Use of Ultrasound-Accelerated, Catheter-Directed Local Thrombolysis for Venous and Arterial Occlusions in a Pediatric Hospital

Abstract: Objectives. Acute vascular thrombosis is associated with significant morbidity and mortality in children. Traditional therapies with angioplasty and manual aspiration thrombectomy are described in the pediatric population; however, data regarding the use of ultrasound-assisted catheter-directed thrombolysis in a pediatric hospital are lacking. Methods. All patients treated at our center with ultrasound-assisted catheter-directed thrombolysis from 2014-2018 were reviewed. Results. Ten patients with systemic venous (n = 5), pulmonary artery (n = 4), and systemic arterial (n = 1) were treated (20 total vessels), including 2 adults post Fontan palliation. The median age was 11.2 years (range, 9 months to 34.2 years) and median weight was 46.6 kg (range, 6.81-01.6 kg). Therapy was not completed in 1 patient. Significant improvement in clot burden/symptomatic improvement was seen in 8 patients (no improvement seen in 1 patient with acute and chronic thrombosis). There were no major bleeding or neurologic complications related to therapy. Conclusions. The use of ultrasound-assisted catheter-directed thrombolysis in a pediatric center is a valuable modality for treating acute thrombosis with an acceptable safety profile.

J INVASIVE CARDIOL 2018;30(10):387-392.

Key words: occlusions, pediatric cardiology, thrombolysis

Vascular thrombosis is becoming progressively more common in the pediatric population as a result of multiple surgical and percutaneous interventions, use of chronic venous and arterial lines, extracorporeal membrane oxygenation (ECMO), accompanying cardiac dysfunction, coagulopathies, and other co-morbidities.^1-6 Acute central venous and arterial thrombosis accounts for increased morbidity and mortality, especially in the postoperative period. Treatment can be challenging in younger children with hemodynamic instability or multiple co-morbidities.^7-10 Pulmonary embolism (PE) alone has a mortality rate as high as 20% in the pediatric population.⁷ Traditional therapies include aspiration thrombectomy, the use of rheolytic systems, angioplasty, and administration of thrombolytics.⁴ Use of systemic thrombolytics, although effective, has been associated with up to 20% incidence of hemorrhagic complications, limiting its use.¹¹ Several studies in adult patients with PE^12-14 and deep vein thrombosis^15,16 have shown superior outcomes when using ultrasound-assisted catheter-directed thrombolysis. These studies demonstrate that lower doses of thrombolytics can be used with this ultrasound-assisted therapy, thus minimizing systemic side effects, while at the same time being efficacious. However, to our knowledge, reports of its use in the pediatric population are limited to one small series of patients with PE¹⁷ and a single patient we previously reported within a cohort of patients in whom a variety of other devices were used.⁴ The objective of this study was to assess the efficacy and safety specifically of ultrasound-assisted, catheter-directed thrombolysis for acute arterial and venous thrombosis based on our initial experience in a pediatric center.

Methods

A retrospective review of all patients treated with ultrasound-assisted, catheter-directed thrombolysis utilizing the EkoSonic Endovascular system (EKOS) at Texas Children’s Hospital from January, 2014 to July, 2018 was performed. Adult patients with or without congenital heart disease who were referred for thrombectomy were included. One patient with presumed PE, which later was diagnosed as metastasized osteosarcoma confirmed by pathology, was excluded. The study was performed in accordance with the Baylor College of Medicine Institutional Review Board guidelines and policy. 

The EkoSonic Endovascular system. The EkoSonic Endovascular system utilizes a combination of a high-frequency, low-power ultrasound, microsonic device (MSD) for acoustic pulse thrombolysis and local thrombolytic delivery. This results in faster fibrinolysis using lower doses of thrombolytic agents. In addition, there is no hemolysis or fracture of the clot, reducing the risk of distal embolization and renal injury. The infusion catheter, the Intelligent Drug Delivery catheter (IDDC), is a 5.4 Fr multilumen catheter with treatment zones ranging between 6-50 cm. Tissue plasminogen activator (tPA) is infused via the delivery catheter along with saline coolant usually infused between 5-35 mL/hr along with low-dose systemic heparin to reduce the increased thrombin activity associated with thrombolytic use. 

Procedural techniques. The procedure was performed under general anesthesia and biplane fluoroscopy in all patients. The decision to use the EKOS system and additional thrombolytic therapy or interventions was based on operator preference. Generally, the EKOS endovascular system was used for 12-24 hours; however, repeat cycles of therapy were used in some instances. Drug concentration and infusion rates for tPA and saline coolant were altered in smaller children or those with fluid restriction to minimize fluid load. Success of thrombolysis was defined as complete or nearly complete (>50%) resolution of the thrombus with angiographic improvement in flow across the affected vessel. Patients were maintained on systemic heparin while receiving tPA infusion, unless contraindicated. Transition to anticoagulants post treatment was based on provider preference. Vessel patency post treatment was evaluated by angiography or computerized tomography (CT) scans. Additional or follow-up interventions on the vessels involved were also reviewed. 

Statistical methods. As this is a descriptive study, data are presented as aggregate data, using medians and ranges or counts and percentages. 

Results 

Targeted thrombolytic therapy with the EKOS endovascular system was performed in 20 vessels in 10 patients (Table 1). There were 3 adult patients, 2 with congenital heart disease and 1 with short-gut syndrome who was cared for at our institution since infancy due to venous occlusions.  The median age was 11.2 years (range, 9 months to 34.2 years) and median weight was 46.6 kg (range, 6.8-101.6 kg). Risk factors for thromboses and presenting features can be seen in Table 1.

Massive or submassive PE was treated in 4 patients, 2 of whom were single ventricle patients post Fontan palliation (one postpartum) with bilateral PE involving the central and post-hilar branches. Of the patients with systemic venous thrombosis (n = 5) or systemic arterial thrombosis (n = 1), 4 had previous intervention on the vessels involved, including angioplasty and surgical repair in 1 patient, angioplasty with implantation of bioabsorbable stent in 1 patient, and previous thrombectomy related to a dialysis catheter in 1 patient. The fourth patient underwent mechanical thrombectomy followed by 24-hour infusion of systemic tPA with minimal change in clot burden. Localized thrombolytic therapy with EKOS was therefore utilized with substantial improvement. 

Dose and duration of tPA. Infusion rate for tPA in older patients ranged between 0.5-1 mg/hr/catheter. A lower dose was used for prolonged treatment. Three patients with bilateral PE had 2 catheters placed simultaneously. In 2 patients, where the EKOS endovascular system was used for >48 hours, localized tPA infusion was continued via the delivery catheter without the further assistance of the MSD. Median duration of tPA infusion and MSD use was 23 hours (range, 6.5-98.5 hours) and 20.5 hours (range, 6.5-89.5 hours), respectively. Median total tPA dose was 16.2 mg (range, 1-67.5 mg). 

Adjunct therapy. Adjunct therapy (at the time of placement or removal of the EKOS endovascular system) was used in 7 patients, including mechanical thrombectomy in 3 patients, angioplasty in 2 patients, and thrombectomy with angioplasty in 2 patients with underlying stenoses of the vessels involved. One patient did not complete therapy. He had complete occlusion of the superior vena cava and left innominate vein with partial occlusion of the inferior vena cava in the immediate post-transplant period, for which therapy with the EKOS endovascular system was initiated. However, he developed progressive right ventricular dysfunction with hemodynamic compromise, requiring ECMO support 6-7 hours after initiating treatment. The EKOS endovascular system was removed and he underwent successful surgical thrombectomy at the time of ECMO cannulation and subsequent angioplasty.

Immediate results. Therapy was not completed in 1 patient (described above). Significant improvement in clot burden/symptoms was seen in 8 patients (no improvement seen in 1 patient with acute and chronic arterial thrombosis). Angiographic/CT-based improvement on follow-up imaging was seen in 7 of the 8 patients who underwent successful therapy (Figures 1 and 2). One patient post Fontan palliation with bilateral pulmonary embolism did not receive follow-up imaging due to immediate postpartum status, but had significant symptomatic improvement following 12 hours of therapy. 

Adverse events. There were no major bleeding, vascular, neurologic, or infectious complications noted during or after therapy with the EKOS system. There was minimal oozing from the access-site sheath in 1 patient which improved with placement of a Safeguard pressure-assisted device (Merit Medical Systems). 

Follow-up. Median follow-up was 12.3 months (range, 3 days to 3.9 years). There was 1 transplant-related mortality 8 months later, unrelated to the treated thrombosis. Follow-up imaging by CT scan or angiography was available in the 7 patients in whom immediate success was documented, with no recurrence of thrombosis at the treated sites. Of the patients with systemic vein or arterial thrombosis, 5 underwent repeat catheterization. Angioplasty with stenting was performed in 3 patients at the affected site to treat residual stenoses. These 3 patients had interventions for known stenoses prior to the episode of thrombosis. Two patients did not require any intervention on follow-up catheterization. 

Discussion 

In this study, we report our initial experience using ultrasound-accelerated, catheter-directed local thrombolysis in a pediatric hospital. We found that this modality was effective in treating thrombosis in a variety of locations, while importantly not resulting in any important adverse events. Specifically, we did not encounter any bleeding-related complications.

Administration of local tPA is one of the mainstay treatments for acute thromboses. However, bleeding-related complications including neurological events from intracranial hemorrhage may occur. The use of ultrasound-accelerated, catheter-directed local thrombolysis with the EKOS endovascular system utilizes ultrasound technology that reduces the dose of tPA required to effectively treat acute thrombotic events. In the prospective, multicenter, Seattle II study,¹³ use of the EKOS endovascular system in adults was found to effectively treat PE while minimizing bleeding complications, with no intracranial hemorrhage. Similarly, in the randomized OPTALYSE trial,¹⁴ low-dose tPA with a shorter duration of therapy using the EKOS endovascular system was found to effectively treat PE with a low rate of major bleeding (1 patient with an intracranial hemorrhage). The use of catheter-directed tPA using the EKOS endovascular system is limited in children. There is only one published series reported earlier from our center with PE in 5 patients treated successfully using tPA (0.75-2 mg/hr for 24 hours) without complications.¹⁷ Similarly, in the current series, all 4 patients with PE responded successfully to a lower dose and in general with a shorter duration of tPA through the EKOS endovascular system without complications (0.25-1 mg/hr, with shortest duration of 8 hours). 

In addition, our experience is the first to illustrate the utility of the EKOS endovascular system in other vascular sites with acute/subacute venous or arterial occlusion. All patients with systemic venous occlusion at various sites responded to this therapy in addition to adjunctive therapy for successful resolution and 1 patient with chronic arterial occlusion was not responsive (due to acute and chronic thrombosis) and required mechanical thrombectomy. Children are at increased risk for bleeding complications when tPA is used for the treatment of acute thrombotic events. Given this, the use of ultrasound-accelerated, catheter-directed local thrombolysis seems to be an attractive alternative in children. This dose-reduction strategy is particularly attractive for the young pediatric population, patients who have had recent cardiac surgery/other surgical procedures, or children with congenital heart disease, who appear to be at the highest risk for bleeding complications with tPA therapy.¹⁸ 

As per current recommendations for adult patients, tPA is infused at 0.5-2 mg/hr/catheter through the IDDC.¹⁴ There are few data regarding dosing in children. Low-dose infusion rates of 0.03-0.06 mg/kg/hr (range, 30-60 µg/kg/hr) have been recommended for systemic and local use in children.^19,20 The dosage of tPA to be used in children (not of adult size) is weight based, and highly variable based on institutional experiences. It is unknown what the optimal dose in children is when using ultrasound-accelerated, catheter-directed local thrombolysis, for which larger, prospective studies are necessary. There has been a gradual change in recommended tPA dose and duration of treatment when using ultrasound-accelerated, catheter-directed local thrombolysis, from 12-24 hours to 2-6 hours based on adult studies.^12-14 This change in treatment, along with investigating decreased dosing rates, is something that we are interested in implementing and studying in the pediatric population in the future. 

While admittedly, not all patients in this study were children, the patients in this study who were adult sized are an important population to consider in pediatric centers. Adults with congenital heart disease are commonly cared for in pediatric centers and have unique, complex medical needs. Teenagers who are adult sized without congenital heart disease are also cared for in pediatric centers based on individual center’s expertise and may present with acute thrombotic complications. Hence, it is vital that interventional cardiologists and other specialists in pediatric centers are familiar with ultrasound-accelerated, catheter-directed local thrombolysis and its potential advantages.

Study limitations. This study is limited by its sample size and retrospective nature. In addition, there was no comparison group in this study and it is possible that other modalities used to treat acute thrombosis could have resulted in similar efficacy and safety profiles. Regardless, this study enhances our knowledge of the applicability of this therapy to this unique population.

Conclusion

In summary, the use of ultrasound-accelerated, catheter-directed local thrombolysis in a pediatric center is practical, safe, and effective. Further studies are necessary to determine optimal tPA dosing and duration needed when using this therapy. In addition, miniaturization of this technology will allow for more widespread use in pediatrics, particularly in the arterial systems of smaller children. 

References

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From the Lillie Frank Abercrombie Section of Cardiology, CE Mullins Cardiac Catheterization Laboratories, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas.    

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted July 28, 2018, provisional acceptance given August 7, 2018, final version accepted August 19, 2018.

Address for correspondence: Asra Khan, MD, The Lillie Frank Abercrombie Section of Cardiology, Texas Children’s Hospital, Baylor College of Medicine, 6621 Fannin Street, West Tower, 19th Floor, Suite 19345-C, Houston, TX 77030. Email: axkhan2@texaschildrens.org