Newly developed techniques such as erector spinae block,1 quadratus lumborum block,2 or transverse abdominis block3 rely on the migration of local anesthetic along fascial planes. These infiltrations, however, may behave in an unpredictable way,4 and therefore, investigations of the interaction between the anatomy and the infiltration itself may provide a better understanding of the technique and thus increase their reliability, repeatability, and the overall success of these blocks.5–7
The transverse abdominis plane (TAP) block relies on the infiltration of local anesthetic in between the transverse abdominis and the internal oblique muscles of the abdominal wall. The rationale is that the local anesthetic will migrate and distribute along this fascial plane and come into contact with the peripheral nerves originated in the ventral branches of the relevant spinal nerves.8 The TAP block is most often clinically used to provide analgesia in surgical procedures involving the abdominal wall, such as celiotomies,9 or abdominal wall wound repairs.10 Veterinary clinical studies9,11–13 evaluating the efficacy and duration of the TAP block are scarce. Based on, Luis Campoy, LV, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, unpublished data, 2020, the analgesia provided by this block may start fading beyond 6 hours. In the search for an extended duration, the use of bilateral catheters placed in the transversus abdominis plane14 or the use of liposome-encapsulated suspensions of local anesthetic is gaining some traction.
In the study reported here, our goal was to compare the duration and analgesic quality of 0.25% bupivacaine mixed with 0.5 µg/mL dexmedetomidine as coadjuvant (BUP-DEX), with a commercial liposomal encapsulated bupivacaine formulation expanded with bupivacaine and dexmedetomidine as coadjuvant (BLS) and a negative control (CTRL) as part of a transverse abdominis plane (TAP) block in female shelter dogs undergoing elective ovariohysterectomy.
We hypothesized that the postoperative time to need rescue analgesia would happen later and abdominal wall desensitization would last longer following BLS infiltration, compared with BUP-DEX infiltration and that these results for the dogs in the 2 treatment groups would differ from those of the dogs in the CTRL group.
Materials and Methods
This study (protocol ID No. 111919-14) was approved by the Cornell University Veterinary Clinical Studies Committee. Twenty-six female mixed-breed shelter dogs scheduled for elective ovariohysterectomy performed by veterinary students at Cornell University Primary Care Surgery Service entered this prospective study between January 28 and December 8, 2020. The dogs were all classified as American Society of Anesthesiologists physical status15 1 or 2 based on results of physical examination and basic point of care blood work (PCV and concentration of total solids, glucose, BUN, and creatinine).
The candidate treatments were randomized (closed envelope) into 1 of 3 groups: BUP-DEX, BLS, or CTRL group. Dogs assigned to the BUP-DEX group received TAP block with 0.25% bupivacaine (0.5% Bupivacaine HCl Injection USP; Hospira) enhanced with dexmedetomidine (Dexdomitor; Zoetis) at 0.5 µg/mL (0.5% bupivacaine with 1 µg/mL dexmedetomidine was diluted with 0.9% saline [NaCl] solution [Sodium Chloride Injection; Hospira] in a 50:50 dilution) at a total injectate volume of 0.8 mL/kg. Dogs assigned to the BLS group received a TAP block with a bupivacaine liposome injectable suspension containing 13.3 mg/mL bupivacaine (Nocita; Elanco) at 0.4 mL/kg expanded with 0.5% bupivacaine potentiated with 1 µg/mL dexmedetomidine at 0.4 mL/kg. Dogs assigned to the CTRL group served as a negative controls and received no TAP block or sham treatment.
Anesthesia was standard and the same for all animals. Briefly, animals received oral omeprazole (Omeprazole Delayed Release; Apotex; 1 mg/kg, PO) and maropitant (Cerenia; Zoetis; 2 mg/kg, PO) the evening prior to their procedure. Premedication consisted of a combination of dexmedetomidine (3 µg/kg, IM) and hydromorphone (Baxter Healthcare; 0.1 mg/kg, IM). Anesthesia was induced with propofol (PropoFlo; Abbott Laboratories) to effect until optimal intubating conditions were achieved. Following endotracheal intubation, anesthesia was maintained with isoflurane (Isoflurane USP; Phoenix Pharmaceutical) in oxygen (Fio2 = 1) delivered through a circle system and mechanically ventilated to maintain normocapnia (Petco2 between 35 and 40 mm Hg). Routine basic patient monitoring (Cardell Touch; Veterinary Monitor; Midmark Corporation) included pulse oximetry, capnography, ECG, noninvasive blood pressure measurements, and esophageal temperature measurements.
At time 0, following aseptic preparation of the abdominal wall and with the dog already in dorsal recumbency, an ultrasound-guided TAP block was carried out for each dog using an ultrasound machine (Sonosite Edge; Fujifilm Sonosite) and a high-frequency (12- to15-MHz) linear array transducer (HFL50; Fujifilm Sonosite). With the transducer oriented in a caudocranial direction and as abaxial as possible from midline, a 21-gauge X 100-mm insulated needle (NB2110; Mila International) was introduced in-plane. The puncture site was located cranial to the iliac crest. The target intermuscular plane was defined as immediately deep to the fascia located on the surface of the transverse abdominis plane. Hydrodissection of the correct muscular plane was confirmed using an initial test dose of the allocated treatment injectate (between 0.5 and 1 mL per dog, with the lower volumes used in the smaller dogs). The needle was advanced in a cephalad direction as the tissue was being hydrodissected so that when the injection was complete, most of the needle shaft was located within the appropriate muscular plane. The length of the needle introduced varied with the dog size. The same technique was performed on the contralateral side.
The Short Form of the Glasgow Composite Measure Pain Scale (CMPS-SF)16 was used to assign pain scores on a scale from 0 (no signs of pain) to 26 (signs of extreme pain, such as screaming, crying, chewing on the painful area, refusing to move, nonresponsive to stimuli, or rigidity). Pain scores were evaluated by someone unaware of treatment allocation at baseline, 4, 6, 12, 24, 48, 72, and 96 hours after time 0. Hydromorphone (0.05 mg/kg, IM) rescue analgesia was administered to dogs that had a pain score > 5 at any checkpoint or that displayed compatible signs of pain (eg, crying, whimpering, or hunched posture) between checkpoints. If this was the case, it was recorded in the next evaluation point.
With the dogs blindfolded to minimize possible anticipation, superficial pain was evaluated with the use of tissue forceps by pinching the skin of the 4 abdominal quadrants (Q1 = right cranial, Q2 = left cranial, Q3 = left caudal, and Q4 = right caudal) and abdominal wall pain was evaluated by exerting standardized pressure with a blunt object (ie, the tip of a reflex hammer handle) in the aforementioned quadrants. Superficial and abdominal wall pain scores and descriptions were categorized as 0 and blocked = no response; 1 and partial block = some response, such as turning the head toward the palpation site, flinching, or tensing the abdomen; or 2 and no block = marked response, such as clear whining or growling. The function was considered as returned when the scores were 1 or greater. Additionally, sedation was evaluated at each of the same time points. Sedation scores were assigned on a scale of 0 to 3, in which 0 = fully alert and able to stand and walk; 1 = alert and able to maintain sternal recumbency; 2 = drowsy but able to maintain sternal recumbency but unable to stand; or 3 = fast asleep. Food and water were offered at each time point. As part of the CMPS-SF, dogs were put on a leash and encouraged to come outside of the cage. The cages were then visually inspected for any signs of urination or defecation. Parameters such as time to return to eating, drinking, urinating, and defecating were recorded.
All evaluations were conducted by individuals who were blinded to the randomization process and treatment allocation. There were 3 different scorers, all trained and experienced in the CMPS-SF as well as the sensory and sedation scoring systems. Each dog was scored by the same individual from beginning to end. The 3 different individuals scored a similar number of dogs.
Statistical analysis
Sample size was calculated a priori. Assuming BUP-DEX and BLS would produce a sensory disruption for a mean ± SD of 6 ± 2 and 12 ± 4 hours, respectively (based on Luis Campoy, LV, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, unpublished data, 2020), a minimum sample size of 8 dogs per group was calculated using the duration of sensory blockade as the main outcome variable (1 tail). Alpha and the desired statistical power were set at 0.05 and 95%, respectively (G*Power Version 3.1.5; Franzs Faul).
Linear mixed-effect models were used for comparing the pain and sedation scores and response to superficial and deep palpation at each quadrant with the fixed effects of treatment, time, and the interaction of treatment and time. To account for the repeated measurements, random effects of each individual dog and the interaction of dog and treatment were included in the model. A Tukey honestly significant difference test (Tukey HSD) was used to test differences among sample means for significance. “Time to” variables (ie, time to need of rescue analgesia, sensory, walk, eat, drink, defecate, and urinate) were evaluated using survival analysis. Additionally, the Manthel-Cox test was used to compare the survival curves. Duration of effect for the sensory function was defined as the time at which a subject first achieved a score of 1. The cranial and caudal quadrants were analyzed separately. Results for the yes or no variables, such as incidence of need of rescue analgesia, were compared with the χ2 test.
Data were tested for normality by observing the distribution of the residuals. Results of parametric and nonparametric data were presented as mean ± SD or as median and range, respectively. All statistical analyses were carried out using available software (JMP Pro, version 16.1.0; SAS Institute Inc for the mixed-effect model and Tukey HSD; Prism, version 6, GraphPad Software for the survival analysis and Manthel-Cox tests; and Excel 2019, Microsoft Corp for the χ2 test). For all analyses, statistical significance was set at P ≤ .05.
Results
There were 27 dogs with a median age of 2 years (range, 1 to 9 years) and a mean ± SD body weight of 20.8 ± 8.3 kg enrolled in the study, with 9 dogs/group. One dog, however, had to be excluded from the CTRL group due to surgical complications, leaving 8 dogs in this particular group. The mean ± SD duration of anesthesia was 207 ± 19, 220 ± 30, and 234 ± 18 minutes for the BUP-DEX, BLS, and CTRL groups, respectively.
The pain scores were significantly affected by time (P < .001), treatment (P < .002), and the interaction of treatment and time (P < .001). The CTRL group had significantly greater scores than the BUP-DEX and BLS groups, but no differences were found between the BUP-DEX and BLS groups (Figure 1).
Median pain scores on the basis of the Short Form of the Composite Measure Pain Scale (CMPS-SF) of the Glasgow Composite Scale (0 [no signs of pain] to 26 [signs of extreme pain, such as screaming, crying, chewing on the painful area, refusing to move, nonresponsive to stimuli, or rigidity]) for 26 shelter dogs that were randomly assigned to receive either a transverse abdominis plane (TAP) block with bupivacaine-dexmedetomidine (BUP-DEX group; n = 9), a TAP block with bupivacaine liposome suspension (BLS group; 9), or no TAP block (CTRL group; 8) at time 0 (before undergoing elective ovariohysterectomy) and then evaluated at 4, 6, 12, 24, 48, 72, and 96 hours later between January 28 and December 8, 2020. The horizontal dotted line represents the threshold for administering rescue analgesia (score = 6). The median pain score for the CTRL group exceeded this threshold at the 4-hour evaluation point. The CTRL group had significantly greater scores than the BUP-DEX and BLS groups, but no differences were found between the BUP-DEX and BLS groups.
Citation: American Journal of Veterinary Research 83, 9; 10.2460/ajvr.22.03.0037
The proportion of dogs that needed rescue analgesia was significantly (P = .044) higher for the CTRL group (7/9) than for the BUP-DEX group (4/9) and BLS group (3/9; Supplementary Figure S1). Time to the need of rescue analgesia was significantly (P = .003) shorter for the CTRL group. All of the 7 dogs that needed hydromorphone as rescue analgesia in the CTRL group had received it by 4 hours after time 0. In this group, 2 dogs received 2 doses of rescue analgesia and 1 received 3 doses. Of the 4 dogs that needed rescue analgesia in the BUP-DEX group, 3 needed it by the 4-hour checkpoint and 1 by the 6-hour checkpoint. Similarly, the 3 dogs that needed rescue analgesia in the BLS group had received it by the 4-hour checkpoint.
The superficial and abdominal wall pain scores were not significantly affected by treatment, time, or their interaction in any of the 4 quadrants (Supplementary Figure S2). The return of the sensory function (score 1 or greater) was significantly (P = .016) different between groups only for the cranial quadrants (Q1 and Q2; Figure 2). The sedation scores were significantly affected by time (P < .001) and treatment (P < .041). The CTRL group had greater sedation scores than the other 2 treatments (Supplementary Figure S3). Regarding the evaluated parameters related to return to normal behavior (ie, time to walk, eat, drink, defecate, and urinate), no significant differences were observed in any of the evaluated outcome variables.
Percentages of dogs in the BUP-DEX group (n = 9), BLS group (n = 9), and CTRL group (n = 8) described in Figure 1 with a sensory function score of 1 (some response, such as turning the head toward the palpation site, flinching, or tensing the abdomen) or greater for the right and left cranial abdominal quadrants (A and B, respectively) and left and right caudal abdominal quadrants (C and D, respectively) when evaluated at 4, 6, 12, 24, 48, 72, and 96 hours following time 0.
Citation: American Journal of Veterinary Research 83, 9; 10.2460/ajvr.22.03.0037
Discussion
Results of the present study appeared to favor the use of a TAP block as shown by the lower pain scores and lower need for rescue analgesia as evaluated under these circumstances. However, no differences were noted in any of the “time to return to normal behavior” variables such as time to walk, eat, drink, defecate, or urinate. Moreover, the addition of a BLS formulation did not appear to introduce any further benefit beyond that provided by the BUP-DEX.
There were clear differences in the pain scores and the need and timing for rescue analgesia. The CTRL group had higher pain scores and needed analgesia more frequently and at an earlier stage than the other 2 groups. Most of the dogs in the CTRL group (7/8) needed analgesia by the 4-hour evaluation point, whereas only 4 of 9 dogs in the BUP-DEX group and 3 of 9 dogs in the BLS group needed rescue analgesia once over the entire duration of the observational period. It appeared that the benefit came from the TAP block and not from the treatment since no differences were found between the BUP-DEX and BLS groups.
Interestingly, no differences in the superficial or abdominal wall palpation scores could be perceived between any of the groups. We found very low scores on both parameters in all groups. One possible explanation could be that the scores in the CTRL group may have been masked by the opioid administered. When broken down into cranial and caudal quadrants, the time to return of the sensory function (evaluated by skin pinching) was only different at the cranial quadrants indicating a possible better cranial distribution of the injectate. Rescue analgesia in this CTRL group occurred prior to the 4-hour evaluation point in 7 of 8 individuals; thus, by the first evaluation point, the majority of individuals had already been under the effects of a potent analgesic. Additionally, 3 of these received more than 1 dose. This could have accounted for a blunted response to palpation. The sedation scores were also significantly greater in this group. This may corroborate this theory.
The ventral branches of the spinal nerves corresponding to T10, T11, T12, T13 (costoabdominal nerve), L1 (cranial iliohypogastric nerve), L2 (caudal iliohypogastric nerve), and L3 (ilioinguinal nerve) were the target of our TAP block. As an aside note, in order to block the skin, the lateral cutaneous branch needs to be blocked. In an effort to block the lateral cutaneous branch before it crosses over the transverse abdominis, internal and external oblique muscles, and subsequently run superficial to the abdominal wall, we located our puncture site as abaxial (proximal) as possible. Additionally, the target intermuscular plane to deposit the local anesthetic solution or suspension was defined as immediately deep to the fascia located on the surface of the transverse abdominis plane. For each dog, our needle’s final location was deep to the fascia that is present on the surface of the transverse abdominis muscle.8 This is a fascia that is not easily initially noted but, on closer inspection, it can be observed in the ultrasonographic image in the majority of dogs. The nerves run on the surface of the transverse abdominis muscle, deep to this fascia, and therefore, a failed or not so dense block may result if the needle is superficial to this fascia. The abdominal wall palpation scores were low in the BUP-DEX and BLS groups, indicating lack of muscle sensory function. Our abdominal wall palpation technique perhaps only tested the muscular abdominal wall and peritoneum and not the internal organs. However, the pain scores and opioid consumption were consistently low in the 2 blocked groups. We do not fully understand why since it is generally accepted that this block is only effective as treatment of somatic pain. However, some evidence may suggest that this block may also reduce visceral pain.10,17 The reality is that we still do not fully understand how fascial anatomy interacts with local anesthetic and its subsequent migration after injection.4–7
The longer duration of action (72 hours)18 claimed by the manufacturer of the commercial preparation of a BLS used in this study and approved to use in dogs and cats in the United States (Nocita; Elanco) did not appear to further the benefit that the TAP block provided. This could have been due to a lack of sensitivity of our scoring system at picking up subtle signs of pain beyond 24 hours, and therefore, our BLS could have outlasted the duration of the immediate and acute postoperative pain, beyond which, prolonged local anesthetic duration did not provide any extra benefit. Vaisanen et al19 reported that signs associated with pain in dogs following soft tissue surgery were noticeably diminished (although still present) as soon as 24 hours postoperatively. Thus, this theory could have been a plausible explanation. Alternatively, the liposomes in the suspension perhaps could have been too large to migrate and distribute throughout the tissues as well as the slow release of free bupivacaine from the vesicles may also help explain this apparent lack of benefit.
The formulation of BLS used in the present study results in the release of a small fraction of free bupivacaine from the vesicles over time. As per the manufacturer’s package insert, it may not be indicated “for pre-incisional or pre-procedural loco-regional anesthetic techniques that require deep and complete sensory block in the area of administration.” The practice of volume expansion is also described in the package insert should the recommended volume of 0.4 mL/kg is not deemed sufficient. This expansion is only recommended with normal saline or lactated Ringer’s solution.18 However, in order to overcome both problems (not enough volume and lack of surgical sensory density), the package insert of its human equivalent (Exparel; Pacira),20 alternatively describes the expansion of this compound with bupivacaine HCl (“bupivacaine HCl and Exparel may be administered simultaneously in the same syringe, and bupivacaine HCl may be injected immediately before Exparel as long as the ratio of the milligram dose of bupivacaine HCl solution to Exparel does not exceed 1:2”). This practice is also described by Hadzic et al21 and has been proven safe in human medicine. There is evidence that peak plasma concentration following administration of either BLS or bupivacaine HCl are offset by many hours. Plasma concentrations following administration of BLS are still very low.22 Enomoto et al23 reported plasma concentrations following injection of BLS in dogs of approximately 3- to 6-fold lower than those seen after an equivalent dose of bupivacaine HCl solution, with a mean ± SD maximum plasma concentration (Cmax) of approximately 500 ± 500 ng/mL after a 9-mg/kg dose. For context, seizures have been reported to occur at bupivacaine Cmax of 18 µg/mL (18,000 ng/mL).24
The benefits from a better analgesia quality manifested by lower pain scores, less need for rescue analgesia, and therefore, lower opioid consumption. However, these did not translate into an earlier return of any of the behavioral parameters evaluated, that is return to walk, eat, drink, defecate, or urinate.
Limitations to this study included that the CTRL group was not a sham treatment group (saline treatment), and therefore, this study cannot demonstrate that the drugs had an effect that was independent from the technique itself. In client-owned animals, it is hard to justify a sham group when harm can be caused by the technique itself. Another limitation included the fact that we did not have a system to test for internal organ pain (deep palpation). Our only surrogate was the pain scores and need for rescue analgesia. A model including deep palpation may have been more definitive. One additional limitation included the fact that all our time data referred to the time of block and not the recovery time. This was intentional since we find that this is a more objective way to evaluate the duration of the block although it may have acted as a confounder in some of the other “time to” variables.
In conclusion, a TAP block appeared to provide adequate analgesia for abdominal surgery using a spay run by veterinary students as a model. The addition of a bupivacaine liposome-encapsulated formulation to the injectate did not seem to provide any extra benefit under these specific conditions.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org
Acknowledgments
No external funding was used in this manuscript. The authors declare that there were no conflicts of interest.
Shalini Radhakrishman and Rhiannon M. Pavlinac were fourth-year veterinary students at Cornell University College of Veterinary Medicine. Jessica L. Sieger, Claudia S. Colon, and Steven R. Magidenko were third-year veterinary students at Cornell University College of Veterinary Medicine.
References
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