hepatic or renal disease Significant hepatic dysfunction Pregnancy Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions Septic thrombophlebitis or occluded AV cannula at seriously infected site Advanced age (e.g., over 75 years old) Patients currently receiving oral anticoagulants, e.g., warfarin sodium Any other condition in which bleeding would be particularly difficult to manage because of its location As with any medication, avoid use in patients with documented hypersensitivity to this medication or related products.
Interactions	The risk of bleeding is increased when fibrinolytic agents are combined with antiplatelet agents or anticoagulants.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Combining fibrinolytic agents and heparin can be confusing. Heparin should never be given concurrently when urokinase, streptokinase, or APSAC are used to treat any condition. Instead, heparin is started when the thrombin time or the aPTT is at or below a level that is twice the normal control value. Heparin should be given concurrently with alteplase or reteplase for treatment of acute MI. Neither heparin nor aspirin should be given concurrently when tissue plasminogen activator is used for acute ischemic stroke. When tissue-type plasminogen activators are used for pulmonary embolism, heparin may be given concurrently or it may be held and restarted after the end of fibrinolytic therapy or when the thrombin time or the aPTT is at or below a level that is twice the normal control value. Coagulation studies should be performed 4 hours after the initiation of fibrinolytic therapy.

 

Drug Name	Urokinase - Urokinase is a direct plasminogen activator produced by human fetal kidney cells grown in culture. Urokinase is relatively low in antigenicity. At the time of this writing, production of urokinase and many other human cell culture products has been put on hold because of concerns about viral infections that can colonize human cell production facilities. When used for localized fibrinolysis, urokinase is given as a local catheter-directed continuous infusion directly into the area of thrombus with no loading dose. When used for pulmonary embolism, a loading dose is necessary.
Adult Dose	Loading dose: 250,000 U over 30 min Maintenance dose: Infuse 100,000 U/hr for 12-72 hrs
Pediatric Dose	Loading dose: 4,400 U/kg over 10 min Maintenance dose: Infuse 4,400 U/kg/hr for 12-72 hrs
Contraindications	All fibrinolytics are contraindicated in the following situations: Active internal bleeding History of cerebrovascular accident Recent intracranial or intraspinal surgery or trauma Intracranial neoplasm, arteriovenous malformation, or aneurysm Known bleeding diathesis Severe uncontrolled hypertension In the following conditions, the risks of fibrinolytic therapy may be increased and should be weighed against the anticipated benefits: Recent major surgery Recent puncture of noncompressible vessels Cerebrovascular disease Recent gastrointestinal or genitourinary bleeding Recent trauma Hypertension: systolic BP 180 mm Hg and/or diastolic BP 110 mm Hg High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation Acute pericarditis Subacute bacterial endocarditis Hemostatic defects including those secondary to severe hepatic or renal disease Significant hepatic dysfunction Pregnancy Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions Septic thrombophlebitis or occluded AV cannula at seriously infected site Advanced age (e.g., over 75 years old) Patients currently receiving oral anticoagulants, e.g., warfarin sodium Any other condition in which bleeding would be particularly difficult to manage because of its location As with any medication, avoid use in patients with documented hypersensitivity to this medication or related products.
Interactions	The risk of bleeding is increased when fibrinolytic agents are combined with antiplatelet agents or anticoagulants.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Combining fibrinolytic agents and heparin can be confusing. Heparin should never be given concurrently when urokinase, streptokinase, or APSAC are used to treat any condition. Instead, heparin is started when the thrombin time or the aPTT is at or below a level that is twice the normal control value. Heparin should be given concurrently with alteplase or reteplase for treatment of acute MI. Neither heparin nor aspirin should be given concurrently when tissue plasminogen activator is used for acute ischemic stroke. When tissue-type plasminogen activators are used for pulmonary embolism, heparin may be given concurrently or it may be held and restarted after the end of fibrinolytic therapy or when the thrombin time or the aPTT is at or below a level that is twice the normal control value. Coagulation studies should be performed 4 hours after the initiation of fibrinolytic therapy.

 

Drug Name	Streptokinase - Streptokinase is highly antigenic, and there is a high likelihood that treatment will be interrupted due to allergic drug reactions. Chills, fever, nausea, and skin rashes are frequent (up to 20%). Blood pressure and heart rate drop in about 10% of cases during or shortly after treatment. Late complications that may be seen can include purpura, respiratory distress syndrome, serum sickness, Guillain-Barrsyndrome, vasculitis, and renal or hepatic dysfunction.
Adult Dose	The loading dose of streptokinase is 2000 U/lb infused over 10 minutes. Maintenance dose: 2000 u/lb/hr for 24 h
Pediatric Dose	Use the same regimen as in adults.
Contraindications	Because it is highly antigenic, streptokinase is contraindicated in patients with a prior to the drug within the past 4 years and in those with a recent streptococcal infection. All fibrinolytics are contraindicated in the following situations: Active internal bleeding History of cerebrovascular accident Recent intracranial or intraspinal surgery or trauma Intracranial neoplasm, arteriovenous malformation, or aneurysm Known bleeding diathesis Severe uncontrolled hypertension In the following conditions, the risks of fibrinolytic therapy may be increased and should be weighed against the anticipated benefits: Recent major surgery Recent puncture of noncompressible vessels Cerebrovascular disease Recent gastrointestinal or genitourinary bleeding Recent trauma Hypertension: systolic BP 180 mm Hg and/or diastolic BP 110 mm Hg High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation Acute pericarditis Subacute bacterial endocarditis Hemostatic defects including those secondary to severe hepatic or renal disease Significant hepatic dysfunction Pregnancy Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions Septic thrombophlebitis or occluded AV cannula at seriously infected site Advanced age (e.g., over 75 years old) Patients currently receiving oral anticoagulants, e.g., warfarin sodium Any other condition in which bleeding would be particularly difficult to manage because of its location As with any medication, avoid use in patients with documented hypersensitivity to this medication or related products.
Interactions	The risk of bleeding is increased when fibrinolytic agents are combined with antiplatelet agents or anticoagulants.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Combining fibrinolytic agents and heparin can be confusing. Heparin should never be given concurrently when urokinase, streptokinase, or APSAC are used to treat any condition. Instead, heparin is started when the thrombin time or the aPTT is at or below a level that is twice the normal control value. Heparin should be given concurrently with alteplase or reteplase for treatment of acute MI. Neither heparin nor aspirin should be given concurrently when tissue plasminogen activator is used for acute ischemic stroke. When tissue-type plasminogen activators are used for pulmonary embolism, heparin may be given concurrently or it may be held and restarted after the end of fibrinolytic therapy or when the thrombin time or the aPTT is at or below a level that is twice the normal control value. Coagulation studies should be performed 4 hours after the initiation of fibrinolytic therapy.

Drug Category: Anticoagulants - Heparin augments the activity of antithrombin III and prevents the conversion of fibrinogen to fibrin. Full-dose low-molecular-weight heparin (LMWH) or full-dose unfractionated IV heparin should be initiated at the first suspicion of DVT or PE.

With proper dosing, several low-molecular-weight heparin products have been found safer and more effective than unfractionated heparin both for prophylaxis and for treatment of DVT and PE. It is not necessary nor useful to monitor the aPTT when giving LMWH, because the drug is most active in a tissue phase, and does not exert most of its effects on coagulation factor IIa.

There are many different low-molecular-weight heparin products available around the world. Because of pharmacokinetic differences, dosing is highly product-specific. At this writing, there are three LMW heparin products available in the United States : Enoxaparin (Lovenox), Dalteparin (Fragmin), and Ardeparin (Normiflo). Enoxaparin is the only one of these currently labeled by the FDA for treatmentof DVT. Each has been approved by the FDA at a lower dose for prophylaxis, but all appear to be safe and effective at some therapeutic dose in patients with active DVT or PE.

Fractionated low molecular weight heparin (LMWH) administered subcutaneously is now the preferred choice for initial anticoagulation therapy. Unfractionated IV heparin can be nearly as effective, but is more difficult to titrate for therapeutic effect. Warfarin maintenance therapy may be initiated after 1-3 d of effective heparinization.

The weight-adjusted heparin dosing regimens that are appropriate for prophylaxis and treatment of coronary artery thrombosis are too low to be used unmodified in the treatment of active DVT and PE. Coronary artery thrombosis does not result from hypercoagulability, but rather from platelet adhesion to ruptured plaque. In contrast, patients with DVT and PE are in the midst of a hypercoagulable crisis and aggressive countermeasures are essential to reduce mortality and morbidity.

In a hemodynamically unstable patient heparin therapy alone is not adequate therapy. Heparin is essential because it inhibits clot extension, but is not sufficient because it is incapable of dissolving existing clot. The variable clot resolution that occurs in patients treated with heparin is due to natural fibrinolytic processes. Fibrinolytic agents, on the other hand, act directly and rapidly to dissolve existing clot. In hemodynamically unstable patients, use of anticoagulants alone (failure to administer a fibrinolytic agent) is associated with a high mortality.

Drug Name	Enoxaparin - Enoxaparin was the first LMWH released in the USA . It is the only LMWH now approved by the FDA both for treatment and for prophylaxis of DVT and PE. LMWH has been widely used in pregnancy, although clinical trials are not yet available to demonstrate that it is as safe as unfractionated heparin. Except in overdoses, there is no utility in checking the PT or the APTT, as the APTT does not correlate with the anticoagulant effect of fractionated LMWH.
Adult Dose	For treatment of DVT and PE: 1 mg/kg enoxaparin sc q 12h or 1.5 mg/kg enoxaparin sc qd For prophylaxis against DVT: 30 mg enoxaparin sc q 12h For DVT prophylaxis in abdominal surgery: 40 mg enoxaparin sc qd, with the first dose given 2 hours prior to surgery.
Pediatric Dose	For treatment of acute DVT or PE: 1 mg/kg sc q 12h
Contraindications	Avoid use in patients with documented hypersensitivity to this medication or related products and those with major bleeding and thrombocytopenia.
Interactions	Use LMWH with care in patients receiving platelet inhibitors or oral anticoagulants such as aspirin, NSAIDs, dipyridamole, salicylates, sulfinpyrazone, and ticlopidine. Each of these drugs can potentiate the risk of bleeding in patients receiving heparins.
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Reversible elevation of hepatic transaminases is occasionally seen. Heparin-associated thrombocytopenia has been seen with fractionated low-molecular-weight heparin. For significant bleeding complications, 1.0 mg of protamine sulphate will reverse the effect of approximately 1.0 mg of enoxaparin.

 

Drug Name	Dalteparin - Dalteparin is a LMWH with many similarities to enoxaparin, but with a different dosing schedule. Dalteparin is approved for DVT prophylaxis in patients undergoing abdominal surgery. Except in overdoses, there is no utility in checking the PT or the APTT, as the APTT does not correlate with the anticoagulant effect of fractionated LMWH.
Adult Dose	For DVT prophylaxis in patients undergoing abdominal surgery: 2500 U sc qd
Contraindications	Avoid use in patients with documented hypersensitivity to this medication or related products and those with major bleeding and thrombocytopenia.
Interactions	Use LMWH with care in patients receiving platelet inhibitors or oral anticoagulants such as aspirin, NSAIDs, dipyridamole, salicylates, sulfinpyrazone, and ticlopidine. Each of these drugs can potentiate the risk of bleeding in patients receiving heparins.
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Reversible elevation of hepatic transaminases is occasionally seen. Heparin-associated thrombocytopenia has been seen with fractionated low-molecular-weight heparin. If necessary, 1 mg protamine can neutralize 100 units of dalteparin.

 

Drug Name	Ardeparin - Ardeparin is a LMWH that was recently released in the United States for DVT prophylaxis in patients undergoing hip and knee surgery. Except in overdoses, there is no utility in checking the PT or the APTT, as the APTT does not correlate with the anticoagulant effect of fractionated LMWH.
Adult Dose	For DVT prophylaxis in patients undergoing hip and knee surgery: 50 U/kg q 12 h sc
Contraindications	Avoid use in patients with documented hypersensitivity to this medication or related products and those with major bleeding and thrombocytopenia.
Interactions	Use LMWH with care in patients receiving platelet inhibitors or oral anticoagulants such as aspirin, NSAIDs, dipyridamole, salicylates, sulfinpyrazone, and ticlopidine. Each of these drugs can potentiate the risk of bleeding in patients receiving heparins.
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Reversible elevation of hepatic transaminases is occasionally seen. Heparin-associated thrombocytopenia has been seen with fractionated low-molecular-weight heparin. If necessary, 1 mg protamine can neutralize 100 units of ardeparin.

 

Drug Name	Unfractionated heparin - When unfractionated heparin is used, the APTT should not be checked until 6 h after the initial heparin bolus, as an extremely high or low value during this time should not provoke any action.
Adult Dose	Initial bolus: 120-140 u/Kg IV or approximately 10,000 u/70 Kg Initial infusion: 20 u/kg/h IV After the bolus, the APTT should be checked q6h until stable, and heparin dosing should be adjusted as follows: If the APTT is low (less than 1.5 times the control value), rebolus with 5000 u and increase the drip by 10% If the APTT is high (more than 2.5 times the control value), just decrease the drip 10% If the APTT is extremely high (>100 seconds), hold the heparin drip for 1 h and decrease the drip 10%
Pediatric Dose	Pediatric loading dose: 100 u/kg/h Maintenance infusion: 15-25 u/kg/h Increase the dose by 2-4 u/kg/h q6-8h prn using PTT results.
Contraindications	Avoid use in patients with documented hypersensitivity to heparin. Contraindications include subacute bacterial endocarditis, active noncompressible bleeding, and any history of heparin-induced thrombocytopenia.
Interactions	Digoxin, nicotine, tetracycline, and antihistamines may decrease the effects of this drug. NSAIDs, ASA, dextran, dipyridamole, and hydroxychloroquine may increase heparin toxicity and the risks of bleeding.
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	The most important risk associated with unfractionated heparin is that it will be ineffective because of insufficient doses. All forms of heparin may cause hemorrhagic complications and all can trigger immune thrombotic thrombocytopenia 1-2 weeks after the beginning of treatment. Heparin-associated thrombocytopenia (HAT) is very serious, causes widespread thrombosis that is refractory to treatment and can be fatal if not recognized quickly and managed appropriately. If significant bleeding complications develop, 15 mg of protamine sulphate (infused over 3 min) will usually reverse the anticoagulant effect of unfractionated heparin. Some preparations contain benzyl alcohol as a preservative. Benzyl alcohol, used in large amounts, has been associated with fetal toxicity (gasping syndrome). The use of preservative-free heparin is recommended in neonates. Use with caution in patients diagnosed with shock or severe hypotension.

 

Drug Name	Warfarin - Warfarin interferes with hepatic synthesis of vitamin K-dependent coagulation factors. Warfarin should never be given to patients with thrombosis until after the patient has been fully anticoagulated with heparin because the first few days of warfarin therapy produce a hypercoagulable state. Failing to anticoagulate with heparin before starting warfarin will cause clot extension and recurrent thromboembolism in about 40% of patients, compared with 8% of those who receive full-dose heparin before starting warfarin. Heparin should be continued for the first 5-7 d of oral warfarin therapy, regardless of the prothrombin time, to allow time for depletion of procoagulant vitamin K dependent proteins. The anticoagulant effect of warfarin is adjusted by varying the dose to keep the International Normalized Ratio (INR) within a target range. An INR target range of 2.5 to 3.5 makes sense for DVT and PE because the rate of recurrence increases dramatically when the INR drops below 2.5 and decreases when the INR iskept above 3.0. The risk of serious bleeding (including hemorrhagic stroke) is approximately constant when the INR is between 2.5 and 4.5, but rises dramatically when the INR is 5.0 or higher. In the United Kingdom , a higher INR target of 3.0 - 4.0 is more often recommended. The best evidence suggests that 6 mo of anticoagulation reduces the rate of recurrence to half of the recurrence rate observed, when only 6 weeks of anticoagulation is given. Long-term anticoagulation is indicated for patients with an irreversible underlying risk factor with recurrent DVT or recurrent PE. Procoagulant vitamin K-dependent proteins are responsible for a transient hypercoagulable state when warfarin is first started and when it is stopped. This is the phenomenon that occasionally causes warfarin-induced necrosis of large areas of skin or of distal appendages. Heparin is always used to protect against this hypercoagulability when warfarin is started, but when warfarin is stopped the problem resurfaces, causing an abrupt temporary rise in the rate of recurrent venous thromboembolism. At least 186 different foods and drugs have been reported to interact with warfarin. Clinically significant interactions have been verified for a total of 26 common drugs and foods, including 6 antibiotics and 5 cardiac drugs. Every effort should be made to keep the patient adequately anticoagulated at all times because procoagulant factors recover first when warfarin therapy is inadequate. Patients who have difficulty maintaining adequate anticoagulation while taking warfarin may be asked to limit their intake of foods that contain vitamin K. Foods that have moderate to high amounts of vitamin K include brussel sprouts, kale, green tea, asparagus, avocado, broccoli, cabbage, cauliflower, collard greens, liver, soybean oil, soybeans, certain beans, mustard greens, peas (blackeyed peas, split peas, chick peas), turnip greens, parsley, green onions, spinach, and lettuce.
Adult Dose	Initial dose: 5-15 mg/d po qd After initial anticoagulation is obtained, the dose is adjusted according to the desired INR.
Pediatric Dose	Administer a weight-based dose of 0.05-0.34 mg/kg/d and adjust the dose according to the desired INR. Infants may require doses at the high end of this range.
Contraindications	Warfarin should be avoided or used with extreme caution in patients with hereditary or acquired deficiencies of protein C or protein S, because these deficiencies are associated with a higher incidence of tissue necrosis following warfarin administration. Avoid use in patients with documented hypersensitivity to warfarin or related products, in those with severe liver or kidney disease, and in those with gastrointestinal ulcers.
Interactions	Many medications may affect warfarin activity. Drugs that may decrease anticoagulant effects include griseofulvin, nafcillin, phenytoin, rifampin, barbiturates, carbamazepine, glutethimide, estrogens, cholestyramine, colestipol, spironolactone, oral contraceptives, vitamin K, and sucralfate. Some of the medications that may increase the anticoagulant effects of warfarin include oral antibiotics, ethacrynic acid, miconazole, nalidixic acid, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, sulfonylureas, allopurinol, chloramphenicol, phenylbutazone, phenytoin, propoxyphene, cimetidine, disulfiram, metronidazole, sulfonamides, gemfibrozil, acetaminophen, anabolic steroids, ketoconazole, and sulindac.
Pregnancy	X - Contraindicated in pregnancy
Precautions	Do not switch brands after achieving a satisfactory therapeutic response. Use with caution in patients with active tuberculosis or diabetes. Exercise caution in patients with protein C or S deficiency, because they are at high risk of developing skin necrosis. Warfarin is teratogenic and is contraindicated in pregnancy.

 

.

FOLLOW-UP

 

Further Inpatient Care:

• Any degree of hemodynamic compromise or of hypoxemia is an indication that the patient should be assigned to an observation unit rather than to a regular floor bed.
  
  These patients have exhausted their cardiopulmonary reserves and because PE is a disease of many frequent recurrences, many of these patients will suddenly worsen at some point during their hospitalization.

 

Complications:

• A large proportion of patients with PE will develop recurrent PE and cor pulmonale.
  
  Most patients with PE that originated as leg vein thrombosis will go on to develop permanent leg swelling, discomfort, discoloration, atrophic skin changes, and a high likelihood of chronic nonhealing ulcerations.
  
  

MISCELLANEOUS

Medical/Legal Pitfalls:

• Because PE is both extremely common and fairly difficult to diagnosis, many patients are seen in the ED and later die from undiagnosed PE. In fact, respiratory complaints are the most common complaints in patients who are seen alive in the ED and later die unexpectedly. A small number of often-repeated mistakes in diagnosis and treatment are responsible for a large proportion of the bad outcomes with serious legal repercussions.
  
  The most common and most serious of these errors are:

• Dismissing complaints of unexplained shortness of breath as anxiety or hyperventilation without an adequate workup.

• Dismissing complaints of unexplained chest pain as musculoskeletal pain without an adequate workup.

• Failure to properly diagnose and treat symptomatic DVT.

• Failure to recognize that DVT below the knee is just as serious as more proximal DVT.

• Failure to order a V/Q scan when a patient has symptoms consistent with PE.

• Failure to pursue the diagnosis after a V/Q scan that is not perfectly normal.

• Failure to start full-dose heparin at the first real suspicion of PE, before the V/Q scan.
  
• Failure to give fibrinolytic therapy immediately when a patient with PE becomes unstable.

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