The CIS Power-Pulse Spray Technique

Introduction

Thrombus is now accepted as playing a key role in patients with acute myocardial infarction (AMI), unstable angina, acute coronary syndromes (ACS), deep venous thrombosis (DVT), pulmonary embolus (PE), and acute limb ischemia (ALI). Angioscopic evidence of thrombus was noted in a significant percentage of patients presenting with ACS and AMI by White et al.¹ and large acute and subacute thrombus burdens are often associated with ALI, DVT, and PE. Thrombus formation is a complex process. It culminates in a final common pathway, with the thrombin cleavage of fibrinogen to fibrin. Fibrin strands then bind with activated and aggregated platelets and red blood cells to form thrombus. Plasmin cleaves fibrin strands, leading to clot dissolution. Plasminogen is converted to plasmin by naturally occurring tissue plasminogen activator (t-PA), which is secreted by normal vascular endothelium. Therefore, endogenous t-PA is essential in achieving the delicate balance between hemostasis and fibrinolysis. Currently, all available thrombolytic agents are plasminogen activators. It is well-known that acute lower extremity arterial thrombotic occlusive disease can lead to acute critical limb ischemia (ALI) with impending limb loss if rapid revascularization is not provided. Open surgical thrombectomy, percutaneous chemical thrombolysis (CT) and percutaneous rheolytic thrombectomy (RT) are accepted CLI treatments, but the mortality, morbidity, and limb loss rates have remained alarmingly high.^2–4 Recently RT and CT have demonstrated improved outcomes, yet both possess limitations, including long infusion and procedure times, incomplete thrombus removal, embolic complications, bleeding, and increased hospital resource utilization and costs.^5,6 The incidence of DVT alone is approximately 48 per 100,000 persons per year in large community-wide studies, with an in-hospital case-fatality rate from complications of thromboembolism at 12%.⁷ Thus, over 300,000 hospitalizations per year can be directly attributed to DVT. Venous thrombotic disease, both DVT and PE, is an under-diagnosed medical problem that may result in high rates of significant patient morbidity and mortality. The consequences of chronic venous insufficiency (CVI), the post-thrombotic or post-phlebotic syndrome, is a major medical problem and often results in a significant morbidity and compromise of lifestyle for an affected patient.^8,9 CVI, secondary to post-phlebotic syndrome, occurs in 66% of patients at 5 years following an episode of DVT and accounts for up to 75% of all cases of venous ulcerations.^10–13 It is estimated that approximately 650,000 PEs occur each year and 70% of the diagnoses are made antemortem. DVT and PE is the third most common cardiovascular disease after coronary artery disease and PVD-stroke. The mortality of PE is 8% if identified and treated correctly, but 30% when untreated.¹⁴ RT and CT have also been recently reported in the treatment of both DVT and PE with potentially improved outcomes.^15–17 The novel “Power-Pulse Spray” (“P-PS”) technique was developed at the Cardiovascular Institute of the South (CIS), in concept, to simultaneously maximize the advantages and benefits of both RT and CT, while minimizing their disadvantages and limitations in an effort to rapidly reperfuse the ischemic limb, rapidly remove acute and subacute thrombus in DVT and PE, lessen risks and complications, decrease ICU and hospital resource utilization, and improve clinical outcomes.¹⁸ The P-PS technique has recently received FDA market clearance for the use of AngioJet (Possis Medical, Inc., Minneapolis, MN) for power pulse spray delivery of a physician-specified fluid such as a thrombolytic agent via the AngioJet catheter.

Case Presentation #1

A 71-year-old white female with a history of diabetes, stroke, MI, PVD, hypertension, and a prior CABG presented with an acute onset of left leg and foot pain, coolness, and weakness of six-hour duration. Physical examination revealed a cold, pulseless, ischemic left foot. An urgent contralateral approach peripheral angiogram revealed a flush total occlusion of the proximal left common iliac artery below the aortic bifurcation. The thrombotic occlusion was crossed using a 0.035” glidewire and the CIS “P-PS” technique and protocol was used for revascularization. A diffuse “culprit lesion” was unmasked after the pulsed thrombolytic was allowed to “lyse” for 30 minutes . A single balloon-expandable stent and long self-expanding stent was deployed, providing revascularization in a total procedural time of 65 minutes. ICU monitoring was not required, limb salvage was achieved, and the patient was asymptomatic at 36-hour discharge and at 30-day follow-up. A 30-day postprocedural angiogram revealed excellent results.

Case Presentation #2

A 69-year-old white male with a history of diabetes, MI, PVD, CABG, and previous left femoral-popliteal bypass graft (FPBG) presented with 6-hour onset of acute left leg pain and weakness. Physical examination revealed a cold, pulseless, ischemic left foot. An emergent contralateral angiogram revealed a total occlusion of the left common femoral artery and the previous FPBG, which was identified by a previously placed metal “anastomotic graft marker” (AGM). The occluded graft was crossed using a 0.035” glidewire and the CIS “P-PS” protocol was used for successful revascularization. The AGM facilitated intubating and crossing the graft after failure to cross the occluded native SFA. AGMs placed after CABG have proven beneficial to both the patient and the cardiologist by decreasing contrast utilization, radiation exposure, and procedural time by 30%, and improved graft patency.^19,20 It can be theorized that less wire and catheter manipulations will decrease the potential for intimal injury and post-CABG graft patency salvage rates are improved in patients with AGMs. We strongly advocate AGM placement on all PVD anastomoses.

Rheolytic Thrombectomy — AngioJet The AngioJet RT System uses a complex mixture of rapid fluid streaming and hydrodynamic forces to fracture thrombus, allowing extraction at the catheter tip using negative pressure (Bernoulli/Venturi principle. The RT System includes a Drive Unit console, pulsatile pump set, and catheter. The system is activated by depressing a foot pedal. Various RT catheters have been developed and tailored to specific clinical applications. The device is currently approved for use in coronary artery and saphenous vein grafts, infrainguinal peripheral arteries, and hemodialysis access conduits. The RT system has shown promising results in treating acute CLI, and is rapidly emerging as a first line therapeutic option for the management of ALI.^21,22 The recently introduced 6 Fr Xpeedior RT catheter has become our group’s first-line treatment of choice in patients with ALI.

The CIS “P-PS” Technique

RT and CT each have advantages and disadvantages, risks and limitations. No single treatment modality has become the “gold standard,” and successful outcomes often require creative combination therapy. To address the limitations of monotherapy, we developed the novel power-pulse spray (“P-PS”) technique. The total or subtotal iliofemoral or bypass graft thrombotic occlusion is crossed using standard techniques with a 0.035” guidewire. This step is often facilitated with a 5-Fr Terumo glide-catheter (Boston Scientific Corporation, Maple Grove, MN). Initially, the 6 Fr AngioJet catheter and RT system is set up and primed in its “thrombectomy mode” with normal saline. A “lytic bag” is then created by adding either 1,000,000IU UK or 10mg TNK to 50cc of normal saline, and is then exchanged for the saline prime. A stopcock is added and closed to the outflow port RT catheter manifold, thus converting the RT system to its “P-PS” mode. It is important to advance the RT catheter slowly, at 0.5 to 1.0 mm increments through the entire thrombosed segment, using a single foot pedal pump/pulse per advanced increment. The RT system is set to deliver 0.6ml volume of lytic solution per each pedal pump/pulse. The infused volume meter on the device unit console is set at zero at the initiation of the “P-PS” mode, allowing calculation of the total lytic volume and dose. A single antegrade and retrograde RT pass in the “P-PS” mode is recommended; the RT catheter is then removed. The concentrated pulsed lytic is allowed to “lyse” for 30 minutes as the RT system is converted back to its thrombectomy mode. It is important to evacuate the residual 12ml of lytic outside the patient to avoid infusing additional lytic. The AngioJet RT catheter is then reintroduced with a single antegrade and retrograde pass, followed by immediate angiography.

CIS Results in ALI

Our recent experience with a group of 49 patients presenting with acute CLI and angiographically evident iliofemoral arterial thrombotic occlusion is presented. Forty-nine arteries (15 iliac, 22 SFA, 12 bypass graft) were treated via “P-PS” technique: i) Using a 6 Fr RT catheter, NS prime was exchanged for thrombolytic solution (Group I: 10–20mg TNK/50 cc NS, N=25; Group II: 1,000,000 UK/50 cc NS, N=24); ii) The outflow port was closed, then the catheter was advanced at 1 mm increments while pulsing lytic agent; iii) After 30 minutes of local thrombolysis, RT and definitive treatment of the underlying stenosis were performed. Procedure success was 23/25 (92%) and 22/24 (91.6%) for Group I and II respectively. The mean total procedure time was 72 minutes and 75 minutes in Group I and II respectively. Thirty-day limb salvage was 91% in both groups. There were no major surgical complications in either group and equivalent minor complications (8%). Procedure time ranged from 40–110 minutes (mean = 72) in Group I and from 45–116 minutes (mean = 75) in Group II. It was thus essentially equivalent in both dosage groups (overall mean = 73.5). The iliac artery procedure times were generally shorter (mean = 59 minutes, range = 40–78) as compared to the SFA and FPBG procedures (mean = 79 minutes, range = 54–115). There were no major or vascular complications requiring surgery in either group. Two minor hematomas ( 25% (mean drop = 12.4%). The FPBG subset responded exceptionally well, with a 100% success rate and mean total procedure time of 61 minutes. There were no clinically or angiographically apparent embolic complications. Only two patients in each group required ICU care monitoring, primarily for pre-existing coronary artery disease and ventricular dysrhythmias. The Ankle Brachial Index (ABI) mean improvement was 0.31 ± 0.16 with a range of 0.14 – 0.41. Forty of 49 (81.6%) were available for 30-day duplex ultrasound. Thirty-seven of 40 (92.5%) limbs had 50% restenosis at the percutaneous transluminal angioplasty (PTA)/stent site by duplex ultrasound velocity and waveform analysis. Two of three patients underwent repeat angiography and repeat PTA/stenting, both superficial femoral artery, and the third patient was treated medically. All patients experienced clinical improvement after completion of lysis and revascularization. Four procedural failures were due to an inability to cross the lesion and 2/4 (50%) underwent surgical revascularization. Both procedural failures not undergoing surgical revascularization required major amputations during that admission. We have used the “P-PS” technique in multiple other vascular applications, including PE, DVT, A-V dialysis graft thrombosis, IVC thrombosis, SVC syndrome and Padget-Schroder Syndrome, or effort thrombosis. We report a recent case of massive IVC thrombosis with impending PE. We have further utilized this technique successfully in a wide variety of arterial and venous applications, including A-V dialysis access graft thrombosis, SVC and IVC thrombosis, Padgett-Schroder Syndrome, iliofemoral DVT, and thrombosis of peripheral venous and arterial stents. Our most recent application was via a left brachial approach in an occluded iliofemoral extension limb of an endograft implanted for endovascular exclusion of a large abdominal and iliac artery aneurysm.

Case Presentation #3

A 63-year-old obese male from out of state presented to the ER with acute chest pain and severe dyspnea. Past medical history included 2 previous DVTs, 2 previous PEs, chronic coumadin therapy, and a Greenfield IVC filter placed 2 years prior. The patient was on chronic coumadin therapy, but had been noncompliant for several days. ABGs included PH = 7.31, PCO2 = 24, PT = 13.8, PTT = 24, INR = 1.9, and PO2 = 49 on a 100% non-rebreathing mask. The chest x-ray, EKG, echocardiogram and single-slice chest CT scan were all nondiagnostic as to the patient’s symptoms. A V/Q lung scan was “highly suspicious” for acute and chronic bilateral PE and a venous ultrasound suggested bilateral iliofemoral DVT. Physical examination revealed an obese male in acute respiratory distress with significant bilateral lower extremity edema. A clinical diagnosis of acute PE with possible IVC thrombosis was made and the patient was heparinized and transferred urgently to the cath lab for venography and possible IVC RT, CT or treatment with the “P-PS” technique. Venography was performed via a right femoral approach and revealed no significant bilateral iliac or IVC thrombosis, but did reveal a massive friable thrombus of the mid and upper IVC above the previously placed IVC filter. Adjuvant medical treatment included Decadron 8 mg, bivalirudin (Angiomax, The Medicines Company, Parsippany, NJ), tirofiban (Aggrastat, Guilford Pharmaceuticals, Baltimore, MD) and dobutamine (Dobutrex, Eli Lilly & Company, Indianapolis, IN). The immediate concern was that the massive IVC thrombus could embolize, resulting in a fatal PE with any manipulation from below. Therefore, an Optease (Cordis Corporation, Miami Lakes, Florida) temporary IVC filter was placed above the thrombus and below the right atrium via a left jugular approach. The “P-PS” technique was performed via the jugular venous access and was not performed over a guidewire. This allowed reforming of the AngioJet tip, allowing a wider “360º sweep” of the catheter during the “P-PS” technique, facilitating pulsed deposition of the high-dose concentrated lytic through the 32 mm diameter IVC and into the massive thrombus. After 30 minutes of “lysis,” the “P-PS” was completed per protocol and IVC venography revealed almost complete removal of the massive thrombus. The patient remained hemodynamically stable and the oxygen saturations improved. The bivalirudin and tirofiban were continued for 12 hours overnight. Repeat venography revealed complete resolution of the thrombus. The Optease filter was retrieved. The patient developed no bleeding complications or signs of systemic lysis, and was discharged 72 hours later, fully anticoagulated on coumadin.

CIS Experience

The “P-PS” technique was designed to simultaneously maximize the advantages and benefits of both CT and RT therapy while minimizing their disadvantages and limitations in an effort to lessen risks and complications, rapidly perfuse the acutely ischemic limb, decrease CT exposure, decrease overall treatment times, ICU stays, and hospital resource utilizations, therefore improving outcomes in patients presenting with acute CLI. A pulse-spray technique had been previously described,^22–24 but is cumbersome, requires frequent manual injections or an automated injection device, is time-consuming, has a definite risk of downstream embolization, often requires additional continuous lytic infusions or RT, and has not been validated in clinical trials. Our “P-PS” technique differs in that high-dose, concentrated lytic is “power pulse sprayed” under high pressure and allowed to lyse for only 30 minutes. In theory, this allows “softening” of the thrombus by maximizing the thrombus surface area on which lytic agent is exposed, therefore facilitating mechanical extraction with the RT device by converting “insoluble” thrombus unretrieveable by RT into “more soluble” thrombus that is retrievable by RT. Attempts to validate this concept are ongoing. Several key concepts and components of the “P-PS” technique require comment. The RT catheter is intentionally not used first in its normal “thrombectomy mode” in an effort to avoid distal embolization. Distal embolization has been reported with both RT (3-15%) and CT (3-18%) but is generally accepted to be 25–27 Embolization can occur with the reinstitution of blood flow through the involved vessel as loosely attached or partially lysed thrombus can flow to the downstream vascular bed as the thrombus “melts” with CT. Embolization can also occur with the mechanical dislodgment or “pushing” of insoluble thrombus downstream with RT.^25,26 The “PPS” technique allows high-dose, concentrated lytic to be deposited directly into the existing thrombus when not being exposed to downstream blood flow. The methodical, short 1 mm increment advancements of the “PPS” technique may allow more efficient RT with less risk of embolization by eliminating the “melting” effect and the “pushing” effect. We observed no clinical or angiographic evidence of distal embolization in our experience. In theory, the delivery of lytic under high pressure leads to maximum thrombus penetration and mixing, therefore allowing maximal lytic exposure and lysis in this rich “clot-bound-fibrin-thrombin” environment . The clinical benefits of direct thrombin inhibition with bivalirudin in the treatment of AMI and peripheral vascular disease have been recently reported.²⁸ The decreased bleeding complications reported and the pharmacological property of bivalirudin-inhibiting “clot bound thrombin” prompted our adoption of bivalirudin as our anticoagulation foundation in the treatment of arterial and venous thrombosis. The multi-center APPROVE trial has been completed, validating the safety and efficacy of utilizing bivalirudin in the interventional treatment of PVD as compared to heparin. Similar to the large percutaneous coronary interventions (PCI) REPLACE-2 results, the APPROVE trial provides more observational data that bivalirudin may have a safer profile than heparin in treating PVD, while we await definitive randomized data.³⁰ The strategy of peri- and post procedural glycoprotein IIb/IIIa (GPIIb/ IIIa) inhibition has its basis from the encouraging results of several PCI trials, including GUSTO V, where there was a significant reduction in the composite endpoints of death, reinfarction, and urgent revascularization at 7 days in patient with acute coronary syndromes.^30,31 GPIIb/IIIa inhibition may decrease the risks of periprocedural subacute peripheral stent thrombosis, distal embolic events, and distal “no flow” phenomenon, as seen in complex PCI. The addition of GPIIb/IIIa inhibition to this current P-PS treatment strategy did not adversely affect bleeding complications. GPIIb/ IIIa inhibition may even have a greater potential to improve outcomes in the interventional treatment of complex PVD than its role in PCI. It has been theorized that the use of GPIIb/IIIa agents in ALI may lessen the risk of clinically significant distal embolization during revascularization.³⁰ The concept of achieving maximum local clot lysis with minimal systemic lytic effect appears achievable when considering the superior pharmacological properties of urokinase (UK) (UK, Abbott Laboratories, Abbott Park, IL) and Tenecteplase (TNK, Genentech, San Francisco, CA). UK is indicated for thrombolysis in PE but has the largest volume of literature available in ALI. UK is a two-chain serine protease compound obtained from tissue culture of kidney cells with a molecular weight of 32,000 – 54,000 daltons, a serum T1/2 of 14 minutes, and high fibrin specificity. A large clinical experience has shown UK to be safe and effective in treating ALI. TNK was designed with a high fibrin affinity and selectivity, low systemic effect, significant lytic potency and a 22-minute serum half-life (T1/2). None of our patients experienced a significant (> 25%) fibrinogen drop. Therefore, it is likely that most of the lytic dose in the “P-PS” technique is removed during the antegrade and retrograde thrombectomy passes. However, this remains to be validated. In our experience, there was no clinical difference utilizing TNK or UK in the “P-PS” technique. We have no experience with other thrombolytics utilizing the “P-PS” technique. The most encouraging initial result with the “P-PS” technique was the overall mean total procedure time or revascularization time of 73 minutes for this simultaneous combination of two “monotherapies,” CT and RT. Review of the CT literature reveals a revascularization trend from 1–2 days in the 1980s and early 1990s, to 12–24 hours in the last 5 years.^32–34 In a meta-analysis of 15 thrombolysis trials utilizing rt-PA, only 33% (6/18) reported a mean lysis time (MLT), with a range of 6–24 hours and 3.5 hours being the shortest MLT.³³ Kandarpa et al.³⁵ reported a mean time to reperfusion of 110 minutes in 28 occluded arteries but noted 89% need additional infusion of rt-PA for complete lysis, with an overall MLT of 17 hours with the pulsed spray technique. A review of the AngioJet literature reveals that the AngioJet can substantially remove thrombus burden in a majority of patients and serve as monotherapy “stand alone” therapy in 20-50% of cases, but clearly at least 50% will also require adjuvant CT.^{25,27-29,36,38} Conclusion The “P-PS” technique is a novel combination therapy simultaneously utilizing RT (AngioJet) and CT (UK or TNK) which recently received FDA market clearance for use of the AngioJet for power-pulse spray delivery of physician-specified fluids (thrombolytics) with an FDA-approved “P-PS” kit. The “P-PS” technique offers several potential advantages compared to more traditional monotherapy thrombectomy or thrombolytic strategies for patients with a wide variety of arterial and venous thromboses. The CIS “Power-Pulse Spray” technique is a tool that potentially will allow clinicians to achieve rapid arterial and venous thrombolysis and thrombectomy in minutes, not hours or days, and “treat ALI, PE, and DVT like the acutely ischemic LAD.”

Dr. Allie, Chris Hebert, and Dr. Walker have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the contexts of the subject of this article.

The authors can be contacted at David.Allie@cardio.com