Tsuyoshi Mitarai
BACKGROUND
In an autopsy series of hospital deaths, pulmonary embolism (PE) was found in approximately 15% of the cases and—after excluding incidental PE—to be a primary or contributing cause of death in 3.4% to 8.9% of cases.1–5 In only 30% of this group had there been an antemortem suspicion or diagnosis of PE, a statistic that fueled the argument that PE is an underdiagnosed disease.3–6 Conversely, another study, done after the introduction of multidetector row computed tomographic pulmonary angiography (MDCTPA) in 1998, pointed to the possible overdiagnosis of PE.7 No significant change in the incidence of PE was reported between 1993 and 1998 (from 58.8 to 62.3 per 1,00,000; annual percentage change [APC] 0.5%). Between 1998 and 2006, when the use of MDCTPA increased 7- to 13-fold,8–11 an 81% increase in incidence of PE was reported (from 62.1 to 112.3 per 1,00,000; APC 7.1%).7 Despite this improved detection of PE, reduction in PE-associated mortality has been modest,7raising concern that we are diagnosing and treating (and sometimes overdiagnosing/overtreating) patients with low-risk PE and an intrinsically low mortality rate, while underdiagnosing and/or undertreating patients with high-risk PE. This hypothesis is supported by the findings in the Emergency Medicine Pulmonary Embolism in the Real World Registry (EMPEROR).12 In the analysis of 1,880 emergency department (ED) patients with confirmed PE (88% diagnosed with CTPA), the all-cause mortality rate at 30 days was only 5.4%.12 Although only 3% of the registry had a systolic blood pressure (SBP) <90 mm Hg at presentation, 30-day mortality of this subgroup was much higher than those with SBP >90 (14.0% vs. 1.8%).13 Furthermore, only 15.5% (9/58) of this high-risk subgroup received reperfusion therapy (systemic thrombolytic therapy or embolectomy).13 The review of data from the Nationwide Inpatient Sample also shows underutilization of reperfusion therapy among PE patients with shock or ventilator dependence (30%, 1.2%, and 0.3% for systemic thrombolytic therapy, surgical embolectomy, and catheter embolectomy, respectively). The review also reports higher case fatality rate attributable to PE not treated versus treated with systemic thrombolytic therapy (42% vs. 8.4%).14 To improve the mortality outcome of this disease, there needs to be an improvement in the care of patients in the high-risk PE subgroups. This chapter focuses on the diagnostic approach and management of unstable patients with suspected and confirmed PE in the ED. A discussion of the diagnosis and management of PE in stable patients may be found elsewhere.15–18
CLASSIFICATION OF ACUTE PULMONARY EMBOLISM
One of the hallmarks of PE is its wide spectrum of clinical presentation. The mortality rate of PE ranges from approximately 1% for low-risk PE to 65% for massive PE with cardiac arrest.19–22Classification of PE into different risk subgroups is important for appropriate prognostication, treatment selection, and disposition. Classification of PE based solely on the degree of clot burden fails to account for the patient's underlying cardiopulmonary reserve or physiologic response against the clot. In fact, anatomically massive PE—defined by an angiographic obstruction of >50% or obstruction of two lobar arteries—is rarely associated with shock and accounts for only 50% of fatal PE8; in patients with saddle emboli, only 8% to 14% are reported to have sustained hypotension.23,24 Right ventricular (RV) failure and associated hemodynamic compromise, on the other hand, reflect both embolism size as well as underlying cardiopulmonary status and serve as a better indicator of clinical outcome.6,25–27In 2011, the American Heart Association (AHA) proposed classifying PE into three groups based on the patient's physiologic response to the embolus: massive, submassive, and low-risk PE.28 The European Society of Cardiology (ESC) guidelines use the terms high-risk, intermediate-risk, and low-risk PE.15
Massive PE is defined as an acute PE accompanied by any of the following:
ESC guidelines include a drop of SBP > 40 mm Hg over 15 minutes in this category.15,22
Submassive PE is defined as an acute PE without hypotension with any of the following:
o Troponin I > 0.4 ng/mL or troponin T > 0.1 ng/mL
o RV systolic dysfunction or dilation (apical four-chamber RV diameter divided by LV diameter > 0.9) on echocardiography
o RV dilation on CT (four-chamber RV diameter divided by LV diameter > 0.9)
o Brain natriuretic peptide (BNP) > 90 pg/mL
o N-terminal pro-BNP > 500 pg/mL
o Electrocardiographic (ECG) changes (new complete or incomplete right bundle branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion)
Low-risk PE encompasses all other patients with PE not included in these first two categories.
In large registries, massive PE accounts for <5% of patients with acute PE,12,29 but it is associated with a high mortality rate. The International Cooperative Pulmonary Embolism Registry (ICOPER) reported 90-day mortality rates of nonmassive and massive PE to be 15.1% and 58.3%, respectively.29 The Management Strategy and Prognosis of Pulmonary Embolism Registry (MAPPET) reported an in-hospital mortality rate of 8.1% for submassive PE, 15% for massive PE meeting hypotension criteria without signs of shock or vasopressor use, 25% for massive PE with signs of shock or requiring use of vasopressors, and 65% in patients requiring cardiopulmonary resuscitation (CPR).22 A conceptual guide to the triage of PE patients by clinical severity subgroups is shown in Figure 11.1. The determination of which low-risk PE patients may be treated as an outpatient is outside the scope of this chapter.
FIGURE 11.1 Triage concept of acute pulmonary embolism: Three PE risk subgroups and potential disposition site. PE, pulmonary embolism; ICU, Intensive Care Unit.
MASSIVE PULMONARY EMBOLISM
Pathophysiology
The relative utility of various therapies for massive PE, including inotropic and vasopressor drugs, has yet to be assessed in a robust trial. However, a rational management strategy can be guided by an understanding of the pathophysiology of cardiovascular compromise in these patients (Fig. 11.2).
FIGURE 11.2 Pathophysiology of pulmonary embolism. Large arrows indicate how patients with massive PE can continue to deteriorate without a recurrent PE. PE, pulmonary embolism; RV, right ventricular; RVEDV, right ventricular end-diastolic volume; RVEDP, right ventricular end-diastolic pressure; O2, oxygen; TR, tricuspid regurgitation; LV, left ventricle; RVSV, right ventricular stroke volume; SV, stroke volume; RVCPP, right ventricular coronary perfusion pressure; MAP, mean arterial pressure.
Acute PE produces an increase in pulmonary vascular resistance (PVR) through not only mechanical obstruction but also pulmonary artery vasoconstriction from hypoxia,30 neural reflexes,31 and humoral factors.32 This sudden increase in PVR is poorly tolerated by the right ventricle (RV), which cannot generate mean pulmonary artery pressures (PAPs) of ≥40 mm Hg.33 The increase in RV afterload results in a proportional decrease in RV stroke volume (RVSV) as well as RV dilation.34,35 The decrease in RVSV compromises left ventricle (LV) preload and, thus, LV stroke volume (LVSV), which—once a patient's compensatory sympathetic tachycardia and increased systemic vascular resistance (SVR) are no longer sufficient—eventually results in systemic arterial hypotension.
The accompanying RV dilation/increased RV end-diastolic volume (RVEDV) further complicates this process in several ways: (1) It produces significant tricuspid regurgitation (TR), which results in increased RV preload.36 A volume-overloaded RV will eventually take residence on the descending portion of the Frank-Starling curve, further decreasing RVSV.34 (2) It causes a shift of the interventricular septum toward the left ventricle, as well as an increase in pericardial constraint; both of these effects result in a drop of LV preload and thus a drop in LVSV.36–39 (3) It causes an elevation in RV end-diastolic pressure (RVEDP), which results in an increase in RV wall stress (RV wall stress = RV radius × RVEDP) and an associated decrease in RV coronary perfusion pressure (RVCPP) (RVCPP = Mean arterial pressure − RVEDP).6 This increase in RV wall stress and decrease in RVCPP will produce higher RV oxygen demand and lower oxygen supply, respectively. These changes—particularly in the context of systemic hypotension—can easily precipitate RV ischemia or infarction.40–43 Figure 11.2 demonstrates this vicious cycle, which explains how patients with massive PE can continue to deteriorate without a recurrent PE.
Considerations during Patient Stabilization
Untreated patients with massive PE can further decompensate through a loss of physiologic compensation, recurrent PE, and/or in response to interventions. Two-thirds of patients with a fatal PE die within the first hour of presentation.6 Careful stabilization, rapid diagnostic efforts, and appropriate treatment of suspected massive PE therefore need to take place simultaneously. The concept of a golden hour should be applied to these patients just as with patients with major trauma, ST elevation myocardial infarction (STEMI), and acute stroke.6 Understanding the physiology of massive PE as described above illuminates several key points that are important in stabilization of such patients in the ED:
Diagnostic Evaluation
Massive PE poses unique challenges for the emergency physician: time constraints, physiology that is unforgiving in response to common stabilizing measures, and diagnostic uncertainty where clinical instability may preclude or delay confirmatory diagnostic studies. A step-by-step diagnostic approach to suspected massive PE is proposed below:
Step 1. Suspecting massive PE among hypotensive patients:
Massive PE should be considered in all hypotensive patients, especially with suggestive symptoms. In the MAPPET study, which included both massive and submassive PE, acute onset of symptoms (<48 hours), dyspnea, and syncope were reported in 70%, 96%, and 35% of patients, respectively.22 In the subgroup analysis of massive PE patients in the ICOPER study, reported symptoms included dyspnea (81%), chest pain (40%), and syncope (39%).60
Step 2: Transthoracic echocardiogram:
TTE is a noninvasive and easily repeatable bedside procedure that can be performed by the emergency physician without interfering with ongoing stabilizing interventions. In cases of massive PE, TTE may demonstrate RV dilation and hypokinesis, septal shift, and tricuspid regurgitation (TR). While the absence of these echocardiographic findings does not rule out PE (sensitivity 60% to 70%), it effectively eliminates PE as a cause of hemodynamic instability and encourages a search for alternative explanations of a patient's hypotension.15 The presence of such TTE findings should change the urgency of a confirmatory PE study and justifies the initiation of stabilizing maneuvers discussed above. Finally, TTE will identify emboli in transit in 4% to 18% of patients with acute PE61–64 and can help identify other causes of shock, including cardiac tamponade, aortic dissection, hypovolemia, LV dysfunction, and valvular insufficiency (see Chapter 6).15
Step 3: Confirmatory studies for massive PE:
Pending a confirmatory study, therapeutic anticoagulation with intravenous unfractionated heparin (UFH) should be started (in the absence of a drug contraindication) for all patients in whom there is high or intermediate suspicion of PE.28 The standard dose of UFH for the treatment of PE is an 80 unit/kg IV bolus followed by 18 unit/kg/min.65
Given its widespread availability, diagnostic accuracy, and short study time, MDCTPA is the study of choice for confirmation of massive PE. Because of the frequent finding of proximal or central pulmonary circulation clot in massive PE, MDCTPA is usually able to confirm the diagnosis.15,66 Even in patients with renal insufficiency, the risk of contrast-induced nephropathy is likely outweighed by the risk of delay in the diagnosis and treatment.
Although its availability in the ED may be limited, transesophageal echocardiogram (TEE) should be considered in cases in which a patient has an IV contrast allergy or is hemodynamically too unstable to be transported to CT. In patients with suspected PE noted to have RV dysfunction on TTE, TEE has been shown to have a sensitivity of 80% to 96.7% and specificity of 84% to 100% for massive PE (by detection of proximal clots).67–70
Ventilation/perfusion (V/Q) studies require a prolonged departure from the ED and have limited utility in a patient with massive PE. Similarly, lower extremity Doppler ultrasound, while increasing the likelihood of PE diagnosis if positive, neither confirms nor excludes a diagnosis of massive PE.
A confirmatory diagnosis of massive PE, while not required before initiating therapeutic anticoagulation, is preferred before initiating reperfusion therapy such as systemic thrombolytic therapy, surgical embolectomy, or catheter-directed therapy (CDT). However, if severe hemodynamic instability does not permit additional testing, aggressive measures may be warranted based on clinical suspicion and TTE findings alone.15 One study tested an institution-specific algorithm for suspected PE in ED patients with the goal of implementing appropriate treatment, including reperfusion therapy, in a timely manner. Twenty-one of the 204 patients had a shock index (SI) (SI = HR/SBP, normal range 0.5 to 0.7) of ≥1; of these, 14 demonstrated RV dysfunction on TTE. All 14 patients with RV dysfunction received reperfusion treatment without a confirmatory study (systemic thrombolysis, 7; catheter fragmentation, 4; and surgical embolectomy, 3) with an averaged time interval between ED admission and start of reperfusion therapy of 32 ± 12 minutes. In all 14 patients, PE was confirmed after initiation of reperfusion therapy.71
Management Guidelines
Systemic Thrombolytic Therapy
The Food and Drug Administration (FDA) has approved the following three drugs in the treatment of massive PE15,28:
Systemic thrombolytic therapy is associated with more rapid clot lysis than heparin therapy alone.76–81 In a study comparing a 2-hour infusion of 100 mg of alteplase (a recombinant tissue plasminogen activator [rt-PA]) combined with heparin versus heparin alone, at the 2-hour mark the alteplase group showed a 12% decrease in vascular obstruction, 30% reduction in mean PAP, and 15% increase in cardiac index. No changes were observed in the heparin group except for an 11% rise in mean PAP.79 One week postintervention, however, the severity of vascular obstruction79,82 and reversal of RV dysfunction83 were similar in both groups.6,15,28 Systemic thrombolytic therapy has been shown to have greatest benefit when started within 48 hours of symptom onset80 but may still be useful for patients who have had symptoms for up to 14 days.15,84
A mortality benefit of thrombolysis has not been found in patients with nonmassive PE and remains speculative in patients with massive PE, since there exists no large randomized controlled trial in this subgroup. One meta-analysis failed to demonstrate a superiority of thrombolysis compared with heparin alone with regard to recurrent pulmonary embolism or death as a composite outcome. However, when the study restricted analysis to trials that included massive PE patients, the composite outcome was 9.4% with the thrombolysis group versus 19.0% with heparin alone (odds ratio 0.45; NNT = 10).85In a large retrospective study that analyzed patients with a diagnosis of PE and shock or ventilator dependence, the case fatality rate attributable to PE was higher among patients not receiving systemic thrombolytic therapy (42% vs. 8.4%).14
The three drugs listed above appear to be comparable in efficacy and bleeding risk, provided doses are equivalent and given over the same time period.72,73 Shorter infusion regimens (i.e., ≤2 hours) are preferred as they are associated with lower bleeding risk and more rapid clot lysis.86 Drug delivery via peripheral IV is preferred, as pulmonary artery catheters are associated with an increased bleeding risk at the insertion site without an increase in efficacy.86,87 IV UFH should be discontinued during systemic thrombolytic therapy.15,28 Activated partial thromboplastin time (aPTT) should be checked after the completion of alteplase, and maintenance IV heparin should be restarted without a bolus if aPTT is <80 seconds (if not, it should be checked again in 4 hours).88
An alteplase bolus regimen (0.6 mg/kg, maximum of 50 mg) given over 15 minutes appears to be comparable in both efficacy and bleeding risk to the more commonly used 100-mg infusion given over 2 hours.74,75 Limited data exist for more rapid bolus infusions. In a study of a 2-minute alteplase infusion protocol (0.6 mg/kg ideal body weight, maximum dose not specified) versus heparin alone, a significant mean relative improvement in perfusion after 24 hours was reported (measured by perfusion lung scan, 37% vs. 18.8%, respectively) without an increase in major bleeding (minor bleeding was 45% vs. 4%).81 In patients in extremis, including cardiac arrest from massive PE, a bolus dose should be given.86 However, thrombolysis for undifferentiated cardiac arrest is not recommended.28
All thrombolytic drugs carry a risk of bleeding. The cumulative rate of major bleeding and intracranial/fatal hemorrhage in early trials was shown to be to be 13% and 1.8%, respectively.73,74,79,81,82,87,89–92 Life-threatening hemorrhage is less common in more recent trials.78,91 Thrombolysis-related major bleeding is also less frequent when noninvasive imaging methods are used for PE diagnosis.93 Of note, massive PE patients have higher bleeding rates when compared to patients with nonmassive PE, regardless of whether they are receiving thrombolysis plus heparin or heparin alone.85,88 A retrospective chart review of patients who received IV alteplase 100 mg for PE between 1996 and 2004 showed a significant increase in bleeding risk among patients with hemodynamic instability requiring vasopressors prior to treatment (multivariate analysis: odds ratio 115).94 Systemic thrombolytic therapy is nevertheless recommended for patients with massive PE considered to have acceptably low bleeding risk.15,28,86 Absolute contraindications to systemic thrombolytic therapy for PE (listed after this paragraph) are extrapolated from guidelines for ST-segment elevation MI95; clinicians are, however, encouraged to judge the relative merits of the therapy on a case-by-case basis.28 Absolute contraindications to systemic thrombolytic therapy for MI might become relative in a patient with immediately life-threatening high-risk PE.15 Despite the recommendations of current guidelines and evidence in favor of systemic thrombolytic therapy in massive PE, this therapy continues to be grossly underutilized.13,14
Absolute contraindications to systemic thrombolytic therapy in PE28:
Surgical Embolectomy
Historically, surgical embolectomy for PE was considered an option of last resort, reserved for patients in cardiogenic shock or requiring CPR.15,96,97 However, as mortality rates have improved from 57% in the 1960s98 to 26% (16% to 46%) in the late 1980s/early 1990s,99 this procedure has reemerged as a viable treatment option for massive PE. Certain authors have attributed this change not to surgical technique, but rather to a more expeditious diagnostic approach and to advances in the perioperative management of these patients, specifically the preoperative application of CPB in moribund patients.99 A more rigorous and discriminating patient selection process has likely also contributed to the improved outcomes. For example, instead of undergoing surgical embolectomy, patients with acute PE superimposed on chronic thromboembolic pulmonary hypertension are now transferred to centers that specialize in pulmonary endarterectomy.15,100 The wide range of mortality rates reported in various case series reflects the importance of presurgical clinical status on postsurgical outcome; patients with no preoperative CPR, intermittent CPR with stable hemodynamics on arrival to the OR, and continuous CPR on arrival to the OR were reported to have mortality rate of 10%, 40%, and 80%, respectively.101
A recent study, extended inclusion criteria for surgical embolectomy to include hemodynamically stable patients with large clot and RV dysfunction, demonstrated an even lower mortality rate of 6%.96Although extending the indications to include submassive PE remains controversial, this and another recent series (0% perioperative mortality, 8% 30-day mortality)97 suggest that surgical embolectomy is not as futile as once believed, provided there is appropriate patient selection and consideration of technical factors.
If surgical expertise and resources are available, indications for surgical embolectomy for massive PE are the presence of a contraindication to systemic thrombolytic therapy, failed systemic thrombolytic therapy, or hemodynamic instability that is likely to cause death before systemic thrombolytic therapy can take effect.86 A surgical approach may also be appropriate in the case of impending paradoxical embolism (thrombus entrapped within a patent foramen ovale [PFO]).28 Absolute contraindications to systemic thrombolytic therapy are present in approximately one-third of massive PE88(although this number varies depending on what is considered to be an absolute vs. relative contraindications). Failure of systemic thrombolytic therapy is defined as persistent clinical instability and residual echocardiographic RV dysfunction at 36 hours and is reported to occur in 8.2% of cases.102 In these cases, rescue embolectomy is recommended over repeat systemic thrombolytic therapy.102
Catheter Embolectomy
The goal of the CDT is rapid central clot debulking to relieve life-threatening heart strain and improve pulmonary perfusion.103 Modern CDT for massive PE is defined as the use of low-profile catheters and devices (<10 F) for the purpose of catheter-directed mechanical fragmentation and/or aspiration of emboli, as well as optional intraclot thrombolytic agent injection.103 To avoid the risk of perforation, CDT is recommended only for use on major branches of the pulmonary artery and should be terminated as soon as hemodynamics improves, regardless of angiographic result.15,104 However, because successful clot fragmentation increases the surface area of thrombus, some authors advocate giving an extended intraclot infusion of low-dose thrombolytics, especially to patients with residual elevation of PA pressure with right heart strain.103,105,106
Large randomized controlled trials on CDT have been hindered by device variations, lack of well-established protocols, and feasibility issues. A meta-analysis of 35 studies conducted from January 1990 through September 2008 evaluated the safety and efficacy of CDT for massive PE.107 Clinical success—defined as stabilization of hemodynamics, resolution of hypoxia, and survival to hospital discharge—was 86.5%.103,107 In 96% of patients, systemic thrombolytic therapy was not given, and CDT was used as the first adjunct to heparin.107 Approximately 30% of patients received mechanical fragmentation and/or aspiration of emboli only, and 60% of patients received an extended thrombolytic infusion through the catheter.107 The pooled risk of major procedural complications (e.g., groin hematoma requiring transfusion) was 2.4%.107
CDT shares the same indications as surgical embolectomy and is a relatively safe and highly effective treatment option for massive PE in an experienced center. Knowledge of local expertise should guide the emergency physician's decision to pursue one or the other option,28 and establishing a transfer protocol is encouraged in facilities that lack either option. A management algorithm for suspected massive PE in the ED is shown in Figure 11.3.
FIGURE 11.3 Management algorithm for suspected massive PE. PE, pulmonary embolism; TTE, transthoracic echocardiogram; IV, intravenous; UFH, unfractionated heparin; BP, blood pressure; RV, right ventricular; ECLS, extracorporeal life support; CTPA, computed tomographic pulmonary angiography; CT, computed tomography; Cr, creatinine; TEE, transesophageal echocardiogram; min., minutes.
Adjunctive Therapies
Inferior Vena Cava (IVC) Filter
Subgroup analysis of massive PE patients in the ICOPER showed reduced 90-day mortality among patients with IVC filters (hazard ratio 0.12). However, only 11 of 108 patients with massive PE in this registry received an IVC filter. Some authors of case series for surgical embolectomy and catheter embolectomy advocate the use of IVC filters for their patients with massive PE, given relatively the low procedural risk and potentially lethal nature of recurrent PE in this group.96,99,106,108 In the absence of data from large randomized controlled trials, AHA guidelines state that placement of an IVC filter may be considered for patients with acute PE with very poor cardiopulmonary reserve, including those with massive PE.28
Extracorporeal Life Support (ECLS)
ECLS can be lifesaving for massive PE patients who are too unstable to tolerate other interventions or have failed reperfusion therapy.109 Bedside cannulation and placement on ECLS are possible during cardiac arrest, and patients can be transferred to institutions with higher levels of care while receiving ECLS.109 A study of 21 patients with massive PE receiving ECLS (8 in cardiac arrest at ECLS initiation) demonstrated a mortality rate of 38% and mean ECLS bypass duration of 4.7 days.109 Of note, 10/13 survivors in this study required no additional therapy other than anticoagulation. Excluding patients in hypercoagulable states, the study noted that these 10 patients had sufficient amount of emboli autolysis to allow recovery of RV function within 5 days.109 A recent case series of patients with massive PE requiring ECLS (9/10 in cardiac arrest) reported a 30-day mortality of 30%.110 Of note, 8 out of 10 patients had CDT while on ECLS, which improved hemodynamics and allowed early weaning of ECLS (mean ECLS bypass was 48 ± 44 hours).110 Although this was a small study without a comparative group, it suggests that early CDT to shorten ECLS bypass time may have both clinical and financial benefit, given the complications associated with prolonged ECLS. However, it should also be noted that a small case series of successful CDT during cardiac arrest (6/7 survived) suggests less of a need for ECLS if expertise with CDT is readily available in a given facility.111 There are no guidelines to define the exact role of ECLS in massive PE. Facilities that can offer this option should have a treatment algorithm developed by an interdisciplinary team.
Inhaled Nitric Oxide (INO)
INO induces pulmonary artery vasodilation without generating systemic hypotension, making it a physiologically attractive adjunct in the management of massive PE. INO may help stabilize patients with suspected massive PE while definitive diagnostic tests or interventions are arranged. In a small case series of patients with massive PE requiring intubation, INO at a dose of 10–20 ppm was shown to rapidly improve oxygenation and hemodynamics.112 Given the known risk of hemodynamic deterioration following intubation and mechanical ventilation in patients with massive PE, having INO readily available in this setting is a reasonable strategy.
HIGH-RISK SUBMASSIVE PULMONARY EMBOLISM
Many patients with submassive PE will have a benign clinical course with appropriate anticoagulation; others will experience clinical deterioration due to a loss of physiologic compensation or recurrent embolic events. In a prospective clinical outcome study of 209 patients with confirmed PE, 65 (31%) were found to be normotensive with RV dysfunction on initial TTE; of these, 10% developed shock within the first 24 hours despite initiation of heparin therapy; half of these 10% died.113 Important issues that remain to be addressed include: (1) How to identify submassive PE patients with poor short-term prognosis who may benefit from ICU admission (Fig. 11.1), and (2) What treatment beyond anticoagulation can be provided to improve the outcome of this subgroup.
Research has assessed a variety of risk-stratification tools for normotensive patients with PE. Current risk stratification tools include clinical scores (e.g., the pulmonary embolism severity index [PESI],114 simplified PESI115), biomarkers (e.g., troponin,116,117 highly sensitive troponin T assay,118 heart-type fatty acid–binding protein,119 brain-type natriuretic peptides [BNP]/N-terminal–pro-BNP [NT-proBNP]120), cardiopulmonary imaging (e.g., RV dysfunction in CT/TTE),121 or combinations of these indicators.122–124 Unfortunately, identification of a definitive risk assessment tool has been hampered by a paucity of studies focusing on short-term mortality/deterioration risk (i.e., within the first 48 hours) and lack of a universally accepted definition of RV dysfunction and threshold values for diagnostic biomarkers.
Even if such a high-risk subgroup can be successfully identified, it remains unclear what therapeutic interventions would prove safe and superior to the current approach of anticoagulation with the option of subsequent reperfusion therapy for patients who further deteriorate. In a trial comparing heparin plus alteplase versus heparin alone for submassive PE, the requirement for escalation of treatment was significantly lower in the first group (10.2% vs. 24.6%), but no difference in all-cause mortality was observed (3.4% vs. 2.2%).91 The study showed that in the majority of submassive PE patients who experience subsequent deterioration, providers had sufficient time to intervene with reperfusion therapy. Preemptive reperfusion therapy with the goal of reducing short-term mortality therefore appears unjustified at this time.
The use of preemptive reperfusion therapy to prevent long-term RV dysfunction is also of questionable value. In patients with submassive PE who survive to receive 1 week of anticoagulation alone, the degree of pulmonary vascular obstruction and reversal of RV dysfunction appear similar to patients who receive systemic thrombolytic therapy.6,15,28 Reperfusion therapy may possibly have benefit in preventing persistent or worsening RV systolic pressure (RVSP) in the long term (i.e., 6 months),125 but the clinical significance of changes (or lack thereof) in RVSP have yet to be demonstrated in a large-scale study.
Four major interventions are being investigated in the treatment of the high-risk subgroup in submassive PE. The use of systemic rt-PA, soon to be addressed by the ongoing PEITHO trial (tenecteplase vs. placebo); surgical embolectomy, as described in more recent surgical case series96; CDT with extended catheter-based infusion of rt-PA126; and half-dose alteplase as described in the MOPETT trial.127Besides safety, clinically meaningful outcome benefits should be demonstrated before these strategies can routinely be recommended over anticoagulation alone in this subgroup of patients
CONCLUSION
Massive PE comprises a small fraction of PE, particularly now that we are detecting a greater number of lower-risk patients with the advent of MDCTPA; it remains, however, an undertreated, lethal, and challenging condition to manage. Optimal management requires a sophisticated understanding of the unique physiology of PE, an efficient and systemic approach to diagnosis and treatment, and an institution-based management algorithm based on available resources and expertise. If there are no contraindications, systemic thrombolytic therapy should be offered to patients with confirmed massive PE, as well as suspected massive PE with suggestive TTE findings when there is no time for confirmatory study due to imminent risk of death. A decision to withhold thrombolysis based on the risk of bleeding needs to be followed by an attempt to provide either surgical or catheter-directed embolectomy in massive PE. As for submassive PE, a large-scale study is needed to determine what risk factors predict short-term (i.e., <48 hours) deterioration. The challenge remains to identify the high-risk subgroup in patients with submassive PE who may benefit from more aggressive care, and it is still unknown what specific preemptive reperfusion therapy should be offered to them.
LITERATURE TABLE
CI, confidence interval; HR, hazard ratio; NNT, number needed to treat; OR, odds ratio.
REFERENCES
1.Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and at autopsy. Chest. 1995;108(4):978–981.
2.Rubinstein I, Murray D, Hoffstein V. Fatal pulmonary emboli in hospitalized patients: an autopsy study. Arch Intern Med. 1988;148(6):1425–1426.
3.Goldhaber SZ, Hennekens CH, Evans DA, et al. Factors associated with correct antemortem diagnosis of major pulmonary embolism. Am J Med. 1982;73(6):822–826.
4.Clagett GP, Reisch JS. Prevention of venous thromboembolism in general surgical patients. Results of meta-analysis. Ann Surg. 1988;208(2):227–240.
5.Moser KM, Fedullo PF, LitteJohn JK, et al. Frequent asymptomatic pulmonary embolism in patients with deep venous thrombosis. JAMA. 1994;271(3):223–225.
6.Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest. 2002;121(3):877–905.
7.Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171(9):831–837.
8.Wittram C, Meehan MJ, Halpern EF, et al. Trends in thoracic radiology over a decade at a large academic medical center. J Thorac Imaging. 2004;19(3):164–170.
9.Donohoo JH, Mayo-Smith WW, Pezzullo JA, et al. Utilization patterns and diagnostic yield of 3421 consecutive multidetector row computed tomography pulmonary angiograms in a busy emergency department. J Comput Assist Tomogr. 2008;32(3):421–425.
10.Auer RC, Schulman AR, Tuorto S, et al. Use of helical CT is associated with an increased incidence of postoperative pulmonary emboli in cancer patients with no change in the number of fatal pulmonary emboli. J Am Coll Surg. 2009;208(5):871–878; discussion 878–880.
11.Weir ID, Drescher F, Cousin D, et al. Trends in use and yield of chest computed tomography with angiography for diagnosis of pulmonary embolism in a Connecticut hospital emergency department. Conn Med. 2010;74(1):5–9.
12.Pollack CV, Schreiber D, Goldhaber SZ, et al. Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry). J Am Coll Cardiol. 2011;57(6):700–706.
13.Lin BW, Schreiber DH, Liu G, et al. Therapy and outcomes in massive pulmonary embolism from the emergency medicine pulmonary embolism in the real world registry. Am J Emerg Med. 2012;30(9):1774–1781.
14.Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med. 2012;125(5):465–470.
15.Torbicki A, Perrier A, Konstantinides S, 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;29(18):2276–2315.
16.Fesmire FM, Brown MD, Espinosa JA, et al. Critical issues in the evaluation and management of adult patients presenting to the emergency department with suspected pulmonary embolism. Ann Emerg Med. 2011;57(6):628–652.e675.
17.Church A, Tichauer M. The emergency medicine approach to the evaluation and treatment of pulmonary embolism. Emerg Med Pract. 2012;14(12):1–22.
18.Aujesky D, Roy PM, Verschuren F, et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet. 2011;378(9785):41–48.
19.Post F, Mertens D, Sinning C, et al. Decision for aggressive therapy in acute pulmonary embolism: implication of elevated troponin T. Clin Res Cardiol. 2009;98(6):401–408.
20.Palmieri V, Gallotta G, Rendina D, et al. Troponin I and right ventricular dysfunction for risk assessment in patients with nonmassive pulmonary embolism in the emergency department in combination with clinically based risk score. Intern Emerg Med. 2008;3(2):131–138.
21.Bova C, Pesavento R, Marchiori A, et al. Risk stratification and outcomes in hemodynamically stable patients with acute pulmonary embolism: a prospective, multicentre, cohort study with three months of follow-up. J Thromb Haemost. 2009;7(6):938–944.
22.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(5):1165–1171.
23.Ryu JH, Pellikka PA, Froehling DA, et al. Saddle pulmonary embolism diagnosed by CT angiography: frequency, clinical features and outcome. Respir Med. 2007;101(7):1537–1542.
24.Sardi A, Gluskin J, Guttentag A, et al. Saddle pulmonary embolism: is it as bad as it looks? A community hospital experience. Crit Care Med. 2011;39(11):2413–2418.
25.McIntyre KM, Sasahara AA. Correlation of pulmonary photoscan and angiogram as measures of the severity of pulmonary embolic involvement. J Nucl Med. 1971;12(11):732–738.
26.McDonald IG, Hirsh J, Hale GS, et al. Major pulmonary embolism, a correlation of clinical findings, haemodynamics, pulmonary angiography, and pathological physiology. Br Heart J. 1972;34(4):356–364.
27.Alpert JS, Smith R, Carlson J, et al. Mortality in patients treated for pulmonary embolism. JAMA. 1976;236(13):1477–1480.
28.Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation.2011;123(16):1788–1830.
29.Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353(9162):1386–1389.
30.Alpert JS, Godtfredsen J, Ockene IS, et al. Pulmonary hypertension secondary to minor pulmonary embolism. Chest. 1978;73(6):795–797.
31.Stein M, Levy SE. Reflex and humoral responses to pulmonary embolism. Prog Cardiovasc Dis. 1974;17(3):167–174.
32.Malik AB. Pulmonary microembolism. Physiol Rev. 1983;63(3):1114–1207.
33.McIntyre KM, Sasahara AA. The hemodynamic response to pulmonary embolism in patients without prior cardiopulmonary disease. Am J Cardiol. 1971;28(3):288–294.
34.Matthews JC, McLaughlin V. Acute right ventricular failure in the setting of acute pulmonary embolism or chronic pulmonary hypertension: a detailed review of the pathophysiology, diagnosis, and management. Curr Cardiol Rev. 2008;4(1):49–59.
35.Zamanian RT, Haddad F, Doyle RL, et al. Management strategies for patients with pulmonary hypertension in the intensive care unit. Crit Care Med. 2007;35(9):2037–2050.
36.Haddad F, Doyle R, Murphy DJ, et al. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure. Circulation. 2008;117(13):1717–1731.
37.Taylor RR, Covell JW, Sonnenblick EH, et al. Dependence of ventricular distensibility on filling of the opposite ventricle. Am J Physiol. 1967;213(3):711–718.
38.Jardin F, Dubourg O, Gueret P, et al. Quantitative two-dimensional echocardiography in massive pulmonary embolism: emphasis on ventricular interdependence and leftward septal displacement. J Am Coll Cardiol. 1987;10(6):1201–1206.
39.Belenkie I, Dani R, Smith ER, et al. Ventricular interaction during experimental acute pulmonary embolism. Circulation. 1988;78(3):761–768.
40.Vlahakes GJ, Turley K, Hoffman JI. The pathophysiology of failure in acute right ventricular hypertension: hemodynamic and biochemical correlations. Circulation. 1981;63(1):87–95.
41.Coma-Canella I, Gamallo C, Martinez Onsurbe P, et al. Acute right ventricular infarction secondary to massive pulmonary embolism. Eur Heart J. 1988;9(5):534–540.
42.Adams JE III, Siegel BA, Goldstein JA, et al. Elevations of CK-MB following pulmonary embolism. A manifestation of occult right ventricular infarction. Chest. 1992;101(5):1203–1206.
43.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(3):227–229.
44.Ducas J, Prewitt RM. Pathophysiology and therapy of right ventricular dysfunction due to pulmonary embolism. Cardiovasc Clin. 1987;17(2):191–202.
45.Molloy WD, Lee KY, Girling L, et al. Treatment of shock in a canine model of pulmonary embolism. Am Rev Respir Dis. 1984;130(5):870–874.
46.Ghignone M, Girling L, Prewitt RM. Volume expansion versus norepinephrine in treatment of a low cardiac output complicating an acute increase in right ventricular afterload in dogs. Anesthesiology. 1984;60(2):132–135.
47.Hirsch LJ, Rooney MW, Wat SS, et al. Norepinephrine and phenylephrine effects on right ventricular function in experimental canine pulmonary embolism. Chest. 1991;100(3):796–801.
48.De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010;362(9):779–789.
49.Goldstein JA, Harada A, Yagi Y, et al. Hemodynamic importance of systolic ventricular interaction, augmented right atrial contractility and atrioventricular synchrony in acute right ventricular dysfunction. J Am Coll Cardiol. 1990;16(1):181–189.
50.Layish DT, Tapson VF. Pharmacologic hemodynamic support in massive pulmonary embolism. Chest. 1997;111(1):218–224.
51.Jardin F, Genevray B, Brun-Ney D, et al. Dobutamine: a hemodynamic evaluation in pulmonary embolism shock. Crit Care Med. 1985;13(12):1009–1012.
52.Roberts DH, Lepore JJ, Maroo A, et al. Oxygen therapy improves cardiac index and pulmonary vascular resistance in patients with pulmonary hypertension. Chest. 2001;120(5):1547–1555.
53.Moloney ED, Evans TW. Pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndrome. Eur Respir J. 2003;21(4):720–727.
54.Viitanen A, Salmenpera M, Heinonen J. Right ventricular response to hypercarbia after cardiac surgery. Anesthesiology. 1990;73(3):393–400.
55.Balanos GM, Talbot NP, Dorrington KL, et al. Human pulmonary vascular response to 4 h of hypercapnia and hypocapnia measured using Doppler echocardiography. J Appl Physiol (1985). 2003;94(4):1543–1551.
56.Rosenberger P, Shernan SK, Shekar PS, et al. Acute hemodynamic collapse after induction of general anesthesia for emergent pulmonary embolectomy. Anesth Analg. 2006;102(5):1311–1315.
57.Tsapenko MV, Tsapenko AV, Comfere TB, et al. Arterial pulmonary hypertension in noncardiac intensive care unit. Vasc Health Risk Manag. 2008;4(5):1043–1060.
58.Vieillard-Baron A, Loubieres Y, Schmitt JM, et al. Cyclic changes in right ventricular output impedance during mechanical ventilation. J Appl Physiol. 1999;87(5):1644–1650.
59.Jardin F, Vieillard-Baron A. Is there a safe plateau pressure in ARDS? The right heart only knows. Intensive Care Med. 2007;33(3):444–447.
60.Kucher N, Rossi E, De Rosa M, et al. Massive pulmonary embolism. Circulation. 2006;113(4):577–582.
61.Casazza F, Bongarzoni A, Centonze F, et al. Prevalence and prognostic significance of right-sided cardiac mobile thrombi in acute massive pulmonary embolism. Am J Cardiol. 1997;79(10):1433–1435.
62.Ferrari E, Benhamou M, Berthier F, et al. Mobile thrombi of the right heart in pulmonary embolism: delayed disappearance after thrombolytic treatment. Chest. 2005;127(3):1051–1053.
63.Pierre-Justin G, Pierard LA. Management of mobile right heart thrombi: a prospective series. Int J Cardiol. 2005;99(3):381–388.
64.Torbicki A, Galie N, Covezzoli A, et al. Right heart thrombi in pulmonary embolism: results from the International Cooperative Pulmonary Embolism Registry. J Am Coll Cardiol. 2003;41(12):2245–2251.
65.Raschke RA, Gollihare B, Peirce JC. The effectiveness of implementing the weight-based heparin nomogram as a practice guideline. Arch Intern Med. 1996;156(15):1645–1649.
66.Agnelli G, Becattini C. Acute pulmonary embolism. N Engl J Med. 2010;363(3):266–274.
67.Pruszczyk P, Torbicki A, Pacho R, et al. Noninvasive diagnosis of suspected severe pulmonary embolism: transesophageal echocardiography vs spiral CT. Chest. 1997;112(3):722–728.
68.Steiner P, Lund GK, Debatin JF, et al. Acute pulmonary embolism: value of transthoracic and transesophageal echocardiography in comparison with helical CT. AJR Am J Roentgenol. 1996;167(4):931–936.
69.Wittlich N, Erbel R, Eichler A, et al. Detection of central pulmonary artery thromboemboli by transesophageal echocardiography in patients with severe pulmonary embolism. J Am Soc Echocardiogr. 1992;5(5):515–524.
70.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(5):429–433.
71.Kucher N, Luder CM, Dornhofer T, et al. Novel management strategy for patients with suspected pulmonary embolism. Eur Heart J. 2003;24(4):366–376.
72.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(5):1057–1063.
73.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(1):24–30.
74.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(3):712–717.
75.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(3):718–724.
76.Tibbutt DA, Davies JA, Anderson JA, et al. Comparison by controlled clinical trial of streptokinase and heparin in treatment of life-threatening pulmonay embolism. Br Med J. 1974;1(5904):343–347.
77.Urokinase pulmonary embolism trial. Phase 1 results: a cooperative study. JAMA. 1970;214(12):2163–2172.
78.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(8844):507–511.
79.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(3):520–526.
80.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(6):465–470.
81.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(6):1473–1479.
82.The urokinase pulmonary embolism trial. A national cooperative study. Circulation. 1973;47(suppl 2):II1–II108.
83.Konstantinides S, Tiede N, Geibel A, et al. Comparison of alteplase versus heparin for resolution of major pulmonary embolism. Am J Cardiol. 1998;82(8):966–970.
84.Daniels LB, Parker JA, Patel SR, et al. Relation of duration of symptoms with response to thrombolytic therapy in pulmonary embolism. Am J Cardiol. 1997;80(2):184–188.
85.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(6):744–749.
86.Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e419S–e494S.
87.Verstraete M, Miller GA, Bounameaux H, et al. Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism. Circulation. 1988;77(2):353–360.
88.Kucher N, Goldhaber SZ. Management of massive pulmonary embolism. Circulation. 2005;112(2):e28–e32.
89.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(2):239–245.
90.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(8606):293–298.
91.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(15):1143–1150.
92.Kanter DS, Mikkola KM, Patel SR, et al. Thrombolytic therapy for pulmonary embolism. Frequency of intracranial hemorrhage and associated risk factors. Chest. 1997;111(5):1241–1245.
93.Stein PD, Hull RD, Raskob G. Risks for major bleeding from thrombolytic therapy in patients with acute pulmonary embolism. Consideration of noninvasive management. Ann Intern Med. 1994;121(5):313–317.
94.Fiumara K, Kucher N, Fanikos J, et al. Predictors of major hemorrhage following fibrinolysis for acute pulmonary embolism. Am J Cardiol. 2006;97(1):127–129.
95.Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation. 2004;110(9):e82–e292.
96.Leacche M, Unic D, Goldhaber SZ, et al. Modern surgical treatment of massive pulmonary embolism: results in 47 consecutive patients after rapid diagnosis and aggressive surgical approach. J Thorac Cardiovasc Surg. 2005;129(5):1018–1023.
97.Kadner A, Schmidli J, Schonhoff F, et al. Excellent outcome after surgical treatment of massive pulmonary embolism in critically ill patients. J Thorac Cardiovasc Surg. 2008;136(2):448–451.
98.Cross FS, Mowlem A. A survey of the current status of pulmonary embolectomy for massive pulmonary embolism. Circulation. 1967;35(suppl 4):I86–I91.
99.Stulz P, Schlapfer R, Feer R, et al. Decision making in the surgical treatment of massive pulmonary embolism. Eur J Cardiothorac Surg. 1994;8(4):188–193.
100.Hoeper MM, Mayer E, Simonneau G, et al. Chronic thromboembolic pulmonary hypertension. Circulation. 2006;113(16):2011–2020.
101.Ullmann M, Hemmer W, Hannekum A. The urgent pulmonary embolectomy: mechanical resuscitation in the operating theatre determines the outcome. Thorac Cardiovasc Surg. 1999;47(1):5–8.
102.Meneveau N, Seronde MF, Blonde MC, et al. Management of unsuccessful thrombolysis in acute massive pulmonary embolism. Chest. 2006;129(4):1043–1050.
103.Kuo WT. Endovascular therapy for acute pulmonary embolism. Journal of vascular and interventional radiology: JVIR. 2012;23(2):167–179 e164; quiz 179.
104.Uflacker R. Interventional therapy for pulmonary embolism. J Vasc Interv Radiol. 2001;12(2):147–164.
105.Schmitz-Rode T, Kilbinger M, Gunther RW. Simulated flow pattern in massive pulmonary embolism: significance for selective intrapulmonary thrombolysis. Cardiovasc Intervent Radiol. 1998;21(3):199–204.
106.de Gregorio MA, Laborda A, de Blas I, et al. Endovascular treatment of a haemodynamically unstable massive pulmonary embolism using fibrinolysis and fragmentation. Experience with 111 patients in a single centre. Why don't we follow ACCP recommendations? Arch Bronconeumol. 2011;47(1):17–24.
107.Kuo WT, Gould MK, Louie JD, et al. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol. 2009;20(11):1431–1440.
108.Dauphine C, Omari B. Pulmonary embolectomy for acute massive pulmonary embolism. Ann Thorac Surg. 2005;79(4):1240–1244.
109.Maggio P, Hemmila M, Haft J, et al. Extracorporeal life support for massive pulmonary embolism. J Trauma. 2007;62(3):570–576.
110.Munakata R, Yamamoto T, Hosokawa Y, et al. Massive pulmonary embolism requiring extracorporeal life support treated with catheter-based interventions. Int Heart J. 2012;53(6):370–374.
111.Fava M, Loyola S, Bertoni H, et al. Massive pulmonary embolism: percutaneous mechanical thrombectomy during cardiopulmonary resuscitation. J Vasc Interv Radiol. 2005;16(1):119–123.
112.Summerfield DT, Desai H, Levitov A, et al. Inhaled nitric oxide as salvage therapy in massive pulmonary embolism: a case series. Respir Care. 2012;57(3):444–448.
113.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(24):2817–2822.
114.Aujesky D, Obrosky DS, Stone RA, et al. A prediction rule to identify low-risk patients with pulmonary embolism. Arch Intern Med. 2006;166(2):169–175.
115.Jimenez D, Aujesky D, Moores L, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med. 2010;170(15):1383–1389.
116.Jimenez D, Uresandi F, Otero R, et al. Troponin-based risk stratification of patients with acute nonmassive pulmonary embolism: systematic review and metaanalysis. Chest. 2009;136(4):974–982.
117.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(6):1947–1952.
118.Lankeit M, Friesen D, Aschoff J, et al. Highly sensitive troponin T assay in normotensive patients with acute pulmonary embolism. Eur Heart J. 2010;31(15):1836–1844.
119.Dellas C, Puls M, Lankeit M, et al. Elevated heart-type fatty acid-binding protein levels on admission predict an adverse outcome in normotensive patients with acute pulmonary embolism. J Am Coll Cardiol. 2010;55(19):2150–2157.
120.Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis. Am J Respir Crit Care Med. 2008;178(4):425–430.
121.Sanchez O, Trinquart L, Colombet I, et al. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. Eur Heart J. 2008;29(12):1569–1577.
122.Lankeit M, Jimenez D, Kostrubiec M, et al. Predictive value of the high-sensitivity troponin T assay and the simplified Pulmonary Embolism Severity Index in hemodynamically stable patients with acute pulmonary embolism: a prospective validation study. Circulation.2011;124(24):2716–2724.
123.Kang DK, Sun JS, Park KJ, et al. Usefulness of combined assessment with computed tomographic signs of right ventricular dysfunction and cardiac troponin T for risk stratification of acute pulmonary embolism. Am J Cardiol. 2011;108(1):133–140.
124.Lankeit M, Gomez V, Wagner C, et al. A strategy combining imaging and laboratory biomarkers in comparison with a simplified clinical score for risk stratification of patients with acute pulmonary embolism. Chest. 2012;141(4):916–922.
125.Kline JA, Steuerwald MT, Marchick MR, et al. Prospective evaluation of right ventricular function and functional status 6 months after acute submassive pulmonary embolism: frequency of persistent or subsequent elevation in estimated pulmonary artery pressure. Chest.2009;136(5):1202–1210.
126.Kucher N, Boekstegers P, Muller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129(4):479–486.