PULMONARY EMBOLISM DR FRANK EDWIN CCN Course. Oct 2012 INTRODUCTION (PE) is a common and potentially lethal disease. The diagnosis is often missed because patients with PE present with nonspecific signs and symptoms. Most patients succumb to PE within the first few hours of the event. PE is not a disease; rather, it is a complication of DVT . PE - PATHOGENESIS PATHOGENESIS NATURAL HISTORY OF VENOUS THROMBOSIS Venous stasis Injury to the intima Hypercoagulability Most pulmonary emboli are multiple, and the lower lobes are involved more commonly than the upper lobes RISK FACTORS (VIRCHOW’S TRIAD) VENOUS STASIS Immobility (bed rest, travel) Paralysis (CVA, SCI) Obesity Heart/respiratory failure Casting ENDOTHELIAL INJURY Trauma (orthopedic) Major surgery (orthopedic) Central venous catheters HYPERCOAGULABILITY Previous DVT/PE Malignancy Inflammatory conditions (SLE) Sepsis Increased estrogen Acquired/inherited disorders Protein S or C deficiency ATIII deficiency Factor V Leiden mutation PATHOPHYSIOLOGY HEMODYNAMIC CONSEQUENCES PE reduces the crosssectional area of the pulmonary vascular bed Increased pulmonary vascular resistance Increased right ventricular afterload Right ventricular failure may ensue RESPIRATORY CONSEQUENCES Increased alveolar dead space Bronchoconstriction Hypoxemia Hyperventilation Regional loss of surfactant Pulmonary infarction PRESENTATION Nonspecific 4 presentation types based on • the acuity and • severity of pulmonary arterial occlusion High index of suspicion required PRESENTATION Massive PE Acute pulmonary infarction Acute embolism without infarction Multiple pulmonary emboli MASSIVE PULMONARY EMBOLISM Large emboli compromise pulmonary circulation sufficiently to produce circulatory collapse and shock The patient has: • • • • • weakness, hypotension; Pallor & diaphoresis, oliguria; and impaired sensorium ACUTE PULMONARY INFARCTION Approximately 10% of patients have occlusion of a peripheral pulmonary artery causing parenchymal infarction Acute onset of pleuritic chest pain, breathlessness, and hemoptysis The chest pain may be indistinguishable from ischemic myocardial pain. ACUTE EMBOLISM WITHOUT INFARCTION Nonspecific symptoms • Unexplained dyspnea • Substernal discomfort MULTIPLE PULMONARY EMBOLI 2 subsets of patients: • Repeated documented episodes of pulmonary emboli over years, PULMONARY HYPERTENSION & COR PULMONALE • No previously documented pulmonary emboli but have widespread obstruction of the pulmonary circulation with clot • gradually progressive dyspnea, • intermittent exertional chest pain, • eventually pulmonary hypertension and cor pulmonale COMMONEST SYMPTOMS Dyspnea (73%) Pleuritic chest pain (66%) Cough (37%) Hemoptysis (13%) ATYPICAL SYMPTOMS • • • • • • • • Seizures Syncope Abdominal pain Fever Productive cough Wheezing Decreasing level of consciousness New onset of atrial fibrillation Pleuritic chest pain without other symptoms or risk factors may be a presentation of PE PHYSICAL SIGNS Massive pulmonary embolism • These patients are in shock. They have systemic hypotension, poor perfusion to the extremities, tachycardia, and tachypnea. • Additionally, signs of pulmonary hypertension such as palpable impulse over second left interspace, loud P2, right ventricular S3 gallop, and a systolic murmur louder on inspiration at left sternal border (tricuspid regurgitation) may be present PHYSICAL SIGNS Acute pulmonary infarction • These patients have decreased excursion of involved hemithorax, palpable or audible pleural friction rub, and even localized tenderness. • Signs of pleural effusion, such as dullness upon percussion and diminished breath sounds, may be present PHYSICAL SIGNS Acute embolism without infarction • These patients have nonspecific physical signs that may easily be secondary to another disease process. • Tachypnea and tachycardia frequently are detected, pleuritic pain sometimes may be present, crackles may be heard in the area of embolization, and local wheeze may be heard rarely PHYSICAL SIGNS Multiple pulmonary emboli or thrombi • Pulmonary hypertension and Cor pulmonale. • Elevated JVP • Hepatomegaly, ascites, & dependent pitting edema. PHYSICAL SIGNS • Tachypnea (70%) • Crepitations (51%) • Tachycardia (30%) • Fourth heart sound (24%) • Loud S2 (23%) MAJOR DIFFERENTIALS Myocardial infarction Aortic dissection Pneumonia Pericarditis Myocarditis Cor pulmonale Herpes Zoster INVESTIGATIONS Lab Studies Imaging Studies Electrocardiogram LAB STUDIES-ABG Arterial blood gases • ABGs – • Low PO2, • Low PCO2, & • Respiratory alkalosis;. IMAGING STUDIES - CXR • Important in assessing alternative diagnoses • Commonly normal • Westermark sign (dilatation of pulmonary vessels and a sharp cutoff), • Atelectasis • A small pleural effusion & an elevated diaphragm. V/Q SCAN IN PE NON-INVASIVE TESTS FOR LOWER EXTREMITY DVT Compression ultrasonography: Color-flow Doppler imaging and compression ultrasonography have a high sensitivity (89-100%) and specificity (89-100%) for detection of proximal DVT in symptomatic patients. However, compression ultrasonography has a low sensitivity (38%) and a low positive predictive value (26%) in patients without symptoms of DVT. Patients with positive findings for DVT can be anticoagulated irrespective of their V/Q scan results SPIRAL CHEST CT SCAN Spiral CT can visualize main, lobar, and segmental pulmonary emboli with a reported sensitivity of greater than 90%. The spiral CT scan can detect emboli as small as 2 mm that are affecting up to the seventh order division of the pulmonary artery. The only problem with spiral CT is that small subsegmental emboli may not be detected. The CT scan has another benefit, an alternate diagnosis may be suggested in up to 57% of the patients. CHEST CT SCAN IN PE PULMONARY ANGIOGRAPHY • Pulmonary angiography remains the gold standard for the diagnosis of PE. • Positive results consist of a filling defect or sharp cut-off of the affected artery. • Negative pulmonary angiogram findings, even if falsenegative, exclude clinically relevant PE PULMONARY ANGIOGRAM IN PE PULMONARY ANGIOGRAM IN PE Normal V/Q Scan33PULMONARY J. Galvin, M.D. J.Choi, B.S. The Diagnosis of P. E. Virtual Hospital:http://www.vh.org/Providers EMBOLISM Pulm. Embolism CT 34PULMONARY J. Galvin, M.D. J.Choi, B.S. The Diagnosis of P. E. Virtual Hospital:http://www.vh.org/Providers EMBOLISM Pulm. Embolism CT J. Galvin, M.D. J.Choi, B.S. The Diagnosis of P. E. Virtual Hospital: http://www.vh.org/Providers 35PULMONARY EMBOLISM Pulmonary Arteriogram J. Galvin, M.D. J.Choi, B.S. The Diagnosis of P. E. Virtual Hospital: http://www.vh.org/Providers 36PULMONARY EMBOLISM ECHOCARDIOGRAPHY This modality generally has limited accuracy in the diagnosis of PE. Transesophageal echocardiography may identify central PE, and the sensitivity for central PE is reported to be 82%. Overall sensitivity and specificity for central and peripheral PE is 59% and 77%. Echocardiography may demonstrate right ventricular dysfunction in acute PE, predicting a higher mortality and possible benefit from thrombolytic therapy ELECTROCARDIOGRAM • The most common ECG abnormalities of PE are tachycardia and nonspecific ST-T wave abnormalities. • The classic finding of right-heart strain demonstrated by an S1-Q3-T3 pattern is observed in only 20% of patients with proven PE. • The ECG is most useful in R/O an MI TREATMENT PREVENTION OF DVT/PE-modify risk factors MEDICAL TREATMENT SURGICAL TREATMENT PREVENTION OF DVT LIFESTYLE MODIFICATIONS • Avoid obesity and inactivity • Avoid dehydration • Avoid cigarette smoking • Maintain normal blood pressure MECHANICAL MEASURES • Vascular compression stockings • Intermittent pneumatic compression boots PHARMACOLOGICAL MEASURES • Injectable medications – UFH, LMWH • Oral medications – warfarin, ??aspirin COMBINED APPROACHES MEDICAL TREATMENT THROMBOLYTIC THERAPY • This should be considered for patients who are: • Hemodynamically unstable • Patients who have right-heart strain • High-risk patients with underlying poor cardiopulmonary reserve. THROMBOLYTIC THERAPY The role of thrombolytic therapy in the management of acute PE remains controversial. The currently accepted indications for thrombolytic therapy include hemodynamic instability or right ventricular dysfunction demonstrated on echocardiography Thrombolytic therapy should only be considered in patients with massive PE complicated by shock THROMBOLYTIC AGENTS Streptokinase Urokinase Tissue plasminogen activator THROMBOLYSIS THROMBOLYTICS VRS UFH More rapid improvements in pulmonary vascular resistance Improved RV function BUT Significantly more bleeding complications ANTICOAGULATION Heparin & Warfarin mostly used Heparin anticoagulation: aim for 2x baseline aPTT An initial bolus of 80 U/kg is followed by an infusion of 18 U/kg/h. The heparin dose is further adjusted to maintain an aPTT in the therapeutic range Heparin therapy generally is overlapped with Warfarin for a minimum of 4-5 days Warfarin anticoagulation: aim for INR of 2-3 APTT & PT Blood clots in 4-8 min in a glass tube Chelation of Ca2+ prevents clotting Recalcified plasma clots in 2-4 min Addition of negatively charged phospholipids and kaolin (aluminium silicate) shortens clotting time to 26-33 sec – aPTT  Addition of ‘thromboplastin’ (a saline extract of brain – tissue factor and phospholipids) shortens clotting time to 12-14 sec – prothrombin time (PT)     Nature of Heparin • Heparin is heterogeneous with respect to – molecular size (3,000-30,000; mean of 15000) – anticoagulant activity, and – pharmacokinetic properties • Anticoagulant profile and clearance are influenced by molecular weight • HMW species cleared from the circulation more rapidly than the LMW species. • Differential clearance results in accumulation in vivo of the LMW species. Molecular Weight Distribution of Heparin Mechanism of action of heparin • Antithrombin III–glycosylated circulating plasma protein • Antithrombin III inhibits thrombin (IIa), Xa, IXa and VIIa • The above reaction goes 1000 to 3000 times faster with heparin. Anticoagulant Properties of Heparin • Inhibits the thrombin-mediated conversion of fibrinogen to fibrin • Inhibits activated factors XII, XI, IX, X and II • Inhibits activation of fibrin stabilizing enzyme • Binding of heparin to von Willebrand factor also inhibits von Willebrand factor-dependent platelet function. • A unit (USP unit) = quantity of heparin that prevents 1.0 ml of citrated sheep plasma from clotting for 1 hour after the addition of 0.2 ml of 1% CaCl2 Pharmacokinetics of heparin • Not absorbed orally: given IV or SC • Bioavailability reduced by SC route in low to moderate doses (up to 30,000 U/24hrs). • Subject to plasma binding and elimination by mononuclear phagocyte system (RE system) • Half-life varies with the dose: – ~ 30 min following an IV bolus of 25 U/kg, – ~ 60 min with a bolus of 100 U/kg, – ~150 min with a bolus of 400 U/kg. • Plasma clearance via RE system and the kidneys Uses of heparin • Treatment of DVT (5-10days) • Prophylaxis of DVT & PE – 5,000 U sc every 8 to 12 h results in 60 to 70% risk reduction. • Unstable Angina and NQMI – reduces the risk of developing recurrent angina or acute MI • Acute MI – reduces re-infarction & mortality • Coronary Angioplasty – reduces early thrombotic occlusion Uses of heparin • Open-heart surgery for cardiopulmonary bypass • Hemodialysis • Drug of choice for anticoagulation during pregnancy – does not cross the placenta – not associated with fetal malformations • Recurrent venous thromboembolism while on appropriate doses of oral anticoagulants. • Selected patients with disseminated intravascular coagulation Dosing • Depends on target • Generally, bolus of 80 U/kg • Continuous IV infusion of 18U/kg/hr • Adjust to maintain APTT of 2-2.5 baseline value • For SC route, divide total daily dose into two 12hr injections • SC route delays immediate anticoagulation by at least 1 hr unless IV Laboratory Monitoring • The APTT - measure ~ 6 h after the bolus dose of heparin, and adjust IV dose based on the result. • For sc injection (35,000 U/24 h), the anticoagulant effect delayed for ~1 h; peak plasma levels occur at ~ 3 h. • Anti Factor Xa heparin assay • Anti Xa level of 0.35-0.70 U/ml = patient/control APTT ratio of 1.5-2.5 LMW Heparins • Development of LMWHs for clinical use was stimulated by – reduced antifactor IIa activity relative to antifactor Xa activity – a more favorable benefit-risk ratio – superior pharmacokinetic properties. LMW Heparins • LMWs have a lower ratio of antifactor IIa to antifactor Xa activity. • They are monitored by the antifactor Xa heparin assay, • Less effect on the activated partial thromboplastin time (APTT). • LMWH can be administered in either the in-hospital or out-of-hospital setting subcutaneously • No need for laboratory monitoring Structure and Pharmacology • Derived from heparin by chemical or enzymatic depolymerization, yielding fragments approximately one third the size of heparin. • Mean molecular weight of 4,500 to 5,000 daltons • Cleared principally by the renal route • Longer plasma half-life and better bioavailability at low doses than UFH, • More predictable dose response. Clinical Applications • Prevention of Venous Thrombosis • Treatment of Venous Thromboembolism • Unstable Angina and NQMI LMWH reduced the risk of death or MI by approximately 80% in combination with aspirin • Treatment of PE Neutralizing Heparin • IV protamine, ~ 100-U UFH per milligram of protamine • Neutralization of heparin after a sc dose may require a prolonged infusion or a repeated injection of protamine. • Other methods include – – – – Hexadimethrine, Heparinase (neutralase), PF4, Extracorporeal heparin removal devices, • Protamine neutralizes LMWH incompletely DURATION OF ANTICOAGULATION • A patient with a first thromboembolic event occurring in the setting of reversible risk factors such as immobilization, surgery, or trauma, should receive warfarin therapy for 3-6 months. • In the absence of an identifiable risk factor, the first idiopathic thromboembolic event should be treated for a minimum of 6 months. DURATION OF ANTICOAGULATION II • Warfarin treatment for longer than 6 months: • Recurrent venous thromboembolism • Continuing risk factors - malignancy, immobilization, or morbid obesity. • Life-long anticoagulation: • PE + Preexisting irreversible risk factors eg. Antithrombin III deficiency, Protein S and C deficiency or the presence of Antiphospholipid antibodies. DURATION OF THERAPY SURGICAL CARE Inferior vena cava (IVC) filters: • Acute PE with an absolute contraindication to anticoagulant therapy • recent surgery, hemorrhagic stroke, or significant active or recent bleeding. • Massive PE who survived but in whom recurrent embolism will be invariably fatal • Objectively documented recurrent PE despite adequate anticoagulation. IDEAL IVC FILTER • Easy and safe placement by percutaneous technique • Biocompatible and mechanically stable • Ability to trap emboli without causing occlusion of the vena cava IVC FILTER SURGICAL CARE Pulmonary embolectomy – massive PE not likely to survive conservative treatment Pulmonary thrombo-endarterectomy – chronic recurrent PE