ENDOVASCULAR TREATMENT OF ACUTE PULMONARY EMBOLISM

Thromboembolism of pulmonary artery is life-threatening condition due to acute right ventricle failure and cardiogenic shock. System thrombolysis is the main way of reperfusion in massive pulmonary embolism with a very high risk of fatal hemorrhage complications. There is a popular revascularization method in two last decades such as endovascular treatment. It allows to recover the blood flow into occluded pulmonary arteries up to three weeks after confirmed embolism episode and to decrease major bleeding risks. Now trials corroborate the high efficacy and safety of interventional treatment the usage of which would allow to improve prognosis in massive pulmonary embolism.


Introduction
Pulmonary embolism (PE) is a life-threatening condition that is responsible for more than 300,000 deaths every year in the United States. It is estimated that more than 600,000 patients develop symptomatic PE annually. [1,2] The mortality rate in the first 3 months following a diagnosis of PE ranges from 15%-18%. [3,4] Massive PE, characterized by circulatory collapse or hemodynamic instability from acute PE, is a highly lethal condition associated with a 3-fold increased inpatient mortality compared with patients who do not have hemodynamic instability. [5,6] Most PE-associated deaths are the result of acute massive PE and typically occur within 1 hour of presentation. [7] It is noteworthy that although PE lethality data are comparable to those of acute myocardial infarction, the overall mortality rate associated with this devastating condition has not improved significantly in the past 3 decades. [3,[8][9][10] The optimal treatment strategies for patients with acute PE have been a subject of controversy, because no randomized controlled trials exist to support an ideal therapeutic modality. For patients with hemodynamic instability from massive PE, systemic thrombolysis is considered to be the standard of care. [2,[11][12][13][14][15] Researchers have reported that catheter-directed thrombolytic (CDT) therapy can facilitate thrombus dissolution through the infusion of a high concentration of thrombolytic agents directly into the thrombus, resulting in shorter infusion times and lower thrombolytic doses. Recent advances in catheter-based thrombolytic therapy have led to the development of ultrasound-accelerated CDT therapy, a novel therapeutic strategy with promising application in patients with acute PE. In this article, treatment indications for acute PE and the therapeutic modality of ultrasound-accelerated thrombolysis for acute massive PE are discussed.

Indications for Advanced Therapy for Acute Pulmonary Embolism
In the 2008 publication, Evidence-Based Clinical Practice Guidelines, by the American College of Chest Physicians, treatment of PE, therapeutic strategies, and advanced interventions such as anticoagulation, thrombolysis, percutaneous embolectomy, and/or inferior vena cava filter placement were recommended on the basis of appropriate risk stratification in highly selected patients who have PE-related hemodynamic instability. [18] A separate consensus guideline by the 2008 European Society of Cardiology Task Force on PE Management outlined many similar diagnostic criteria and therapeutic recommendations in patients with massive PE who have experienced cardiogenic shock. Table 1 highlights the treatment recommendation from these 2 consensus guidelines for patients with PE-related hemodynamic compromise. On the basis of clinical evidence, [17][18][19][20] clinical parameters that warrant early and aggressive catheter-based interventions for acute massive PE require 1 or more of the following conditions: Arterial hypotension, defined as systolic arterial pressure ≤ 90 mm Hg, a drop in systolic arterial pressure ≥ 40 mm Hg for ≥ 15 minutes, or ongoing administration of catecholamine for the treatment of systemic arterial hypotension; Cardiogenic shock with peripheral hypoperfusion and hypoxia; Circulatory collapse, including syncope or need for cardiopulmonary resuscitation; Echocardiographic findings indicating right ventricular dilatation and/or pulmonary hypertension; Subtotal or total filling defect in the left and/or right main pulmonary artery determined by chest computed tomography (CT) scan or by conventional pulmonary angiography; or Widened arterial-alveolar O2 gradient (> 50 mm Hg).

Ultrasound-Accelerated Thrombolytic Therapy for Pulmonary Embolism
The efficacy of CDT therapy with intrapulmonary thrombolytic infusion in patients with acute massive PE has been reported in several studies to lead to an overall remarkable treatment success. [8,[21][22][23][24][25][26][27] This strategy requires selective infusion catheter placement in the pulmonary artery within the embolus, followed by continuous infusion of thrombolytic drugs for a specified period of time.
Ultrasound-accelerated catheter-directed thrombolysis is a novel treatment in which pulmonary artery thrombolytic therapy is delivered through an infusion catheter that emits ultrasound energy to accelerate the thrombolytic cascade. This treatment is achieved using the EkoSonic® Endovascular System (EKOS Corporation; Bothell, WA), which is approved by the US Food and Drug Administration for pulmonary artery infusion. The system uses a 5.2-French multilumen sideport infusion catheter, with infusion lengths of 6-50 cm depending on the length of the thrombotic occlusion. Once the EkoSonic catheter is positioned in the pulmonary artery, an ultrasound core wire containing a series of ultrasound transducer elements (2.2 MHz, 0.45 W) is positioned within the infusion catheter ( Figure 1). The ultrasound catheter is then connected to a control unit that provides continuous monitored variables, including temperature and ultrasound energy power output in the treatment zone by means of thermocouples incorporated in the catheter, and automatically adjusts power to optimize lysis of the intravascular thrombosis. The acoustic streaming energy dissociates the fibrin and increases the fibrin porosity without causing distal embolization, which also facilitates the penetration of thrombolytic agents into the thrombus for receptor binding. Two recent clinical reports (including our own institutional experience) about patients who have experienced acute massive PE and who were treated with ultrasound-accelerated thrombolytic therapy, showed promising clinical outcomes with dramatic hemodynamic improvement. [21,25]

Figure 1. (A)
The EkoSonic Endovascular System consists of a multilumen infusion catheter with a removable coaxial ultrasound transducer core, which is connected to a control unit that delivers lower-energy high-frequency ultrasound energy with concomitant thrombolytic drug infusion into the thrombus. (B) Schlieren photograph of an EkoSonic catheter that emits ultrasound energy. The acoustic streaming energy dissociates the fibrin and increases the fibrin porosity without causing distal embolization, which also facilitates the penetration of thrombolytic agent into the thrombus for receptor binding.

Clinical Experience With Ultrasound-Enhanced Catheter-Directed Thrombolysis for Pulmonary Embolism
Clinical experience with interventional treatment in patients with acute massive PE from our institution was recently reported. [25] A total of 25 patients underwent 33 catheter-directed interventions for massive PE during a 10-year period. Interventional treatment strategies in these patients included CDT therapy (CDT group, n = 11) or ultrasound-accelerated thrombolytic therapy using the EkoSonic system (EKOS group, n = 15). Preinterventional and postinterventional pulmonary angiography were analyzed for evidence of thrombus removal on the basis of published criteria as reported by Miller and associates. Relevant clinical factors, including hypercoagulable risk factors for PE, thrombolytic dose, infusion time, percentage lysis on the basis of angiographic analysis, and treatment complications were compared between the 2 treatment groups. Complete thrombolysis was defined as more than 90% thrombus removal, near complete lysis was defined as 75%-90% thrombus removal, and partial lysis was defined as 50%-75% thrombus removal. Follow-up pulmonary angiography was performed 12-48 hours after the initiation of catheter-based interventions to determine the need to continue or stop thrombolysis. Helical CT angiogram of the chest was performed whenever clinical indications were present (Figure 2). Our clinical experience showed that successful catheter-based interventions were initiated, because the infusion catheters were positioned appropriately within the thrombus in all patients in both groups. In the EKOS group, tissue plasminogen activator (tPA) was administered to all patients, with a mean tPA dose rate of 0.86 ± 0.16 mg/hour for a mean total tPA dose of 17. and partial thrombolysis was achieved in 2 patients (14.3%). [2] Comparative analysis between the 2 treatment groups on the basis of thrombus removal showed that the EKOS group had improved treatment success compared with the CDT group (P < .02). The preinterventional MS was 17.29 ± 3.86 which was reduced to 7.38 ± 2.26 following CDT therapy (Table 2). With respect to tPA dosage and infusion time, these were lower in the EKOS group compared with the CDT group (P < .001). The MS scores were statistically significant in both EKOS and CDT groups following respective interventional treatment (P < .002). No significant difference in relative MS improvement was observed between groups. [25]  This study demonstrated remarkable therapeutic efficacy of both CDT and ultrasound-accelerated thrombolytic therapy in patients with acute massive PE. The treatment success of CDT and EKOS interventions is evidenced by the 30-day survival rates, which were 86% and 91%, respectively. [25] The findings of this study underscored the beneficial role for endovascular interventions in patients with acute massive PE.

Conclusions
The results of our own institutional experience highlight a potential therapeutic benefit in patients with acute massive PE whose hemodynamic instability or cardiogenic shock could be improved with endovascular interventions using ultrasound-accelerated CDT therapy. This modality is a beneficial treatment option in patients who have acute massive PE with contraindications to systemic thrombolysis, when time to administer systemic thrombolytic agents is lacking, or when no improvement follows standard intravenous thrombolytic administration.
In institutions with appropriate clinical expertise, ultrasound-accelerated CDT therapy is an important component of the therapeutic armamentarium for patients with acute massive PE.