Feasibility of Microbubble-Accelerated Low-Dose Thrombolysis of Peripheral Arterial Occlusions Using an Ultrasound Catheter.

PURPOSE: Intra-arterial administration of microbubbles (MBs) through an ultrasound (US) catheter increases the local concentration of MBs into the thrombus and may further enhance outcomes of contrast-enhanced sonothrombolysis (CEST). The objective of this study was to evaluate the feasibility and lytic efficacy of intra-arterial infusion of MBs during US-enhanced thrombolysis in both in vitro and in vivo peripheral arterial occluded models. MATERIALS AND METHODS: SonoVue and Luminity MBs were infused at a flow rate of 20 mL/h through either the drug delivery lumen of the US catheter (DDC, n=20) or through the tube lumen of the vascular phantom (systematic infusion, n=20) during thrombolysis with a low-dose urokinase (UK) protocol (50 000 IU/h) with(out) US application to assess MB survivability and size by pre-treatment and post-treatment measurements. A human thrombus was placed into a vascular phantom of the flow system to examine the lytic effects of CEST by post-treatment D-dimer concentrations measurements of 5 treatment conditions (saline, UK, UK+US, UK+US+SonoVue, and UK+US+Luminity). Thrombolytic efficacy of localized MBs and US delivery was then investigated in vivo in 5 porcine models by arterial blood flow, microcirculation, and postmortem determined thrombus weight and remaining length. RESULTS: US exposure significantly decreased SonoVue (p=0.000) and Luminity (p=0.000) survivability by 37% and 62%, respectively. In vitro CEST treatment resulted in higher median D-dimer concentrations for the SonoVue (0.94 [0.07-7.59] mg/mL, p=0.025) and Luminity (0.83 [0.09-2.53] mg/mL, p=0.048) subgroups when compared with thrombolysis alone (0.36 [0.02-1.00] mg/mL). The lytic efficacy of CEST examined in the porcine model showed an improved median arterial blood flow of 21% (7%-79%), and a median thrombus weight and length of 1.02 (0.96-1.43) g and 2.25 (1.5-4.0) cm, respectively. One allergic reaction and 2 arrhythmias were observed due to the known allergic reaction on lipids in the porcine model. CONCLUSION: SonoVue and Luminity can be combined with an US catheter and could potentially accelerate thrombolytic treatment of peripheral arterial occlusions. CLINICAL IMPACT: Catheter-directed thrombolysis showed to be an effective alternative to surgery for acute peripheral arterial occlusions, but this technique is still associated with several limb and life-threatening complications. The effects of thrombolysis on clot dissolution may be further enhanced by intra-arterial administration of microbubbles through an ultrasound catheter. This study demonstrates the feasibility and lytic efficacy of intra-arterial infusion of microbubbles during US-enhanced thrombolysis in both in vitro and in vivo peripheral arterial occluded models.

Image Fusion During Standard and Complex Endovascular Aortic Repair, to Fuse or Not to Fuse? A Meta-analysis and Additional Data From a Single-Center Retrospective Cohort.

PURPOSE: To determine if image fusion will reduce contrast volume, radiation dose, and fluoroscopy and procedure times in standard and complex (fenestrated/branched) endovascular aneurysm repair (EVAR). MATERIALS AND METHODS: A search of the PubMed, Embase, and Cochrane databases was performed in December 2019 to identify articles describing results of standard and complex EVAR procedures using image fusion compared with a control group. Study selection, data extraction, and assessment of the methodological quality of the included publications were performed by 2 reviewers working independently. Primary outcomes of the pooled analysis were contrast volume, fluoroscopy time, radiation dose, and procedure time. Eleven articles were identified comprising 1547 patients. Data on 140 patients satisfying the study inclusion criteria were added from the authors' center. Mean differences (MDs) are presented with the 95% confidence interval (CI). RESULTS: For standard EVAR, contrast volume and procedure time showed a significant reduction with an MD of -29 mL (95% CI -40.5 to -18.5, p<0.001) and -11 minutes (95% CI -21.0 to -1.8, p<0.01), respectively. For complex EVAR, significant reductions in favor of image fusion were found for contrast volume (MD -79 mL, 95% CI -105.7 to -52.4, p<0.001), fluoroscopy time (MD -14 minutes, 95% CI -24.2 to -3.5, p<0.001), and procedure time (MD -52 minutes, 95% CI -75.7 to -27.9, p<0.001). CONCLUSION: The results of this meta-analysis confirm that image fusion significantly reduces contrast volume, fluoroscopy time, and procedure time in complex EVAR but only contrast volume and procedure time for standard EVAR. Though a reduction was suggested, the radiation dose was not significantly affected by the use of fusion imaging in either standard or complex EVAR.

Microbubbles and Ultrasound Accelerated Thrombolysis for Peripheral Arterial Occlusions: The Outcomes of a Single Arm Phase II Trial.

OBJECTIVE: Acute peripheral arterial occlusions can be treated by catheter directed thrombolysis (CDT). However, CDT is time consuming and accompanied by the risk of bleeding complications. The addition of contrast enhanced ultrasound and microbubbles could improve thrombus susceptibility to thrombolytic agents and potentially shorten treatment time with a lowered risk of bleeding complications. This article reports the outcomes of the safety and feasibility of this novel technique. METHODS: In this single arm phase II trial, 20 patients with acute lower limb ischaemia received CDT combined with an intravenous infusion of microbubbles and locally applied ultrasound during the first hour of standard intra-arterial thrombolytic therapy. The primary endpoint was safety, i.e., occurrence of serious adverse events (haemorrhagic complications and/or amputation) and death within one year. Secondary endpoints included angiographic and clinical success, thrombolysis duration, additional interventions, conversion, and quality of life. RESULTS: The study included 20 patients (16 men; median age 68.0 years; range, 50.0 - 83.0; and 40% native artery and 60% bypass graft). In all patients, the use of microbubble contrast enhanced sonothrombolysis could be applied successfully. There were no serious adverse events related to the experimental treatment. Duplex examination showed flow distal from the occlusion after 23.1 hours (range 3.1 - 46.5) with a median thrombolysis time of 47.5 hours (range 6.0 - 81.0). The short term ABI and pain scores significantly improved; however, no changes were observed before or after thrombolysis in the microcirculation. Overall mortality and amputation rates were both 2% within one year. The one year patency rate was 55%. CONCLUSION: Treatment of patients with acute peripheral arterial occlusions with contrast enhanced sonothrombolysis is feasible and safe to perform in patients. Further research is necessary to investigate the superiority of this new treatment over standard treatment.

Intravenous Targeted Microbubbles Carrying Urokinase versus Urokinase Alone in Acute Peripheral Arterial Thrombosis in a Porcine Model.

BACKGROUND: Standard therapy in acute peripheral arterial occlusion consists of intra-arterial catheter-guided thrombolysis. As microbubbles may be used as a carrier for fibrinolytic agents and targeted to adhere to the thrombus, we can theoretically deliver the thrombolytic medication locally following simple intravenous injection. In this intervention-controlled feasibility study, we compared intravenously administered targeted microbubbles incorporating urokinase and locally applied ultrasound, with intravenous urokinase and ultrasound alone. METHODS: In 9 pigs, a thrombus was created in the left external iliac artery, after which animals were assigned to either receive targeted microbubbles and urokinase (UK + tMB group) or urokinase alone (UK group). In both groups, ultrasound was applied at the site of the occlusion. Blood flow through the iliac artery and microcirculation of the affected limb were monitored and the animals were euthanized 1 hr after treatment. Autopsy was performed to determine the weight of the thrombus and to check for adverse effects. RESULTS: In the UK + tMB group (n = 5), median improvement in arterial blood flow was 5 mL/min (range 0-216). Improvement was seen in 3 of these 5 pigs at conclusion of the experiment. In the UK group (n = 4), median improvement in arterial blood flow was 0 mL/min (-10 to 18), with slight improvement in 1 of 4 pigs. Thrombus weight was significantly lower in the UK + tMB group (median 0.9383 g, range 0.885-1.2809) versus 1.5399 g (1.337-1.7628; P = 0.017). No adverse effects were seen. CONCLUSIONS: Based on this experiment, minimally invasive thrombolysis using intravenously administered targeted microbubbles carrying urokinase combined with local application of ultrasound is feasible and might accelerate thrombolysis compared with treatment with urokinase and ultrasound alone.

Therapeutic application of contrast-enhanced ultrasound and low-dose urokinase for thrombolysis in a porcine model of acute peripheral arterial occlusion.

BACKGROUND: The addition of local ultrasound (US) with a contrast agent to standard intra-arterial thrombolysis can accelerate the thrombolytic treatment of stroke and myocardial infarction. The contrast agent consists of microsized gas-filled bubbles that collapse when exposed to US, causing destabilization of the clot and making the clot surface more susceptible to fibrinolytics. In this study, we investigated the effect of additional US and microbubbles on standard low-dose intra-arterial thrombolysis in a porcine model of extensive peripheral arterial occlusion. METHODS: Extensive arterial thrombosis was induced in 10 pigs in the 4-cm external iliac artery by clamping and injection of 100 IU of bovine thrombin. A transcutaneous laser Doppler flow probe and an ultrasonic perivascular flow probe assessed microcirculation and arterial flow respectively. The urokinase-only (UK) group (n = 4) received standard thrombolytic therapy: intra-arterial bolus injection of 500,000 IU, followed by a continuous low-dose urokinase (50,000 IU/h) infusion through an intra-arterial catheter and local intermittent application of US, 1 second on, 5 seconds off, to visualize vascular patency during the first hour of therapy and to ensure microbubbles replenished the proximal portion of the occluded artery. The urokinase plus microbubbles (UK+) group (n = 6) received the same urokinase therapy with a concomitant intravenous infusion of microbubbles and local intermittent application of US. The contrast infusion protocol consisted of a bolus of two vials of 5 mL in the first 15 minutes and then three times 5 mL slowly hand-injected continuously during the next 45 min. After 3 hours of therapy, the animals were euthanized, and thrombi were harvested and weighed. All organs were cut in thin slices and macroscopically inspected for potential (hemorrhagic) adverse events, and tissue samples were taken. RESULTS: Median thrombus weights were 1.1 g (range, 0.8-1.3 g) in the UK+ group vs 1.6 g (range, 1.3-1.9 g) in the UK group (P = .01). Arterial blood flow increased in four of six pigs in the UK+ group by a mean 61% vs in one of four in the UK group, with 1%. Microcirculation and lower limb arterial pressure levels improved after the start of therapy in the UK+ group, contrary to a trend of decline in the UK group. No signs of bleeding complications were observed in either group. CONCLUSIONS: In this experimental pilot study, the addition of contrast-enhanced US accelerated the thrombolytic effect of low-dose intra-arterial thrombolysis in peripheral arterial occlusions. Further clinical studies are warranted.

Endovascular Graft Suprarenal Bare Metal Stent Separation After Endovascular Aneurysm Repair: Case Reports and Literature Review.

Objective: Suprarenal bare metal stent separation is a rare complication after endovascular aneurysm repair. In this report, two new cases of this type of device failure are presented and the literature is reviewed to identify similar cases and evaluate associated clinical characteristics. Methods: A literature search was conducted in March 2022 using PubMed, Embase, and The Cochrane Library, with MeSH terms including aortic aneurysm, stents, and device failure. Two authors independently selected studies eligible for inclusion. Results: Twelve patients with endovascular graft suprarenal bare metal stent separation were identified. Endovascular aneurysm repair (EVAR) devices were implanted between May 1996 and November 2017. Suprarenal bare metal stent separation was detected after a median duration of five years post-operatively. Conclusion: Endovascular graft suprarenal bare metal stent separation demands a high level of awareness. A better understanding of the involved failure mechanisms and associated risk factors is required to further optimise EVAR follow up protocols.

Thoracic sympathectomy for digital ischemia: a summary of evidence.

BACKGROUND: Thoracic sympathectomy is used in the management of a variety of upper limb disorders. We have analyzed the evidence for thoracic sympathectomy in the management of digital ischemia. METHODS: We reviewed the English literature between 1980 and 2010. Our analysis included reports with the clinical end points of relief, recurrence of symptoms or healing of ulcers, or both. Primary Raynaud disease (PRD) and secondary Raynaud phenomenon (SRP) were analyzed separately. RESULTS: An initial postoperative positive effect was reported in 92% of PRD patients and in 89% of SRP patients. Long-term beneficial effect was 58% for PRD and 89% for SRP. Ulcer healing or improvement was achieved in 95%. CONCLUSIONS: The available evidence suggests that thoracic sympathectomy has a role in the treatment of severe PRD and SRP, albeit with better results in SRP patients than in PRD patients. In case of digital ulceration, thoracic sympathectomy may maximize tissue preservation or prevent amputation.

Therapeutic Use of Microbubbles and Ultrasound in Acute Peripheral Arterial Thrombosis: A Systematic Review.

Catheter-directed thrombolysis (CDT) for acute peripheral arterial occlusion is time consuming and carries a risk of major hemorrhage. Contrast-enhanced sonothrombolysis (CEST) might enhance outcomes compared with standard CDT. In the study described here, we systematically reviewed all in vivo studies on contrast-enhanced sonothrombolysis in a setting of arterial thrombosis. A systematic search of the PubMed, Embase, Cochrane Library and Web of Science databases was conducted. Two reviewers independently performed the study selection, quality assessment and data extraction. Primary outcomes were recanalization rate and thrombus weight. Secondary outcome was any possible adverse event. The 35 studies included in this review were conducted in four different (pre)clinical settings: ischemic stroke, myocardial infarction, (peripheral) arterial thrombosis and arteriovenous graft occlusion. Because of the high heterogeneity among the studies, it was not possible to conduct a meta-analysis. In almost all studies, recanalization rates were higher in the group that underwent a form of CEST. One study was terminated early because of a higher incidence of intracranial hemorrhage. Studies on CEST suggest that adding microbubbles and ultrasound to standard intra-arterial CDT is safe and might improve outcomes in acute peripheral arterial thrombosis. Further research is needed before CEST can be implemented in daily practice.

Microbubbles and UltraSound-accelerated Thrombolysis (MUST) for peripheral arterial occlusions: protocol for a phase II single-arm trial.

INTRODUCTION: Acute peripheral arterial occlusions can be treated with intra-arterial catheter-directed thrombolysis as an alternative to surgical thromboembolectomy. Although less invasive, this treatment is time-consuming and carries a significant risk of haemorrhagic complications. Contrast-enhanced ultrasound using microbubbles could accelerate dissolution of thrombi by thrombolytic medications due to mechanical effects caused by oscillation; this could allow for lower dosages of thrombolytics and faster thrombolysis, thereby reducing the risk of haemorrhagic complications. In this study, the safety and practical applicability of this treatment will be investigated. METHODS AND ANALYSIS: A single-arm phase II trial will be performed in 20 patients with acute peripheral arterial occlusions eligible for thrombolytic treatment. Low-dose catheter-directed thrombolysis with urokinase will be used. The investigated treatment will be performed during the first hour of thrombolysis, consisting of intravenous infusion of 4 Luminity phials (6 mL in total, diluted with saline 0.9% to 40 mL total) of microbubbles with the use of local ultrasound at the site of occlusion. Primary end points are the incidence of complications and technical feasibility. Secondary end points are angiographic and clinical success, duration of thrombolytic infusion, treatment-related mortality, amputations, additional interventions and quality of life. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained in 2015 from the Medical Ethics Committee of the VU University Medical Center, Amsterdam, the Netherlands. A statement of consent for this study was given by the Dutch national competent authority. Data will be presented at national and international conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: Dutch National Trial Registry: NTR4731; European Clinical Trials Database of the European Medicines Agency: 2014-003469-10; Pre-results.

Minimally Invasive, Laparoscopic, and Robotic-assisted Techniques Versus Open Techniques for Kidney Transplant Recipients: A Systematic Review.

CONTEXT: Literature on conventional and minimally invasive operative techniques has not been systematically reviewed for kidney transplant recipients. OBJECTIVE: To systematically evaluate, summarize, and review evidence supporting operating technique and postoperative outcome for kidney transplant recipients. EVIDENCE ACQUISITION: A systematic review was conducted in PubMed-Medline, Embase, and Cochrane Library between 1966 up to September 1, 2016, according to Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. Articles were included and scored by two independent reviewers using Group Reading Assessment and Diagnostic Evaluation (GRADE), Newcastle-Ottawa Quality Assessment Scale (NOS), and Oxford guidelines for level of evidence. Main outcomes were graft survival, surgical site infection, incisional hernia, and cosmetic result. In total, 18 out of 1954 identified publications were included in this analysis. EVIDENCE SYNTHESIS: Included reports described conventional open, minimally invasive open, laparoscopic, and robotic-assisted techniques. General level of evidence of included studies was low (GRADE: 1-3; NOS: 0-4; and Oxford level of evidence: 4-2). No differences in graft or patient survival were found. For open techniques, Gibson incision showed better results than the hockey-stick incision for incisional hernia (4% vs 16%), abdominal wall relaxation (8% vs 24%), and cosmesis. Minimally invasive operative recipient techniques showed lowest surgical site infection (range 0-8%) and incisional hernia rates (range 0-6%) with improved cosmetic result and postoperative recovery. Disadvantages included prolonged cold ischemia time, warm ischemia time, and total operation time. CONCLUSIONS: Although the level of evidence was generally low, minimally invasive techniques showed promising results with regard to complications and recovery, and could be considered for use. For open surgery, the smallest possible Gibson incision appeared to yield favorable results. PATIENT SUMMARY: In this paper, the available evidence for minimally invasive operation techniques for kidney transplantation was reviewed. The quality of the reviewed research was generally low but suggested possible advantages for minimally invasive, laparoscopic, and robot-assisted techniques.

Saved from a fatal flight: A ruptured splenic artery aneurysm in a pregnant woman.

INTRODUCTION: The reported prevalence of a SAA varies between 0.01 and 10.4% [1], and since SAAs often remain asymptomatic, the true prevalence is uncertain. The reported SAAs occur more frequently in younger patients, with 58% diagnosed in women of childbearing age; 95% of these are diagnosed during pregnancy. PRESENTATION OF CASE: A 26-year-old woman, thirty-one weeks pregnant, was about to board an airplane for a three hour flight from the Netherlands to Turkey. Just before entering the plane, she suddenly felt a severe abdominal pain. Ultrasound guided aspiration of the abdominal fluid showed blood and supported the decision to perform urgent laparotomy. A caesarean section was performed. After further inspection a ruptured SAA was encountered. The splenic artery was ligated proximally and distally to the rupture in order to stop the bleeding. As the hilar localization of the aneurysm interfered with a primary vascular reconstruction, a splenectomy was performed. The mother and baby survived. DISCUSSION: Although rupture of a SAA is rare, its consequences can be devastating for both mother and child. The literature shows a higher incidence of ruptured SAA in pregnant women, although there is a difficulty in recognizing hemodynamic instability in pregnancy due to the increase in circulating volume. CONCLUSION: In case of pregnant women with acute abdomen and hypovolemia, emergency physicians, surgeons, anesthesiologists, and gynecologists should be aware of the possibility of a ruptured SAA, apart from more common causes like placental abruption, placenta percreta, or uterine rupture. Early recognition and prompt multidisciplinary treatment might save the life of mother and child.

Contrast-enhanced sonothrombolysis in a porcine model of acute peripheral arterial thrombosis and prevention of anaphylactic shock.

Acute peripheral arterial thrombosis can be threatening to life and limb. Dissolution of the thrombus local catheter-directed intra-arterial infusion of fibrinolytic agents such as urokinase is the standard therapy for thrombosis; however, this method is time-intensive, and amputation of the affected limb is still needed in 10-30% of cases. Furthermore, thrombolytic therapy carries the risk of bleeding complications. The use of small gas-filled bubbles, or ultrasound contrast agents (UCAs), in combination with ultrasound has been investigated as an improved thrombolytic therapy in acute coronary and cerebral arterial thrombosis. The authors describe a porcine model of acute peripheral arterial occlusion to test contrast-enhanced sonothrombolysis approaches that combine ultrasound, UCAs and fibrinolytic agents and recommend a strategy for preventing severe allergic reactions to UCAs in the pigs.