Introduction
Enucleation is a procedure commonly performed by both veterinary ophthalmologists and general practitioners. Eye removal is an end-stage treatment warranted in cases of protracted ocular pain as a result of inflammation, glaucoma, neoplasia, and penetrating ocular injuries.
Local anesthesia is an important component of multimodal pain control for patients undergoing enucleation. Agents such as bupivacaine block sodium channels, thus preventing depolarization of the nerve, action potential formation, and impulse transmission.1 Previous studies have shown lower postoperative pain scores following use of local blocks over systemic opioids.2 Many established methods for local ophthalmic blocks exist; one that is commonly performed is the inferotemporal retrobulbar block.3 While technically simple, these procedures take skill to perform and do carry risk, albeit low.4 Risks reported in physician literature include perforation of the globe, hemorrhage, nausea, respiratory arrest, blindness, seizures, and coma. The complication rate in people is reported at < 2% for local adverse events and < 1% for systemic adverse events.5,6 Similar complications have been predicted but are rarely reported in veterinary medicine. Very few cases of intrathecal injection leading to brain stem anesthesia are reported, none involving dogs.4,7–10 One paper4 comparing dogs that received retrobulbar blocks with those that did not receive one prior to enucleation demonstrated no increased risk of major or minor complications. While complications are uncommon, veterinarians may feel uncomfortable performing this technique, particularly general practitioners who may not perform periocular injections with regularity. Thus, clinicians may choose to omit this step prior to enucleation. Additionally, disease such as extensive periocular neoplasia or severe corneal infections may preclude administration of preoperative blocks to prevent seeding of disease into the orbit. Previous studies have demonstrated mixed success at postoperative pain control with omission of retrobulbar blocks and application of local anesthetics directly into the orbital space following eye removal.11–13
A proposed alternative to the retrobulbar injection is a subcutaneous line block of bupivacaine at the closure of surgery. Bupivacaine liposome injectable suspensions (BLIS) have become a popular choice for longer-lasting local analgesia following soft tissue and orthopedic surgeries. Nocita (Elanco) is a liposome-encapsulated bupivacaine approved for use in dogs following cranial cruciate ligament surgery and cats following onchyectomy.14 A single injection of Nocita is effective for up to 72 hours, although some studies suggest that certain uses may lead to a shorter duration of action.15–17 Therefore, it may be an effective bridge to control immediate postoperative pain as a sole analgesic or until systemically administered medications reach therapeutic concentrations.
The objective of this study was to compare the effectiveness of preoperatively delivered retrobulbar bupivacaine to postoperative liposome-encapsulated bupivacaine (Nocita) for analgesia following enucleation. A secondary objective of this study was to compare the validated Glasgow Composite Measure Pain Scale Short Form to a modified pain scoring system used in previous studies evaluating analgesia following enucleation.8,11,13,18,19 This scale, which we have termed the University of Wisconsin Ocular Pain Scale, was originally adapted for use assessing ocular pain by Myrna et al.8
Methods
Animals
This study was approved by the University of Wisconsin-Madison School of Veterinary Medicine IACUC and Research Animal Resources and Compliance (V006454). Client-owned dogs were admitted to the teaching hospital for unilateral enucleation secondary to a variety of ocular diseases. Clients were questioned regarding patient history, and patients were enrolled if deemed qualified with owner consent. Dogs were excluded from the study if they were receiving bilateral enucleations, had a history of chronic systemic pain control medication usage (NSAID, tramadol, or gabapentin use for over 2 weeks or within 24 hours of surgery), or had temperaments that were not suitable for repeated pain scoring. Additionally, animals were excluded if they demonstrated clinical signs consistent with brachycephalic obstructive airway disease due to anesthetic concerns and the need for additional medications deemed necessary by the supervising anesthesiologist.
Procedure
Dogs underwent baseline pain scoring using both pain score methods (UW Ocular Pain Scale and Glasgow Composite Measure Pain Scale Short Form) as well as routine ophthalmic and general physical examinations. Baseline diagnostics were performed as indicated, including CBC, serum biochemistry, and diagnostic imaging (thoracic radiography and abdominal ultrasonography).
Dogs were premedicated with hydromorphone (0.1 mg/kg) and midazolam (0.1 mg/kg) IM. An IV catheter was placed when the patient was deemed appropriately sedate (typically 20 minutes after premedication). General anesthesia was induced with propofol (1 to 7 mg/kg) or alfaxalone (0.5 to 2.5 mg/kg) to effect. An endotracheal tube was placed, and anesthesia was maintained with isoflurane or sevoflurane in oxygen to effect. Additional drugs to support dogs under general anesthesia were administered as indicated by the supervising anesthesiologist (eg, maropitant, atropine, dopamine, glycopyrrolate). All patients received intraoperative cefazolin (22 mg/kg, IV, once at incision). A bolus of hydromorphone (0.05 mg/kg) was administered if the patient was responsive to surgical manipulation after adjusting inhalant to achieve appropriate anesthetic depth. No additional pain medications were administered (eg, lidocaine, ketamine, carprofen) at any point during general anesthesia or postoperative hospitalization. Use of intraoperative drugs was sorted into 3 groups for statistical evaluation: those to support heart rate (atropine, glycopyrrolate), those to support blood pressure (dopamine, norepinephrine), and those to support anesthetic depth or pain response (propofol, alfaxalone, hydromorphone).
Dogs were randomly assigned in blocks of 6 to 1 of 2 treatment groups: the retrobulbar bupivacaine group (RB) or line block liposome-encapsulated bupivacaine group (LB). Appropriate drugs were drawn up in a syringe covered with color-specific cohesive elastic tape by a veterinarian or technician not masked to treatment groups. Pain scorers remained masked to treatment groups throughout the study. To facilitate masking of pain scorers, each dog received the injection as indicated by treatment group as well as a sham injection as described below.
Dogs in the RB group received a preoperative inferotemporal retrobulbar block of 0.5% preservative-free bupivacaine approximately 20 minutes prior to the start of surgery by a trained ophthalmology resident. Dosing was as follows: 2 mg/kg diluted to a volume of 2 mL with sterile saline for dogs weighing < 5 kg, 2 mL for dogs weighing between 5 and 15 kg, and 3 mL for dogs weighing over 15 kg. The dosing protocol ensured doses administered were < 2 mg of bupivacaine/kg to avoid reaching a toxic dose, as established in previous studies.20 At the completion of surgery, a line block of sterile saline in volume dosing described below for the LB group was performed.
Dogs in the LB group received a retrobulbar block of sterile saline in the same volume dosing as described above for the retrobulbar injection. Immediately following completion of surgery (last skin suture placed), dogs received a line block of liposome-encapsulated bupivacaine (Nocita) at 0.4 mL/kg with a maximum volume of 3 mL. Injections were performed by a nonmasked ophthalmology resident, ophthalmologist, or anesthesiologist; the periocular skin was cleaned after the injection to ensure the pain scorer remained masked to treatment groups. The injection was performed with a 25-gauge or larger needle (to ensure liposomes were not lysed21) as a line block, circumferentially, and approximately 1 to 1.5 cm around the incision and into the subcutaneous and periocular muscular layers.
All dogs received a transpalpebral enucleation without placement of a prosthetic. A lag time of 20 minutes between retrobulbar injection and initiating surgery was ensured. Senior veterinary students in their clinical year were allotted the first 20 minutes of surgery. The remainder of surgery was completed by an ophthalmology resident. Dogs were monitored by the anesthesia team until normotensive, normothermic, spontaneously ventilating, and swallowing. Pain scoring was commenced following extubation (time 0). If dogs were noted to be excessively dysphoric by the supervising anesthesiologist, a small bolus of propofol (0.5 to 2 mg/kg, IV) or acepromazine (0.01 mg/kg, IV) was administered. If propofol was indicated, the pain score time points reset when the patient was recovered from administration. No patients included in the statistical evaluation had prolonged dysphoria that required additional intervention. The incision was iced for 10 to 15 minutes immediately postoperatively, and an e-collar was placed.
Pain was assessed at specific set points (baseline/preoperatively, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours postextubation). Two pain score scales were used at each time point: the UW Ocular Pain Scale and the Glasgow Composite Pain Scale Short Form (Supplementary Materials S1 and S2). Patients were rescued if either pain score recommended intervention. Pain scoring was performed by 1 of 2 trained, masked observers (TAO or ophthalmology technician). If dogs met criteria for 1 or both pain score systems used, they received a rescue dose of hydromorphone (0.05 mg/kg, IV or IM). Dogs were discharged 24 hours after extubation with systemic pain control medications (NSAIDs or gabapentin). Patients were reevaluated with the ophthalmology service or their primary veterinarian for suture removal and incision evaluation 10 to 14 days after surgery.
Statistical analysis
A total sample size of 40 patients (40 eyes) randomized 1:1 per group was calculated to give 81% power for a 2-sided .05-level test to detect an anticipated 40–percentage point difference between groups with respect to the risk of needing rescue medication (50% for Nocita vs 10% for RB). Continuous data were summarized using the mean and SD or median and IQR and compared between groups (RB vs Nocita) using t tests or nonparametric methods (rank sum test). Categorical factors were summarized with frequencies and percentages and compared between groups using the Boschloo exact unconditional test.22 The likelihood of needing rescue within 24 hours was summarized using the relative risk and risk difference. Time to first rescue was described using a Kaplan-Meier plot and summarized with an estimated hazard ratio from a Cox proportional hazard model. All analyses were performed using R (version 4.2.2; The R Project for Statistical Computing). Agreement between the different pain scales was quantified using the Gwet coefficient of agreement.23
Results
Thirty-nine patients (40 eyes) were included for statistical evaluation, with 20 eyes in each group. One patient was enrolled for the study twice at separate time points separated by 11 months. The patient was randomly assigned to different groups, and the 2 events were analyzed separately. The patient was not rescued in either group. There was a large variety of breeds enrolled in the study, with the most common breed being a mixed-breed dog (n = 12), followed by Boston Terrier (3). There were no statistically significant differences between the RB and LB groups in terms of patient age, sex, weight, affected eye, or duration of surgery (Table 1). The primary diagnosis prior to enucleation was glaucoma (17 and 12 dogs), corneal ulceration/rupture (1 and 6 dogs), phthisis bulbi (1 and 1), intraocular neoplasia (1 and 0), and panuveitis (0 and 1) in the RB and LB groups, respectively.
Characteristics of the study sample with comparisons between treatment groups.
| RB (n = 20) | LB (n = 20) | P value | |
|---|---|---|---|
| Age (y) | |||
| Mean (SD) | 10 (4.2) | 8.6 (3.7) | .273 |
| Sex (n [%]) | |||
| Female | 15 (75) | 10 (50) | .117 |
| Male* | 5 (25) | 10 (50) | |
| Weight (kg) | |||
| Median (IQR) | 21.6 (7.4–32.5) | 11.5 (7.8–23.7) | .525 |
| Eye (n [%]) | |||
| Left eye (OS) | 12 (60) | 10 (50) | .611 |
| Right eye (OD) | 8 (40) | 10 (50) | |
| Duration of surgery (min) | |||
| Mean (SD) | 64.8 (9.8) | 67.6 (11.8) | .413 |
RB = Retrobulbar block. LB = Line block (Nocita).
*All dogs were sterilized, except 1 male in the LB group.
Baseline pain scores were not significantly different between groups (UW Ocular Pain Scale difference between groups, –0.40 [95% CI, –1.52 to +0.72]; Glasgow Pain Scale difference between groups, 0.012 [95% CI, –0.054 to +0.078]). When comparing the use of medical intraoperative heart rate, blood pressure, or anesthetic plane support, there were no significant differences in use between groups (Table 2).
Intraoperative and postoperative interventions with comparisons between treatment groups. Results are presented as frequencies and percentages (in parentheses). Rescue is the need for hydromorphone intervention as defined by either the University of Wisconsin Ocular Pain Scale or Glasgow Pain Scale.
| RB (n = 20) | LB (n = 20) | P value | |
|---|---|---|---|
| Glycopyrrolate or atropine used | |||
| Yes | 8 (40) | 4 (20) | .188 |
| No | 12 (60) | 16 (80) | |
| Dopamine or norepinephrine used | |||
| Yes | 4 (20) | 2 (10) | .432 |
| No | 16 (80) | 18 (90) | |
| Propofol, alfaxalone, or hydromorphone used | |||
| Yes | 5 (25) | 5 (25) | 1.000 |
| No | 15 (75) | 15 (75) | |
| No. of categories of drugs (above) used* | |||
| 0 | 9 (45) | 12 (60) | .260 |
| 1 | 6 (30) | 5 (25) | |
| 2 | 4 (20 | 3 (15) | |
| 3 | 1 (5) | 0 (0) | |
| Rescued at least once postoperatively | |||
| Yes | 8 (40) | 5 (25) | .106 |
| No | 12 (60) | 15 (75) |
Categorical factors are reported as frequency and percent.
RB = Retrobulbar block group. LB = Line block (Nocita) group.
*Cochran-Armitage test of trend.
Four dogs in each group required intraoperative dosing of propofol or alfaxalone. One dog in each treatment group received intraoperative hydromorphone. Six patients required either a low dose of propofol (1 to 2 mg/kg, IV) or acepromazine (0.01 to 0.02 mg/kg, IV) upon recovery to manage dysphoria (2 in the RB group, 4 in the LB group). These medications were not considered to impact the ability to perform pain scoring, and patients were included in the statistical analysis. Two of the dysphoric patients (both from the LB group) required rescue dosing of hydromorphone during pain scoring. In the RB group, 8 of 20 (40%) patients required rescue dosing postoperatively. In the LB group, 5 of 20 (25%) individuals required rescue dosing. There was no significant difference in rescue rates between the groups (P = .352). Time to first rescue also did not differ between groups (hazard ratio for LB vs RB = 0.56; 95% CI, 0.18 to 1.76; P = .317). Additionally, for patients that required rescue, the total number of rescues needed over the 24-hour monitoring period was not significantly different.
There appeared to be strong chance-corrected agreement (Gwet agreement coefficient = 0.83; 95% CI, 0.67 to 1.00) involving rescue by the Glasgow scale and the UW Ocular Pain Scale. When examining each individual rescue time point (with some patients having multiple rescues), there was agreement between systems in many rescue time points (17/22). There were few time points in which rescue was indicated by the UW Ocular Pain Score System (5/22), but the rescue threshold was not reached on the Glasgow System. There were no time points in which rescue was recommended by the Glasgow System and not the UW system. Further statistical evaluation of the 2 pain score systems will be performed in future studies.
Discussion
This study did not identify a significant difference in postoperative pain scores, rates of rescue analgesia administration, or intraoperative management of patients when receiving preoperative retrobulbar blocks versus postoperative line blocks. A power calculation done prior to starting patient recruitment suggested we would be able to detect a 40% difference between groups with 40 patients. While this is a large difference, we did feel it would be a clinically significant one. A larger study would be needed to determine whether there is a < 40% difference. While anesthetic techniques should strive to provide the most well-rounded multimodal pain control techniques, this study provides insight that preoperative local blocks for enucleation are not necessary for all cases if an alternative block can be performed. As complication rates following retrobulbar blocks are low, clinicians should not avoid retrobulbar blocks altogether. However, for inexperienced practitioners or for patients with significant periocular disease or periocular, conjunctival, or corneal neoplasia in which blocks must be avoided, the clinician can feel comfortable omitting this step in exchange for other pain control methods such as BLIS products.
Retrobulbar blocks are a frequently used local anesthetic technique for dogs undergoing enucleation. The length of action of nonliposomal bupivacaine is 3 to 15 hours, with 8 hours being typically expected.16,24 Local anesthesia decreases the MAC of inhalant required for an adequate surgical plane of anesthesia.1 Retrobulbar blocks may also decrease the risk of inducing an oculocardiac reflex during surgical manipulation of the globe.25 Our study did not evaluate monitoring parameters but did assess related outcomes. When patients become “reactive” during general anesthesia, troubleshooting by increasing inhalant concentration is often performed, along with the addition of various systemic medications to deepen the anesthetic plane. Higher inhalant usage can induce hypotension and bradycardia; thus, usage of drugs to support the cardiovascular system can be used as markers of deeper general anesthetic planes and higher inhalant usage.1 We expected that patients without local anesthesia (LB group) would require higher levels of inhalant and thus more cardiovascular support. If inhalant was not increased sufficiently, boluses of induction agent or intraoperative opioid usage would be expected. However, our study did not identify a need for increased heart rate or blood pressure support, nor intraoperative use of induction agents or opioids in the LB group compared to the RB group. This lack of difference may be a result of hydromorphone use in the premedication protocol, as it should still be in therapeutic concentrations throughout surgery. Comparison of groups without the confounding factor of opioid administration would be favorable; however, this is an unethical approach for patient care, particularly in the LB group. If hydromorphone had been withheld, the lack of preemptive nociception blockade in the LB group may have been more detectable. Two patients in the study received intraoperative hydromorphone. Pains scoring for these patients was still initiated following extubation. We expect that initial pain scores were lower due to additional hydromorphone that was administered. However, as we were more interested in comparing the need for intervention rather than the timing to intervention, they were not excluded from analysis.
Nocita is a BLIS approved for injection into muscle, fascia, and subcutaneous tissue following specific surgeries; thus, the use in our study was off-label.14 Previous studies have demonstrated effective pain control with use of Nocita.16,24 Bupivacaine liposome injectable suspension products are composed of a phospholipid bilayer surrounding an aqueous center; the structure decreases the rate of metabolism and extends the time of activity to approximately 72 hours.26,27 Comparison of comfort for at least 3 days following surgery would have been ideal to assess whether this prolonged activity was clinically evident via reduced pains scores in the LB group; however, this was not feasible in a clinical setting and would have been confounded by the use of systemic NSAIDs 24 hours after surgery. Due to liposome size, Nocita diffuses poorly, and users must be careful to inject into each desired tissue plane.14,24 Our study aimed to evaluate Nocita injected into the subcutaneous and periocular muscle of the eye. Because of the restricted ability of Nocita to diffuse from the injection site, a main concern for postoperative enucleation patients is limited pain control deeper within the orbit. However, patients within the LB group were not more painful postoperatively than those within the RB group. Bupivacaine liposome injectable suspension products are safe to use in combination with systemic NSAIDS, opioids, epinephrine, and steroids and around suture material and surgical implants.26–28 Risks are limited, with mild inflammation around the injection site being the most common side effect.24,26,28,29 Patients in the LB group of our study did have subjectively more bruising following surgery; however, there were no cases of prolonged healing, incisional infections, or incisional dehiscence. There are no controlled studies evaluating the safety of orbitally delivered BLIS, and the authors do not recommend retrobulbar administration.30 It is notable that when used at closure, BLIS products do not cause surgical site desensitization, and combination with preoperative blocks (retrobulbar block) should be considered. Lastly, Nocita may be cost prohibitive when used in a smaller hospital setting. Bupivacaine liposome injectable suspension bottles are preservative free and thus cannot be stored for long periods of time after opening. It is recommended that vials be used within 4 days; when aseptic technique is used, it has been shown to remain sterile for up to 5 days.31
Identifying the extent of ocular or orbital pain is very difficult in veterinary patients. In this study, we compared the UW Ocular Pain Scale to the widely used and validated Glasgow Short Form Pain Scale and found good agreement. We found that the UW Ocular Pain Scale may be more sensitive to ocular pain compared to the Glasgow Short Form, as more patients were rescued using this scale than the Glasgow scale. Additional studies should be performed to statistically compare the 2 pain scales. For most focal painful conditions, palpation remains one of the most consistent and reliable indicators for veterinary professionals32; however, there are very limited studies evaluating the sensitivity and specificity for palpation and pain in veterinary patients.33
Lastly, it is important to note that rescue rates were high in both groups (40% in the RB group, 25% in the LB group), despite administration of local anesthesia. This rate is higher than what previous studies have identified, which may be secondary to patient selection or variability in pain scoring between individuals.8,11,12 These findings support the use of multimodal pain control and attentive pain control assessment for all patients following enucleation.
There were limitations to this study. One limitation was the lack of confirmation of an appropriately administered retrobulbar block. All blocks were performed by trained ophthalmology residents. A recent study19 evaluating a blindly performed inferotemporal retrobulbar block versus an ultrasound-guided supratemporal technique suggested that those receiving blind inferotemporal blocks required more intraoperative analgesics compared to the ultrasound-guided technique. However, the authors of that study did not find a significant difference in pain scores postoperatively. Ultrasound-guided versus blindly administered retrobulbar blocks in horses did not reveal a significant difference in local anesthetic delivery accuracy between groups.34 While pupil size is an effective indicator to confirm intraconal administration of anesthetics, authors avoided evaluation in this study to remain masked to treatment groups. One patient in each group received intraoperative hydromorphone at the discretion of the anesthetist. Intraoperative use likely affected postoperative pain scores for these patients for the first 2 to 4 hours.35 However, as patients were monitored for 24 hours, intraoperative use was not anticipated to change the outcome for the individual patient. Another variable in the study included varying surgical skills of veterinary students. Ideally, a single surgeon would have completed all surgeries; however, this is not feasible in a veterinary teaching hospital and better mimics the clinical situation for the variety of surgeons in practices. Additionally, nearly all patients in our study were receiving enucleations for a painful condition. Removal of a painful nidus despite surgical manipulation rapidly improves patient comfort. This can make assessment for postoperative comfort difficult, and subtle differences between groups may be missed. Lastly, patient behavior and clinical environment may play a role in accurately assessing pain control in the patients, and pain scoring may have been affected.
Use of preoperative bupivacaine retrobulbar blocks and postoperative Nocita line blocks were equally effective at postoperative pain control with similarly low complication rates.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
Acknowledgments
The authors would like to thank University of Wisconsin Ophthalmology technician Kim Sherman for her expertise on participant organization, drug dosing, and drug preparation. The authors would also like to thank the Anesthesiology and Ophthalmology Services for their participation and assistance with patient care.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the generation of this manuscript.
Funding
The authors have nothing to disclose.
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