Evaluation of the usage of incisional liposomal bupivacaine as a local anaesthetic for dogs undergoing limb amputation

Abstract Background Bupivacaine lioposomal suspension has recently emerged in the veterinary field for local analgesia. Objective To describe the extra‐label administration of bupivacaine liposomal suspension at the incision site of dogs undergoing limb amputation and characterize any complications. Study Design Nonblinded retrospective study. Animals Client‐owned dogs undergoing limb amputation from 2016 to 2020. Methods Medical records of dogs undergoing limb amputation with concurrent use of long‐acting liposomal bupivacaine suspension were reviewed for incisional complications, adverse effects, hospitalization length, and time to alimentation. Data were compared to a control group (CG) of dogs who underwent a limb amputation procedure without concurrent use of liposomal bupivacaine suspension. Results Forty‐six dogs were included in the liposomal bupivacaine group (LBG) and 44 cases in the CG. The CG had 15 incidences of incisional complications (34%) compared to 6 within the LBG (13%). Four dogs required revisional surgery in the CG (9%) whereas none of the dogs required revisional surgery in the LBG. Time from surgery to discharge was statistically higher in the CG compared to the LBG (p = 0.025). First time to alimentation was statistically higher in the CG (p value = 0.0002). The total number of rechecks needed postoperatively revealed the CG having a statistically significant increase in recheck evaluations (p = 0.001). Conclusions Extra‐label administration of liposomal bupivacaine suspension was well‐tolerated in dogs undergoing limb amputation. Liposomal bupivacaine usage did not increase incisional complication rates and its use allowed for a quicker time to discharge. Clinical significance Surgeons should consider inclusion of extra‐label administration of liposomal bupivacaine in analgesic regimens for dogs undergoing limb amputation.


INTRODUCTION
A multimodal analgesic approach to perioperative pain control has become the standard of care in veterinary orthopaedic surgery. Currently there are many analgesic techniques utilised in dogs undergoing orthopaedic surgery including epidural analgesic administration (Marucio et al., 2014;Odette & Smith, 2013;Smith & Yu, 2001) intraarticular analgesic infusion (Soto et al., 2014;Gurney & Leece, 2014;Dutton et al., 2014), intraperitoneal administration (Costa et al., 2019), continuous rate intravenous infusion of analgesics (Wagner, 2002;Steagall et al., 2006) and oral analgesic administration (Wagner, 2002;Cardozo et al., 2014;Davila et al., 2013). Regional analgesic methods are a very attractive form of perioperative analgesia, as many of the side effects of systemic opioid analgesics can be avoided or decreased (Carpenter et al., 2004;Wolfe et al., 2006;Abelson et al., 2009;Lemke & Dawson, 2000). Opioids have traditionally been the analgesic class used most commonly for orthopaedic surgery but are known to cause undesirable postoperative side effects such as dysphoria (Becker et al., 2013;Kongara, 2018), gastrointestinal dysfunction such as ileus (Brock et al., 2012;Johnson, 1981), disruption of temperature regulation (Adler et al., 1988) and even adverse immunomodulatory effects (Odunayo et al., 2010). Consequently, efficacious and safe alternatives for postoperative analgesia are continuously sought in veterinary medicine.
A bupivacaine liposomal injectable suspension (LBS) has previously emerged in human medicine as an adjunctive method of multimodal analgesic approach in the postoperative period. Studies comparing LBS to traditional nonliposomal local analgesics have shown superior efficacy of the liposomal bupivacaine in surgery (Barrington et al., 2017;Johnson et al., 2017). A study reviewing LBS used in patients undergoing total knee arthroplasty revealed that its use significantly reduced postoperative pain, opioid consumption, and time to first opioid rescue administration, without any safety concerns (Barnes et al., 2020). A review article of LBS use in plastic and reconstructive surgery revealed it to be efficacious, allowed for a decrease in hospitalisation time, and showed no serious adverse incisional effects with its use (Vyas et al., 2016). In addition, the need for opioid use in the immediate postoperative period was significantly lower than in the control group in people undergoing orthopaedic surgery with no increased risk of wound complications (Robbins et al., 2015).
LBS has been recently introduced into the veterinary field, specifically for postoperative analgesia use in dogs undergoing stifle surgery (Nocita, 2018). Previous studies have shown that dogs undergoing stifle surgery responded favourably to the use of incisional liposomal buivacaine (Reader et al., 2020;Lascelles & Kirkby Shaw, 2016 The purpose of this study was to evaluate the extra-label use of LBS as a local incisional and subepineural block in dogs undergoing limb amputation and to evaluate for any possible complications. The amount of analgesia required postoperatively and first time to alimentation and hospitalisation length will be investigated concurrently. The authors hypothesise that the use of LBS within incisional closing layers and subepineurally will not be associated with an increase in incidence of incisional complications outside of those previously published.

Statistical analysis
Normally distributed variables were summarised as means (standard deviation), skewed variables as median (range)

RESULTS
A total of 49 cases were identified in which LBS was used concurrently with a limb amputation procedure. Data were available for all but three of the cases that had incomplete records and were subsequently excluded from the study for a total of 46 cases included in LBG. A total of 44 cases were identified within the CG ranges. The average age of the dogs in the LBG was 8.9 ± 2.7 years (range 2 years to 15 years) and 7.6 ± 2.7 years (range 1.9 years to 12.4 years) for the CG. There There were a higher number of patients who received an epidural within the CG (n = 12) compared to the LBG (n = 1). Patients in the control group were kept on continuous rate infusions of analgesic medication for a higher average length in hours compared to the liposomal bupivacaine group that was statistically significant (p = 0.0001).
The number of continuous rate infusions was also statistically higher in the control group compared to the liposomal bupivacaine group (p = 0.0007).
Other parameters that were evaluated included the length in time from surgery to discharge between the groups which was statistically higher in the control group (

DISCUSSION
Results of the present study reveal that there was no increase in postoperative incisional complications with use of LBS as a local incisional and peri-neural peripheral block for limb amputation procedures compared to the internal control group. The rate of incisional complications in patients with use of LBS was 13%, which is comparable to previously reported incisional complication rates evaluated in dogs with limb amputation procedures of 12.8% (Lascelles & Kirkby Shaw, 2016).
Although not statistically significant, the percentage of incisional complications observed in the LBG was more than halved when compared to the internal control group rate of 34%. Additionally, none of the incisional complications noted in the LBG required revisional surgery, whereas 9% of patients within the control group had to undergo revisional surgery.
LBS is labelled to provide locoregional postoperative analgesia for up to 72 h post administration at the site of injection (Robbins et al., 2015). Currently there are two veterinary studies showing LBS to be highly efficacious in local pain management in stifle surgery (Nocita, 2018;Reader et al., 2020). The half-life of bupivacaine is 4.8 h compared to LBS which is 36.2 h (Raske et al., 2015). The higher incidence of incisional complications in this study control group could be theorised to be correlated with discomfort postoperatively after discharge from hospital. When evaluating postoperative communications performed as early as 24 h after discharge through the first recheck examination in our study population, it was noted that owners in the control group were noted to have an increase in reported active attempts to lick or chew at the incision. It could be extrapolated that liposomal bupivacaine, due to its longer length of action of up to 72 h could prevent attention to incision during the inflammatory phase of wound healing.
Previous studies have shown that patients that have been provided adequate analgesia within the first three days postoperatively have lower pain scoring but do not differ after 72 h (Costa et al., 2019).
Opioid usage in the postoperative setting can be associated with numerous negative side effects, amongst which include decreased gastrointestinal motility (Reid et al., 2007;Mehendale & Yuan, 2006) and dysphoria (Lemke & Dawson, 2000;Russell et al., 1982). The use of liposomal bupivacaine has previously shown to decrease the amount of opioid treatments while in hospital (Nocita, 2018). These findings were also found in our study population as the number and length of hours of continuous rate infusions used were significantly lower in the liposomal bupivacaine group compared to the control. Recovery quality has been previously assessed in dogs using an opioid model consisting of fentanyl versus other nerve blockage (epidural, peripheral nerve block) which revealed a significant worsening of recovery quality in those in the opioid group (Garofalo et al., 2012). A set of patients in the liposomal bupivacaine group were managed without continuous rate infusions consisting of opioids, with intermittent opioid administration used postoperatively. Many of these patients only received one dose immediately postoperatively with quick transition to oral analgesics.
This could account for the decrease in undesirable opioid effects within the liposomal group, which could account for the quicker time to first alimentation and discharge compared to the control group.
The data revealing time to first alimentation further supports this as the control group was statistically noted to have their first alimentation much later postoperatively (average 15.3 h) than the liposomal bupivacaine group (average 9.6 h) or did not eat at all in hospital (n = 13 CG; n = 2 LBG).
Inherent limitations were present due to the retrospective nature of this study. The lack of standardisation of analgesic medication and reasons for selection of specific analgesic protocols was not specifically relayed in clinical records and suspected surgeon dependent.
The most significant and major limitation was that no statements could be made on efficacy as pain scoring was only present in 32% of patients in the control group and could not be directly compared with the liposomal bupivacaine group. This discrepancy reflects changes in hospital policy with implementation of consistent pain scoring in postoperative patients during the course of the study. When reviewing pain scores for the liposomal bupivacaine group using the Colorado State University Canine Acute Pain Assessment scoring system (Romano et al., 2016), all recorded values were below the threshold for reevaluation for rescue analgesia of ≥ 2 signifying mild to moderate pain (Romano et al., 2016). In order to comment on efficacy however, a prospective, blinded, clinical trial would be required to fully evaluate LBS efficacy on pain response using pain scoring.
From the results of this study, we can conclude that the extralabel administration of LBS was well-tolerated and effective in dogs undergoing limb amputation. LBS usage did not increase incisional complication rates and its use allowed for a generalised decrease in opioid usage and quicker time to discharge. To the authors knowledge this is the first published used of subepineural liposomal bupivacaine in amputations. A separate prospective, blinded, clinical trial would be required to fully evaluate LBS efficacy on pain response using pain scoring. Although not to be used as a sole analgesic modality, there are many potential uses for LBS as a local incisional analgesic that warrants further study.