High Intermediate Risk Pulmonary Embolism: The Use of Very Low Dose Catheter-Directed Ultrasound-Accelerated Thrombolysis

In the for in-hospital mortality rates are 25% and 65%, respectively Intermediate Risk PE represents a group characterized by the of right ventricular dysfunction ABSTRACT Objective: To determine the hemodynamic benefit, clot burden reduction and safety utilizing an ultra-low dose of Tissue Plasminogen Activator (TPA) with Catheter directed Ultrasound accelerated thrombolysis (USAT) in the management of high Intermediate Risk Pulmonary Embolism. Design: Retrospective, observational case series. Setting: Single Center Academic Community Hospital. Patients: Fifty-two consecutive patients (27 males) with high Intermediate Risk PE treated with USAT were analyzed. Measurements and Main Results: Forty-nine patients underwent bilateral USAT with 0.5 mg/hr/catheter of TPA (unilateral: 1.0 mg/hr). Mean duration of therapy was 22.08 + 4.90 hours. Changes in pulmonary artery pressure (PAP), Clot obstruction index by Miller score and procedure related bleeding complications were assessed. Paired t-testing was used to determine significance Mean RV/LV ratio was 1.52 + 0.36. Miller score decreased 55.0% (mean 19.7 + 3.8 to 8.9 + 4.7; p value < 0.0001). The systolic PAP decreased 7.3% from 63.6 + 15.1 mmHg to 59.0 + 17.5 mmHg (p value = 0.0045). The mean PAP decreased 5.4% from 37.5 + 8.0 mmHg to 35.5 + 9.1 mmHg (p value = 0.0097). No procedural or bleeding related complications occurred. Conclusion: Low dose USAT with 0.5mg/hr/catheter with TPA for 24 hours is highly effective in reducing clot burden and PAP without bleeding or procedural related complications in high Intermediate Risk PE. Catheter-Directed Ultrasound-Accelerated Thrombolysis.

(RVD) without systemic hypotension [2,4]. Estimates of in-hospital mortality for such patients have been as low as 2-3% as reported in a recent multicenter trial [5]. Despite the overall low mortality rate, 5-25% will demonstrate hemodynamic and clinical worsening requiring hemodynamic support and/or rescue thrombolysis [5,6].

Substantial variability exists in clinical outcomes in Intermediate
Risk PE. In patients with RVD on echocardiogram combined with elevated troponin I mortality rates have been reported between 8-15% [7,8]. Patients with RVD and concomitant lower extremity deep venous thrombosis (DVT) have a PE-related mortality of nearly 20%, approximating that of massive, High-Risk PE [7].

Standardized
Procedure of Catheter-Directed Ultrasound-Accelerated Thrombolysis After successful device placement, patients were transferred to the medical intensive care unit for continuous monitoring. Treatment was continued for up to 24 hours, at which time the EKOS® devices were exchanged for angiographic catheters, and repeat pulmonary arteriography was performed in the interventional radiology suite to reassess clot burden, pulmonary arterial perfusion, and pulmonary arterial pressures. The introducer sheath(s) were removed, and hemostasis was obtained by manual compression.

Anticoagulation Therapy
IV unfractionated heparin was utilized in all patients prior to, during, and immediately following USAT. Prior to undergoing USAT, unfractionated heparin was administered utilizing a standard weight-based nomogram. Activated partial thromboplastin time (aPTT) was monitored with a therapeutic target range of 68-101 seconds. During USAT, a low dose unfractionated heparin protocol was instituted. The rate of heparin infusion was adjusted to achieve and maintain an aPTT between 40-60 seconds. Following catheter removal, the standard weight-based nomogram was resumed, targeting an aPTT of 68-101 seconds. Subsequent anticoagulation was left to the discretion of the treating physician.

Primary Outcomes
The primary outcomes assessed in this study were the change

Secondary Outcomes
The secondary outcomes assessed included bleeding, procedural related complications and all cause in-hospital mortality. Major bleeding complications were defined as ICH or bleeding severe enough to warrant cessation of therapy or blood product transfusion. Minor bleeding complications were defined as bleeding manageable with local compression, sheath upsizing, or unfractionated heparin and/or thrombolytic dose reduction [8].
Bleeding complications were assessed during USAT and up to 72 hours following catheter removal.

Statistical Analysis
Paired t-test was performed to test the hypotheses that the pre-USAT mean pulmonary artery pressure, pre-USAT pulmonary artery systolic pressure and pre-USAT Miller score were equal to the post-USAT mean pulmonary artery pressure, post-USAT pulmonary artery systolic pressure and post-USAT Miller score, respectively. The normality assumption for performing paired t-test was satisfied for all three comparisons by using kurtosis, skewness and shapiro-wilk test.

Clinical Characteristics
During the study period, 52 patients (27 males

Medical comorbidities
Hypertension, n 28 Recent Surgery, n 9 History of cancer, n Asthma, n 6 Hormonal therapy, n 2 Cardiac disease, n 3 Splenectomy, n 1

Admission details
Troponin

Procedural Details
Bilateral catheters were utilized in 49 of 52 patients.

Change in Pulmonary Arterial Pressures
Overall, there was a statistically significant reduction in the pulmonary artery systolic pressure and mean pulmonary artery pressure immediately following USAT.

Safety
No procedural related complications occurred. There were no major or minor bleeding complications. No patient received blood transfusions.

Mortality
The in-hospital mortality rate for this cohort was 1.9% (n=1/52). the patient progressed to brain death.

Discussion
Intermediate Risk PE accounts for over 30% of all hospitalized PE [26]. The in-hospital mortality rate in such patients is estimated at 2-3% based on contemporary studies [5].  [15], has been associated with major bleeding complications in Intermediate Risk PE, including intracranial hemorrhage [5].
In this report, a non-bolus, fixed, low dose, USAT protocol is utilized in the treatment of high Intermediate Risk PE. This protocol proved to be highly effective in reducing clot burden and acute pulmonary hypertension without bleeding related complications.
We hypothesize that our excellent safety profile is related to the lack of upfront r-tPA bolus, the low dose hourly infusion rate of r-tPA, and the utilization of low dose IV unfractionated heparin for which an aPTT of 40-60 seconds is targeted during USAT. The inhospital mortality rate for this cohort was 1.9% (n=1/52). The one death was attributed to recurrent PE with paradoxical embolism through a documented Patent Foramen Ovale (PFO). The embolism unfortunately resulted in a catastrophic cerebral vascular accident.
A PFO in PE is associated with an increased risk of complications [28].

Funding
No source of funding.