IV Regional Limb Perfusion Research Articles

Faster perfusate instillation time results in more systemic leakage of amikacin sulfate when performing intravenous regional limb perfusion in horses.

To evaluate if a difference in synovial amikacin concentrations exists in the radiocarpal joint (RCJ) following different durations of instillation of an IV regional limb perfusion (IVRLP) perfusate. 7 healthy horses. Horses received 2 IVRLPs with 2 g amikacin diluted to 60 mL with 0.9% NaCl via the cephalic vein in a crossover study design with a wash-out period between procedures. Instillation of the perfusate was administered over a 1-minute (technique 1) and 5-minute (technique 5) period. Concentrations of amikacin within the RCJ were measured at time (T) 5, 10, 15, 20, 25, and 30 minutes after instillation of the perfusate. Systemic concentrations of amikacin were measured at T0, 5, 10, 15, 20, 25, 29 minutes, and 1 minute after tourniquet removal (T31). Amikacin concentrations were determined by fluorescence polarization immunoassay. The median maximum concentration (CMAX) of amikacin within the RCJ for technique 1 was 338.4 µg/mL (range, 60 to 4,925 µg/mL), while the median CMAX for technique 5 was higher at 694.8 µg/mL (range, 169.2 to 3,410 µg/mL; P = .398). There was a higher amikacin blood concentration over time for technique 1 compared to technique 5 (P = .004). Administration of perfusate at different rates did not significantly affect synovial concentration of amikacin within the RCJ when performing IVRLP. However, increased systemic leakage was noted when the perfusate was administered over 1 minute, which might affect synovial concentrations in a larger group of horses.

Increasing tourniquet number has no effect on amikacin concentration within the radiocarpal joint in horses undergoing intravenous regional limb perfusion.

To determine whether IV regional limb perfusion (IVRLP) performed in the cephalic vein with a wide rubber tourniquet (WRT) applied proximal and distal to the carpus results in a higher peak concentration (Cmax) of amikacin in the radiocarpal joint (RCJ), compared with the Cmax for IVRLP using a single WRT proximal to the carpus. 7 healthy adult horses. Horses underwent IVRLP using standing sedation with 2 g of amikacin sulfate diluted to 60 mL by use of saline (0.9% NaCl) solution in the cephalic vein with 2 different tourniquet techniques; proximal WRT (P) and proximal and distal WRT (PD). Synovial fluid was collected from the RCJ at 5, 10, 15, 20, 25, and 30 minutes after IVRLP. Tourniquets were removed after the 30-minute sample was collected. Blood samples from the jugular vein were collected at 5, 10, 15, 20, 25, 29, and 31 minutes after IVRLP. Amikacin concentration was quantified by a fluorescence polarization immunoassay. Median peak concentration (Cmax) of amikacin and time to maximum drug concentration (Tmax) within the RCJ were determined. Median peak concentration in the RCJ was 1331.4 μg/mL with technique P and 683.1 μg/mL with technique PD. Median Tmax occurred at 30 minutes with technique P and 25 minutes with technique PD. No significant (Cmax, P = 0.18; Tmax, P = 0.6) difference in amikacin Cmax or Tmax between techniques was detected. Placement of 2 WRTs offers no advantage to a single proximal WRT when performing IVRLP to deliver maximal amikacin concentrations to the RCJ using IVRLP.

Time required to achieve maximum amikacin concentration in the synovial fluid of the tarsocrural joint following administration of the drug by intravenous regional limb perfusion in horses.

To determine the median time to maximum concentration (tmax) of amikacin in the synovial fluid of the tarsocrural joint following IV regional limb perfusion (IVRLP) of the drug in a saphenous vein of horses. 7 healthy adult horses. With each horse sedated and restrained in a standing position, a 10-cm-wide Esmarch tourniquet was applied to a randomly selected hind limb 10 cm proximal to the point of the tarsus. Amikacin sulfate (2 g diluted with saline [0.9% NaCl] solution to a volume of 60 mL) was instilled in the saphenous vein over 3 minutes with a peristaltic pump. Tarsocrural synovial fluid samples were collected at 5, 10, 15, 20, 25, and 30 minutes after completion of IVRLP. The tourniquet was removed after collection of the last sample. Amikacin concentration was quantified by a fluorescence polarization immunoassay. Median maximum amikacin concentration and tmax were determined. 1 horse was excluded from analysis because an insufficient volume of synovial fluid for evaluation was obtained at multiple times. The median maximum synovial fluid amikacin concentration was 450.5 μg/mL (range, 304.7 to 930.7 μg/mL), and median tmax was 25 minutes (range, 20 to 30 minutes). All horses had synovial fluid amikacin concentrations ≥ 160 μg/mL (therapeutic concentration for common equine pathogens) at 20 minutes after IVRLP. Results suggested that, in healthy horses, maintaining the tourniquet for 20 minutes after IVRLP of amikacin in a saphenous vein was sufficient to achieve therapeutic concentrations of amikacin in the tarsocrural joint.

Tarsocrural joint polymyxin B concentrations achieved following intravenous regional limb perfusion of the drug via a saphenous vein to healthy standing horses.

To determine whether therapeutic concentrations (> 0.5 to 1.0 μg/mL) of polymyxin B (PB) were achieved in the tarsocrural joint of horses when the drug was administered by IV regional limb perfusion (IV-RLP) via a saphenous vein at doses of 25, 50, and 300 mg and to describe any adverse systemic or local effects associated with such administration. 9 healthy adult horses. In the first of 2 experiments, 6 horses each received 25 and 50 mg of PB by IV-RLP via a saphenous vein with at least 2 weeks between treatments. For each treatment, a tourniquet was placed at the midmetatarsus and another was placed midway between the stifle joint and tarsus. Both tourniquets were removed 30 minutes after the assigned dose was administered. Blood and tarsocrural joint fluid samples were collected for determination of PB concentration before and at predetermined times after drug administration. In experiment 2, 4 horses were administered 300 mg of PB by IV-RLP in 1 randomly selected pelvic limb in a manner identical to that used in experiment 1. For all 3 doses, the mean synovial fluid PB concentration was > 10 times the therapeutic concentration and below the level of quantification at 30 and 1,440 minutes after drug administration, respectively. No adverse systemic or local effects were observed following PB administration. Results suggested that IV-RLP of PB might be a viable alternative for treatment of horses with synovial infections caused by gram-negative bacteria.

Time required to achieve maximum concentration of amikacin in synovial fluid of the distal interphalangeal joint after intravenous regional limb perfusion in horses.

OBJECTIVE To determine the maximum concentration (Cmax) of amikacin and time to Cmax (Tmax) in the distal interphalangeal (DIP) joint in horses after IV regional limb perfusion (IVRLP) by use of the cephalic vein. ANIMALS 9 adult horses. PROCEDURES Horses were sedated and restrained in a standing position and then subjected to IVRLP (2 g of amikacin sulfate diluted to 60 mL with saline [0.9% NaCl] solution) by use of the cephalic vein. A pneumatic tourniquet was placed 10 cm proximal to the accessory carpal bone. Perfusate was instilled with a peristaltic pump over a 3-minute period. Synovial fluid was collected from the DIP joint 5, 10, 15, 20, 25, and 30 minutes after IVRLP; the tourniquet was removed after the 20-minute sample was collected. Blood samples were collected from the jugular vein 5, 10, 15, 19, 21, 25, and 30 minutes after IVRLP. Amikacin was quantified with a fluorescence polarization immunoassay. Median Cmax of amikacin and Tmax in the DIP joint were determined. RESULTS 2 horses were excluded because an insufficient volume of synovial fluid was collected. Median Cmax for the DIP joint was 600 μg/mL (range, 37 to 2,420 μg/mL). Median Tmax for the DIP joint was 15 minutes. CONCLUSIONS AND CLINICAL RELEVANCE Tmax of amikacin was 15 minutes after IVRLP in horses and Cmax did not increase > 15 minutes after IVRLP despite maintenance of the tourniquet. Application of a tourniquet for 15 minutes should be sufficient for completion of IVRLP when attempting to achieve an adequate concentration of amikacin in the synovial fluid of the DIP joint.

Effects of regional limb perfusion volume on concentrations of amikacin sulfate in synovial and interstitial fluid samples from anesthetized horses.

OBJECTIVE To evaluate the effect of volume of IV regional limb perfusion (IVRLP) on amikacin concentrations in synovial and interstitial fluid of horses. ANIMALS 8 healthy adult horses. PROCEDURES Each forelimb was randomly assigned to receive IVRLP with 4 mL of amikacin sulfate solution (250 mg/mL) plus 56 mL (total volume, 60 mL) or 6 mL (total volume, 10 mL) of lactated Ringer solution. Horses were anesthetized, and baseline synovial and interstitial fluid samples were collected. A tourniquet was placed, and the assigned treatment was administered via the lateral palmar digital vein. Venous blood pressure in the distal portion of the limb was recorded. Additional synovial fluid samples were collected 30 minutes (just before tourniquet removal) and 24 hours after IVRLP began; additional interstitial fluid samples were collected 6 and 24 hours after IVRLP began. RESULTS 30 minutes after IVRLP began, mean amikacin concentration in synovial fluid was significantly greater for the large-volume (459 μg/mL) versus small-volume (70 μg/mL) treatment. Six hours after IVRLP, mean concentration in interstitial fluid was greater for the large-volume (723 μg/mL) versus small-volume (21 μg/mL) treatment. Peak venous blood pressure after large-volume IVRLP was significantly higher than after small-volume IVRLP, with no difference between treatments in time required for pressure to return to baseline. CONCLUSIONS AND CLINICAL RELEVANCE Study findings suggested that large-volume IVRLP would deliver more amikacin to metacarpophalangeal joints of horses than would small-volume IVRLP, without a clinically relevant effect on local venous blood pressure, potentially increasing treatment efficacy.

Quantitative assessment of two methods of tiludronate administration for the treatment of lameness caused by navicular syndrome in horses.

To determine effects of 2 tiludronate administration protocols on measures of lameness in horses with navicular syndrome (NS). 12 horses with bilateral forelimb NS. Horses were randomly assigned to receive tiludronate (1 mg/kg), diluted in 5 L of isotonic electrolyte solution and delivered through a jugular vein catheter (systemic treatment group; n = 6), or tiludronate (0.1 mg/kg), diluted with saline (0.9% NaCl) solution to a total volume of 35 mL and delivered into the lateral digital vein of each forelimb with an IV regional limb perfusion (IVRLP) technique (IVRLP group; 6). Mean peak vertical ground reaction force (pVGRF) measured with a stationary force plate and subjective lameness scores (SLSs) were recorded before (day -1) and at predetermined time points after tiludronate administration on day 0. Mean pVGRFs (standardized as percentage body weight of force) and mean SLSs for the most lame forelimb and for both forelimbs of horses in each group were compared with day -1 values to determine treatment effect. Mean pVGRF for both forelimbs and for the most lame forelimbs of systemically treated horses were significantly increased on days 120 and 200, compared with day -1 results. No significant difference in mean pVGRF was observed for IVRLP-treated horses. The SLSs were not improved at any time point following systemic treatment and were improved only on day 120 following IVRLP. Tiludronate (1 mg/kg, IV) as a single systemic treatment appeared to be beneficial for horses with NS, but no horses were judged as sound during the study period. Additional research on IVRLP with tiludronate is needed before this method can be recommended.

Effect of emptying the vasculature before performing regional limb perfusion with amikacin in horses

Emptying the vasculature with an Esmarch bandage before i.v. regional anaesthesia is commonly performed in human patients to prevent leakage of the solution under the tourniquet but there is no evidence for its efficacy in horses for antimicrobial i.v. regional limb perfusion (IV-RLP). To determine the effect on synovial fluid concentration of amikacin of emptying the vasculature before performing IV-RLP. Crossover experiment. Eight clinically healthy horses underwent 2 IV-RLP with amikacin in a randomised, crossover design. Horses received an IV-RLP with amikacin with or without exsanguination before applying a pneumatic tourniquet at the level of the forearm. Blood was collected from the jugular vein (before tourniquet removal) and synovial fluid from the radiocarpal and metacarpophalangeal joints (5 min after tourniquet removal and at 24 h) for amikacin determination. The procedure was video recorded to assess horse movement. There was no difference in amikacin concentrations in the plasma or synovial fluid from the radiocarpal joint between groups. There was a higher concentration of amikacin in the synovial fluid from the metacarpophalangeal joint immediately after tourniquet removal in the group with exsanguination of the limb prior to IV-RLP (mean ± s.d.: no exsanguination 49.7 ± 53.7 μg/ml, exsanguination 257.4 ± 149.7 μg/ml, P = 0.04). Horse movement did not differ significantly between groups. Emptying the vasculature with an Esmarch bandage before IV-RLP can improve amikacin concentrations in the metacarpophalangeal joint of horses with no effect on the levels of amikacin in the radiocarpal joint.

Clinical and pharmacokinetic effects of regional or general anaesthesia on intravenous regional limb perfusion with amikacin in horses

Antimicrobial i.v. regional limb perfusion (IV-RLP) is clinically performed on anaesthetised or sedated horses with or without regional anaesthesia. To date, no scientific data are available on the clinical and pharmacokinetic effects of these anaesthetic protocols on antimicrobial IV-RLP, which is believed to result in better tourniquet efficiency due to decreased movement. To determine the effects of regional or general anaesthesia on the clinical and synovial pharmacokinetic parameters of amikacin administered by IV-RLP to horses. Experimental crossover study. Eight healthy horses received 4 treatments of amikacin IV-RLP in a randomised, blinded, crossover design: standing sedation without regional anaesthesia (CNT); standing sedation with i.v. regional anaesthesia; standing sedation with perineural regional anaesthesia (PNA); or general anaesthesia. Synovial fluid amikacin concentrations were measured over 24 h and regional pharmacokinetic parameters calculated. Heart and respiratory rates, visual analogue scale of discomfort, number of times the limb was lifted and number of additional sedations administered were recorded. Analysis of variance crossover analysis was applied with significance level at P < 0.05. Amikacin concentrations and regional pharmacokinetic parameters did not differ significantly among treatments. Visual analogue scores (mean ± s.d.) were significantly lower with PNA (19 ± 15) vs. i.v. regional anaesthesia (69 ± 36) or CNT (81 ± 13; P < 0.001). Significantly less lifting of the limb (mean ± s.d.) occurred with PNA (20 ± 20) vs. CNT (54 ± 22; P < 0.04). Perineural regional anaesthesia before IV-RLP was most effective in providing comfort to standing, sedated horses without significantly affecting the regional pharmacokinetic parameters of amikacin. High variability of synovial amikacin concentrations was present. The use of general anaesthesia for IV-RLP is not justified based on this study.

Comparison of two tourniquets and determination of amikacin sulfate concentrations after metacarpophalangeal joint lavage performed simultaneously with intravenous regional limb perfusion in horses

To determine whether joint lavage performed simultaneously with IV regional limb perfusion (IVRLP) reduces the effectiveness of IVRLP and to compare 2 types of tourniquets used for this procedure in horses. 11 adult horses. 2 groups of 6 horses were tested by use of a pneumatic or an Esmarch tourniquet (1 horse was tested twice [once in each group]). Standing IVRLP with amikacin (500 mg) was performed for 30 minutes. Simultaneously, the metacarpophalangeal joint was lavaged with 2 L of lactated Ringer's solution and the egress fluids were collected. Samples of the distal interphalangeal joint synovial fluid and blood from the digital and jugular veins were collected at set time intervals. Amikacin concentrations in all fluids were determined via fluorescence polarization immunoassay. Less amikacin was measured in the systemic circulation with the Esmarch tourniquet than with the pneumatic tourniquet. Amikacin concentrations in the synovial fluid from the distal interphalangeal joints of the Esmarch tourniquet group ranged from 45.1 to 1,968 μg/mL and in the pneumatic tourniquet group ranged from 1.7 to 92.3 μg/mL after 30 minutes of IVRLP. Total loss of amikacin in the egress fluids from the joint lavage ranged from < 1.36 to 7.72 mg for the Esmarch tourniquet group and from < 1.20 to 1.75 mg for the pneumatic tourniquet group. On standing horses, IVRLP performed simultaneously with joint lavage resulted in negligible loss of amikacin in the egress lavage fluids. The Esmarch tourniquet was more effective in preventing loss of amikacin from the distal portion of the limb, easier to use, and less expensive than the pneumatic tourniquet.

Effect of topical application of 1% diclofenac sodium liposomal cream on inflammation in healthy horses undergoing intravenous regional limb perfusion with amikacin sulfate

To determine whether topical application of 1% diclofenac sodium cream would decrease inflammation at sites of IV regional limb perfusion (IVRLP) in healthy horses. 6 healthy adult horses (12 forelimbs). Bilateral IVRLP with 2.5 g of amikacin sulfate was performed twice in each horse, with 24 hours between each session. Horses were treated with topical 1% diclofenac liposomal cream (treated limbs) or a placebo cream (control limbs). All injection sites were evaluated before the first IVRLP session and 24 hours after the second session by means of ultrasonographic examination by a trained ultrasonographer who was unaware of the treatment received. Circumferential measurements and subjective visible inflammation scores were recorded by a veterinarian who was also unaware of treatment received. After IVRLP, control limbs had a significantly greater increase in subcutaneous thickness, compared with treated limbs. Ultrasonographic and visual assessment scores were significantly higher in control versus treated limbs. The mean change in limb circumference was greater, but not significantly so, in control limbs, compared with treated limbs. Topical application of 1% diclofenac sodium liposomal cream to sites of IVRLP in healthy horses decreased inflammation as judged by visual assessment and ultrasonography. Decreased inflammation may allow extended use of IVRLP and may result in a reduction in pain in treated horses.

Evaluation of safety and pharmacokinetics of vancomycin after intraosseous regional limb perfusion and comparison of results with those obtained after intravenous regional limb perfusion in horses

To evaluate the clinical effects and pharmacokinetics of vancomycin in plasma and synovial fluid after intraosseous regional limb perfusion (IORLP) in horses and to compare results with those obtained after IV regional limb perfusion (IVRLP). 6 horses. 1 forelimb of each horse received vancomycin hydrochloride (300 mg in 60 mL of saline [0.9% NaCl] solution) via IORLP; the contralateral limb received 60 mL of saline solution (control). Solutions were injected into the medullary cavity of the distal portion of the third metacarpal bone. Synovial fluid from the metacarpophalangeal (MTCP) and distal interphalangeal (DIP) joints and blood were collected prior to perfusion and 15, 30, 45, 65, and 90 minutes after beginning IORLP, and synovial fluid from the MTCP joint only and blood were collected 4, 8, 12, and 24 hours after beginning IORLP. Plasma urea and creatinine concentrations and clinical appearance of the MTCP joint region and infusion sites were determined daily for 7 days. Results were compared with those of a separate IVRLP study. Clinical complications were not observed after IORLP. Mean vancomycin concentration in the MTCP joint was 4 microg/mL for 24 hours after IORLP. Compared with IORLP, higher vancomycin concentrations were detected in the DIP joint after IVRLP. Compared with IVRLP, higher vancomycin concentrations were detected in the MTCP joint for a longer duration after IORLP. IORLP with 300 mg of vancomycin in a 0.5% solution was safe and may be clinically useful in horses. Intravenous and intraosseous routes may be better indicated for infectious processes in the DIP and MTCP joints, respectively.

Evaluation of safety and pharmacokinetics of vancomycin after intravenous regional limb perfusion in horses

To evaluate clinical variables, regional concentrations, and pharmacokinetics of vancomycin in the synovial fluid of distal forelimb joints of horses after IV regional limb perfusion. 6 horses. Vancomycin was administered via IV regional limb perfusion to the distal portion of the forelimbs of anesthetized horses. Drug (300 mg of vancomycin hydrochloride in 60 mL of saline [0.9% NaCl] solution) was infused into 1 forelimb, whereas the contralateral limb served as a control and was perfused with 60 mL of saline solution. Solutions were injected into the lateral digital vein after digital exsanguination. Synovial fluid from the metacarpophalangeal (MTCP) and distal interphalangeal (DIP) joints and systemic blood were collected prior to perfusion and 15, 30, 45, 65, and 90 minutes after initiation of the infusion. Synovial fluid from the MTCP joint and blood were also obtained at 4, 8, 12, and 24 hours after infusion. Plasma urea and creatinine concentrations, degree of lameness, and certain clinical variables involving the MTCP joint and infusion site were assessed for 7 days. Results were compared between the vancomycin treatment and control groups. No complications or significant differences in renal function, lameness, or clinical variables were observed between groups. Vancomycin concentrations exceeded 4 microg/mL in MTCP joints for approximately 20 hours. Higher concentrations were reached in DIP joints than in MTCP joints. IV regional limb perfusion with 300 mg of vancomycin as a 0.5% solution was safe and may be useful in horses as treatment for distal limb infections.