Abstract
Objective
To use contrast venography and intravascular pressure monitoring to determine optimal perfusion volumes during IV regional limb perfusion (IVRLP) and to determine systemic, articular, and osseous concentrations of amikacin achieved following IVRLP in dogs.
Methods
Animals were anesthetized and had lateral saphenous vein catheters placed. Incremental IV contrast venography with pressure monitoring was performed on one limb with a tourniquet proximal to the stifle to estimate vascular filling volume. Intravenous regional limb perfusion was performed on the contralateral hindlimb using 5 mg/kg amikacin, IV, diluted to the total filling volume. Systemic blood samples and synovial fluid were collected prior to infusion and immediately prior to and 30 minutes after tourniquet removal. Tibial bone marrow aspirates were collected after tourniquet removal. Samples were analyzed for amikacin concentration.
Results
Contrast IVRLP perfused the pelvic limb distal to the tourniquet with a median volume of 10 mL (range, 6 to 16 mL) and perfusion pressure of 77.5 mm Hg (range, 37 to 130 mm Hg). The median systemic amikacin concentration with the tourniquet in place was low (0.6 μg/mL) and increased to 11.5 μg/mL following removal. The amikacin concentrations in synovial fluid and bone marrow were 109.8 and 49.7 μg/mL, respectively, with high interdog variability.
Conclusions
Contrast venography and tissue amikacin levels suggest that IVRLP is feasible in the canine pelvic limb as the amikacin concentrations in 75% of synovial fluid and 33% of bone marrow samples exceeded 10 times the MIC required to inhibit 90% of isolates (MIC90) reported for Staphylococcus pseudintermedius.
Clinical Relevance
This study offers a baseline protocol for canine IVRLP for use in limb infections. Further studies should focus on drug delivery optimization and clinical application.
The incidence of surgical site infections in small-animal orthopedic surgery varies widely, from 4.7% to 12%, based on wound classification and surgical procedure.1–3 Septic arthritis and osteomyelitis are particularly catastrophic and may result in rapid deterioration of joint tissues, nonunion, or bone sequestration if untreated.1,4,5 Infections are further complicated by the increasing prevalence of antibiotic-resistant bacterial strains; for example, methicillin-resistant Staphylococcus pseudintermedius has been reported in 40% of surgical site infections.6 Collectively, these infections result in substantial patient morbidity and mortality, often with prolonged, expensive, and complicated recoveries.7,8
The mainstay of therapy for orthopedic infections is prolonged targeted oral antimicrobial administration.3,9 Increasing antimicrobial resistance limits oral therapeutic options, and effective parenteral drugs may result in detrimental side effects.9,10 Animal model studies11–14 suggest that combined local and systemic antibiotic delivery significantly accelerates and increases the likelihood of bacterial eradication. Localized therapy has been shown to be effective for the treatment of septic arthritis and osteomyelitis using intra-articular antibiotics15 or antibiotic beads14,16 for isolated challenging cases. Based on these data, there is a critical need for additional local treatment strategies for orthopedic infections in dogs.
Intravenous regional limb perfusion (IVRLP) is used extensively in equine practice for the management of distal limb infections, including septic arthritis and osteomyelitis.13,17–21 It is hypothesized that pressure gradients created during IVRLP between the intravascular and extravascular compartments increase capillary hydrostatic pressure and open capillaries obstructed by fibrin,13 thus maximizing diffusion of the perfusate into the synovial fluid, tissues, and bone. Additionally, high, prolonged local concentrations of antibiotic achieved in the regional vasculature during IVRLP may facilitate higher doses delivered to the site of infection of targeted structures.
Aminoglycosides are typically used due to their concentration-dependent bactericidal activity and their postantibiotic effect.17 Individual bacteria are assessed as susceptible to antibiotics based on their MIC value, which can range depending on the bacterial strain evaluated. The MIC can vary based on specific bacterial populations but has been reported for certain S pseudintermedius colonies as 8 μg/mL,22 with susceptibility breakpoints reported typically as > 16 μg/mL.23 In the horse, IVRLP with amikacin can achieve concentrations above the MIC for over 24 hours in the synovial fluid and 8 hours in bone, with minimal leakage into systemic circulation, limiting toxic effects.13 Achieving high concentrations of amikacin (10-fold the MIC) regionally is desirable as a marked improvement in the impact of amikacin on bacteria is reached at drug concentrations > 8-fold the MIC of that isolate.24 However, the impact on specific bacterial strains can be variable based on the strain or resistance mechanism.17,25 In studies17–19,26,27 on rabbits and horses with experimentally induced septic arthritis, antibiotic treatment via IVRLP resulted in far reduced bacterial counts compared to systemic treatment, leading to elimination of the infection in many cases.
Despite the widespread use of IVRLP in horses, this treatment strategy has not been evaluated in dogs. A case report28 using a regional limb perfusion technique has been described in a single dog, but amikacin concentrations achieved in local tissues were not reported. Given the rapid increase in resistant infections in small animals, there is a great need for novel therapeutic strategies. The objectives of this study were to (1) determine the effective volumes and intravascular pressure necessary for IVRLP to achieve vascular filling in the pelvic limb and (2) describe antimicrobial concentrations achieved in systemic, articular, and osseous tissues after IVRLP in dogs. We hypothesized that amikacin administered by IVRLP would reach therapeutic concentrations in synovial fluid and bone greater than the published MIC for S pseudintermedius.
Methods
Study design
All work was conducted under an approved IACUC protocol (V005663). Research dogs were purpose-bred Beagles purchased or donated from a commercial research animal facility. Four research dogs were used in a pilot study to refine the IVRLP technique before commencing the main study that used 12 dogs. There was a 2-year delay between the first 6 and last 6 dogs due to university restrictions on live dog research during the COVID-19 pandemic. A sample individual-dog study timeline is detailed in Figure 1. Patients were weighed immediately before inclusion in the study. Dogs were premedicated with 0.1 mg/kg hydromorphone, IM, to allow placement of a 20-gauge IV cephalic catheter. Anesthesia of the dogs was induced with 4 to 6 mg/kg propofol, IV, titrated to effect and maintained under intubated general anesthesia (isoflurane in 100% oxygen) for the duration of the study. The dogs received lactated Ringer solution (5 mL/kg/h, IV), a jugular catheter was placed for sampling, and routine anesthetic monitoring was conducted throughout, including capnography, noninvasive arterial blood pressure, ECG monitoring of heart rate and rhythm, and pulse oximetry. Each dog had the right or left pelvic limb perfused with either contrast or antimicrobial perfusion, respectively, based on a random number generator. Limb circulatory isolation with tourniquet placement was identical for contrast and antimicrobial perfusion. Dogs were humanely euthanatized with IV pentobarbital after the final time point of sample collection while still under anesthesia. No further postmortem analysis was undertaken.
Sample timeline for IV regional limb perfusion sampling in experimental dogs. Note that each individual dog had the laterality of the limb used for each portion of the study randomly allocated. L = Left. R = Right.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.25.03.0098
Contrast perfusion
After aseptic preparation of the pelvic limb, a 22-gauge, 1.5-inch IV catheter was placed in the lateral saphenous vein with its tip pointing distally and the insertion point distal to the stifle. The IV catheter was attached to a 3-way stopcock connected to a pressure transducer (DTX Plus transducer set; McKesson Medical-Surgical Inc) to allow for continuous pressure monitoring using a digitized blood pressure monitoring system. A 2-inch-wide medical-grade latex tourniquet was placed as high as possible in the inguinal region proximal to the stifle joint, encircling the limb at the level of the midfemur. Tourniquets were placed by wrapping the latex band circumferentially a minimum of 10 times around the limb under maximum tension with > 75% overlap of layers; the end of the tourniquet was then secured using a hitch knot to the previous wrap.29 A solution of 50% radiographic contrast agent (iohexol) in saline was injected into the catheter at 1- to 2-mL increments; at each increment, direct intravascular pressure was recorded. Orthogonal radiographs were obtained to subjectively estimate vascular filling using the stifle and metatarsal and digital vasculature as the main reference points (Figure 2). Limbs were infused until (1) there was radiographic or clinical evidence of extravasation of fluid at the location of venipuncture or (2) there was contrast medium identified within the digital vasculature and the patient became reactive (signs of trembling and/or body movement). The final intravascular pressure and volume of solution injected were recorded at the end point, and the tourniquet was removed. After tourniquet removal, the intravascular pressure was recorded to evaluate the ability to return to baseline as an indirect method of assessing local vascular trauma.
Serial contrast radiographs taken (A) immediately before (0 mL), (B) approximately 5 minutes after (3 mL), and (C) approximately 10 minutes after (8 mL) of IV regional limb perfusion contrast administration. Yellow arrows highlight the areas of visible contrast in the distal limb vasculature. There is slight extravasation of contrast within this portion of the limb, dictating the end point of contrast administration.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.25.03.0098
Amikacin perfusion
The tourniquet was placed on the opposite hindlimb (Supplementary Figure S1). Intravenous regional limb perfusion was performed with amikacin sulfate (5 mg/kg, equal to a third of the systemic dose, within similar ranges as equine studies17,18,21,27) diluted with sterile saline, injected slowly over 2 to 3 minutes. The total perfusion volume for each dog was determined by the contrast study in the contralateral limb. The tourniquet was maintained for 30 minutes after perfusion commenced and then removed.
Sample collection and processing
Time points were defined as baseline before tourniquet placement (time = 0 minutes), immediately before tourniquet removal (time = 30 minutes), and 30 minutes after tourniquet removal (time = 60 minutes; Figure 1). Blood samples were collected from a jugular catheter at all time points. Synovial fluid was collected using a 22-gauge needle with aseptic technique from an untreated control elbow joint (time = 0 minutes) for baseline measurements, and from the stifle of the perfused pelvic limb (time = 30 minutes). Bone marrow aspirate specimens were collected using a Jamshidi needle from the proximal tibia of the perfused pelvic limb (time = 30 minutes). All blood, synovial fluid, and bone samples were collected in heparinized tubes and stored on ice until sampling was complete.
Analysis of serum, synovial fluid, and bone marrow plasma
Samples were processed as recommended by the commercial laboratory used for previous equine IVRLP studies30 (University of California-Davis Veterinary Diagnostic Laboratory). Samples were centrifuged (5 minutes at 1,700 X g), and the supernatant was carefully decanted in order to generate a cell-free sample. Due to COVID-19 restrictions on live animal research, samples from the first 6 dogs were stored at −80 °C until completion of the in vivo portion of the study. Samples from the remaining 6 dogs were refrigerated at −20 °C for the final week of the study before shipping all samples on dry ice to the laboratory for analysis as recommended. Amikacin concentrations were determined using a commercially available fluorescence polarization immunoassay (Roche Diagnostics GmBH) with an analyzer for quantitative determination of amikacin. The limit for detection of the assay was < 0.6 μg/mL. Testing was performed at the University of California-Davis Veterinary Clinical Laboratory, and the guidelines for safe systemic amikacin trough levels were used for interpretation.
Statistical analysis
Data were examined for normality and reported as mean ± SD or median and range as appropriate. Descriptive observations were reported for contrast radiographic observations. Based on the previous determination of a MIC required to inhibit 50% of isolates and a MIC required to inhibit 90% of isolates (MIC90) for S pseudintermedius in dogs, a MIC value of 8 μg/mL was utilized for analysis in this study.22 Based on clinical recommendations, we determined the proportion of synovial fluid and bone samples that exceeded the threshold of 10-fold above this MIC value.24
Results
Pilot study
We explored several concepts, including the (1) location, orientation, and size of the IV catheter; (2) regional IV pressure monitoring; (3) tourniquet location; and (4) sampling technique and volume from bones and joints. Dogs were anesthetized, and IVRLP with contrast with pressure monitoring was performed as in the main study. Small variations in tourniquet location in the groin had a large impact on the region perfused. Threading of the catheter in a distal orientation was difficult. Intravenous regional limb perfusion pressure monitoring was variable and often spiked immediately after injection before normalizing. Stifle arthrocentesis yielded only a small volume of joint fluid and was not repeatable within a single joint; therefore, serial sampling was not performed as would be the typical technique reported in horses.
Study results
All 12 dogs were perfused with radiographic contrast and amikacin without complications. The median dog weight was 11.75 kg (range, 8.4 to 13.2 kg). The IVRLP technique was feasible and was able to be completed in all evaluated patients. The lateral saphenous vein catheter was placed with its tip pointing distally to direct the perfusion toward the distal limb. Catheter placement was challenging, with mild extravasation of blood in 2 cases, but ultimately achieved in all cases.
Contrast radiography
With increasing perfusate volume, microvasculature was visible throughout the distal limb but was not visible proximal to the tourniquet. The median volume of contrast required to reach the end point was 10 mL (range, 6 to 16 mL; Supplementary Table S1) and varied by dog size and precise tourniquet location. Normalized to body weight, the mean total volume used was 0.9 mL/kg (range, 0.5 to 1.3 mL/kg). All dogs successfully showed perfusion of the paw pad microvasculature at the end point (Figure 2). There was some variation in vessel perfusion based on the precise tourniquet location above the stifle joint. The more proximal position of the tourniquet on the limb allowed for contrast perfusion of more proximal vessels. Specifically, the tourniquet position at the midfemoral level allowed contrast perfusion of the caudal femoral vascular branching, compared with tourniquet position just proximal to the stifle joint only isolated terminal vasculature branching below the joint (Figure 3).
Intravenous regional limb perfusion contrast radiographs in 2 different dogs demonstrating variation in venous perfusion based on tourniquet location more proximal (A) and more distal (B). The IV catheter is located in the lateral saphenous with attached extension tubing. The tourniquet is denoted by the multiple asterisks (*). Additional caudal femoral venous contrast is seen with more proximal tourniquet placement.
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.25.03.0098
The median baseline IV pressure of the pelvic limb with the tourniquet in place was 33 mm Hg (range, 28 to 36 mm Hg; Supplementary Table S1). The venous pressures peaked immediately after perfusate administration and then slowly decreased to a stable state over a period of approximately 10 to 30 seconds, which was recorded as the end pressure before adding the next incremental volume. The median end perfusion pressure was 77.5 mm Hg (range, 37 to 130 mm Hg).
Amikacin IVRLP
Amikacin treatment was restricted to the distal limb by the tourniquet, with undetectable systemic plasma levels in 10 of 12 dogs. The remaining 2 dogs had 4.4 and 4.6 μg/mL of plasma amikacin concentrations with the tourniquet in place. Systemic amikacin concentrations increased to a median of 11.5 μg/mL (range, 9.4 to 15.3 μg/mL) after tourniquet removal (Figure 4).
Plasma amikacin concentrations throughout the study period. The tourniquet was removed after 30 minutes. Samples that are reported as zero were below the limit of detection of the assay (< 0.6 μg/mL).
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.25.03.0098
Amikacin was detected in the perfused stifle synovial fluid in all dogs, with a median of 109.8 μg/mL (range, 8.3 to 774 μg/mL; Table 1). Amikacin concentrations were more variable in perfused tibial bone marrow aspirate, with a median concentration of 49.7 μg/mL (range, 14.9 to 2,426.4 μg/mL). Individual dog data were variable both within the synovial fluid and bone marrow aspirate assessed (Figure 5; Supplementary Table S1). Using a MIC90 of 8 μg/mL for amikacin, the 10-fold threshold was exceeded in 9 of 12 synovial fluid samples and 4 of 12 bone marrow samples.
Amikacin concentrations detected in plasma, synovial fluid, and tibial bone marrow aspirate before amikacin administration, 30 minutes after amikacin administration, and 30 minutes after tourniquet removal (60 minutes after amikacin administration) during IV regional limb pelvic perfusion in dogs.
| 30 minutes after amikacin administration | 30 minutes after tourniquet removal | ||||
|---|---|---|---|---|---|
| Baseline | Median | Range | Median | Range | |
| Plasma (μg/mL) | < 0.6 | < 0.6 | 0–4.6 | 11.5 | 9.4–15.3 |
| Synovial fluid (μg/mL) | < 0.6 | 109.8 | 8.3–774 | – | |
| Bone marrow (μg/mL) | 49.7 | 14.9–2,426.4 | – | ||
Synovial fluid and bone marrow amikacin concentrations achieved 30 minutes after administration. The dotted line represents the clinical drug target concentration of 10 times the MIC required to inhibit 90% of isolates for Staphylococcus pseudintermedius (8 μg/mL).
Citation: American Journal of Veterinary Research 2025; 10.2460/ajvr.25.03.0098
Discussion
This study explored the feasibility of IVRLP in dogs.28 The methods used in this study were extrapolated from horses and represent a unique collaboration between large-animal and small-animal surgeons. Contrast venography confirmed the ability to isolate and perfuse the terminal vasculature of the distal limb, with no observed damage to vascular integrity. Intravenous regional limb perfusion with amikacin resulted in increased joint and bone tissue concentrations while maintaining systemic levels within previously reported ranges.
The efficacy of regional limb perfusion is measured by quantifying the peak antibiotic concentration (Cmax) achieved in target tissues and calculating the ratio of Cmax to the MIC, determined for the antibiotic and bacteria of interest.18 A Cmax-to-MIC ratio of at least 8:1 to 10:1 has been recommended for aminoglycosides to be effective.24 Nine of 12 synovial fluid samples and 4 of 12 bone marrow samples evaluated exceeded the clinical recommendation of concentrations greater than 10 times this MIC value. Achieving concentrations of 8- to 10-fold the MIC have been associated with an 85% to 90% response rate for infection resolution.24 While the desired concentration was not achieved in the remaining synovial fluid and bone marrow samples, resistant organisms may still experience a reduction in growth when exposed to lower amikacin concentrations,31 and some degree of antimicrobial effect would still be expected. For example, achieving 6-fold the MIC of a bacterium has been shown to have a 70% response rate24 as well as improved patient outcomes in human patients.32 Additionally, these results are based on the MIC90 value reported for S pseudintermedius but may not be reflective of the MIC for different bacterial isolates. Staphylococcus pseudintermedius is considered susceptible to amikacin at MIC values up to 16 μg/mL. If an isolate had a MIC value closer to this breakpoint value, the concentrations achieved in synovial fluid and bone marrow in the majority of our study cases would be insufficient to meet clinical recommendations. We used the extrapolated dose from equine literature of a third of the systemic amikacin dose. However, this was lower than one previous canine regional limb perfusion case report28 that used a full systemic dose (15 mg/kg). Higher doses of amikacin could be considered, and/or the antimicrobial selection, based on clinical culture and susceptibility testing. In addition, the utility of documenting the duration of amikacin presence within the localized tissues could be helpful as the area under the curve of a time concentration graph has been shown to be more predictive of antibiotic efficacy.24
While some study dogs did reach concentrations greater than the target 10-fold higher than the reported MIC90 for common bacteria, this was less consistent than reported in the equine literature.17,18,27 In certain equine reports,18 the synovial amikacin concentration frequently exceeded 200 to 500 μg/mL, which was seldom achieved in the synovial fluid samples of the current study. This could be due to anatomic differences, tourniquet location, or the relative volume of limb that is perfused between species. The relative muscle and soft tissue mass in the lower half of a dog limb may be greater than the extremity of a horse limb typically isolated for IVRLP and may create a larger area of distribution. This may also create a separate reservoir or sink for the antimicrobial, leaving less perfusate volume and drug available to reach the joint.
Systemic amikacin levels remained low during the study period for all dogs after tourniquet release and below the published laboratory peak concentration range for amikacin.33 While toxic peak levels for amikacin in dogs have not been well established, the systemic amikacin concentrations remained at lower levels than previously described in pharmacokinetic studies33 and similar to what has been reported in equine cases.34,35 The serum amikacin concentrations measured were also well within the recommended peak amikacin concentrations reported in human literature.10 Amikacin toxicity is related to the duration of exposure to high systemic concentrations rather than spikes in drug concentration, and more importance is placed upon achieving low-trough amikacin concentrations.24,33 While our sample points may not have assessed the exact peak concentration in individual dogs, given the rapid peak and short half-life of amikacin,33 we do not anticipate clinical concerns from the dose used in this study.
There was a large variation in synovial and bone marrow amikacin concentrations in our study. Although we did a pilot study of 4 dogs to develop the IVRLP methods, there may have been slight differences in sample collection and processing that impacted our data. The perfusion volume varied based on the contrast venogram performed in the contralateral limb of the same dog, which have impacted tissue perfusion. Variation in the tourniquet position between limb pairs may have affected perfusion as a more proximal position on the limb may have included additional vascular branching and a larger vascular pool. This was particularly evident in cases in which the tourniquet was at the midfemur level that showed contrast perfusion of the femoral vasculature. We attempted to standardize our procedure by placing the tourniquet as proximal as possible; however, variation in dog and limb conformation impacted how proximal we could secure the tourniquet. This observation would have clinical ramifications for regional limb perfusion use in dogs with long, skinny legs compared to short, stocky limbs. This variation also limits any correction of perfusion volume and pressure data with amikacin concentrations in this study as would be typical in equine regional limb perfusion data.
Minor technical complications were encountered during the procedure, including extravasation at the catheter site. Placing the IV catheter in a distal direction was difficult, presumably related to venous branching, valves, or tapering of the vessel diameter. In horses, this challenge has been addressed by using a butterfly catheter needle that will not collapse and is less susceptible to movement. We attempted to isolate the distal pelvic limb through tourniquet placement proximal to the stifle joint as this would be the most useful clinically to enable perfusion of the stifle and proximal tibia. The visibility of vessels and the contrast-filled vessel density surrounding the stifle joint improved with tourniquets placed midfemur. Therefore, placement as far proximal as possible would be recommended in cases of stifle joint infections to ensure adequate perfusion around the region of interest. Given that we observed some variation in contrast perfusion despite a standardized tourniquet approach, it is likely that subtle tourniquet variation may have impacted the volume required to achieve vascular filling as well as amikacin concentrations achieved in tissues. We did not explore the use of an Esmarch bandage before tourniquet placement and IVRLP, which has been shown to prevent leakage in horses and people, but this could be explored in future work.34,36
We anticipated that vascular filling volume would depend on dog size. Surprisingly, we found that volumes were variable despite similar dog size. Normalized to body weight, injection volumes were larger at 0.9 mL/kg when compared with equine studies37 (approx 0.1 to 0.2 mL/kg). However, given the larger proportion of muscle mass in the canine pelvic limb compared to the equine distal limb, volume and pressure comparisons may not be relevant. The importance of perfusate volume in IVRLP is unclear as several equine studies19,37 demonstrated that perfusate volume has no impact on synovial antibiotic concentrations, whereas other studies35,38 demonstrated increased antibiotic concentration with increased perfusate volume. Despite widespread study in horses, a variety of volumes, tourniquet types, and limb preparations have been described.18
Venous pressure was monitored during the evaluation of limb contrast venograms to help determine effective perfusion volume. Although it is unclear if perfusion pressure or drug concentration gradient is key for driving antibiotic diffusion, perfusion pressures in the study dogs were similar to those described in horses.29,38,39 Monitoring intravascular pressure during IVRLP administration with a standard invasive blood pressure monitoring as reported in this study was technically simple and may be useful clinically to maintain a safe pressure while optimizing vascular filling and drug dose.
There are limitations to consider when interpreting our results. This was an exploratory, in vivo experimental study, and sample size was limited, consistent with similar equine IVRLP research. A single breed was studied, so extrapolation to other dog sizes and conformations may impact the optimal dose and drug metabolism.33 Normal dogs were studied, which may not represent an accurate clinical target as equine studies40 demonstrated that increased drug distribution in infected or inflamed joints is altered. There was a necessary COVID-19–related delay between perfusion of the first 6 and last 6 dogs, which may have impacted our findings as samples from the initial dogs were stored at −80 °C for some time before analysis. While this storage method was used in prior studies30 and approved by the laboratory, the duration of stability was outside the scope of this study and may represent additional variation. Finally, while the commercial amikacin assay has been validated for serum and synovial fluid, the protocol used to create a cell-free sample of bone marrow was based on consultation with a biochemist collaborator at our university and has not been validated for this assay. Amikacin concentration measurement over time was also not possible due to limitations in repeated collection of sufficient joint fluid for analysis; therefore, more work is needed to understand the longevity of this approach in dogs.
In conclusion, this study describes the effective development of a canine IVRLP technique by extrapolation from equine research. The perfusate dosage used to achieve increased synovial antimicrobial concentrations serves as a starting point for future research and clinical application. The use of infusion pressure monitoring and contrast radiography may help guide individual case management. Amikacin concentrations obtained in local tissues exceeded the clinical recommendation based on the MIC90 reported for a common canine bacterial isolate (S pseudintermedius) in some dogs while maintaining relatively low systemic concentrations. Variation between dogs suggests that further methodological refinement is needed. In our study, IVRLP was not as consistent as previously described within horses, but with refinement it may represent a promising local approach to combat challenging infections in dogs.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
Acknowledgments
The authors would like to acknowledge the assistance of Henry Benchimol for his technical assistance through the study period as well as Dr. Peter Muir for his expertise and critique throughout the study process.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the composition of this manuscript.
Funding
This project was funded by the Veterinary Orthopedic Society.
ORCID
Tatiana H. Ferreira https://orcid.org/0000-0002-4199-3948
Jason A. Bleedorn https://orcid.org/0000-0003-2987-7722
References
- 1.↑
Gallagher AD, Mertens WD. Implant removal rate from infection after tibial plateau leveling osteotomy in dogs. Vet Surg. 2012;41(6):705–711. doi:10.1111/j.1532-950X.2012.00971.x
- 2.
Priddy NH II, Tomlinson JL, Dodam JR, Hornbostel JE. Complications with and owner assessment of the outcome of tibial plateau leveling osteotomy for treatment of cranial cruciate ligament rupture in dogs: 193 cases (1997-2001). J Am Vet Med Assoc. 2003;222(12):1726–1732. doi:10.2460/javma.2003.222.1726
- 3.↑
Bennett D, Taylor D. Bacterial infective arthritis in the dog. J Small Anim Pract. 1988;29(4):207–230. doi:10.1111/j.1748-5827.1988.tb02278.x
- 4.↑
Smith RL, Schurman DJ. Bacterial arthritis: a staphylococcal proteoglycan-releasing factor. Arthritis Rheum. 1986;29(11):1378–1386. doi:10.1002/art.1780291111
- 5.↑
Smith RL, Schurman DJ. Comparison of cartilage destruction between infectious and adjuvant arthritis. J Orthop Res. 1983;1(2):136–143. doi:10.1002/jor.1100010204
- 6.↑
Nazarali A, Singh A, Moens NM, et al. Association between methicillin-resistant Staphylococcus pseudintermedius carriage and the development of surgical site infections following tibial plateau leveling osteotomy in dogs. J Am Vet Med Assoc. 2015;247(8):909–916. doi:10.2460/javma.247.8.909
- 7.↑
Nicoll C, Singh A, Weese JS. Economic impact of tibial plateau leveling osteotomy surgical site infection in dogs. Vet Surg. 2014;43(8):899–902. doi:10.1111/j.1532-950X.2014.12175.x
- 8.↑
Weese JS. A review of post-operative infections in veterinary orthopaedic surgery. Vet Comp Orthop Traumatol. 2008;21(2):99–105. doi:10.3415/vcot-07-11-0105
- 9.↑
Weese JS. A review of multidrug resistant surgical site infections. Vet Comp Orthop Traumatol. 2008;21(1):1–7. doi:10.3415/VCOT-07-11-0106
- 10.↑
Jenkins A, Thomson AH, Brown NM, et al. Amikacin use and therapeutic drug monitoring in adults: do dose regimens and drug exposures affect either outcome or adverse events? A systematic review. J Antimicrob Chemother. 2016;71(10):2754–2759. doi:10.1093/jac/dkw250
- 11.↑
Peterson LC, Kim SE, Lewis DD, Johnson MD, Ferrigno CRA. Calcium sulfate antibiotic-impregnated bead implantation for deep surgical site infection associated with orthopedic surgery in small animals. Vet Surg. 2021;50(4):748–757. doi:10.1111/vsu.13570
- 12.
Clements DN, Owen MR, Mosley JR, Carmichael S, Taylor DJ, Bennett D. Retrospective study of bacterial infective arthritis in 31 dogs. J Small Anim Pract. 2005;46(4):171–176. doi:10.1111/j.1748-5827.2005.tb00307.x
- 13.↑
Werner LA, Hardy J, Bertone AL. Bone gentamicin concentration after intra-articular injection or regional intravenous perfusion in the horse. Vet Surg. 2003;32(6):559–565. doi:10.1111/j.1532-950x.2003.00559.x
- 14.↑
Rand BC, Penn-Barwell JG, Wenke JC. Combined local and systemic antibiotic delivery improves eradication of wound contamination: an animal experimental model of contaminated fracture. Bone Joint J. 2015;97-B(10):1423–1427. doi:10.1302/0301-620X.97B10.35651
- 15.↑
Hewes CA, Macintire DK. Intra-articular therapy to treat septic arthritis in a dog. J Am Anim Hosp Assoc. 2011;47(4):280–284. doi:10.5326/JAAHA-MS-5667
- 16.↑
Ham K, Griffon D, Seddighi M, Johnson AL. Clinical application of tobramycin-impregnated calcium sulfate beads in six dogs (2002-2004). J Am Anim Hosp Assoc. 2008;44(6):320–326. doi:10.5326/0440320
- 17.↑
Rubio-Martínez LM, Cruz AM. Antimicrobial regional limb perfusion in horses. J Am Vet Med Assoc. 2006;228(5):706–655. doi:10.2460/javma.228.5.706
- 18.↑
Biasutti SA, Cox E, Jeffcott LB, Dart AJ. A review of regional limb perfusion for distal limb infections in the horse. Equine Vet Educ. 2021;33(5):263–277. doi:10.1111/eve.13243
- 19.↑
Redding LE, Elzer EJ, Ortved KF. Effects of regional limb perfusion technique on concentrations of antibiotic achieved at the target site: a meta-analysis. PLoS One. 2022;17(4):e0265971. doi:10.1371/journal.pone.0265971
- 20.
Errico JA, Trumble TN, Bueno AC, Davis JL, Brown MP. Comparison of two indirect techniques for local delivery of a high dose of an antimicrobial in the distal portion of forelimbs of horses. Am J Vet Res. 2008;69(3):334–342. doi:10.2460/ajvr.69.3.334
- 21.↑
Murphey ED, Santschi EM, Papich MG. Regional intravenous perfusion of the distal limb of horses with amikacin sulfate. J Vet Pharmacol Ther. 1999;22(1):68–71. doi:10.1046/j.1365-2885.1999.00180.x
- 22.↑
Rubin JE, Ball KR, Chirino-Trejo M. Antimicrobial susceptibility of Staphylococcus aureus and Staphylococcus pseudintermedius isolated from various animals. Can Vet J. 2011;52(2):153–157.
- 23.↑
Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk and Dilution Susceptibility Tests for Bacteria Isolated from Animals. 6th ed. Clinical and Laboratory Standards Institute; 2023.
- 24.↑
Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987;155(1):93–99. doi:10.1093/infdis/155.1.93
- 25.↑
Westgate SJ, Percival SL, Knottenbelt DC, Clegg PD, Cochrane CA. Microbiology of equine wounds and evidence of bacterial biofilms. Vet Microbiol. 2011;150(1–2):152–159. doi:10.1016/j.vetmic.2011.01.003
- 26.↑
Finsterbusch A, Argaman M, Sacks T. Bone and joint perfusion with antibiotics in the treatment of experimental staphylococcal infection in rabbits. J Bone Joint Surg Am. 1970;52(7):1424–1432.
- 27.↑
Whitehair KJ, Bowersock TL, Blevins WE, Fessler JF, White MR, Van Sickle DC. Regional limb perfusion for antibiotic treatment of experimentally induced septic arthritis. Vet Surg. 1992;21(5):367–373. doi:10.1111/j.1532-950x.1992.tb01713.x
- 28.↑
Abrams BE, Hottinger H, Selmic LE. Use of regional limb perfusion with amikacin sulphate in the treatment of a severe soft tissue infection in the extremity of a dog. Vet Rec Case Rep. 2019;7(1):e000777. doi:10.1136/vetreccr-2018-000777
- 29.↑
Levine DG, Epstein KL, Ahern BJ, Richardson DW. Efficacy of three tourniquet types for intravenous antimicrobial regional limb perfusion in standing horses. Vet Surg. 2010;39(8):1021–1024. doi:10.1111/j.1532-950X.2010.00732.x
- 30.↑
Kilcoyne I, Nieto JE, Knych HK, Dechant JE. Time required to achieve maximum concentration of amikacin in synovial fluid of the distal interphalangeal joint after intravenous regional limb perfusion in horses. Am J Vet Res. 2018;79(3):282–286. doi:10.2460/ajvr.79.3.282
- 31.↑
Caron JP, Bolin CA, Hauptman JG, Johnston KA. Minimum inhibitory concentration and postantibiotic effect of amikacin for equine isolates of methicillin-resistant Staphylococcus aureus in vitro. Vet Surg. 2009;38(5):664–669. doi:10.1111/j.1532-950X.2009.00551.x
- 32.↑
Ruiz J, Ramirez P, Company MJ, et al. Impact of amikacin pharmacokinetic/pharmacodynamic index on treatment response in critically ill patients. J Glob Antimicrob Resist. 2018;12:90–95. doi:10.1016/j.jgar.2017.09.019
- 33.↑
KuKanich B, Coetzee JF. Comparative pharmacokinetics of amikacin in Greyhound and Beagle dogs. J Vet Pharmacol Ther. 2008;31(2):102–107. doi:10.1111/j.1365-2885.2008.00938.x
- 34.↑
Sole A, Nieto JE, Aristizabal FA, Snyder JR. Effect of emptying the vasculature before performing regional limb perfusion with amikacin in horses. Equine Vet J. 2016;48(6):737–740. doi:10.1111/evj.12501
- 35.↑
Oreff GL, Dahan R, Tatz AJ, Raz T, Britzi M, Kelmer G. The effect of perfusate volume on amikacin concentration in the metacarpophalangeal joint following cephalic regional limb perfusion in standing horses. Vet Surg. 2016;45(5):625–630. doi:10.1111/vsu.12490
- 36.↑
Alkabes SB, Adams SB, Moore GE, Alkabes KC. Comparison of two tourniquets and determination of amikacin sulfate concentrations after metacarpophalangeal joint lavage performed simultaneously with intravenous regional limb perfusion in horses. Am J Vet Res. 2011;72(5):613–619. doi:10.2460/ajvr.72.5.613
- 37.↑
Jurek KA, Schoonover MJ, Williams MR, Rudra P. Effect of perfusate volume on amikacin concentrations after saphenous intravenous regional limb perfusion in standing, sedated horses. Vet Surg. 2022;51(4):665–673. doi:10.1111/vsu.13789
- 38.↑
Godfrey JL, Hardy J, Cohen ND. Effects of regional limb perfusion volume on concentrations of amikacin sulfate in synovial and interstitial fluid samples from anesthetized horses. Am J Vet Res. 2016;77(6):582–588. doi:10.2460/ajvr.77.6.582
- 39.↑
Moser DK, Schoonover MJ, Holbrook TC, Payton ME. Effect of regional intravenous limb perfusate volume on synovial fluid concentration of amikacin and local venous blood pressure in the horse. Vet Surg. 2016;45(7):851–858. doi:10.1111/vsu.12521
- 40.↑
Taintor J, Schumacher J, DeGraves F. Comparison of amikacin concentrations in normal and inflamed joints of horses following intra-articular administration. Equine Vet J. 2006;38(2):189–191. doi:10.2746/042516406776563233
