Acute Pulmonary Embolism SB Gupta

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1 Acute Pulmonary Embolism 2010 SB Gupta Pulmonary Embolism accounts for more than 650,000 cases each year and as many as 300,000 deaths annually in the US alone. PE is the 3rd most common cause acute cardiovascular emergency after MI and stroke. PE is still one of the important causes of in-hospital morbidity and mortality and it is the most common cause of preventable hospital death 1. PE occurs on account of dislodgement of thrombus that breaks off and travels in the blood and finally lodges in the pulmonary vasculature. Deep Vein Thrombosis (DVT) is one of the most important precursors for PE apart from rare embolization of cardiac thrombi. Causation of DVT is classically linked to: Virchow's Triad - Alterations in blood flow (stasis): best rest, inactivity/ immobilization, CHF, paralysis - Injury to endothelium: trauma, surgery - Thrombophilia: Factor V Leiden, Protein C or S deficiency, etc. The risk factors for DVT are : Age >50 History of varicose veins History of MI History of malignancy History of atrial fibrillation History of ischemic stroke History of diabetes mellitus Previous Venous Thromboembolism (VTE), obesity, pregnancy VTE occurs more frequently in orthopedic surgery as compared to general surgery. The risk of VTE is highest in first 2 weeks after the surgery and remains high for next 2-3 months. There is significant reduction in VTE if thromboprophylaxis is instituted and the incidence depends upon the duration of thromboprophylaxis - longer the duration, lesser the incidence 2,3. PE occurs most commonly in post operative settings within 3-7 days of surgery and in 10% the cases it is fatal within the first hour. In most of such cases the diagnosis may go unrecognized. 5-10% of the cases present with shock and hypotension and approx. 50% of the patients with features of RV dysfunction (RVD) without shock. In approximately two-thirds of the cases there is complete resolution of the perfusion defects. More than 90% of the deaths occur in untreated patients and less than 10% of the deaths occur in the treated group 1,2,3,4,5. Chronic thromboembolic pulmonary hypertension (CTEPH) develops in 0.5-5% of the treated patients. Recurrence of DVT occurs at the rate of 50% within 3 months with proximal DVT if not treated and those who have been treated adequately for 3-12 months, the rate are events per 100 patient-years 1,2. PATHOPHYSIOLOGY When > 30-50% of the pulmonary arterial bed is occluded, the consequences of pulmonary embolism are apparent and those are mainly haemodynamic. Large and/or multiple emboli increase the pulmonary vascular resistance abruptly which the right ventricle (RV) is not able to cope up and leads to acute RV dysfunction and can lead to : Sudden death - due to electromechanical dissociation Syncope and/or hypotension due to acute RV failure

2 400 Medicine Update-2011 which may progress to shock and may ultimately lead to death. Diastolic LV dysfunction occurs because of bulging of interventricular septum (IVS) on the left side leading to reduced cardiac output. Patient may deteriorate after hours due to recurrent embolization and/or progressive RV dysfunction - secondary haemodynamic destabilization. Ventilation-perfusion mismatch leads to severe hypoxaemia and respiratory insufficiency. Stratification of Pulmonary Embolism Considering the several risks of early death (In-hospital or 30 day mortality), PE is stratified into 3 classes : High Risk Non-High Risk Intermediate Risk Low Risk High Risk Patients (Short Term Mortality > 15%) - Shock or Hypotension (Underlying RV Dysfunction and Myocardial Injury) Intermediate Risk (Short Term Mortality %) - Has evidence of RV Dysfunction and/or Myocardial Injury (No hypotension or shock). Low Risk (Short Term Mortality < 1%) - No Shock or Hypotension or evidence of RV Dysfunction or Myocardial Injury. High Risk patients need aggressive management e.g. Thrombolysis or embolectomy. Intermediate Risk patients need hospitalization while low risk patients can be discharged early or can be managed on home treatment basis 6,7,8. CLINICAL PRESENTATION PE is a difficult diagnosis that may be missed because of a nonspecific clinical presentation. Therefore, high index of suspicion is the key in diagnosing PE. The clinical features are as follows : Asymptomatic Sudden onset of unexplained dyspnea Pleuritic chest pain Tachypnea Tachycardia Anxiety/agitation, cough, hemoptysis, syncope, fever, cyanosis, isolated crackles, pleural friction rub, loud P2, right-sided S3, pulmonary insufficiency murmur, elevated JVP, right ventricular heave, acute worsening of heart failure or lung disease Anderson et al 9 presented the frequency of symptoms and signs in their study, as follows : Observation Rate Dyspnea 77% Chest pain 55% Cyanosis 18% Hemoptysis 13% Syncope 10% In the most severe cases, shock and arterial hypotension may be present. Presence of predisposing factors for VTE will enhance the probability of PE, however 30% of the cases, PE occur in the absence of any predisposing factors. Hypoxia is a very common presentation of PE, but 20% of the cases will have normal PaO 2. CLINICAL PROBABILITY Wells et al 10 described the Canadian Rule for predicting PE clinically for three levels predictions (Low, Intermediate or high) or two levels predictions ( PE unlikely or PE Likely). Revise Geneva Rule 11 is also for clinical prediction. The proportion of PE is around 10% in low probability, 30% in moderate and 65% in high probability category. (Table I) Diagnostic Work Up Routine investigations like ECG, X-rays and Arterial Blood Gas analysis are found abnormal in most of the situations, however the findings are non-specific. Chest X-ray: abnormal in 88% of acute PE Atelectasis (60-70%): most common finding in PE without infarction Classic findings: Westermark sign (increased lucency in area of embolus) Hampton Hump (wedge-shaped pleural-based infiltrate) Abrupt cutoff of vessel Pleural effusion EKG Most common: sinus tachycardia +/- nonspecific STsegment and T-wave changes Classic S1-Q3-T3 pattern Other signs of right heart strain (i.e. new RBBB and ST changes in V1,2 ) ABG Normal does NOT rule out PE

3 Medicine Update Table I. Scoring System for predicting PE on clinical grounds Revised Geneva Score Wells Score Variable Points Variable Points Predisposing factors Predisposing factors Age > 65 years + 1 Previous DVT or PE Previous DVT or PE + 3 Recent Surgery or Surgery or Fracture within 1 month + 2 immobilization Active Malignancy + 2 Cancer + 1 Symptoms Unilateral lower limb pain + 3 Haemoptysis + 1 Haemoptysis + 2 Clinical Signs Heart Rate Heart Rate beats/min + 3 > 100 beats/min beats/min + 5 Clinical signs of DVT + 3 Pain on lower limb deep vein at Clinical judgment Palpation and unilateral oedema + 4 Alternative diagnosis less likely than PE + 3 Clinical Probability Total Clinical Probability (3 levels) Total Low 0-3 Low 0-1 Intermediate 4-10 Intermediate 2-6 High 11 High 7 Clinical Probability (2 levels) Total PE Unlikely 0-4 PE Likely > 4 Westermark Sign Hampton Hump X-ray showing pulmonary infarction and plate-like atelectasis Fig.1: Typical X-rays in patients of Pulmonary Embolism Classic findings: Hypoxia, hypocapnia, respiratory alkalosis, increased A-a gradient SPECIFIC INVESTIGATIONS D-dimer Plasma D0dimer, a degradation product of crosslinked fibrin is found to be elevated in the presence of acute clot. Negative predictive value of D-dimer is high i.e. Normal D-dimer value in a case of suspected PE almost rules out PE. D-dimer value of < 500 µg/l almost rules out PE and 3 months thromboembolic risk in such patients is < 1% 12. D-dimer is elevated in several other clinical conditions such as cancer, infection, inflammation etc, hence the positive predictive value of D-dimer in confirming PE is low. Compression Ultrasonography and CT venography DVT in lower limb may be the cause in almost 90% of the cases of PE. Compressive Venous Ultrasonography (CUS) has

4 402 Medicine Update-2011 almost replaced venography. CUS has a sensitivity of 90% and specificity of 95% in proximal DVT. CUS demonstrates DVT in 30-50% of the cases of PE 13,14. And in a suspected case of PE, if CUS demonstrates DVT, no further testing is required and patient to be treated as a case of PE. CT Venography for the diagnosis of DVT is marginally better, but adds significant amount of irradiation. Echocardiography RV dilatation is found in at least 25% of patients with PE. Echocardiography has not been considered a good diagnostic tool in evaluation of patients with suspected PE. However, in patient with shock and/or hypotension, absence of echocardiographic signs of RV overload or dysfunction practically excludes PE. Echocardiography also gives useful (non-diagnostic) and high probability of PE15. Normal V/Q scans in a suspected case of PE almost rules out PE. Nondiagnostic scan with low clinical probability is acceptable criteria for ruling out PE. Computed Tomography (CT) Since the introduction of Multi Detector Computed Tomography (MDCT), CT angiography has become the investigation of choice for pulmonary vascularature imaging in a suspected case of PE. PIOPED II has reported the sensitivity and specificity, 83% and 96% respectively16. Four recent studies provide evidence in favour of CT as a stand-alone investigation to exclude PE.A negative MDCT in non-high clinical probability group almost excludes PE. However in high risk group, patient with negative MDCT Fig.2: Echocardiogram suggesting a PE. Diastole on the left, systole on the right information in patients with shock and/or hypotension to rule out other causes like cardiac tamponade, acute MI or acute valvular dysfunction. Ventilation Perfusion (V/Q) Scan V/Q scan is an established test for the diagnosis of PE. The test is performed by injection of Technetium (Tc) - 99m labeled macro-aggregated albumin particles (Perfusion) and inhalation of Xenon (Xe) gas, Tc-99m labeled aerosols or Tc-99m labeled carbon microparticles (Ventilation), Perfusion-Ventilation mismatch is noted in cases of PE. North American PIOPED trial classified V/Q scans into 4 categories ; Normal or near-normal, low, intermediate Fig.4: Helical CT showing Bilateral PE needs to undergo further work up by CUS and V/Q scan. MDCT showing a thrombus up to the segmental level can be taken as adequate evidence of PE in most instances. Pulmonary Angiography Though Pulmonary Angiography remained the gold standard for diagnosis of PE as it could visualize thrombi as small as 1 or 2mm even in the subsegmental arteries, but with the advent of MDCT angiography, pulmonary angiography is rarely employed. The mortality due to pulmonary angiography in a pooled analysis of 5 series (total 5696 patients) reported as 0.2% (0-0.3%). DIAGNOSTIC STRATEGIES Diagnostic Strategies is shown in Fig.5. Fig.3: Ventilation-Perfusion (VQ) showing Mismatch PROGNOSTIC ASSESSMENT Shock and hypotension are the principal markers of high risk of early death in acute PE. Posthoc analysis of ICOPER

5 Medicine Update Suspected high-risk PE i.e.with shock or hypotension CT immeidately available No Yes Echocardiography RV Overload No Yes CT available and Patient stabilized CT No other tests available or patient unstable Positive PE-specific treatment Justified Consider Thrombolysis / not justified Embolectomy Negative Search for other causes Thrombolysis / Embolect Suspected non-high risk PE i.e. without shock or hypotension Assess clinical probability of PE Low/Intermediate Clinical Probability or PE Unlikely High Clinical Probability or PE Unlikely D-dimer Negative No Tretment Positive MDCT MDCT No PE PE No PE PE No Treatment Treatment No Treatment or Investigate further Treatment Fig.5: Diagnostic Strategies Adapted from ESC Gudelines 8 data revealed 90-day all-cause mortality rate was 52.4% in patients with SBP < 90 mm Hg compared with 14.7% in normotensive patients 6. On MDCT, combination of RV/LV ratio > 1.0 and CT-derived vascular obstruction index > 40% increased the PPV for 3-month PE-related mortality to 18.8% and RV/LV ratio of, 1.0 was associated with uneventful outcome was 100%17. Elevated levels of BNP or NT-proBNP or Cardiac Troponins

6 404 Medicine Update-2011 were associated with worse outcomes in patients of suspected PE. However, negative predictive value for both cardiac Recommendations : Acute Treatment Class Level High-risk Pulmonary Embolism Anticoagulation with unfractionated heparin should be initiated without delay in patients with high-risk PE I A Systemic hypotension should be corrected to prevent progression of RV failure and death due to PE I C Vasopressive drugs are recommended for hypotensive patients with PE I C Dobutamine and dopamine may be used in patients with PE, low cardiac output and normal blood pressure IIa B Aggressive fluid challenge is not recommended III B Oxygen should be administered in patients with hypoxaemia I C Thrombolytic therapy should be used in patients with high-risk PE presenting with cardiogenic shock I A and/or persistent arterial hypotension Surgical pulmonary embolectomy is a recommended therapeutic alternative in patients with I C high-risk PE in whom Thrombolysis is absolutely contraindicated or has failed Catheter embolectomy or fragmentation of proximal arterial clots may be considered as an alternative to IIb C surgical treatment in high-risk patients when Thrombolysis is absolutely contraindicated or has failed Non-high-risk pulmonary embolism Anticoagulation should be started without delay in patients with high or intermediate clinical I C probability of PE while diagnostic workup is still going Use of LMWH or fondaparinux is the recommended form of initial treatment for most patients with I A non-high-risk PE In patients at high risk of bleeding and in those with severe renal dysfunction, unfractionated heparin I C with an aptt target range of times normal is recommended form of initial treatment Initial treatment with unfractionated heparin, LMWH or fondaparinux should be continued for at least I C 5 days and may be replaced by vitamin K antagonists only after achieving target INR levels for at least 2 consecutive days Routine use of Thrombolysis in non-high-risk PE patients is not recommended, but it may be IIb B onsidered in selected patients with intermediate-risk PE Thrombolytic therapy should not be used in patients with low-risk PE III B Adapted from ESC Guidelines 8 biomarkers had good prognosis. TREATMENT Thrombolysis Thrombolytic therapy rapidly resolves thromboembolic obstruction and exerts beneficial effects on haemodynamic parameters like pulmonary arterial pressure or cardiac index in several published randomized trials. Overall, approximately 92% of patients can be classified as responders to thrombolysis based on clinical and echocardiographic improvement within first 36 hours 18. The greatest benefit of thrombolytic therapy is observed when treatment is initiated within 48 hours of symptom onset, but Thrombolysis can still be used in patients who have had symptoms for 6-14 days. Approved thrombolytic regimens for pulmonary embolism Streptokinase Urokinase rtpa IU as a loading dose over 30 min, followed by IU/hr over hr 4400 IU/Kg as a loading dose over 10 min, followed by 4400 IU/Kg/Hr over hr 100 mg over 2 hr or 0.6 mg/kg over 15 min (maximum dose 50 mg) Adapted from ESC Guidelines 8 Preliminary uncontrolled data appear to support the efficacy and safety of tenecteplase in acute PE. Thrombolytic therapy is the first-line treatment in patients with high-risk PE presenting with cardiogenic shock and/or hypotension, with very few absolute contraindications. For non-high-risk patients, routine use of thrombolysis is not recommended, however it may be considered in selected patients with intermediate-risk PE. However, thrombolytic

7 Medicine Update therapy should not be used in low-risk patients. Surgical Pulmonary Embolectomy In 1924, the first successful pulmonary embolectomy was performed. If patient has absolute contraindications for thrombolytic therapy or failure of thrombolytic therapy or has patent foramen ovale (PFO) or intracardiac thrombi, pulmonary embolectomy is the choice 19. Percutaneous catheter embolectomy and fragmentation Such procedures can be performed as an alternative to surgical pulmonary embolectomy. Usually this technique is employed for proximal pulmonary artery clots. Anticoagulant Therapy Anticoagulation with unfractionated heparin, LMWH or fondaparinux shall be instituted without delay and shall be continued for at least 5 days with confirmed PE and those with high or intermediate clinical probability while the diagnostic work up is already going. VKAs should be instituted as soon as possible and preferably on the same day as the initial anticoagulant. Parenteral anticoagulant shall be stopped when the international normalized ratio (INR) lies between 2.0 and 3.0 on 2 consecutive days. REFERENCES 1. Dalen JE, Alpert JS. Natural History of pulmonary embolism. Prog Cardiovasc Dis 1975;17: Dalen JE. Pulmonary embolism: what have we learned since Virchow? Natural history, pathophysiology, and diagnosis. Chest 2002;122: Kearon C. Natural history of venous Thromboembolism. Circulation 2003;107(23 Suppl 1): Wood KE. Major pulmonary embolism: review of a a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest 2002;121: Konstantinides S. Pulmonary Embolism: impact of right ventricular dysfunction. Curr Opin Cardiol 2005;20: Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353: Kasper W, Konstantinides S, Geibel A, Olschewski M, Henrich F, Grosser KD et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 1997;30: Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galie N, Pruszczyk P et al. Guidelines on the diagnosis and management of acute pulmonary embolism. The Task force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008;9: Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, Forcier A, Dalen JE. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med. 1991;151(5): Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with SimpliRED D-dimer. Thromb Haemost 2000;83: Le Gal G, Righini M, Roy PM, Sanchez O, Aujesky D, Bounameaux H et al. Prediction of pulmonary embolism in emergency department: Long-term anticoagulation and secondary prophylaxis To prevent fatal and non-fatal recurrent VTE events in patients of PE, long-term anticoagulant treatment is being given. VKAs are used in the vast majority of patients to keep the target INR between 2.0 and 3.0 for at least 3 months, except for cancer patients where LMWH is preferred anticoagulant and given for 6 months 20. At least two types of oral agents, selective thrombin inhibitors dabigatran and factor Xa inhibitors rivaroxaban and apixaban, who do not require dose adjustment and no need for laboratory monitoring are currently under investigation. IVC Filters Trousseau in 1868 first suggested the interruption of the inferior vena cava as a method for preventing PE. Venous filters became available in late 1960s and percutaneous deployment became possible about 30 years ago. However as on date, the routine use of IVC filters in patients with PE is not recommended and IVC filters may be used when there is absolute contraindication to anticoagulation and a high risk of VTE recurrence. the revised Geneva score. Ann Intern Med 2006;144: Kruip MJ, Slob MJ, Schijen JH, van der HC, Buller HR. Use of a clinical decision rule in combination with D-dimer concentration in diagnostic work up of patients with suspected pulmonary embolism: a prospective management study. Arch Intern Med 2002;162: Kearon C, Ginsberg JS, Hirsh J. The role of venous Ultrasonography in the diagnosis of suspected deep venous thrombosis and pulmonary embolism. Ann Intern Med 1998;129: Perrier A, Bounameaux H. Ultrasonography of leg veins in patients suspected of having pulmonary embolism. Ann Intern Med 1998;128: Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). The PIOPED Investigators. JAMA 1990;263: Stein PD, Fowler SE, Goodman LR, Gottschalk A, Hales CA, Hull RD et al. Multi-detector computed tomography for acute pulmonary embolism. N Eng J Med 006;354: van der Meer RW, Pattynama PM, van Strijen MJ, van den Berg- Huijsmansn IJ, Putter H et al. Right ventricular dysfunction and pulmonary obstruction index in helical CT: prediction of clinical outcome during 3-month follow-up in patients with acute pulmonary embolism. Radiology 2005;235: Meneveau N, Seronde MF, Blonde MC, Legalery P, Didier-Petit K, Briand F et al. Management of unsuccessful thrombolysis in acute massive pulmonary embolism. Chest 2006;129: Yalamanchili K, Fleisher AG, Lehrman SG, Axelrod HI, Lafaro RJ, Sarabu MR et al. Open pulmonary embolectomy for treatment of major pulmonary embolism. Ann Thorac Surg 2004;77: Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous Thromboembolism. J Clin Oncol 2005;23: