Refinement of Vascular Access Port Placement in Nonhuman Primates: Complication Rates and Outcomes

Melanie L Graham,* Lucas A Mutch, Eric F Rieke, Michele Dunning, Elizabeth K Zolondek, Aaron W Faig, Bernhard J Hering, and Henk‑Jan Schuurman

Chronic vascular access is often needed in experimental animal studies, and vascular access ports (VAP) have been proposed as an alternative to conventional venipuncture. We previously reported on VAP implantation by using femoral venous cutdown (FVC) and tunneling. In an attempt to decrease the moderate complications associated with the FVC method, we developed the single-incision, peripheral-insertion (SIPI) method. In a retrospective evaluation, 92 FVC procedures were compared with 113 SIPI procedures in cynomolgus and rhesus macaques and baboons with as much as 2.5 y of follow-up. The rate of complications was significantly lower for the SIPI method than for the FVC method (19.4% versus 33.7%), particularly in regard to infectious compli‑ cations (8.0% versus 27.3%, respectively). In addition, VAP patency for blood sampling and fluid infusion was significantly better for the SIPI method than for the FVC method, with 1-y patency rate of 83% and 46%, respectively, and 2-y patency rate of 74% and 36%, respectively. Additional advantages of the SIPI method include the simplified implantation of the VAP and access in the homecage without any sedation or restraint after appropriate training of animals to cooperate. We conclude that the SIPI method presents an opportunity for refinement and is superior to the FVC method for chronic vascular access.

Abbreviations: FVC, femoral venous cutdown; JVC, jugular venous cutdown; NHP, nonhuman primate; SIPI, single-incision peripheral insertion; VAP, vascular access port.

Conventional approaches to chronic vascular access in nonhu- that NHP can be habituated to manual restraint, such as chair man primates (NHP) require the exposure of animals to repeated restraint or a similar apparatus intended to physically immobilize chemical restraint, jacketing plus tethering to protect chronic cath- the animal. In general, in addition to the stress of restraint itself, eterization, or manual restraint (mechanical such as a board or removing NHP from their homecages for a restraint procedure chair) for compulsory handling. These types of restraint invari- already induces stress, which can adversely affect behavior and ably are associated with stress; the stress of restraint (the ‘alarm contribute to variability in research data.14,29,31-33 reaction’) is associated with changes in physiologic and metabolic Totally implanted vascular access ports (VAP) have been intro- parameters. Chemical restraint (sedation by using barbiturates) duced in the experimental animal setting to enable reliable access, can induce temporary changes in hematologic parameters, includ- improve safety, and increase animal comfort when intermittent ing WBC counts and hematocrit; liver biochemical parameters in- or recurrent venous access is required.3,5-7,10,12,13,17,18,22,23,28,35,38,39 VAP cluding alanine aminotransferase and aspartate aminotransferase; generally enhance the wellbeing of NHP, allowing them to par- and increases in stress hormones, such as cortisol.19,25,29,37 The use ticipate fully in enrichment programs and social group activities of chemical restraint apparently does not influence the response without the restrictions inherent in conventional approaches. The to parenteral glucose loading21 but introduces confounding in car- 2 conventional methods of VAP location implantation in NHP are bohydrate tolerance tests that are based on the absorption of glu- jugular venous cutdown (JVC) and tunneling and femoral venous cose from the gastrointestinal tract;34 therefore, the utility of using cutdown (FVC) and tunneling.24,26,39 The surgical procedure for chemical restraint in models for diabetes or nutrition is affected. conventional placement is relatively invasive, requires general Tethering is a type of stress that induces changes in sympathetic anesthesia, and has a moderate risk of complications.16,24,39 More- arousal in NHP. Although considered a less restrictive form of re- over, both the JVC and FVC methods place the septum of the port straint, tethering is associated with a persistent low level of stress on the dorsal aspect of the animal, limiting the ability to access the including changes in cardiac function.1,8 NHP often try to remove VAP in the familiar homecage. the jacket or tether system—behavior that is a clear indication that We previously reported short-term complications associated habituation is not successful.4 Some groups have demonstrated with FVC placement of VAP in an effort to identify factors that in- fluenced surgical outcomes.16 In that study, follow-up was limited to a 30-d period after implantation to focus observation on com- Received: 07 Jul 2010. Revision requested: 09 Aug 2010. Accepted: 13 Aug 2010. plications strictly related to the surgical procedure. To minimize Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, complications in the current study, we developed and introduced Minnesota. *Corresponding author. Email: [email protected] the single-incision, peripheral-insertion (SIPI) method as a simple

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and reliable method of VAP placement. The SIPI method of VAP 3 VAP. All of these NHP were trained to cooperate by presenting placement accesses the inferior vena cava through cannulation of the port while in the homecage, and all became accustomed to the saphenous vein, allowing for placement of the septum of the routine handling; there was no need for restraint or sedation dur- port on the animal’s leg. NHP can then be trained to cooperatively ing routine vascular access procedures. extend the leg (and VAP) to the handler in the familiar homecage Vascular access ports. Port type and catheter size are described environment, presenting a major opportunity for refinement in in Figure 1; ports are illustrated in Figure 2. VAP were sufficiently animal wellbeing. large to be discerned on palpation but reflected the amount of The aim of the present study was to compare the SIPI method subcutaneous space necessary to accommodate the port head with the conventional FVC approach with respect to complica- reservoir and the placement site. We preferentially selected tions and outcomes, specifically patency. This comparison en- hydromer-coated polyurethane catheters (Hydrocoat catheters, abled us to observe whether a refinement designed for the welfare Access Technologies, Skokie, IL) because of their resistance to of animals might also lead to improvement by limiting model- kinking and their relative strength. Catheter size was either 3.5- or imposed factors that introduce confounding, such as infection, 5-French in accordance with the manufacturer’s recommenda- unplanned surgical procedures, and restraint, thereby increasing tions for NHP. The smallest catheter recommended to meet study confidence in the accuracy of scientific outcomes. To this end, objectives was selected. In the present study, 75% of the study we conducted a retrospective evaluation of both conventional population was implanted with 3.5-French catheters, with the FVC and the SIPI method from implantation to study endpoint, remaining 25% receiving 5-French catheters. All VAP were in- to identify all complications and assess VAP patency. We report spected visually and pressure-tested with saline for defects before here that the SIPI method was as easy as the conventional FVC implantation. approach for VAP placement but presented distinct advantages VAP placement. The technique used for FVC insertion of VAP compared with the conventional FVC approach. has been described previously.16 Briefly, a longitudinal incision was made over a femoral vein in an NHP under general anes- Materials and Methods thesia; the catheter was introduced into the femoral vein and advanced to the inferior vena cava. A second incision was made in This study was approved by the University of Minnesota In- the posterior chest wall, and blunt dissection was used to create stitutional Animal Care and Use Committee and was conducted a conventional port pocket to accommodate the port head. The in compliance with the Animal Welfare Act2 and adhered to prin- catheter was tunneled subcutaneously from the groin incision to ciples stated in the Guide for Care and Use of Laboratory Animals.20 the incision at the posterior chest wall. The VAP was connected We used NHP species commonly used in biomedical research: to the catheter and then secured to the musculature of the chest cynomolgus macaques (Macaca fascicularis), rhesus macaques wall. The groin and chest wall incisions were closed in a normal (Macaca mulatta), and baboons (Papio anubis). fashion. Animals. Two cohorts of animals were studied: one comprised The technique used for SIPI insertion of VAP has been described NHP that underwent conventional VAP placement by FVC, and previously.15 Briefly, after NHP received sedation and local anes- the other included NHP that underwent SIPI for VAP placement. thesia, a single incision was made lateral to the saphenous vein, All animals were purchased from institutionally approved com- and the catheter was introduced into the saphenous vein and mercial vendors. They were housed in pairs or small groups of advanced to the inferior vena cava. By using the same incision, the same sex. They had free access to water and were fed biscuits a conventional port pocket was created through blunt dissection (High-Protein Monkey Chow 5045, Purina Mills, St Louis, MO) to accommodate the port head. The catheter was trimmed and based on body weight. Their diet was enriched liberally with attached to the port, and the port was placed in the pocket. The fresh fruits, vegetables, grains, beans, nuts, and nutritional sup- incision was closed in a normal fashion. plements. The NHP participated in an environmental enrichment VAP removal. The technique used for FVC VAP removal was simi- program that included social play, toys, music, movies, and regular to that for insertion. Briefly, NHP under general anesthesia re- larly scheduled access to large exercise and swimming areas. ceived a longitudinal incision over the femoral vein, the catheter was Between October 1999 and May 2006, 76 NHP (45 male and dissected free of the femoral vein, and the femoral vein was ligated. 31 female; 49 cynomolgus macaques and 27 rhesus macaques) A second incision was made in the posterior chest wall, and blunt underwent VAP implantation by FVC. The macaques weighed dissection was used to free adhesions to the port. The groin and between 1.7 and 7.07 kg, and their age at time of VAP placement chest wall incisions were closed in a normal fashion. The technique ranged between 11 mo and 12 y. The total number of VAP placed used for SIPI VAP removal was performed as previously described.15 in these 76 animals was 92: each of 61 NHP received a single VAP; Briefly, after NHP underwent sedation and local anesthesia, a single 14 macaques received 2 VAP; and a single animal was implanted incision was made just distal to the port. Blunt dissection was used to with 3 VAP. All of these NHP required either chemical (ketamine free any adhesions to the port and to expose the proximal end of the 5 to 15 mg/kg IM) or manual (chairing) restraint for access to catheter. The port and catheter then were removed easily by gentle VAP. traction. Pressure was applied to the venotomy for several minutes. Between August 2006 and May 2010, 93 (71 male and 22 fe- Skin was minimally approximated. male; 65 cynomolgus macaques, 21 rhesus macaques, and 5 ba- Follow-up after VAP placement. VAP were routinely (usually boons) NHP underwent VAP implantation by the SIPI method. weekly) accessed for intravenous drug or fluid administration, The macaques weighed between 2.8 and 10.8 kg, and the baboons biologics administration, and blood sampling. For NHP wait- weighed between 12.3 and 16.7 kg; age at time of VAP placement ing to enroll in experimental studies, regular port maintenance ranged between 3.1 and 12.6 y. The total number of VAP placed was scheduled every 2 to 3 d per protocol for FVC VAP and at in these 93 animals was 113: in 75 animals 1 VAP was implanted; least every 90 d for SIPI VAP. Macaques and baboons were 18 NHP received 2 VAP; and a single animal was implanted with

480 Refinement of VAP placement in nonhuman primates

Figure 1. Catheter and port specifications. A port for implantation from among these 3 devices (all manufactured by Access Technologies, Skokie, IL) was selected according to individual animal characteristics. We found no significant differences between catheter or port types with respect to complications. followed until the endpoint defined by the experimental protocol tion observed (Table 1). In some cases, complications resulted or on 30 June 2010, whichever occurred first. Data were extracted in additional interventions. In cases of wound infection animals from medical records, from VAP placement to endpoint, to assess were given antibiotic therapy for a minimum of 5 consecutive short-term and long-term (all) complications and assess patency days, usually a cephalosporin (that is, cefazolin 50 mg/kg IM) in relation to VAP under general use. As part of the routine health unless sensitivity suggested an alternate. Cases of infection where monitoring program, NHP were observed at least twice daily catheter involvement was obvious necessitated VAP removal. Oc- for general appearance, changes in gait or movement, alertness, cluded VAP often revealed formation of a fibrin sheath or sleeve temperament, interaction with the social group, urination and and damage to the venous intima. This sheath or sleeve can act defecation, and body condition. Hematology and chemistry pro- as a nidus for bacterial action and thrombus formation. This pro- files, body weight, and vital signs were conducted as directed pensity leads to risk of septicemia, obstruction of the vein, pul- by experimental protocol or on clinical indication. In total, 211 monary embolism, and chronic venous insufficiency. This risk records of VAP placement and use were reviewed, from which 6 makes elective removal of obstructed ports desirable, although records were excluded because of insufficient data. Records were removal might not be required because neglected, occluded VAP reviewed for species, age, sex, date of placement, location, type may have no additional problems. Surgical repair or revision was of port, complications, indication for removal (if removed), and necessary in cases of mechanical defect of the port and catheter date of removal. system and certain skin complications in the absence of infection. Statistical analysis. The results were analyzed by using the Complication rates per group were as follows (Figure 3): Fisher exact test to compare proportions (GraphPad, version 3.1a, 31(33.7%) VAP placed by using the FVC method showed com- InStat Software, LaJolla, CA). Data regarding VAP patency un- plications, including 25 infections (27.2%), 8 skin complications derwent Kaplan–Meier analysis, which took into account that (8.7%), 3 traumatic removals (3.3%), and 2 deaths (2.2%). These animals were withdrawn from the study due to meeting primary complications required surgical repair for 7 (7.6%) VAP and ne- protocol endpoints (GraphPad, version 5.0c, Prism, LaJolla, CA). cessitated surgical removal of 18 (19.6%) VAP. In the FVC cohort The level of significance was set at aP level of less than 0.05. (76 NHP), occluded VAP generally were left in place due to the rather invasive procedure required for removal: elective removal Results was performed in only 2 cases (2.2%). In the 3 cases of traumatic removal, NHP removed the sutures and pulled the catheter from In total, 205 subcutaneous central venous access devices were its fixed location in the femoral vein or port head. The resulting placed in 169 NHP between 18 November 1999 and 28 May 2010. wounds were repaired, and the port head was removed surgi- A total of 92 (45%) ports were placed by using the FVC proce- cally. One death was due to catheter detachment, resulting in hy- dure and 113(55%) by using the refinement method, SIPI. Median povolemic shock, and the other death was due to a preexisting duration of port usage was 103 d (range, 1 to 709 d) in the FVC moderate aortic stenosis, resulting in irreversible cardiac depres- cohort and 202 d (range, 1 to 924) in the SIPI cohort. After strati- sion under general anesthesia. fication, NHP remained well matched demographically, with no Ports placed by using the SIPI method manifested 22 cases of significant differences between those with and without complica- complications (19.4% of all 93 NHP in this group), including 9 tions. There was no apparent difference in VAP placement and cases of infection (8%), 15 of skin complications (13.3%), 1 of port complications between different species and no apparent relation- rotation or flip (0.9%), and 2 of reservoir leak (1.8%). These com- ship between body weight or size of the NHP and complications. plications required surgical repair in 4 cases (3.5%) and neces- A maximal catheter:vessel ratio is ideal to minimize stasis and sitated surgical removal of the VAP in 14 cases (12.4%). Due to turbulent flow. Therefore, we studied the relationship between occlusion elective removal was performed in 8 VAP (7.1%) be- animal weight and catheter size selection relative to duration of cause, unlike the FVC method, removal of the SIPI-implanted patency. No significant correlation was observed either in the port was rather simple, quick, and performed using local anes- combined cohorts or after stratification. thesia. In total, 53 complications occurred (25% of all VAP), including Patency was defined by the ability to both infuse fluids and 34 (16.6%) infections, which were the most common complica- withdraw blood. The rates per group were as follows: for FVC

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Discussion VAP present a substantial improvement over conventional approaches of chronic vascular access in NHP, and for this reason we implemented the FVC VAP method at our center.16 However, the FVC VAP method is not without complications; therefore, we searched for improved placement methods and subsequently developed the SIPI method. In this retrospective comparative evaluation of the 2 methods for VAP implantation, we found the SIPI method to be superior to the FVC method. We acknowledge that this comparison was not conducted in a prospective experimental design and that the work with SIPI VAP was done later than that with FVC VAP. However, even after these caveats were taken into account, our experience yielded several aspects in which the SIPI is highly preferred over the JVC and FVC methods. These advantages and disadvantages are summarized in Figure 5 and discussed in the following paragraphs. The SIPI method is preferred at our center because it allows us to perform procedures requiring intravenous access in a cooperative way, with the NHP being in the familiar homecage. Coopera- tive access in the homecage of NHP avoids stress associated with restraint and reduces caretaker time required for VAP maintenance. In our experience, chemical restraint requires a minimum of approximately 30 min for sedation, performance of the procedure, and monitoring to full recovery. Chair restraint even for highly trained animals takes a minimum of approximately 10 min to move the animal from the homecage to the chair, secure the animal correctly in the chair, move the chair to a designated procedure area, and then move the animal back to the cage. Procedures can typically be completed in less than 5 min in the homecage for NHP that are trained to present the VAP. This short time period and lack of sedation are particularly relevant for situations that require repeated access (3 or more procedures) during a short period (24 h), such as in pharmacokinetic experiments, metabolic testing, and intensive fluid management and critical care. For these situations, the use of repeated restraint increases the risk of inadvertent injury to NHP, such as: anorexia, obscured clinical signs, or cage-associated injuries resulting from postsedation ataxia and contusion or abrasion resulting from repeated physical contact with restraint devices. In our experience, cooperative interactions with NHP reduce the risk of injury to both animals and caretakers, leading to homecage access as the most preferred option at our center. Standard venipuncture techniques may be used in NHP already fully acclimated to cooperative homecage handling in the case of VAP dysfunction. From a surgical point of view, SIPI VAP implantation is pre- Figure 2. Vascular access ports. Top, Titanium (model CP4; Access Tech- ferred because it uses a simple technique, similar to that practiced nologies, Skokie, IL). Center, Polysulfone (model SLA; Access Technolo- in routine central line insertions in patients and companion ani- gies). Bottom, Polysulfone (small PhantomPort; Access Technologies). mals. In addition, SIPI VAP is minimally invasive, because only a single incision is needed with minimal dissection to accommodate ports, 46% were patent at 1 y and 36% at 2 y; for SIPI ports, 83% the port head. This end can easily be accomplished by using seda- were patent at 1 y and 74% at 2 y (Figure 4). In both cohorts, tion in combination with a local anesthetic block, thereby avoid- the decision to replace a VAP reflected both the time remaining ing risks associated with the general anesthesia required for the for the study and surgical site availability. When VAP were not invasive subcutaneous tunneling used in conventional methods. replaced, intravenous access was obtained by using standard SIPI VAP implantation generally takes about 30 min, after which venipuncture. For NHP with FVC VAP, standard venipuncture NHP quickly return to normal activities. These are clear improve- required chemical restraint. In 2 NHP with SIPI VAP, the device ments over the FVC method, which typically takes about 45 min 15 occluded just prior to study end; therefore, replacing the VAP plus additional time for induction of general anesthesia. was considered impractical in these cases. In these 2 NHP, re- Compared with those with the FVC method, the total number peated venipuncture in the homecage was successful because of complications in the SIPI cohort was reduced by 14% (from they were accustomed to routine handling of their legs. 33.7% to 19.4%, Table 1), and multiple, concurrent complications

482 Refinement of VAP placement in nonhuman primates

Table 1. VAP complications No. (%) FVC (n = 92) SIPI (n = 113) P All complications 31 (33.7) 22 (19.4) 0.025

Complications by type Infection (confirmed or suspected) 25 (27.2) 9 (8) 0.0003 Skin (dehiscence or erosion) 8 (8.7) 15 (13.3) not significant Port rotation or flip 0 (0) 1 (0.9) not significant Reservoir leak 0 (0) 2 (1.8) not significant Traumatic removal (by animal) 3 (3.3) 0 (0) not significant Death 2 (2.2) 0 (0) not significant

No. of complications experienced per animal Difference (%) 0 66 (71.7) 91 (80.5) + 8.8 1 25 (27.2) 18 (15.9) −11.3 2 5 (5.4) 4 (3.5) −1.9 3 1 (1.1) 0 (0) −1.1

Figure 4. The primary outcome measured in this retrospective analysis was patency, assessed by using Kaplan–Meier estimates plotted over time after placement. A strict definition of ‘patent’ was used: the VAP had to demonstrate the ability to both infuse and withdraw fluids, because blood sampling and drug administration was required according to protocol. The refined method demonstrated significantly (P < 0.001) Figure 3. Total complications, requirement for reoperation, and mor- improved patency compared with traditional placement. Symbols indi- tality associated with VAP placement using the FVC method and SIPI cate censors for either study endpoint as defined by primary protocol or method, expressed in percentage of all VAP placed. There was a sig- follow-up time point. nificant (P = 0.0249) reduction in the total complication rate with the SIPI method. Some complications were resolved with routine medical management; however, a percentage necessitated surgical revision or 13% and 30%11,16,24,30 and those for jacket and tether systems be- removal. There was no mortality observed with the SIPI method. tween 25% and 30%.9,36 We ascribe this reduction in infectious complications to a lower bacterial density at the leg compared dropped sharply. Using the SIPI method, we observed a signifi- with the groin and to improved acceptance by the NHP. SIPI VAP cant (P < 0.001) decrease in infectious complications, with only implantation is well tolerated by NHP; we have not observed any 8% of SIPI VAP experiencing infection. It is worth mentioning traumatic incidents, and animal compliance exceeded 85% with 15 that this reduction in complications using the SIPI method was this approach. Animal compliance (defined as not disturbing achieved despite the much longer follow-up (median 6.6 mo for the wound site) was previously demonstrated to be protective in 16 the SIPI method and 3.4 mo for the FVC method). The complica- preventing infectious complications. tion rate for the SIPI method is in the same range as that observed Follow-up monitoring demonstrated excellent patency in the in clinical situations27 and is a substantial improvement over what SIPI cohort, with 74% of VAP being patent 2 y after implanta- has previously been reported in animal models.24,36,39 Infectious tion (Figure 4). We largely attribute this result to the absence complications associated with JVC and FVC VAP range between of fixation between the catheter and vessel. This arrangement 483 Vol 60, No 6 Comparative Medicine December 2010

Figure 5. Advantages and disadvantages of various insertion methods for long-term central venous access. accommodates free movement of the tip in the inferior vena cava, ous vascular access ports for chronic vascular access in a porcine thereby decreasing the probability of prolonged contact between model. Contemp Top Lab Anim Sci 44:24–27. the tip and vessel wall that might disturb normal blood flow. In 6. Cowart RP, Payne JT, Turk JR, Tyler JW, Casteel SW. 1999. Factors addition, this lack of fixation has the added value that removal, if optimizing the use of subcutaneous vascular access ports in weaned pigs. Contemp Top Lab Anim Sci 38:67–70. necessitated or elected, is easily done under sedation, without the 7. Craig DJ, Trost JG, Talley W. 1969. A surgical procedure for implan- need for major surgery under general anesthesia. tation of a chronic indwelling jugular catheter in the monkey. Lab NHP are especially good candidates for VAP because of their Anim Care 19:237–239. complex experimental conditions, ability to learn cooperative 8. Crockett CM. 1993. Urinary cortisol responses of longtailed ma- behaviors, and long-term experimental follow-up periods. Be- caques to 5 cage sizes, tethering, sedation, and room change. Am J cause catheters are not externalized with VAP, NHP can remain Primatol 30:55–74. in social groups at all times and can participate without restriction 9. DaRif CA, Rush HG. 1983. Management of septicemia in rhesus in enrichment programs, including those in play and swim areas, monkeys with chronic indwelling venous catheters. Lab Anim Sci 33:90–94. throughout the experimental period. Our experience indicates 10. Evans KL, Smeak DD, Couto CG, Hammer AS, Gaynor JS. 1994. that SIPI VAP provide safe and effective long-term intravenous Comparison of 2 indwelling central venous access catheters in dogs access for successful drawing of blood samples and delivery of undergoing fractionated radiotherapy. Vet Surg 23:135–142. drugs, antibiotics, blood products, fluids, and nutrition. This re- 11. Fitzgerald AL, Dillon LM, Altrogge DM, Bleavins MR, Breider MA. fined method of VAP implantation has the substantial advantage 1996. Use of subcutaneous vascular access ports in common mar- of reduced complications and increased patency and supports mosets (Callithrix jacchus). Contemp Top Lab Anim Sci 35:57–59. cooperative handling, thereby improving overall animal wellbe- 12. Garner D, Laks MM. 1985. New implanted chronic catheter device ing and reducing experimental stress. for determining blood pressure and cardiac output in conscious dog. Am J Physiol 249:H681–H684. 13. Garner D, McGivern R, Jagels G, Laks MM. 1988. A new method for Acknowledgments direct measurement of systolic and diastolic pressures in conscious We acknowledge with gratitude the excellent care the animals received rats using vascular access ports. Lab Anim Sci 38:205–207. from Angela Craig, Theresa DuFour, Jessica Kittredge, and James 14. Golub MS, Anderson JH. 1986. Adaptation of pregnant rhesus Munson. Our study was supported by the Schulze Family Foundation, monkeys to short-term chair restraint. Lab Anim Sci 36:507–511. the National Institutes of Health, and the Juvenile Diabetes Research 15. Graham ML, Rieke EF, Dunning M, Mutch LA, Craig AM, Foundation. Zolondek EK, Hering BJ, Schuurman H, Bianco RW. 2009. A novel alternative placement site and technique for totally implantable vascular access ports in nonhuman primates. J Med Primatol References 38:204–212. 1. Adams MR, Kaplan JR, Manuck SB, Uberseder B, Larkin KT. 16. Graham ML, Rieke EF, Wijkstrom M, Dunning M, Aasheim TC, 1988. Persistent sympathetic nervous system arousal associated with Graczyk MJ, Pilon KJ, Hering BJ. 2008. Risk factors associated with tethering in cynomolgus macaques. Lab Anim Sci 38:279–281. surgical site infection and the development of short-term compli- 2. Animal Welfare Act as Amended. 2007.7 USC §2131-2159. cations in macaques undergoing indwelling vascular access port 3. Bailie MB, Wixson SK, Landi MS. 1986. Vascular access port im- placement. J Med Primatol 37:202–209. plantation for serial blood sampling in conscious swine. Lab Anim 17. Grosse-Siestrup C, Lajous-Petter AM. 1990. Totally implantable Sci 36:431–433. catheter system in the dog. J Invest Surg 3:373–385. 4. Balcombe JP. 2004. Laboratory routines cause animal stress. Con- 18. Henry CJ, Russell LE, Tyler JW, Buss MS, Seguin B, Cambridge temp Top Lab Anim Sci 43:42–51. AJ, Moore ME. 2002. Comparison of hematologic and biochemical 5. Chuang M, Orvieto M, Laven B, Gerber G, Wardrip C, Ritch C, values for blood samples obtained via jugular venipuncture and via Shalhav A. 2005. Comparison of external catheters with subcutane- vascular access ports in cats. J Am Vet Med Assoc 220:482–485.

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