Occlusion of experimentally created fusiform aneurysms with porous metallic stents.

BACKGROUND AND PURPOSE: Carotid fusiform aneurysms are most commonly treated with occlusion of the parent vessel. The purpose of our study was to assess the effectiveness of self-expanding, cobalt-alloy stents in the ablation of experimental fusiform aneurysms with preservation of the parent vessel in a carotid artery model. METHODS: Porous metallic stents were placed endovascularly along the lengths of experimentally created fusiform aneurysms in the carotid arteries of dogs; aneurysms were also created in the animals' opposite carotid arteries to serve as controls. RESULTS: Before stent placement, angiography of the carotid arteries showed large fusiform aneurysms along the lengths of the common carotid arteries and complex patterns of flow. Immediately after stent placement there was disruption of the usual flow patterns within the lumens of the fusiform aneurysms. The lumen between the wall of the aneurysm and stented carotid showed stasis of contrast material and blood. Near-complete ablation of all aneurysms was observed 8 weeks after stent placement. The stented carotid arteries remained widely patent; control aneurysms and carotid arteries were patent and unchanged. Histopathologic analysis revealed fibrotic reactive scar tissue filling the space between the stent wires and outer wall of the fusiform aneurysm. CONCLUSION: Changing blood flow dynamics within an aneurysm can promote thrombus formation. The stent promotes stasis and thrombus within the residual lumen between the stent wall and the outer wall of the aneurysm because its woven wire mesh interferes with usual blood flow patterns, which then promotes formation of thrombus and fibrosis within the residual aneurysmal lumen.

Embolization of experimentally created aneurysms with a laser-activated detachable coil device.

Our experimental study in dogs suggests that laser-activated detachable coil devices show promise in the embolization of carotid aneurysms, allowing the interventionalist greater control than possible with nonretractable coil systems and permitting detachment of the coil from the wire in seconds.

Rapid drug infusion for termination of atrial fibrillation in an experimental model.

Episodes of paroxysmal atrial fibrillation (PAF) in the ambulatory patient might be terminated promptly by intravenous infusion from an implanted drug delivery system. We have explored this concept in a series of experiments using rapid intra-atrial infusions in dogs. In the acute studies, rapid intra-atrial infusions of procainamide were delivered during continual measurements of epicardial monophasic action potentials (MAP), atrial effective refractory periods (ERP), and right to left atrial conduction times (CT) in 9 dogs. In the chronic studies, 20 episodes of sustained PAF were induced in 4 dogs after six weeks of rapid or burst atrial pacing from a specially programmed implanted pacemaker. Rapid infusions of procainamide were then delivered to the right atrium through a previously implanted catheter connected to a subcutaneous access port. Procainamide significantly increased the duration of the atrial MAP, ERP and CT in the acute experiments. It also terminated induced PAF within five minutes of the end of infusion in all twenty of the chronic experiments. We conclude that rapid intra-atrial infusion of procainamide is very effective in this animal model of PAF, and that such infusion prolongs atrial MAP, ERP and CT.

Experimental arteriovenous fistulas: treatment with silicone-covered metallic stents.

PURPOSE: To determine the efficacy of silicone-covered metallic stents in the treatment of experimentally created carotid-jugular fistulas. METHODS: Carotid-jugular fistulas were surgically constructed in six mongrel dogs. Silicone-coated, self-expanding metallic stents were placed across the fistula holes within the carotid artery, and carotid angiography was performed before, immediately after, and 4 and 8 weeks after stent placement. Fistula specimens were resected 2 months after stent placement and analyzed by means of gross and light microscopy. RESULTS: Angiography revealed complete closure of all fistulas immediately after stent deployment. The fistulas remained closed and all carotid arteries remained patent. Marked stenosis within the carotid lumen was seen along the proximal and distal ends of the stents. Gross and micropathologic specimens of the carotid-jugular fistulas revealed fibrous connective tissue and collagen across the fistula holes. Proliferative fibrous connective tissue, collagen, and fibromyoblasts were located at either end of the stents. The wires of the stents indented the intraluminal surface of the carotid arteries. CONCLUSIONS: Silicone-covered stents were effective in closing all experimentally created carotid-jugular fistulas. With further refinements and variations in technique, covered stents may prove a viable alternative to current endovascular devices.

Cryosurgery of breast cancer.

OBJECTIVE: To determine the feasibility and efficacy of cryosurgery of breast cancer. DESIGN: In phase 1, carcinogen-induced mammary adenocarcinomas in 13 Sprague-Dawley rats were treated by cryosurgery and were then examined for histopathologic change. In phase 2, transplantable mammary adenocarcinomas in 50 DBA/IJ mice were treated by cryosurgery to determine the effect of varying tumor temperatures, and duration and number of freeze-thaw cycles on tumor viability. In phase 3, 2- to 3-cm ultrasound-monitored cryolesions were formed in the breasts of 4 dogs and 4 sheep. These animals were followed up for procedure-related complications; the histopathologic necrosis of the cryolesions were correlated with the ultrasound images. Based on the results of these experiments, ultrasound-guided cryosurgery of breast cancer was initiated in a human clinical trial. RESULTS: In phase 1, a single, short-term (< 7 minutes) freeze killed only tumors smaller than 1.5 cm in diameter, despite an apparent decrease to -40 degrees C at the periphery of each tumor. In phase 2, varying the peripheral tumor temperature to as low as -70 degrees C, using a single, short-term (< 7 minutes) freeze did not alter the results from phase 1. If the ice ball fully encompassed the tumor, however, maintaining it for at least 15 minutes achieved 100% tumor kill independent of tumor size. In phase 3, creation of a reproducible ultrasound-monitored cryolesion was facilitated when 2 freeze-thaw cycles were performed. No procedure-related complications were noted. In the human trial, 2 invasive lobular carcinomas from 1 patient were treated by cryosurgery and were negative for persistent tumor by core needle biopsy performed 4 and 12 weeks after a well-tolerated procedure. CONCLUSIONS: In situ breast cryosurgery has been proved to be feasible and efficacious in small and large animal studies and has been successfully performed in 1 patient with breast cancer. The results of this study suggest that ultrasound-guided cryosurgery of breast cancer warrants further investigation.

Feasibility of using a swine portal vein containing a metallic stent for creating a portacaval shunt.

RATIONALE AND OBJECTIVES: We evaluated the feasibility of using a metallic stented portal vein as a conduit for portacaval shunt in pigs. METHODS: A metallic self-expanding stent was placed in the portal vein of five pigs under combined ultrasound and fluoroscopic guidance via a percutaneous transhepatic approach. After 6 weeks, a portacaval shunt was performed using the stented portal vein as a conduit. A single angiogram followed immediately by sacrifice and histologic examination was performed on each pig at a varying time interval postshunt. RESULTS: One pig died 3 days after the shunt procedure because of a presumed surgical technical failure and a consequent thrombosed portal vein. Angiographic patency of the portacaval shunt was confirmed in the four remaining pigs. Postmortem histologic evaluation showed more complete endothelialization and subintimal organization in the more chronic stents. Thrombus occurred only in the stent of the pig that died. There was no significant luminal obstruction in the other four stents. CONCLUSION: Our results suggest that a stented portal vein can be used successfully as a conduit for portacaval shunt in pigs.

Experimental arteriovenous fistulas: treatment with porous metallic stents.

PURPOSE: To determine the efficacy of porous metallic stents in the treatment of experimentally created carotid-jugular fistulas. METHODS: Carotid-jugular fistulas were constructed surgically in five mongrel dogs. Porous metallic stents were placed endovascularly across the fistula holes within the carotid artery; carotid angiography was performed before, immediately after, and 1 and 2 months after stent placement. The fistula specimens were resected 2 months after stent placement; gross and light microscopic analyses were performed. RESULTS: Angiography revealed complete closure of three of the five fistulas 1 month after stent placement; two of the five fistulas remained patent but demonstrated diminished flow rate. All carotid arteries were widely patent throughout the study. Gross pathology of the carotid-jugular specimens revealed fibrous connective tissue and collagen within the fistula hole. A thin layer of endothelium covered the stent wires and the fibrous connective tissue overlying the fistula hole. CONCLUSIONS: The stents were effective in closing three of the five fistulas and reducing flow through the fistulas in the remaining animals. With further refinements and variations in technique, porous metallic stents may prove a viable alternative to current endovascular devices for treatment of certain arteriovenous fistulas.

Characteristics of Nd:YAG sculptured contact probes after prolonged laser application.

This study analyzed the functional and structural characteristics of cone, hemisphere, and modified sculptured contact fibers (1,000 microns) after 1 hour of continuous Nd:YAG laser application. Continuous laser application was performed on live porcine tissue using 20 watts of power. The fiber's appearance under a microscope as well as the power output was recorded after 0, 5, 10, 20, 30, 45, and 60 minutes of continuous laser application. (N = 3 for each fiber). At time 0, all fibers transmitted from 49 to 56% of the initial 20 watts (W); power transmission decreased to less than 9% relative power transmission after 20 minutes and then plateaued. The fibers exhibited severe distortion and carbonization of the surface where laser had been applied with evidence of quartz melting and shattering after only 10 minutes. By 30 minutes of laser application, all three fibers were fractured and essentially indistinguishable from one another; moreover, the fibers exhibited similar power transmission, and cutting and coagulation activity, as determined by a panel of independent, double-blinded surgeons. These data lead us to conclude that 1) Nd:YAG contact laser effects result from thermal heating of the fiber tip with subsequent tissue injury, 2) the unique structural configuration of the fiber's sculptured tip are lost after several minutes of laser application without appreciable change in functional integrity, and 3) fibers may be manually fractured allowing for multiple uses without significant sacrifice of power transmission or surgical utility.

The effect of lasers, electrocautery, and sharp dissection on cutaneous flaps.

This study evaluated the technical ease and wound-healing response of cutaneous flaps constructed on dogs using Nd:YAG laser, CO2 laser, electrocautery, and sharp dissection. Four flaps were constructed on the dorsum of 16 dogs using each of the four modalities. Parameters examined included drainage after both 48 hours and 1 week, time of dissection, bursting strength, and semiquantitative assessments of fibroblast, polymorphonuclear leukocyte, monocyte, and collagen content. Significantly less time was required to construct flaps with electrocautery as compared with CO2 laser, Nd:YAG laser, and sharp dissection (15 versus 18, 20, and 26 minutes, respectively; p < 0.01). Significantly fewer suture ligatures were necessary to obtain hemostasis for electrocautery, CO2 laser, and Nd:YAG laser as compared with sharp dissection (0, 2, and 2 versus 15 sutures, respectively; p < 0.01). Drainage was significantly less for flaps constructed using sharp dissection as compared with both CO2 and Nd:YAG lasers at 48 hours (12 versus 26 cc, p < 0.01, and 20 cc, p < 0.05, respectively). Significantly less drainage was observed after 48 hours for flaps created using electrocautery as compared with CO2 laser (14 versus 26 cc; p < 0.05). Bursting strength of flaps constructed using sharp dissection was significantly greater than that of those constructed using electrocautery, Nd:YAG laser, and CO2 laser (1086 versus 638 gm, p < 0.05, 714 gm, and 571 gm, p < 0.01, respectively). Semiquantitative histologic evaluation revealed a higher collagen content and fibroblast infiltration and less polymorphonuclear leukocyte infiltration in wounds created using sharp dissection as compared with CO2 laser, Nd:YAG laser, and electrocautery.(ABSTRACT TRUNCATED AT 250 WORDS)

Embolization of experimentally created aneurysms with intravascular stent devices.

PURPOSE: To assess the effectiveness of self-expanding, cobalt-alloy stents in the treatment of aneurysms in a canine model and to observe the pattern of blood flow and formation of fibrotic scar tissue. METHODS: Porous metallic stents were endovascularly placed across the necks of experimentally created side aneurysms in the carotid arteries of three dogs; aneurysms were also created in the opposite carotid arteries in these animals to serve as controls. RESULTS: Before stent placement, angiography of the carotid arteries demonstrated whirl-like, vortex flow of blood within the lumens of the aneurysms. Inflow was seen along the distal aneurysm wall; outflow was demonstrated along the proximal wall; slower vortex flow was present in the central lumen. Immediately after stent placement there was disruption of the usual vortex flow with stasis of contrast media and blood within the lumen. Inflow and outflow patterns were no longer seen. Complete ablation of these aneurysms was evident at follow-up angiographic studies--1 week, 1 month, and 2 months after stent placement. The stented carotid arteries remained widely patent; control aneurysms and carotid arteries were patent and unchanged. Histopathologic analysis revealed fibrotic reactive scar tissue completely filling the stented aneurysm pouches. CONCLUSION: Treatment of selected intracranial aneurysms via an endovascular approach has merit and could supplant more invasive, risky, and costly surgical procedures in some cases.

An evaluation of leflunomide in the canine renal transplantation model.

Leflunomide is an isoxazole with newly discovered immunosuppressive properties. Its mechanism of action operates later in the cell cycle than cyclosporine and appears to interfere with lymphocyte IL-2 responsiveness. With the encouraging results from in vitro and small-animal studies, we subjected leflunomide to the rigorous canine renal transplantation model in a dose response protocol. Thirty-eight female mongrel dogs underwent renal transplantation and bilateral nephrectomy. Immunosuppression was stratified from controls with no immunosuppression to monotherapy with leflunomide at 2, 4, 8, and 16 mg/kg/day given orally and in a combination therapy with cyclosporine. To evaluate its toxicity while maintaining a low constant blood level, eight dogs were treated by continuous intravenous infusion at doses of 2, 4, 6, and 8 mg/kg/day. The mean survival time for nonimmunosuppressed controls (n = 2) was 9 days, leflunomide 2 mg/kg/day (n = 2) was 9 days, leflunomide 4 mg/kg/day (n = 4) was 16 days, leflunomide 8 mg/kg/day (n = 5) was 28 days, leflunomide 16 mg/kg/day (n = 7) was 21 days. Cyclosporine alone at 10 mg/kg/day (n = 4) resulted in a mean survival time of 13 days. The mean survival time with the combination of cyclosporine 10 mg/kg/day with leflunomide 4 mg/kg/day (n = 6) was 68 days. The mean survival time for continuous intravenous leflunomide 2 mg/kg/day (n = 2) was 10 days; for leflunomide 4 mg/kg/day, 20 days; for leflunomide 6 mg/kg/day, 14 days; and leflunomide 8 mg/kg/day, 21 days. The mean serum trough levels of leflunomide ranged from 10 micrograms/ml at the 2 mg dose to 55 micrograms/ml for the 16 mg dose, levels that have been well tolerated in man. Leflunomide at 16 mg/kg/day reliably prevented acute allograft rejection, but the dogs died of inanition with normal renal function. Leflunomide at a nontoxic dose of 4 mg/kg/day extended survival to 16 days, but all dogs died of rejection. A combination of inadequate doses of leflunomide (4 mg/kg/day) and cyclosporine (10 mg/kg/day) resulted in all animals having normal renal function and weight for > or = 30 days. Even at a high dose of 16 mg/kg/day, no viral or bacterial infections were noted. These observations in a canine system add to the growing enthusiasm for the evaluation of leflunomide in human transplantation.

Protection of fiber function by para-axial fluid flow in interstitial laser therapy of malignant tumors.

In the past, interstitial laser therapy frequently has failed because of the damage to the bare fiber tip due to intense heat generated at the point of contact. Using a rat mammary tumor model, we describe a method of placing a 600 micron fiber inside a gauge 19 needle cannula after its insertion into the tumor. With this device continuous wave Nd:YAG laser is delivered to the target tumor while 0.9% saline flows para-axially into the tumor. Significant coagulation necrosis was induced with 500 joules at 5 watts, 100 seconds and 1 cc per minute of saline while the needle-fiber is pulled out of the tumor by 10 mm. The mean transmission loss after 500 joules was 2% in ten experiments. The tumor edema due to 1.5 ml of saline was transient. We conclude that successful hyperthermic coagulation necrosis by Nd:YAG laser can be achieved with minimal transmission loss by employing the above technique.

Distribution of a somatostatin analog after continuous intraventricular administration.

Decreased somatostatin in the brains of patients with Alzheimer's disease has led to an investigation of the efficacy of neurotransmitter replacement therapy. The distribution of a somatostatin analog, octreotide, was determined after 2 to 6 days of continuous intraventricular infusion at 40 micrograms/h in dogs. The tissue concentration was greater than 100 ng/g wet weight in all parts of the brain, which is greater than the normal concentration of native somatostatin. There was no reduction in native somatostatin production because of the infusion of the analog. The cerebrospinal fluid octreotide concentration was 1000 times greater than the plasma concentration. The results demonstrate that neurotransmitter replacement for somatostatin can be achieved by chronic intraventricular infusion of a metabolically stable analog.

The role of C-reactive protein and polyarginine in tumor immunotherapy.

C-reactive protein (CRP) is an acute-phase reactant whose serum level rises rapidly in response to tissue injury. C-reactive protein binding to cells can activate the classical complement pathway, and enhance opsonophagocytosis. The polycation poly-L-arginine (PLA) can artificially fix CRP to target cells. The effects of CRP and PLA on tumor growth were evaluated, both independently and synergistically, using the V X 2 tumor line in the rabbit host. Ten normal animals and seven acute-phase animals were bilaterally inoculated with V X 2 cells (control side) and PLA-treated V X 2 cells (experimental side). Tumor growth was significantly retarded on the treatment side (P less than 0.005), in both animal groups. It is concluded that topical PLA is a potent inhibitor of V X 2 tumor growth. Comparison of normal and acute-phase animals revealed no persistent difference in tumor growth for either cell inoculum. Similarly, cell treatment with topical CRP did not inhibit tumor growth, whether PLA was present or not. Thus, circulating and topical CRP did not alter the rate of V X 2 tumor growth. PLA cytotoxicity remains to be evaluated when the agent is administered orthotopically, selectively, or systemically.

A model for the treatment of accidental severe hypothermia.

Central to the controversy that surrounds the treatment of accidental severe hypothermia is the question of how the method of rewarming affects myocardial performance, and therefore survival. We induced severe hypothermia and cardiac arrest in 15 mongrel dogs. Each dog was rewarmed by one of three methods: partial cardiac bypass (Group I); peritoneal dialysis (Group II); or external rewarming with a fluid-circulated blanket (Group III). The cardiac arrest state was supported by partial cardiac bypass in Group I and by standard mechanical cardiopulmonary resuscitation (CPR) in Groups II and III. In all dogs, the hypothermically depressed myocardial performance returned to normal upon rewarming. Groups I and II had similar rewarming times and required similar volumes of crystalloid and bicarbonate solutions to maintain adequate cardiac filling pressures and arterial pH. However, Group III had a significantly slower rewarming time and required significantly greater volumes of crystalloid and bicarbonate solutions. The sole procedural death occurred in Group III. Our results show that partial cardiac bypass, peritoneal dialysis, and the fluid-circulated blanket are equally effective in rewarming severely hypothemic dogs with cardiac arrest, provided that the cardiac arrest is relieved by partial cardiac bypass or standard mechanical CPR and that physiologic levels of intravascular volume, oxygenation, and pH are maintained.

The evaluation of various bioabsorbable materials on the titanium fiber metal tracheal prosthesis.

A new type of tracheal prosthesis was studied. It consists of a rigid, porous cylinder of titanium fiber metal coated with a polymer that provides an initial air seal and then is absorbed to permit subsequent fibrous tissue ingrowth and reepithelialization. Fifteen such cylinders measuring 50 mm by 26 mm were coated with one of the following polymers: polycaprolactone 700 (3 coated internally and 3 externally); a copolymer of 75% poly-L-lactic acid and 25% polyglycolic acid (3 coated internally and 3 externally); and polyglactin 910 (3 coated externally). Fifteen kennel-conditioned mongrel dogs, each randomly assigned to one of these five groups, underwent implantation of the prosthesis through a right thoracotomy into a 5-cm defect in the distal intrathoracic trachea. There were no immediate postoperative deaths, and no instances of major air leak from the prosthesis. One animal died after two weeks secondary to a lower respiratory tract infection. Bronchoscopic evaluation revealed varying degrees of tissue ingrowth into the prostheses, with no evidence of infection or distal accumulation of secretions. Histological evaluation showed superior tissue ingrowth and reepithelialization with internally coated prostheses; two out of three polymers gave good results.