Portosystemic vascular anomalies allow blood returning from the gastrointestinal tract to bypass the liver and return to the systemic circulation, which results in neurotoxin accumulation in the blood and leads to signs of hepatic encephalopathy as well as urinary tract and gastrointestinal tract abnormalities. Medical management may be used to decrease clinical signs; however, surgical management provides a better long-term outcome.1,2
Currently, gradual venous occlusion devices (eg, ameroid constrictors and cellophane bands) are most commonly used for the attenuation of portosystemic shunts. Both of these devices close the shunt vessel primarily via inflammation and thrombosis, rather than via physical occlusion.3–5 This occlusion can occur as early as 10 days after surgery.3–5 Additionally, metal components in ameroid constrictors and hemoclips used for cellophane bands may preclude the ability to obtain accurate postoperative images to determine whether continued shunting is present.4,6–8
To address these limitations, our research group has developed a gradual venous occlusion device that consists of an outer ring of polyether ether ketone encased in silicone tubing and an inner lining of a proprietary blend of polyacrylic acid and inorganic salt in silicone tubing. A recent in vitro study9 of this device indicated that there is reliable gradual occlusion to an internal luminal diameter of < 1 mm over a period of 4 to 6 weeks. Although the ideal time frame for gradual attenuation of portosystemic shunts is unknown, it has been suggested10 that 4 to 6 weeks is an adequate amount of time for the portal system to adapt to the resultant increased blood flow without the postoperative formation of multiple acquired shunts.
The purpose of the study reported here was to evaluate in vivo the closure time for a gradual venous occlusion device when placed around an intra-abdominal vessel in dogs and cats to simulate closure of an extrahepatic portosystemic shunt. We believed that this device would gradually attenuate the vessel over a 6-week period, as determined by use of CTA, which is similar to results for in vitro testing.
Materials and Methods
Animals
Three purpose-bred 1-year-old sexually intact male domestic shorthair cats and 2 purpose-bred 1-year-old sexually intact female Beagles were included in the study. The study was approved by the University of Florida Institutional Animal Care and Use Committee.
Experimental procedures
A prototype of a gradual venous occlusion device was developed (Figure 1). Ethylene oxide was used to sterilize the gradual venous occlusion devices prior to implantation. A gradual venous occlusion device was implanted in each cat and dog, and images were obtained by use of a digital camera before implantation (dogs and cats) and after removal (dogs only). A metric ruler was placed at the bottom of the device for calibration purposes. Images were analyzed with imaging softwarea to determine internal luminal area, internal luminal diameter, and outer diameter.
Photograph of a gradual venous occlusion device. The inner clear layer (white arrow) is silicone tubing filled with a proprietary inorganic salt and polyacrylic acid formulation. The outer blue layer (orange arrow) is an outer ring of polyether ether ketone encased in silicone. Bar = 10 mm.
Citation: American Journal of Veterinary Research 77, 6; 10.2460/ajvr.77.6.653
Anesthesia and implantation
Acepromazine maleate (0.02 mg/kg, IM) and butorphanol tartrate (0.22 mg/kg, IM) were administered as preanesthetic medications. A catheter was then inserted in a cephalic vein. Propofol (up to 4 mg/kg, IV, to effect) was administered to induce anesthesia; anesthesia was maintained with isoflurane in oxygen.
The abdominal area was clipped and aseptically prepared in a standard manner. A ventral midline approach was used to enter the caudal portion of the abdominal cavity. In cats, the external iliac vein was isolated bilaterally by use of Mixter right-angle forceps; the gradual venous occlusion device was placed on the left external iliac vein of all cats (Figure 2). In dogs, the internal iliac vein was isolated bilaterally by use of Mixter right-angle forceps; the gradual venous occlusion device was placed on the left internal iliac vein of one dog and on the right internal iliac vein of the other dog. A small amount of sterile lubricant was placed on the gradual venous occlusion device to facilitate placement. The device was placed around the vessel, and a standard 3-layer closure of the abdomen was performed. Animals were allowed to recover from anesthesia. Hydromorphone (0.1 mg/kg, SC, q 8 h [dogs only]) and carprofen (4.4 mg/kg, SC, q 24 h [dogs only]) or buprenorphine (0.01 mg/kg, SC, q 8 h [cats only]) was administered for 72 hours after surgery.
Photographs depicting placement of a gradual venous occlusion device around the left external iliac vein of a cat. A—The vessel is isolated by use of Mixter right-angle forceps. B—The device is then placed around the isolated vessel. C—The device is maneuvered so that the opening is visible ventrally to ensure that the device is completely around the vessel without impinging on the vessel wall.
Citation: American Journal of Veterinary Research 77, 6; 10.2460/ajvr.77.6.653
Animals were anesthetized by use of the aforementioned regimen on the day after surgery (week 0) and 2, 4, and 6 weeks after surgery for CTA. For dogs, CTA images were obtained with 120 kVp and 250 mAs by use of an 8-slice helical scannerb (slice thickness, 0.5 mm; spiral pitch factor, 1.0). For cats, CTA images were obtained with 100 kVp and 250 mAs by use of a 160-slice multislice scannerc (slice thickness, 0.5 mm; spiral pitch factor, 0.8). Iohexold (2 mL/kg, IV) was administered at a rate of 3 mL/s by use of a pressure injector. Volume of iodinated contrast medium before and after IV administration was determined from the level of the liver to the stifle joints. Acquisition of the volume after contrast administration began automatically when a region of interest drawn within the caudal vena cava at a location caudal to the kidneys reached 180 Hounsfield units. Transverse, sagittal, and dorsal maximum intensity projections and 3-D volume rendering reconstructions were created. Maximal vessel diameter within the device was measured for each animal at each time point.
Ultrasonographye of the iliac veins was performed weekly. Both B-mode and color Doppler ultrasonographic images were obtained and examined to verify the presence or absence of blood flow within the vessel. Pulsed wave Doppler ultrasonography was used to measure flow velocity. Blood flow through the device was subjectively rated as normal, increased, decreased, minimal, or absent at each time point by 1 investigator (RFG).
At the termination of the study, the cats were transferred to another study and adopted by pet owners. The dogs were euthanized at the end of the study by IV administration of propofol (4 mg/kg) followed by pentobarbital sodium (85 mg/kg). The internal iliac veins were harvested and submitted for histologic examination.
Results
Implantation of the device
The gradual venous occlusion device was successfully placed in all animals, and all animals recovered without complications following implantation. Evaluation by use of imaging softwarea revealed that the devices for both dogs and cats prior to implantation had a mean ± SD internal luminal diameter of 3.95 ± 0.14 mm, internal luminal area of 0.135 ± 0.011 cm2, and external diameter of 9.46 ± 0.19 mm.
Cats
The vessel was completely occluded in 2 cats by 6 weeks after surgery as visualized via CTA (Figure 3). Diameter of the left external iliac vein in these 2 cats was 2.7 and 2.9 mm at week 0, 1.3 and 2.6 mm at week 2, 0 and 1.7 mm at week 4, and 0 and 0 mm at week 6. In the third cat, there was partial closure at 6 weeks after surgery. Diameter of the left external iliac vein in this cat was 2.7, 2.2, 0, and 1.5 mm at weeks 0, 2, 4, and 6, respectively. Residual blood flow through the attenuated vessel was evident during CTA of this cat.
Maximum intensity projection of a CTA image obtained 6 weeks after implantation of a gradual venous occlusion device around the left external iliac vein of a cat. The device (arrow) is barely visible on the image. Notice the lack of contrast in the area of the device.
Citation: American Journal of Veterinary Research 77, 6; 10.2460/ajvr.77.6.653
Collateral vessel formation, as determined by use of CTA, was not evident in any of the 3 cats at week 0. Collateral vessel formation was evident in 2 of 3 cats (the 2 with complete closure of the vessel at 6 weeks) at week 2 and in all 3 cats at weeks 4 and 6 after surgery.
Ultrasonography revealed normal blood flow through the vessel in all cats at week 0 and decreased blood flow in all cats at weeks 1 and 2. Blood flow was minimal in 1 cat at week 3, and it remained minimal at weeks 4, 5, and 6. In a second cat, blood flow was decreased at weeks 3 and 4, minimal at week 5, and absent at week 6. The third cat (the one with partial occlusion at week 6 on CTA) had decreased blood flow at week 3 and absent blood flow at weeks 4, 5, and 6. Ultrasonography revealed no blood flow through the gradual venous occlusion device at 6 weeks in 2 cats and only minimal blood flow in the other cat at 6 weeks. The ability to see the external iliac vein during CTA or ultrasonography was not hindered by the implanted device.
Dogs
During CTA, no contrast medium was seen flowing through the gradual venous occlusion device at 6 weeks in either dog. Diameter of the internal iliac vein for the dogs was 2.2 and 2.5 mm at week 0 and 1.2 and 1.7 mm at week 2. Diameter of the internal iliac vein was 0 mm at weeks 4 and 6 in one dog and could not be determined in the other dog because collateral vessel formation in the region of the device made it difficult to accurately measure vessel diameter on CTA images.
Collateral vessel formation was not evident in either dog at week 0 but was evident in 1 dog at week 2; collateral vessel formation was evident in both dogs at weeks 4 and 6 after surgery. Ultrasonography could not be reliably performed in the dogs because there was difficulty obtaining ultrasonographic images of the internal iliac vein.
Gross examination after dogs were euthanized revealed that the gradual venous occlusion device appeared completely occluded around the vessel (with associated vessel closure) in both dogs. A thin layer of fibrin was evident around the device and vessel; however, the device was not adhered to the vessel wall and was easily removed. Evaluation by use of imaging softwareb revealed that the devices for both dogs, respectively, had an internal luminal diameter of 0.7 and 0 mm, internal luminal area of 0.014 and 0 cm2, and external diameter of 10.45 and 11.3 mm.
Histologic examination revealed that there was minimal inflammation in the vessel wall and no evidence of a thrombus within the vessel (Figure 4). There also was no evidence of leakage of the contents of the gradual venous occlusion device.
Photomicrograph of a tissue section of the internal iliac vein of a dog obtained 6 weeks after implantation of a gradual venous occlusion device. Notice that the vessel wall has minimal inflammation and thickening, and there is no evidence of thrombus formation. H&E stain; bar = 100 μm.
Citation: American Journal of Veterinary Research 77, 6; 10.2460/ajvr.77.6.653
Discussion
The gradual venous occlusion device used in the study reported here led to gradual attenuation of an intra-abdominal vessel in cats and dogs within a 6-week period. These results were consistent with in vitro results when the devices were evaluated by use of physiologic solutions at clinically normal body temperature.9 All animals tolerated the device, with no adverse effects noticed throughout the study period. Histologic examination of the vessels of the dogs revealed minimal inflammation of the vessel wall and no thrombus formation at 6 weeks after placement.
Mild residual blood flow was evident in 1 cat during CTA performed 6 weeks after surgery. Ultrasonography revealed that blood flow through the device was absent at weeks 4, 5, and 6. Despite the fact blood flow was not visible during ultrasonography, it was likely present but sufficiently minimal to prevent detection. It is not possible to know the reason that the diameter of the external iliac vein of that cat was 0 mm in diameter at 4 weeks but increased to 1.5 mm at 6 weeks because postmortem examination was not performed and the device could not be examined after the end of the study. It is unknown whether this vessel would have eventually completely closed because the study was terminated at 6 weeks after surgery. The clinical importance of minimal residual blood flow in dogs and cats with portosystemic shunts is not known. In 1 study,4 4 of 22 dogs had residual blood flow (detected with CTA) through the portosystemic shunt after placement of an ameroid constrictor; however, only 1 of those 4 dogs had an elevated shunt fraction. Additionally, investigators in another study11 found that 21 of 99 dogs had persistent shunting as identified by use of portal scintigraphy performed 6 to 10 weeks after placement of an ameroid constrictor, with 13 of 16 having an excellent or good long-term outcome. On the basis of this information, it is reasonable to consider that residual blood flow through a vessel may not result in a negative outcome for a patient as long as adequate partial attenuation is achieved.
Some variability was noticed between blood flow seen ultrasonographically and vessel diameter within the gradual venous occlusion device seen during CTA. Each modality provided unique information in that CTA provided a 3-D view of the device and vessel but did not allow for calculations of blood flow velocity, whereas blood flow velocity through a vessel could be evaluated with ultrasonography. Ideally, both modalities would be used in tandem to determine vessel closure. Further studies are needed to determine the modality that provides the most accurate information regarding vessel closure.
Currently available gradual venous occlusion devices close vessels in vivo via inflammation, fibrosis, thrombosis, or a combination of these processes.3–5 Inflammation can be the result of materials in the device as well as potentially from vessel manipulation and isolation prior to device placement. Cellophane failed to induce complete closure of femoral veins by 6 weeks after implantation in 6 dogs.5 Minimal vessel inflammation was evident in those dogs; however, perivascular foreign body reaction and inflammation led to vessel attenuation. In that same study,5 vessels in dogs treated by use of an ameroid constrictor were closed by 21 days after implantation. The lumen of the ameroid constrictors did not completely close in those dogs, and vessel closure was caused by deposition of dense fibrous tissue surrounding the vessel.5 Similarly, an in vivo clinical study4 found that closure of portosystemic shunts by an ameroid constrictor was the result of soft tissue deposition (which was likely fibrosis) within the ring, rather than by swelling of the casein in the ameroid constrictor. Fibrosis and thrombosis may lead to variability in closure rate and can be unreliable. The device in the study reported here closed veins via physical occlusion of the vessel rather than via inflammation or thrombosis, as indicated by the results of histologic examination.
The ideal time frame for portosystemic shunt closure is not known. Closure times of as few as 10 days have been reported for ameroid constrictors.3 Analysis of results for prior experiments has suggested a gradual occlusion period of 4 to 6 weeks may allow for improved adaptation of the hepatic portal system, which would therefore decrease the likelihood of portal hypertension and development of multiple acquired shunts after surgery in patients with portosystemic shunts.10 Rapid occlusion, which may occur with acute attenuation caused by ligation or with premature thrombosis by use of ameroid constrictors, can lead to portal hypertension or the development of multiple acquired portosystemic shunts.3,12 The gradual venous occlusion device used in the present study resulted in gradual attenuation or closure of an intra-abdominal vessel within a 6-week period. It is expected that there would be similar closure times after placing this device around an extrahepatic portosystemic shunt; however, further studies are necessary to evaluate optimal closure times.
Limitations of the present study included the small number of animals and the inability to obtain ultrasonographic images of the internal iliac vein in the dogs. It was unknown prior to device placement that ultrasonography would be of limited use for evaluation of the internal iliac vein, in contrast to evaluation of the external iliac vein in the cats. However, results of CTA revealed similar occlusion rates for both dogs and cats.
Although results for the present study may differ from results obtained when a device is placed around a portosystemic shunt, the vessels selected for placement of the gradual venous occlusion device were similar in size to most extrahepatic portosystemic shunts in small animals, were in the same intra-abdominal region as portosystemic shunts, and had similar blood flow pressures as for portosystemic shunts. Although the numbers in each group were small, the device did not cause any adverse effects and appeared to be safe for in vivo use.
On the basis of the results of the study reported here, a gradual venous occlusion device appeared to be feasible for use in clinical patients with extrahepatic portosystemic shunts. Future studies include a clinical trial to evaluate the efficacy and clinical outcomes after placement of the device in dogs and cats with extrahepatic portosystemic shunts.
Acknowledgments
Supported in part by the University of Florida Mark S. Bloomberg Memorial Resident Research Fund and the Harold and Vera Morris Research Fund Grant.
This manuscript represents a portion of a thesis submitted by Dr. Wallace to the University of Florida Department of Small Animal Clinical Sciences as partial fulfillment of the requirements for a Master of Science degree.
The authors thank Rick Rizzolo for assistance with development and manufacture of the gradual venous occlusion device and Dr. Jeffrey R. Abbott for assistance with histologic examinations and images.
ABBREVIATIONS
| CTA | Computed tomographic angiography |
Footnotes
Rasband WS. ImageJ, 1997—2012. Bethesda, Md: US National Institutes of Health. Available at: imagej.nih.gov/ij/. Accessed Dec 14, 2012.
Toshiba Aquilion, Toshiba Medical Systems, Otawara, Japan.
Toshiba Prime, Toshiba Medical Systems, Otawara, Japan.
Omnipaque 300, GE Healthcare, Little Chalfont, Buckinghamshire, England.
Philips iU22 ultrasound machine, Philips Medical Systems, Bothell, Wash.
References
1. Greenhalgh SN, Dunning MD, McKinley TJ, et al. Comparison of survival after surgical or medical treatment in dogs with a congenital portosystemic shunt. J Am Vet Med Assoc 2010; 236: 1215–1220.
2. Greenhalgh SN, Reeve JA, Johnstone T, et al. Long-term survival and quality of life in dogs with clinical signs associated with a congenital portosystemic shunt after surgical or medical treatment. J Am Vet Med Assoc 2014; 245: 527–533.
3. Besancon MF, Kyles AE, Griffey SM, et al. Evaluation of the haracteristics of venous occlusion after placement of an ameroid constrictor in dogs. Vet Surg 2004; 33: 597–605.
4. Hunt GB, Culp WTN, Mayhew KN, et al. Evaluation of in vivo behavior of ameroid ring constrictors in dogs with congenital extrahepatic portosystemic shunts using computed tomography. Vet Surg 2014; 43: 834–842.
5. Youmans KR, Hunt GB. Experimental evaluation of four methods of progressive venous attenuation in dogs. Vet Surg 1999; 28: 38–47.
6. Silverman PM, Spicer LD, McKinney R, et al. Computed tomographic evaluation of surgical clip artifact: tissue phantom and experimental animal assessment. Comput Radiol 1986; 10: 37–40.
7. Pechlivanis I, König M, Engelhardt M, et al. Evaluation of clip artifacts in three-dimensional computed tomography. Cent Eur Neurosurg 2009; 70: 9–14.
8. Leeman JJ, Kim SE, Reese DJ, et al. Multiple congenital PSS in a dog: case report and literature review. J Am Anim Hosp Assoc 2013; 49: 281–285.
9. Wallace ML, Ellison GW, Batich C, et al. In vitro development and evaluation of a polyacrylic acid-silicone device intended for gradual occlusion of portosystemic shunts in dogs and cats. Am J Vet Res 2016; 77: 315–322.
10. Vogt JC, Krahwinkel DJ, Bright RM, et al. Gradual occlusion of extrahepatic portosystemic shunts in dogs and cats using the ameroid constrictor. Vet Surg 1996; 25: 495–502.
11. Mehl ML, Kyles AE, Hardie EM, et al. Evaluation of ameroid ring constrictors for treatment of single extrahepatic portosystemic shunts in dogs: 168 cases (1995–2001). J Am Vet Med Assoc 2005; 226: 2020–2030.
12. Landon BP, Abraham LA, Charles JA. Use of transcolonic portal scintigraphy to evaluate efficacy of cellophane banding of congenital extrahepatic portosystemic shunts in 16 dogs. Aust Vet J 2008; 86: 169–179.
