Massive Acute Pulmonary Embolism

Massive Acute Pulmonary Embolism Guy Meyer

CHAPTER

32

Definition

Thrombolytic Agents

Diagnosis of Massive Pulmonary Embolism

Pulmonary Embolectomy

General Medical Support

Conclusion

In-hospital mortality of clinically stable patients without major comorbidity receiving anticoagulant treatment for pulmonary embolism (PE) has been reported to vary between 1% and 2% in recent controlled trials.1,2 By contrast, more than 25% of patients having a pulmonary embolism and low blood pressure die in the hospital.3-5 A subgroup of patients with normal blood pressure who have right ventricular failure on admission as detected by echocardiography may have a higher mortality rate than patients with normal echocardiographic findings.6 Recent data further suggest that cardiac biomarkers, such as troponin and brain natriuretic peptide (BNP), also help identify patients with adverse outcomes among those with normal blood pressure.7,8 Accordingly, it has been suggested that PE be classified into two main categories: (1) massive PE defined by a systolic blood pressure of 90 mm Hg, or a pressure drop of 40 mm Hg for at least 15 minutes, and (2) nonmassive PE.9 An additional category, submassive PE, is considered to be a subcategory of nonmassive PE with evidence of right ventricular dysfunction.9 Suspected cases of massive PE require prompt confirmation using bedside tests. In these patients, supportive measures are needed and thrombolytic therapy is indicated.10 Pulmonary embolectomy is useful in a small subset of patients with massive PE, whereas catheter embolectomy requires additional evaluation. The clinical benefit of thrombolytic therapy in patients with submassive PE is less clear and international experts currently advise against using thrombolytic therapy in these patients.10

Definition Pulmonary vascular obstruction has long been considered the main criteria for defining massive pulmonary embolism; however, recent studies strongly suggest that clinical tolerance rather than vascular obstruction is the main determinant of hospital mortality in patients with PE. As a result, massive PE is now defined as PE with persistent systemic hypotension (i.e. systolic blood pressure of 90 mm Hg for at least 15 minutes or a drop of systolic blood pressure of at least 40 mm Hg).9 Alpert and associates reported on 144 patients with angiographically proven PE: they found that PE-related mortality was 5% in patients with a vascular obstruction below 50% and 16% in those patients with a pulmonary vascular obstruction exceeding 50%. However, the excess mortality in the latter group was limited to patients with cardiogenic shock as a result of PE. The mortality rate was

greater in this group of patients (32%) than in those with high vascular obstruction but normal blood pressure (6%).4 More recently, 1001 patients with pulmonary hypertension because of PE were grouped into four categories by Kasper and associates: (1) those with normal blood pressure; (2) those with isolated arterial hypotension; (3) those with cardiogenic shock; and (4) those who sustained cardiopulmonary resuscitation.5 Hospital mortality was 8% in group 1, 15% in group 2, 25% in group 3, and 65% in group 4. The mortality rate listed in the International Cooperative Pulmonary Embolism Registry (ICOPER) was 58% for patients who were hemodynamically unstable at the time of presentation, and 15% for those who were hemodynamically stable.3 In that study, systolic blood pressure below 90 mm Hg was used as an independent predictor for early death (hazard ratio: 2.9 (95% confidence interval: 1.7 to 5.0). Those patients represented only 4.2% of the total population included in the study. Patients with normal blood pressure have a much better clinical outcome and are considered as having nonmassive PE.9 However, several studies have identified a subgroup of patients considered as having submassive PE with normal blood pressure who may have an increased risk of mortality. Ribeiro and colleagues were the first to suggest that patients with right ventricular failure may have increased mortality. In that study, 126 consecutive patients with PE were examined with echocardiography on the day of diagnosis. Patients were divided into two groups: group A (n = 56) with normal or slightly reduced RV function and group B (n = 70) with moderately or severely reduced RV function. Four deaths occurred in group A and 15 in group B (p = 0.04).6 However, the patient population was composed of stable and unstable patients, and the outcome of patients with normal blood pressure with and without right ventricular dysfunction was not specified. Five studies have evaluated the value of echocardiography as a prognostic tool in hemodynamically stable patients with PE.11-15 Right ventricular dysfunction was associated with a 2.4-fold (95% CI: 1.3 to 4.4) increased risk of hospital mortality. Criteria used to define right ventricular dysfunction differed from one study to another and the risk of death was not adjusted for major confounding factors. More recently, the role of cardiac biomarkers as early predictors of outcome has been investigated in several studies. Four studies assessed brain natriuretic peptide in clinically stable patients with PE.8,13,14,16 A high BNP level was associated with a tenfold increase in the risk of hospital death (95% CI: 3.2 to 35.3).

Massive Acute Pulmonary Embolism

Similarly, increased values of pro-brain natriuretic peptide and troponin are associated with a 5.7-fold (95% CI: 2.2 to 15.1) and 7.5-fold (95% CI: 3.1 to 18.1) increased fatality risk.8,12,17 However, most studies were carried out in individual medical centers and included a small number of patients. Also, the threshold values for each biomarker differed from one study to another and the risk was not adjusted for major confounders. As a result, the role of these biomarkers in selecting patients at risk requires further evaluation in larger multicenter cohorts.

Diagnosis of Massive Pulmonary Embolism The risk of death in patients with massive PE is maximal during the first few hours following their admission to the hospital and prompt diagnostic confirmation and treatment are mandatory. In addition, in-hospital transportation of hemodynamically unstable patients is associated with an increased risk of morbidity and mortality; thus every effort should be made to confirm the diagnosis of suspected massive PE using bedside diagnostic tests. No specific literature is available on the diagnosis of massive PE; however, the basic principles for diagnosing clinically stable patients with suspected PE can probably be applied to unstable patients.18 Indeed, evaluating the clinical probability of PE should be the first step in the diagnosis process. Several rules have been published, but clinical probability can also be based on the clinical gestalt of risk factors, clinical signs and symptoms, chest radiography, blood gas analysis, and ECG.19,20 If the clinical probability is high, which is often the case when massive PE is suspected, a D-dimer test result is of little value.18,21,22 The positive likelihood ratio of bedside transthoracic echocardiography demonstrating right ventricular dilation (5.0; 95% CI: 2.3 to 10.6) is high enough to confirm PE when the clinical probability is high.18 Presence of clots in the right heart chambers is rare and is not required to confirm PE. In addition, ­echocardiography can rule out left ventricular dysfunction and pericardial tamponade,

which may clinically mimic massive PE. Conversely, the negative likelihood ratio of a normal echocardiography (0.6; 95% CI: 0.4 to 0.9) is not low enough to rule out PE when the clinical probability is high.18 If echocardiography is normal, spiral computed tomography of the pulmonary arteries is required to confirm or rule out PE after the patient's hemodynamic status has been stabilized (Fig. 32-1).

General Medical Support Oxygen Arterial hypoxemia is a common finding in patients with acute PE. The degree of hypoxemia is usually moderate; in 81 patients submitted to pulmonary embolectomy, the mean arterial partial pressure of oxygen breathing room air was 51 ± 12 mm Hg at the time of admission.23 Oxygen administration by nasal cannula or facemask is usually sufficient for maintaining arterial oxyhemoglobin saturation within the normal range. Mechanical ventilation is only rarely required and positive pressure must be applied very cautiously because of its detrimental effects on cardiac output in right ventricular failure. Fluid Loading Acute pulmonary artery obstruction increases right ventricular afterload and end-diastolic and end-systolic right ventricular volumes and decreases right ventricular stroke volume. These changes may reduce left ventricular preload and impair left ventricular function as a result of ventricular interdependence, and a decrease in cardiac output with circulatory failure may ensue. Fluid loading increases the right ventricular end-diastolic volume and may increase cardiac output by the Frank-Starling mechanism, but it may also increase the leftward septal displacement, thereby worsening left ventricular diastolic function. Animal studies have addressed this issue with conflicting results. The effect of fluid loading in patients with PE and circulatory failure has been evaluated in two studies.24,25 In 13 mechanically ventilated patients with massive PE, the cardiac index increased

Clinical probability (CP) High

Low or moderate

Echocardiography Treatment

RV dilation

Normal

Spiral CT Treatment

Segmental clot Normal High CP

Treatment Figure 32-1.  Suggested diagnostic algorithm for ­patients with suspected massive pulmonary embolism (PE). RV, right ventricular.

Thrombus

Low or moderate CP

Venous ultrasound Normal

PE ruled out

399

32

Noncoronary Diseases: Diagnosis and Management

from 1.7 ± 0.6 L/min/m2 to 2.0 ± 0.7 L/min/m2 after a 600-mL fluid challenge.25 More recently, we observed a significant 25% increase in the cardiac index from 1.7 ± 0.2 to 2.1 ± 0.2 L/min/m2 in 10 patients after a 500-mL fluid challenge was administered over 15 minutes.24 Inotropic Support Inotropic support is required when shock persists despite fluid loading. Isoproterenol, dobutamine, dopamine, and norepinephrine all improve the hemodynamic status in animals with experimental massive PE and hypotension. However, severe hypotension is rarely observed in patients with massive PE and most of these drugs have not been evaluated in clinical studies. In 10 patients with massive PE, Jardin and colleagues found a 35% increase in the cardiac index during dobutamine infusion as a result of stroke volume increase, whereas the heart rate decreased significantly.26

Thrombolytic Agents Hemodynamic Effects Thrombolytic treatment induces a rapid decline in pulmonary artery resistance in patients with acute PE and pulmonary hypertension. Alteplase, given as a 100 mg dose over 2 hours, reduces the mean pulmonary artery pressure from 30.2 +/- 7.8 mm Hg to 21.0 +/- 6.7 mm Hg and increases the cardiac index from 2.1 +/- 0.5 L/min/m2 to 2.4 +/- 0.5 L/min/m2 after 2 hours, whereas no significant change is observed with heparin.27 Reduction of Pulmonary Vascular Obstruction Thrombolytic treatment reduces vascular obstruction quicker than heparin alone. Pulmonary vascular obstruction as assessed by the Miller index decreased significantly from 28.3 +/- 2.9 to 24.8 +/- 5.2 two hours after the start of alteplase infusion, whereas no significant difference was observed in patients who received heparin alone.27 Importantly, however, the differences between the thrombolysis and the heparin group disappeared after 7 days of follow-up.27 Thus thrombolytic therapy restores

pulmonary vascular flow and right heart hemodynamics faster than heparin alone, but both treatments result in a similar degree of improvement after 1 week. Effects of Thrombolysis on Recurrent PE, Major Bleeding, and Mortality Eleven controlled studies compared thrombolytic therapy with heparin in patients with PE (Table 32-1).27-37 Only one small study included patients with massive PE alone,32 four studies included some patients with massive PE and a majority of patients with submassive PE,28,30,35,37 and six trials included clinically stable patients with or without right ventricular dysfunction.* To date, no study has compared thrombolytic therapy and heparin in patients with submassive PE. Eight studies had an open design and three were placebo controlled. PE diagnosis was confirmed using invasive procedures in seven trials.27-30,35-37 Recurrent PE was objectively confirmed in only two trials.28, 33 Criteria for major bleeding were not explicitly given in some studies and differed significantly among other studies. Overall, only 748 patients were included in these studies, and their outcome was analyzed in four meta-analyses.38-41 The overall death rate was lower for patients who had thrombolytic therapy (4.3%) when compared with those that received heparin alone (5.9%; OR, 0.70; 95% CI, 0.37 to 1.30). The overall rate of major bleeding was 9.1% in patients who were allocated to thrombolytic treatment and 6.1% in those who received heparin. The relative risk for major bleeding associated with thrombolysis was 1.42 (95% CI, 0.81 to 2.46).38 Most major bleeding cases occurred in studies that used central venous access for angiography and invasive hemodynamic monitoring (Table 32-2). Overall, the rate of major bleeding averages 20% in patients receiving fibrinolytic therapy and 12.5% in those receiving heparin. The rate of major bleeding reported in the most recent studies using noninvasive diagnostics and monitoring is far lower, averaging 2% in patients who were receiving thrombolytic treatment and 3% in patients who were receiving heparin.31-34 Intracranial bleeding remains a major concern in patients receiving thrombolytic treatment for PE, with an estimated incidence of intracranial bleeding of 1.9% *References

27, 29, 31, 33, 34, 36.

Table 32-1.  Controlled Trials Comparing Heparin and Thrombolytic Therapy in Patients with PE Study

n

Unstable patients (n)

Fibrinolytic drug

Diagnostic procedure

UPET28

160

Yes (11)

Urokinase

Invasive

Tibbutt37

30

Yes (14)

Streptokinase

Invasive

Ly35

25

Yes (2)

Streptokinase

Invasive

Dotter30

31

Yes (2)

Streptokinase

Invasive

Marini36

30

No

Urokinase

Invasive

PIOPED29

13

No

rtPA

Invasive

Levine34

58

No

rtPA

Noninvasive

Dalla-Volta27

36

No

rtPA

Invasive

Goldhaber31

101

No

rtPA

Mainly noninvasive

Jerjes-Sanchez32

8

Yes (8)

Streptokinase

Noninvasive

Konstantinides33

256

No

rtPA

Mainly noninvasive

rtPA: recombinant tissue-type plasminogen activator

400

Massive Acute Pulmonary Embolism Table 32-2.  Results of the Randomized Trials Comparing Thrombolytic Therapy and Heparin in Patients with PE Major Bleedings* (n)

n Study UPET

Heparin

197328

Tibbutt 197437 Ly

197835

Fibrinolysis

Heparin

Fibrinolysis

Recurrent PE* (n) Heparin

Fibrinolysis

Deaths (n) Heparin

Fibrinolysis

78

82

11

22

15

12

7

6

17

13

1

1

1

0

1

0

11

14

2

4

0

0

2

1

Dotter

197930

16

15

0

0

1

0

2

1

Marini

198836

10

20

0

0

0

0

0

0

4

9

0

1

0

0

0

1

PIOPED 199029 Levine

199034

25

33

0

0

0

0

0

0

Dalla-Volta

199227

16

20

2

3

1

1

1

2

Goldhaber

199331

55

46

1

3

5

0

2

0

4

4

0

0

0

0

4

0

138

118

5

1

4

4

3

4

Jerjes Sanchez 199532 Konstantinides *Some

200233

events (recurrent PE or bleedings) were fatal and counted both as events and in the deaths.

(95% CI, 0.7 to 4.1).42 Risk factors for major bleeding include old age and invasive diagnostic procedures.43 Massive Pulmonary Embolism One single small randomized trial has compared streptokinase with heparin in patients with massive PE. Although 40 patients were expected to be recruited, the trial was terminated early after only eight patients had been included. All patients had cardiogenic shock on inclusion; four were allocated to streptokinase and survived, and four were allocated to heparin and died during the 72 hours following randomization.32 These results prompted the ethics committee to stop the trial. In a recent meta-analysis of the controlled studies comparing thrombolytic therapy with heparin in patients with PE, a subgroup analysis was performed on the five studies that included patients with massive PE and shock.38 The patients allocated to thrombolysis had a mortality rate of 6.2% and those who were receiving heparin alone had a rate of 12.7% (odds ratio, 0.47; 95% CI, 0.20 to 1.10). The difference was significant if recurrent PE and deaths were considered: odds ratio, 0.45; 95% CI, 0.22 to 0.92.38 Notably, however, only a minority of the patients included in those trials had massive PE (see Table 32-1). The high mortality rate seen in patients with massive PE who receive heparin alone, the early hemodynamic improvement observed with thrombolytic therapy, the results of the small randomized study by Jerjes-Sanchez and colleagues, and the recent meta-analysis all suggest that thrombolytic therapy is associated with significant clinical benefit in patients with massive PE. Thus most authorities recommend the use of thrombolytic therapy in this setting.9,10 Submassive Pulmonary Embolism To date, the largest randomized study assessing thrombolytic treatment for submassive PE included 256 patients with PE and normal blood pressure who were allocated to receive either heparin alone or both alteplase and heparin.33 The primary end point consisted of the combination of in-hospital death or clinical deterioration requiring the escalation of treatment. This was

reached in 11% of the patients in the alteplase group and was reached in 24.6% in the heparin group (p = 0.006). The difference was mainly due to the use of secondary open-label thrombolytic therapy, which was more frequent in the patients assigned to receive heparin (23.2%) than in those receiving alteplase (7.6%; p = 0.001). The death rate did not differ significantly between the groups. The unexpected low mortality rate in patients receiving heparin (2%) may be related to the low (30%) proportion of patients with right ventricular dysfunction, or to the early use of rescue thrombolytic treatment for those patients who did not improve with heparin. Overall, thrombolytic therapy was compared with heparin in six studies, in which 494 clinically stable patients with submassive or nonmassive PE were included.* The death rate was 3.3% for those receiving thrombolytic therapy and was 2.4% for those allocated to heparin (OR, 1.16; 95% CI, 0.44 to 3.05). Thus the current evidence from controlled studies does not indicate that patients with submassive PE receiving thrombolytic treatment have a lower in-hospital mortality risk. As mentioned above, however, most of these studies included patients with nonmassive PE resulting in a low death rate in both groups. In addition, the number of patients remains low. As a consequence, the available clinical trials and meta-analyses are underpowered and are unable to detect clinically important differences between thrombolytic therapy and heparin in patients with submassive PE. Some indirect evidence may suggest that thrombolytic therapy may improve the short-term outcome of patients with submassive PE, despite negative results from controlled studies. Goldhaber and coworkers did a post hoc analysis on a subgroup of 36 patients with right ventricular hypokinesis, who were included in their controlled study comparing alteplase and heparin. They observed five PE recurrences (two of them fatal) among 18 patients who were treated with heparin, whereas no deaths or recurrent PE occurred among the 18 patients who received alteplase.31 In the MAPETT study, the death rate was lower for patients receiving thrombolytic treatment, which *References

27, 29, 31, 33, 34, 36.

401

32

Noncoronary Diseases: Diagnosis and Management

was the only independent predictor of a favorable outcome.44 However, this was an observational study and treatments were not randomly allocated. Experts have expressed contradicting opinions on indications for thrombolytic therapy in patients with submassive PE.4,41,45,46 A large international investigatorinitiated randomized study comparing thrombolysis to heparin in 1000 patients with submassive PE, defined by elevated troponin and right ventricular failure (assessed by echocardiography or spiral CT), is under way to clarify this issue. Results of Various Thrombolytic Regimens Various thrombolytic regimens have been evaluated in controlled trials. Urokinase, given as a bolus dose of 4400 IU/kg followed by a 12-hour or 24-hour maintenance infusion of 4400 IU/kg/hr, was compared with streptokinase, given as a 250,000 IU bolus dose followed by a 100,000 IU/hr infusion given over 24 hours, in a large randomized trial.47 The three regimens produced the same degree of hemodynamic and angiographic improvement with no significant differences in terms of major hemorrhage. Recombinant tissue-type plasminogen activator (rtPA) given as a 2-hour 100 mg infusion was compared with a 4400 IU/kg/hr infusion of urokinase, given over 12 or 24 hours.48,49 rtPA led to a faster hemodynamic and angiographic improvement, but the two drugs yielded similar hemodynamic results by the end of the urokinase infusion. Patients receiving rtPA had a nonsignificant reduction in major bleeding.48,49 A similar rtPA regimen was subsequently compared with a shorter urokinase regimen, given as a 3 million IU infusion over 2 hours.50 No differences in hemodynamic improvement and bleeding between the groups were observed, suggesting that when the two drugs are given over the same time period they share similar efficacy and safety. The 2-hour rtPA regimen resulted in faster hemodynamic improvement than a 12-hour streptokinase infusion, whereas no difference was observed when the two drugs were given over the same 2-hour period.51,52 The rate of major bleeding was lower for patients receiving the 2-hour streptokinase infusion than the 2-hour rtPA regimen, but the difference was not significant.51 Two studies compared a rtPA dose of 0.6 mg/kg body weight given over a period of 15 minutes with the 100 mg regimen given over 2 hours.53,54 Hemodynamic improvement was slightly but significantly faster for the 2-hour regimen, but the 0.6 mg/kg dosage was associated with a nonsignificant reduction in major bleeding.53,54 Contraindications to Thrombolytic Therapy For patients with hemodynamic compromise who do not improve with anticoagulation and pressure support, the benefit of thrombolytic treatment outweighs its risk of bleeding, even in the presence of minor contraindications. The main contraindications to thrombolytic therapy are given in Table 32-3. Additional Measures As most bleeding episodes occur at the puncture site, it is mandatory to avoid invasive diagnostic procedures, such as pulmonary angiography, if thrombolytic treatment is being considered. Thrombolytic therapy can be given through a peripheral line. Central venous lines should be avoided. Heparin should be interrupted during thrombolysis and resumed as soon as the activated partial thromboplastin time is within the target range. There are still no data for the combination of thrombolytic and low-molecular weight heparin therapy in PE. 402

Table 32-3.  Contraindications to Thrombolytic Therapy in Pulmonary Embolism Major contraindications to thrombolytic therapy in ­patients with massive PE • Active bleeding • Stroke within the last 2 months • Spontaneous intracranial bleeding at any date Minor contraindications to thrombolytic therapy in ­patients with massive PE • Major surgery within the past 10 days • Major trauma within the past 15 days • Ophthalmologic surgery or neurosurgery within 30 days • Platelet count less than 100,000/mm3

Pulmonary Embolectomy Surgical Pulmonary Embolectomy Pulmonary embolectomy using cardiopulmonary bypass was first reported in 1961 and is now considered to be the best operative technique. In 17 large studies, the operative mortality averages 36%.55 Ideally, pulmonary embolectomy should be attempted only in those patients who will not survive without surgery because of the high mortality rate in patients that have undergone this procedure. However, an unequivocal set of criteria that accurately identifies these patients remains elusive. As a result, the role of surgical embolectomy in the treatment of PE has been the subject of much discussion but few definitive conclusions. According to the last ACCP consensus, the candidate should meet the following criteria: (1) massive PE; (2) shock despite heparin and resuscitation efforts; and (3) failure of thrombolytic therapy or a contraindication for its use.10 In our experience, these patients represent only 3% of those referred for massive PE.23 Percutaneous Procedures Several transvenous procedures have been proposed for pulmonary embolectomy, including suction, clot fragmentation with angiography catheters, ultrasound-assisted aspiration, laserassisted embolectomy, and clot fragmentation using several other devices.56 Most of these procedures have been evaluated in vitro or in animal experiments, but clinical evaluation is still limited to small retrospective case series for most devices.57 In addition, most devices were used with concomitant fibrinolytic treatment and the respective roles of catheter embolectomy and thrombolytic therapy in the patient's outcome is difficult to ascertain.56,57

Conclusion Patients who have massive PE with systemic hypotension and cardiogenic shock have a high mortality rate when receiving heparin alone. Available evidence strongly suggests the use of thrombolytic treatment in these patients. Recent data indicate that patients with so-called submassive PE may have a higher mortality risk than patients with normal right ventricular

Massive Acute Pulmonary Embolism

f­ unction. Controlled studies available to date are insufficiently powered to confirm or exclude the clinical benefit of thrombolytic therapy in those patients. A large randomized controlled trial is currently under way to address this issue. Pulmonary embolectomy should be considered in the few patients with PE and cardiogenic shock receiving full hemodynamic support and who do not improve while receiving thrombolytic treatment or for whom thrombolytic treatment is contraindicated.

References   1. B  uller HR, Davidson BL, Decousus H, et al: Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003;349:1695-1702.   2. Simonneau G, Sors H, Charbonnier B, et al: A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE study group. Tinzaparine ou heparine standard: evaluations dans l'embolie pulmonaire. N Engl J Med 1997;337:663-669.   3. Goldhaber SZ, Visani L, De Rosa M: Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386-1389.   4. Alpert JS, Smith R, Carlson J, et al: Mortality in patients treated for pulmonary embolism. JAMA 1976;236:1477-1480.   5. Kasper W, Konstantinides S, Geibel A, et al: Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 1997;30:1165-1171.   6. Ribeiro A, Lindmarker P, Juhlin-Dannfelt A, et al: Echocardiography Doppler in pulmonary embolism: right ventricular dysfunction as a predictor of mortality rate. Am Heart J 1997;134:479-487.   7. Pruszczyk P, Bochowicz A, Torbicki A, et al: Cardiac troponin T monitoring identifies high-risk group of normotensive patients with acute pulmonary embolism. Chest 2003;123:1947-1952.   8. Pruszczyk P, Kostrubiec M, Bochowicz A, et al: N-terminal pro-brain natriuretic peptide in patients with acute pulmonary embolism. Eur Respir J 2003;22:649-653.   9. Task Force on Pulmonary Embolism, European Society of Cardiology: Guidelines on diagnosis and management of acute pulmonary embolism. Eur Heart J 2000;21:1301-1336. 10. Buller HR, Agnelli G, Hull RD, et al: Antithrombotic therapy for venous thromboembolic disease: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;126:401S-428S. 11. Grifoni S, Olivotto I, Cecchini P, et al: Short-term clinical outcome of ­patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation 2000;101:2817-2822. 12. Kostrubiec M, Pruszczyk P, Bochowicz A, et al: Biomarker-based risk assessment model in acute pulmonary embolism. Eur Heart J 2005;26:2166-2172. 13. Kucher N, Printzen G, Goldhaber SZ: Prognostic role of brain natriuretic peptide in acute pulmonary embolism. Circulation 2003;107:2545-2547. 14. Pieralli F, Olivotto I, Vanni S, et al: Usefulness of bedside testing for brain natriuretic peptide to identify right ventricular dysfunction and outcome in normotensive patients with acute pulmonary embolism. Am J Cardiol 2006;97:1386-1390. 15. Vieillard-Baron A, Page B, Augarde R, et al: Acute cor pulmonale in massive pulmonary embolism: incidence, echocardiographic pattern, clinical implications and recovery rate. Intensive Care Med 2001;27:1481-1486. 16. ten Wolde M, Tulevski II, Mulder JW, et al: Brain natriuretic peptide as a predictor of adverse outcome in patients with pulmonary embolism. Circulation 2003;107:2082-2084. 17. Kucher N, Printzen G, Doernhoefer T, et al: Low pro-brain natriuretic peptide levels predict benign clinical outcome in acute pulmonary embolism. Circulation 2003;107:1576-1578. 18. Roy PM, Colombet I, Durieux P, et al: Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism. BMJ 2005;259-268. 19. Le Gal G, Righini M, Roy PM, et al: Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Intern Med 2006;144:165-171. 20. Perrier A: Pulmonary embolism: from clinical presentation to clinical probability assessment. Semin Vasc Med 2001;1:147-154. 21. Stein PD, Hull RD, Patel KC, et al: D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med 2004;140:589-602. 22. Vieillard-Baron A, Qanadli SD, Antakly Y, et al: Transesophageal echocardiography for the diagnosis of pulmonary embolism with acute cor pulmonale: a comparison with radiological procedures. Intensive Care Med 1998;24:429-433. 23. Meyer G, Tamisier D, Sors H, et al: Pulmonary embolectomy: a 20-year experience at one center. Ann Thorac Surg 1991;51:232-236.

24. M  ercat A, Diehl JL, Meyer G, et al: Hemodynamic effects of fluid loading in acute massive pulmonary embolism. Crit Care Med 1999;27:540-544. 25. Ozier Y, Dubourg O, Farcot JC, et al: Circulatory failure in acute pulmonary embolism. Intensive Care Med 1984;10:91-97. 26. Jardin F, Genevray B, Brun-Ney D, et al: Dobutamine: a hemodynamic ­evaluation in pulmonary embolism shock. Crit Care Med 1985;13:10091012. 27. Dalla-Volta S, Palla A, Santolicandro A, et al: PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. J Am Coll Cardiol 1992;20:520-526. 28. The urokinase pulmonary embolism trial. A national cooperative study. Circulation 1973;47:II1-II108. 29. PIOPED investigators: Tissue plasminogen activator for the treatment of acute pulmonary embolism. A collaborative study by the PIOPED investigators. Chest 1990;97:528-533. 30. Dotter CTSA, Rösch J, Poter JM: Streptokinase and heparin in the treatment of pulmonary embolism: a randomized comparison. Vasc Surg 1979;13:42-52. 31. Goldhaber SZ, Haire WD, Feldstein ML, et al: Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993;341:507-511. 32. Jerjes-Sanchez C, Ramirez-Rivera A, de Lourdes Garcia M, et al: Streptokinase and heparin versus heparin alone in massive pulmonary embolism: a randomized controlled trial. J Thromb Thrombolysis 1995;2:227-229. 33. Konstantinides S, Geibel A, Heusel G, et al: Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143-1150. 34. Levine M, Hirsh J, Weitz J, et al: A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest 1990;98:1473-1479. 35. Ly B, Arnesen H, Eie H, et al: A controlled clinical trial of streptokinase and heparin in the treatment of major pulmonary embolism. Acta Med Scand 1978;203:465-470. 36. Marini C, Di Ricco G, Rossi G, et al: Fibrinolytic effects of urokinase and heparin in acute pulmonary embolism: a randomized clinical trial. Respiration 1988;54:162-173. 37. Tibbutt DA, Davies JA, Anderson JA, et al: Comparison by controlled clinical trial of streptokinase and heparin in treatment of life-threatening pulmonay embolism. BMJ 1974;1:343-347. 38. Wan S, Quinlan DJ, Agnelli G, et al: Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 2004;110:744-749. 39. Agnelli G, Becattini C, Kirschstein T: Thrombolysis vs heparin in the treatment of pulmonary embolism: a clinical outcome-based meta-analysis. Arch Intern Med 2002;162:2537-2541. 40. Dong B, Jirong Y, Liu G, et al: Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev 2006;(2):CD004437. 41. Thabut G, Thabut D, Myers RP, et al: Thrombolytic therapy of pulmonary embolism: a meta-analysis. J Am Coll Cardiol 2002;40:1660-1667. 42. Kanter DS, Mikkola KM, Patel SR, et al: Thrombolytic therapy for pulmonary embolism. Frequency of intracranial hemorrhage and associated risk factors. Chest 1997;111:1241-1245. 43. Mikkola KM, Patel SR, Parker JA, et al: Increasing age is a major risk factor for hemorrhagic complications after pulmonary embolism thrombolysis. Am Heart J 1997;134:69-72. 44. Konstantinides S, Geibel A, Olschewski M, et al: Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation 1997;96:882-888. 45. Konstantinides S: Thrombolysis in submassive pulmonary embolism? Yes. J Thromb Haemost 2003;1:1127-1129. 46. Goldhaber SZ: Thrombolytic therapy for patients with pulmonary embolism who are hemodynamically stable but have right ventricular dysfunction: pro. Arch Intern Med 2005;165:2197-2199, discussion 2204–2205. 47. Urokinase-streptokinase embolism trial. Phase 2 results. A cooperative study. JAMA 1974;229:1606-1613. 48. Goldhaber SZ, Kessler CM, Heit J, et al: Randomised controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988;2:293-298. 49. Meyer G, Sors H, Charbonnier B, et al: Effects of intravenous urokinase versus alteplase on total pulmonary resistance in acute massive pulmonary embolism: a European multicenter double-blind trial. The European cooperative study group for pulmonary embolism. J Am Coll Cardiol 1992;19:239-245. 50. Goldhaber SZ, Kessler CM, Heit JA, et al: Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial. J Am Coll Cardiol 1992;20:24-30. 51. Meneveau N, Schiele F, Metz D, et al: Comparative efficacy of a two-hour regimen of streptokinase versus alteplase in acute massive pulmonary embolism: immediate clinical and hemodynamic outcome and one-year follow-up. J Am Coll Cardiol 1998;31:1057-1063.

403

32

Noncoronary Diseases: Diagnosis and Management 52. M  eneveau N, Schiele F, Vuillemenot A, et al: Streptokinase vs alteplase in massive pulmonary embolism. A randomized trial assessing right heart haemodynamics and pulmonary vascular obstruction. Eur Heart J 1997;18:1141-1148. 53. Goldhaber SZ, Agnelli G, Levine MN: Reduced dose bolus alteplase vs conventional alteplase infusion for pulmonary embolism thrombolysis. An international multicenter randomized trial. The bolus alteplase pulmonary embolism group. Chest 1994;106:718-724. 54. Sors H, Pacouret G, Azarian R, et al: Hemodynamic effects of bolus vs 2-h infusion of alteplase in acute massive pulmonary embolism. A randomized controlled multicenter trial. Chest 1994;106:712-717.

404

55. M  eyer G, Tamisier D, Reynaud P, et al: Acute pulmonary embolectomy. In Braunwald EGS (ed): Cardiopulmonary Diseases and Cardiac Tumors: Atlas of Heart Diseases. Philadelphia, Current Medicine, 1995, pp 6.1-6.12. 56. Meyer G, Koning R, Sors H: Transvenous catheter embolectomy. Semin Vasc Med 2001;1:247-252. 57. Skaf E, Beemath A, Siddiqui T, et al: Catheter-tip embolectomy in the management of acute massive pulmonary embolism. Am J Cardiol 2007;99:415420.