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.

Infrarenal aortic-clamping after renal ischaemia aggravates acute renal failure.

BACKGROUND: Renal failure is a frequent complication of juxtarenal abdominal aortic aneurysm (JAA)-repair. During this operation, suprarenal aortic-clamping is followed by infrarenal aortic-clamping (below renal arteries) to restore renal flow, while performing the distal anastomosis. We hypothesized that infrarenal aortic-clamping, despite restoring renal perfusion provokes additional renal damage. MATERIALS AND METHODS: We studied three groups of rats. After 45min of suprarenal aortic-clamping, group 1 had renal reperfusion for 90min without aortic-clamps (n=7). In group 2, 45min of suprarenal aortic-clamping with a distal clamp on the aortic-bifurcation was followed by 20min of infrarenal aortic-clamping. Renal reperfusion was continued for 70min without aortic-clamps (i.e. 90 min of renal reperfusion; n=8). The sham-group had no clamps (n=7). We measured renal haemodynamics, functional parameters and tissue damage. RESULTS: On suprarenal aortic-clamp removal, renal artery flow, cortical flow and arterial pressures were higher in group 2 than in group 1. We detected increased tubular brush border damage, luminal lipocalin-2 and 30-60% higher renal protein nitrosylation in group 2 when compared to group 1 (P<0·05). Group 2 showed more release of asymmetrical dimethylarginine (ADMA) from the kidneys in the renal vein, therefore indicating diminished clearing capacity (P<0·001). Arginine/ADMA-ratio, which defines the bio-availability of nitric oxide, tended to be lower in group 2 and correlated with renal flow. Furthermore, there were no significant differences found in creatinine levels and renal leucocyte accumulation between group 1 and 2. CONCLUSIONS: Additional infrarenal aortic-clamping leads to increased renal damage and oxidative stress, despite adequate perfusion of kidneys after suprarenal aortic-clamping. This study indicates that the clamping sequence used in JAA-repair causes more than simple renal I/R-injury.

Juxtarenal aortic aneurysm repair.

OBJECTIVES: Juxtarenal aortic aneurysms (JAA) account for approximately 15% of abdominal aortic aneurysms. Despite advances in endovascular aneurysm repair, open repair requiring suprarenal aortic cross-clamping is still the treatment of choice for JAA. We performed a systematic review of the literature to determine perioperative mortality and postoperative renal dysfunction after open repair for non-ruptured JAA. METHODS: The Medline, Embase, and Cochrane databases were searched to identify all studies reporting non-ruptured JAA repair published between January 1966 and December 2008. Two independent observers selected studies for inclusion, assessed the methodologic quality of the included studies, and performed the data extraction. Study heterogeneity was assessed using forest plots and by calculating the between-study variance. Outcomes were perioperative mortality, postoperative renal dysfunction, and new onset of dialysis. Summary estimates with 95% confidence interval (95% CI) were calculated using a random effects model based on the binomial distribution. RESULTS: Twenty-one non-randomized cohort studies from 1986 to 2008, reporting on 1256 patients, were included. Heterogeneity between the studies was low. The mean perioperative mortality was 2.9% (95% CI, 1.8 to 4.6). The mean incidence of new onset of dialysis was 3.3% (95% CI, 2.4 to 4.5). Incidence of postoperative renal dysfunction could be derived from 13 studies and ranged from 0% to 39% (median, 18%). In seven studies, cold renal perfusion during suprarenal clamping was performed in order to preserve renal function; however, based upon the included data, definitive conclusions regarding its efficacy could not be drawn. CONCLUSIONS: Open repair of non-ruptured JAA using suprarenal cross-clamping can be performed with acceptable perioperative mortality; however, postoperative deterioration of renal function is a common complication. Preservation of renal function after JAA repair requires further investigation.

Cyclooxygenase-2 inhibitors enhance shear stress-induced platelet aggregation.

OBJECTIVES: We aimed to investigate the effect of parecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, on in vivo shear stress-induced platelet aggregation in a rat model of arterial bypass with focal narrowing. BACKGROUND: Long-term use of COX-2 inhibitors is associated with increased incidence of adverse cardiovascular events, especially in patients with a history of cardiovascular disease. These patients are at risk for thrombotic occlusion of arterial stenoses initiated by shear stress-induced platelet aggregation. METHODS: To mimic the combination of a tight arterial stenosis and high shear stress in rats, an extracorporeal shunt from carotid to femoral artery was compressed by the rollers of a pump. Platelet aggregation was continuously measured by a photometric detector in the shunt. RESULTS: Pretreatment with parecoxib (20 mg/kg) almost doubled shear stress-induced platelet aggregation (188% vs. 100% in control subjects, p = 0.0003). This was accompanied by a fall in plasma 6-keto-prostaglandin F(1alpha) from 100 +/- 25 pg/ml to 36 +/- 11 pg/ml (p < 0.0001). Enhanced platelet aggregation was also observed with high-dose aspirin (150 mg/kg) (146%; p = 0.02) but not with low-dose aspirin (25 mg/kg), which reduced aggregation (68%; p = 0.01). The effect of parecoxib was neutralized by low-dose (1 mg/kg) clopidogrel (from 188% to 92%; p = 0.0001), but not by low-dose aspirin (from 188% to 177%; p = NS). CONCLUSIONS: In the presence of an arterial stenosis, COX-2 inhibitors enhance shear stress-induced platelet aggregation. This enhancement was prevented by low-dose clopidogrel but not by low-dose aspirin. Clopidogrel might therefore allow COX-2 inhibitors to be used without raising risk of thrombotic occlusion.

Pump-induced platelet aggregation with subsequent hypotension: Its mechanism and prevention with clopidogrel.

OBJECTIVES: Use of extracorporeal circuits in cardiopulmonary bypass and hemodialysis often causes bleeding problems and hypotension. As shown previously, this might be caused by activation of blood platelets due to pumping. The present study investigates the mechanism of pump-induced platelet aggregation and its possible prevention. METHODS AND RESULTS: Continuous measurement of platelet aggregation in an extracorporeal shunt from a carotid to a femoral artery in rats showed that aggregation during the first 10 minutes of pumping was not reduced by coating the tube with albumin or heparin nor by using dalteparin instead of unfractionated heparin as anticoagulant. Also, pump characteristics seemed unimportant because aggregation could already be elicited by single tube compression with one pump roller. It was calculated that during compression wall shear stress in the tube rises far beyond the values known to induce platelet aggregation, occurring also in clinically used roller pumps. A crucial role for adenosine diphosphate was demonstrated by blockade of platelet adenosine diphosphate-P2Y12 receptors with the clinically used drug clopidogrel (50 mg/kg intravenously, n = 8). This prevented platelet aggregation and the fall of systemic blood pressure (to 71% +/- 12% in controls, n = 6) during 2 hours of continuous pumping. CONCLUSION: We conclude that pump-induced platelet aggregation is not caused by factors released from the tube or its coating but is initiated by short bouts of high shear stress, and its continuation is critically dependent on adenosine diphosphate. The latter might have clinical relevance for patients connected to extracorporeal systems.