Review Article

Acute Pulmonary Embolism Advances in Treatment

S Gupta*, Brig MM Gupta**

Abstract

Recent advances in interventional cardiology, pharmacotherapeutics and modern surgical management in tertiary cardiac care centers have tremendously improved the present treatment of Pulmonary Embolism (PE). CT pulmonary angiography (CTPA), nuclear lung scan (V/Q scan), D-dimer test and modern echocardiography have revolutionized the diagnostic methodology and risk assessment criteria. Cardiogenic shock or systolic hypotension (BP < 90 mmHg) and presence of right ventricular dysfunction (or failure) are two principal criteria which govern the severity of pulmonary embolism. While all patients of pulmonary embolism require anticoagulation, systemic thrombolytic therapy is the mainstay of initial treatment in massive and submassive pulmonary embolism. When thrombolysis is contraindicated or has failed, urgent surgical embolectomy or catheter embolectomy may be life saving procedures in severe pulmonary embolism. ©

INTRODUCTION

The management of pulmonary embolism (PE) is one of the greatest challenges in emergency medicine. Guidelines on pulmonary embolism have been published by European Society of Cardiology (ESC, 2000),¹ American College of Emergency Physicians (ACEP, 2003)² and British Thoracic Society (BTS, 2003).³ The mortality in pulmonary embolism remains unacceptably high despite advances in diagnosis and modern reperfusion strategies.

The available records of 2392 patients of PE from the world’s largest International Cooperative Pulmonary Embolism Registry (ICOPER) from 52 large institutions in seven countries has been recently analyzed.⁴ Non-massive pulmonary embolism (with systolic BP ³ 90 mmHg) was diagnosed in 2284 (95.5%) cases; of these 29 (1.2%) were diagnosed at autopsy and 90 days mortality was 332 (14.5%). On the other hand 108 (4.5%) had massive pulmonary embolism (hemodynamically unstable PE with systolic BP < 90 mmHg); of these 16 (0.7%) were diagnosed at autopsy; 90 day mortality was as high as 56 cases (51.9%). On further analysis of treatment strategies in 108 massive PE reperfusion therapies like thrombolysis or surgical embolectomy were not attempted in 73 cases (67.5%) and these patients were treated with anticoagulation only. Reperfusion therapies included thrombolysis in 33 (30.5%), surgical embolectomy in 3 (2.7%) and catheter embolization in 1 (0.9%). Right ventricular dysfunction was identified as the most important prognostic factor responsible for in-hospital deaths. Other unfavorable risk factors were age > 80 years, associated cancer, congestive heart failure and COPD.

ASSESSMENT AND DIAGNOSIS

Pulmonary embolism is commonly the sequel of deep vein thrombosis (DVT) either in the legs, thighs or pelvis. Upper limbs and other sites are rarely involved. Predisposing factors for DVT are immobility, hip/knee replacement surgery, abdominal/pelvic surgery, lower limb fracture, malignancy, long distance air travel and oral contraceptives. PE should be considered in differential diagnosis for unexplained dyspnoea, chest pain, tachypnoea, hemoptysis and syncope in patient with above one or more risk factors. Rapid clinical assessment and risk stratification are essential.⁵ Routine investigations like ECG, chest X-ray and 2D-ECHO may contribute to the diagnosis of PE. But more importantly these help in excluding many common conditions like acute myocardial infarction (MI), acute aortic dissection, pulmonary consolidation, pneumothorax etc. Risk stratification along with D-Dimer test may provide useful data.^6,7 Different types of D-Dimer assay are available – Simpli RED test, Elisa VIDAS test, MDA latex particle immunoassay and turbiditimetric assay. D-Dimer test needs to be carefully interpreted in accordance to the guidelines issued by ACEP (2003)² and BTS (2003).³ The D-Dimer test should be better done quantitatively. A positive D-dimer test should be followed by specific diagnostic tests for PE. A negative D-dimer test in low or intermediate risk patients may exclude the diagnosis of PE. DVT can be diagnosed by real time B-Mode venous compression ultrasonography of lower limbs.

A firm and definitive diagnosis of PE is possible by one or more of following three procedures:- (i) Multidetector computer tomography with CT angiography of pulmonary vasculature (ii) routine pulmonary angiography (iii) Nuclear lung scan : ventilation / perfusion scan (V/Q scan).

CT pulmonary angiography (CTPA/CTA) by modern multidetector CT scanners is the first scanning modality of choice in modern era. These scanners have the capability to scan and image almost the entire pulmonary vasculature. It allows direct visualization of the emboli in the pulmonary arteries. A patient with positive CTPA does not require any further confirmatory test. A negative CTPA has 98% predictive value, 83% sensitivity and 96% specificity.^8,9 CT scans can also identify right ventricular dysfunctions and DVT in the same sitting.

The second scanning modality of choice is the V/Q scan. A perfusion scan is performed with IV Technetium 99 labeled albumin and a ventilation scan using inhaled Xenon 133. A normal V/Q scan usually rules out pulmonary embolism. Abnormal scans are reported as low, medium or high probability with their chances of pulmonary embolism. Low probability lung scan requires further investigation like CTPA or pulmonary angiography.

When CTPA and V/Q scan are not available, pulmonary angiography is the only gold standard investigation to confirm pulmonary embolism. However it is an invasive test and carries a low mortality of 0.5%. After pulmonary angiography, the pulmonary catheter may be used for intrapulmonary administration of a thrombolytic agent like urokinase (UK) or recombinant tissue plasminogen activator (rtPA). In modern era, pulmonary angiography is rarely indicated when CTPA and V/Q Scan are available.

After the diagnosis of pulmonary embolism is established, it is essential to confirm the status of right ventricular function. If right ventricular functions are abnormal, reperfusion therapy is indicated to save the life. Methods to diagnose right ventricular dysfunction are summarized in Table 1. In clinical practice, ECHO and serum biomarkers are important tools to establish right ventricular dysfunction.^10,11

MANAGEMENT

General Management

A suspected case of PE must be managed in ICU with cardiac monitor for pulse rate and rhythm, BP, oxygen saturation and respiratory rate with continuous pulse oximetry with full availability of resuscitative measures. The patient should be on maximal inspired oxygen via face mask. Unfractionated heparin or LMWH should be given to all patients in therapeutic doses until the diagnosis of PE is either confirmed or excluded. A senior consultant specialist should be consulted. Patients in severe pain may need analgesics or 1-2 mg of diamorphine may be given intravenously. Avoid all intramuscular injections. Obtain an IV lifeline and start on crystalloids to maintain venous access. Side by side, investigate the patient to confirm the diagnosis of PE e.g. ECG, ECHO, D-Dimer, V/Q scan or CTPA etc. In the presence of severe hypotension, inotropic support and urgent reperfusion strategy may be required. Patient with cardiac arrest requires urgent cardio respiratory resuscitation.

Classification of Pulmonary Embolism

From point of view of therapy patients suffering from PE can be classified into one of the following subsets.¹¹

(a)   Massive Pulmonary Embolism : when patient is in cardiogenic shock (SBP < 90 mmHg) or cardiac arrest or there is fall in systolic BP by > 40 mmHg for at least 15 minutes. Such cases are characterized by hypotension, tissue hypoperfusion and hypoxemia.

(b)   Submassive Pulmonary Embolism: when SBP >/= 90 mmHg but patient has evidence of right ventricular dysfunction as assessed by echocardiography, CT scan, cardiac catheterization or raised biomarkers (Table 1).

(c)   Stable Pulmonary Embolism : when SBP >/= 90 mmHg and there is no evidence of right ventricular dysfunction.

Massive and submassive pulmonary embolism carries a high mortality. Right ventricular failure remains the most important cause of death. Reperfusion of pulmonary arteries rapidly reverses right ventricular failure and may be life saving. Three major reperfusion options for massive and submassive pulmonary embolism are thrombolysis, surgical embolectomy and catheter embolectomy. US FDA has approved thrombolysis with rtPA as the standard first line therapy. For stable pulmonary embolism, anticoagulation with unfractionated heparin or LMWH or direct thrombin inhibitor (e.g. Lepirudin) and Fondaparinux remains the main stay of therapy. Each of various therapeutic options (anticoagulation, thrombolysis, surgical embolectomy, catheter embolectomy and catheter thrombolysis) needs careful consideration and implementation.¹²

THROMBOLYTIC THERAPY

Thrombolytic therapy is regarded as the gold standard first line treatment for massive and submassive PE. The choice of thrombolytic agent depends upon the local thrombolysis policy of the institution. In today’s era, the choice lies between streptokinase (STK) and recombinant tissue plasminogen activator (rtPA). STK is generally recommended being cheap. STK should be avoided if there is previous history of exposure to STK and after a recent streptococcal infection. There is a real danger of allergic / anaphylactoid reaction by re-exposure to STK. rtPA should be preferred when a fast relief of right ventricular function is desired. US FDA has recommended rtPA (Alteplase) provided contraindications are meticulously excluded (Table 2). Urokinase (UK) is another thrombolytic agent which is usually given through catheter into pulmonary artery. It is wise to get blood grouping, activated partial thromboplastin time (aPTT), prothrombin time, hemoglobin and platelet count done before starting thrombolytic therapy. Heparin is usually withdrawn before thrombolysis. Thrombolytic therapy should be attempted as soon as the diagnosis of PE is established. However thrombolysis remains effective up to 10-14 days after the onset of symptoms of PE. While thrombolysis may be life saving in massive and submassive PE, the extent of long term survival and reduction in mortality at 90 days remains unclear.⁴

Dose Schedules in Pe

1.     Streptokinase (STK)

        IV bolus 250,000 units over 30’ followed by infusion of 100,000 units/hr for 12-24 hours

2.     Recombinant tissue plasminogen activator (rtPA)

        IV bolus of 15 mg in 10’ followed by 85 mg in next 2 hours (total = 100 mg)

        To be followed by heparin infusion on completion of tPA

3.     Urokinase (UK)

        Standard Dose: 4400 Units / Kg directly into pulmonary artery for 10’ followed by

        4400 Units/kg/hr for 12-24 hours.

Drawbacks of Thrombolytic Therapy

High cost, Danger of severe and often fatal bleeding : Intracranial in 1-3%, Life expectancy not necessarily increased, Failed thrombolysis (8-10% cases) and Allergic reaction to STK.

TRIALS INVOLVING rtPA IN PULMONARY EMBOLISM

Recombinant tissue plasminogen activator (rtPA) has been utilized since early 1990s. At least five large randomized trials comparing rtPA with heparin for PE have been published.^13-17

Of these, Alteplase v/s heparin¹⁷ is one of the largest and most recent multicentric randomized placebo controlled trial from Germany. Out of 256 patients of massive and submassive pulmonary embolism, 118 patients received Alteplase (rtPA) plus heparin and 138 patients received Heparin plus placebo. The primary end point was death or clinical deterioration requiring escalation of treatment in form of catecholamine infusion, secondary thrombolysis, endotracheal intubation, cardiopulmonary resuscitation and embolectomy. Criteria of RV dysfunction were largely based upon echocardiography and right heart catheterization. The criteria included (i) right ventricular enlargement without mitral valve or left ventricle (LV) disease. (ii) Pulmonary hypertension as tricuspid regurgitation jet velocity > 2.8 m/sec (iii) Precapillary pulmonary pressure > 20 mmHg with pulmonary capillary wedge pressure of < 18 mmHg. Alteplase was given as bolus of 10mg intravenous followed by 90 mg continuous infusion over 2 hours followed by heparin. Heparin was used as 1000 IU/Hr adjusted to aPTT 2.0-2.5 times the normal. In Hospital clinical events are summarized in Table 3. The incidence of primary end point was significantly higher in the heparin plus placebo group than in the heparin plus Alteplase group (p=0.006). The probability of 30 day event-free survival (according to Kaplan-Meier analysis) was higher in the heparin plus Alteplase group (p = 0.005). Treatment with heparin plus placebo was associated with almost three times the risk of death or treatment escalation than that was associated with heparin plus Alteplase (p = 0.006). No case of fatal bleed or cerebral bleed occurred in heparin plus Alteplase group. Thus, Alteplase when given with heparin improved the clinical outcome of acute submassive pulmonary embolism and prevented clinical deterioration requiring the escalation of treatment during the period of hospitalization.

TRIALS INVOLVING STREPTOKINASE (STK)

Streptokinase was first used for acute pulmonary embolism in 1964.¹⁸ Soon a controlled trial of streptokinase in PE, established the efficacy of STK over heparin.¹⁹ This was followed by more randomized trials of STK.^20-22 A randomized trial of streptokinase versus Alteplase in acute massive pulmonary embolism has been published from a single centre of France.²³ Fifty patients of massive pulmonary embolism were enrolled and divided in a randomized fashion into two groups: (a) rtPA group of 25 patients who received a bolus of 10 mg in 10’ followed 90 mg infusion over 2 hrs followed by heparin 20 IU/kg/hr for 12 hours (b) STK group of 25 patients who received 250,000 units of STK over 15’ as bolus followed by 100,000 Units/hour for 12 hours followed by heparin 10 IU/kg/hr for 12 hours. The authors found no significant difference between the two treatment regimes in terms of right ventricular hemodynamic in the two groups at 12 hrs or 48 hours or 10th day. The efficacy of 12 hour STK was as good as that of rtPA over 2 hours. rtPA however worked faster than STK. Hence for hyper acute case where more rapid thrombolysis is desired, rtPA was considered superior to STK but after 12 hours, STK was as effective as rtPA. The same authors have recently reported²⁴ their experience of thrombolytic therapy in 249 patients with massive and submassive pulmonary embolism – STK 179 (72% cases), rtPA 68 (27%) and Urokinase 2 (1%). Recovery of right ventricular functions was considered as a marker of efficacy of thrombolytic therapy. ECHO, Spiral CT/pulmonary angiography were performed before and after thrombolytic therapy to evaluate residual pulmonary arterial obstruction and pulmonary hypertension and recovery of right ventricular dysfunction e.g. right ventricular dilatation, paradoxical motion of IVS and presence of residual clot/embolus. The authors recommended that STK could be used universally unless a rapid thrombolysis is desired when rtPA should be used.

TRIALS INVOLVING UROKINASE (UK)

Urokinase Pulmonary Embolism Trial (UPET)²⁵ and Urokinase Streptokinase Pulmonary Embolism Trial (USPET)²⁶ are two large trials conducted mostly on hemodynamically stable patients. Urokinase was used initially in a loading dose of 4400 IU/Kg over 10’ followed by 4400 IU/Kg/hr for 12-24 hours. UKEP study research group²⁷ was a multicentric trial on two dosage regimens of Urokinase (UK) in massive pulmonary embolism. 129 patients of PE were analyzed. 67 patients received Urokinase 2000 IU/Kg/hr plus heparin for 24 hours and 62 patients received UK 4400 IU/Kg/hr plus heparin for 12 hours. UK was given by a continuous infusion pump into the pulmonary artery through a pulmonary artery catheter. Pulmonary angiogram were performed before and 30-48 hours after UK. UKEP authors concluded that effective thrombolysis and embolus resolution can be achieved by half of standard dose and without any loading dose, when UK is combined with heparin for at least 24 hours. More recently UK was given by intra-pulmonary route in a loading dose of 3300 IU/Kg in 10’ followed by 1000-1500 IU/Kg/hr for 24 hours with good results.²⁸

Meta-analysis of Thrombolytic Trials

There have at least 4 large meta-analysis studies of randomized controlled trials regarding the efficacy, safety and clinical outcome of thrombolytic therapy.^29-32 The latest meta-analysis³² involved 748 patients of pulmonary embolism from 11 randomized controlled trials. There was no significant reduction in recurrent PE or mortality between thrombolysis vs. heparin groups when all patients (748) of PE were considered. However, in the subgroup of 254 massive PE (hemodynamically unstable group), there was definite and significant improvement by the thrombolytic therapy over heparin (Table 4). Further evaluation of the efficacy and safety of thrombolytic therapy in PE appears warranted.

FAILED THROMBOLYSIS

Definition of failure of thrombolysis:-

a)    Persistent hypotensive state (Systolic BP < 90 mmHg)

b)    ECHO evidence of persistent RV dysfunction

c)     Residual pulmonary vascular obstruction > 30% at the 10th days after thrombolysis on Rt Heart Catheterization or multidetector CTPA.

There is no firm policy or guidelines for the management of failed thrombolysis. Various options are:

a)    Wait and watch using anticoagulants only

b)    Repeat thrombolytic therapy with alternative thrombolytic agent

c)     Rescue surgical embolectomy

d)    Catheter fragmentation / embolectomy

In practice, surgical embolectomy or catheter embolectomy are often restricted to certain specialized tertiary hospitals with available expertise for clinically desperate cases. Many centers advocate repeat thrombolysis.

The data of 488 patients of massive PE who had undergone thrombolysis from Jan 1995 to Jan 2005 from a single centre in France have been recently analyzed.³³ 40 cases (8.2%) failed to respond to thrombolysis. Of these, 14 underwent surgical embolectomy and 26 repeat thrombolysis. The outcome and results are summarized in Table 5. There were more deaths, bleeding and recurrent PE in the medical group undergoing repeat thrombolysis compared to surgical embolectomy. It was concluded that rescue surgical embolectomy led to a better hospital outcome than repeat thrombolysis. Transfer to a selective tertiary cardiac care surgical centre may be a better option than a repeat thrombolysis.

SURGICAL EMBOLECTOMY

Surgical embolectomy is indicated under the following conditions:-

1.     Thrombolysis is contraindicated

2.     Failed thrombolysis

3.     Recurrent PE despite thrombolysis

Modern surgical treatment has improved remarkably in specialized centers and rescue embolectomy for very compromised patients may be life saving.^34-36 More recently Digonnet et al (2007)³⁷ have reviewed the clinical outcome of 21 patients who underwent surgical embolectomy. 14 had massive PE and 7 submassive PE. 43% of massive and 100% of submassive PE survived. A follow-up of 57 ± 12 months did not reveal late death due to recurrent PE. The authors concluded that rescue surgical embolectomy improved the outcome in massive pulmonary embolism. Surgical embolectomy was successful in all cases of submassive PE and may be considered as primary treatment of choice. However, post-operative complications include – acute respiratory distress syndrome, mediastinitis, acute renal failure and neurological complications. The mortality of massive PE is still 30-50% in cases of surgical embolectomy.

CATHETER EMBOLECTOMY

Indications for catheter embolectomy are not clearly defined. Possible indications for catheter embolectomy in massive pulmonary embolism are:-

1.     Thrombolysis either contraindicated or failed

2.     Patient unwilling for surgical embolectomy

3.     Presence of expert interventional cardiologist with availability of catheter device.

Following types of catheter devices have been utilized:-

1.     The Greenfield embolectomy catheter (Boston Scientific)

2.     The Pigtail Rotational catheter (Cook-Europe, The Netherlands)

3.     Amplantz Thrombectomy Device (ATD, Bard Microvena, MN)

4.     The balloon angioplasty and stents (self expanding wall stent and Gianturco Z-Stent).

5.     Hydrodynamic Thrombectomy catheter device (e.g. Angio Jet, X-Peedior, Possus, MN).

6.     Aspirex pulmonary embolism thrombectomy catheter (Straub Medical, Switzerland)

Currently a multinational registry is investigating the effectiveness and safety of catheter devices for pulmonary embolism (38). Catheter embolectomy may be a minimally invasive alternative to surgical embolectomy. Catheter induced fragmentation or thrombectomy may be followed by thrombolytic therapy after about 100-120 minutes with Urokinase/rtPA injected locally through the same pulmonary catheter. Complications of catheter thrombectomy include perforation or dissection of pulmonary artery, pericardial tamponade and injury to the right ventricle cardiac arrhythmias, bleeding and hemolysis. Mortality is around 30%.

ANTICOAGULANT THERAPY IN PULMONARY EMBOLISM

Whether or not a patient undergoes reperfusion therapy in form of thrombolysis or embolectomy, anticoagulation forms a critical and universal component of therapy of PE in all cases. Systemic anticoagulation does not directly address and dissolve the thrombus or clot and relies on body’s own antifibrinolytic system for the clearance of embolus. Anticoagulants help in preventing formation of new thrombus and fibrin deposition and recurrent embolism.

Anticoagulation is done either by unfractionated heparin or low molecular weight heparin (LMWH) or direct thrombin inhibitors or Fondaparinux. The cheapest option is unfractionated heparin. Before starting heparin, screening tests e.g. aPTT, PT and platelet count should be done along with complete hemogram. This is to have pre-treatment data, particularly in patients who have liver or kidney disorders and in patients with a high risk of bleeding. The aPTT is to be maintained 2.0 – 2.5 times the normal under heparin therapy. Heparin is usually given initially as a bolus of 5000-10000 units followed by a continuous infusion. The total daily dose of heparin is around 25,000 units and should not exceed 40,000 units/day. Heparin requires careful daily laboratory monitoring. In case of overdose and bleeding, heparin should be withheld. A few patients may require blood transfusion and specific antidote Protamine Sulfate (1 mg of protamine neutralizes 100 units of heparin). 25-50 mg of protamine may be required IV over 10-30 minutes. LMWH are safer than heparin and have a longer half life. These are given subcutaneously and do not require daily laboratory monitoring. LMWH is usually given as 40-60 mg s/c twice daily.

Both heparin and LMWH are rarely associated with “Heparin induced thrombocytopenia (HIT)” which results from heparin dependent immunoglobulin G antibodies directed against heparin platelet factor 4 complex. HIT is usually seen 4-14 days after heparin therapy. HIT is a serious condition and can cause devastating bleeding and thrombotic complications. HIT does not respond to platelet transfusion. Heparin must be stopped. HIT may respond to plasmapheresis. Anticoagulation is achieved by direct thrombin inhibitors like Argatroban or recombinant Hirudin (Lepirudin).

Fondaparinux is a synthetic polysaccharide with anti-Xa activity. It is as effective as heparin and is not associated with HIT. Dose is weight related and it is given subcutaneously. Usual dose is 5mg for patients under 50 kgs, 7.5 mg for patients 50-100 Kg and 10 mg for patients over 100 Kgs.

Long term anticoagulation is usually achieved by oral anticoagulants (Warfarin or Acenocoumarol). CANADIAN Trial,³⁹ International THRIVE trial⁴⁰ and PREVENT trial⁴¹ have firmly established the role of oral anticoagulation in the prevention of DVT and PE. Oral anticoagulants are given for 3-6 mths. The aim is to maintain prothrombin time/INR 2-3 times of normal. The main danger of prolonged oral anticoagulation is the risk of bleeding.

DVT prevention in hospital practice is a matter of institutional policy and implementation of its directions. Many surgeons and physicians fail to implement DVT prophylaxis due to ignorance or fear of bleeding.

MISCELLANEOUS OPTIONS IN PE

(A) Inferior Vena Caval Filters

These are inserted and positioned percutaneously to prevent emboli from calf and thigh to travel up to the lungs. Most filters are positioned infra-renally (Bird’s nest filter) but can also be placed supra renally (Greenfield filter). These have been advocated in patients where anticoagulation is either contraindicated or fails to prevent recurrent PE. The inferior vena caval filters have not gained popularity because in many cases, the filter itself has served as nidus for further thrombosis and embolism. In a recent large California database study, the filters were associated with significant increase in venous thromboembolism.⁴²

(B) Sildenafil

Sildenafil selectively inhibits cyclic guanosine monophosphate specific phosphodiesterase-5 which is found abundantly in the lungs. By this action, sildenafil enhances nitrous oxide mediated pulmonary vasodilatation and reduces pulmonary arterial pressure.

Sildenafil has been used for treatment of pulmonary hypertension.⁴³ FDA, USA has approved Sildenafil for pulmonary hypertension in June 2005. Ganiere et al (2006)⁴⁴ have reported remarkable improvement 120 minutes after administration of Sildenafil (50 mg tds) in a patient with Massive PE with persistent respiratory failure even after thrombolytic therapy. There was progressive hemodynamic stability. Sildenafil was gradually withdrawn without any adverse effect. The authors concluded that Sildenafil may prove to be useful adjunct to standard thrombolytic therapy. However, further studies are needed to investigate the role of Sildenafil in PE.

CONCLUSION

Pulmonary embolism is a life threatening condition with considerable high mortality. Early recognition and classification into massive, submassive and stable subsets of pulmonary embolism will help in choosing the best treatment options for a particular patient. Systemic thrombolysis remains the mainstay of treatment in massive and submassive pulmonary embolism. If thrombolysis is contraindicated or failed and there is persistent pulmonary vascular obstruction, surgical or catheter embolectomy can prove life saving under expert hands. Anticoagulation is a universal component of therapy in all cases irrespective of thrombolysis or embolectomy.

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