Abstract
Objectives
We evaluated a potential association between the administration of high-dose buprenorphine and perpetuation of hyperthermia in cats following ovariohysterectomy (OVH). We hypothesized that buprenorphine 0.24 mg/kg subcutaneously (SC) would result in longer-lasting postoperative hyperthermia in cats vs a group receiving morphine 0.1 mg/kg SC.
Methods
Anesthetic records from cats admitted for OVH as part of surgical exercises for second year veterinary medicine students in 2018 and 2019 were collected. All cats were sedated with dexmedetomidine 20 µg/kg and morphine 0.1 mg/kg intramuscularly. Anesthesia was induced with propofol and maintained with isoflurane in oxygen. At extubation, cats received morphine 0.1 mg/kg SC in 2018 and buprenorphine 0.24 mg/kg SC in 2019. Temperature was measured rectally prior to sedation, esophageally during anesthesia and rectally at 1, 4 and 16–20 h after extubation. Demographic data and temperature prior to administration of postoperative opioids were compared with t-tests. The effects of treatment (opioids) and time on postoperative rectal temperature and on the incidence of hyperthermia (temperature >39.2°C) were evaluated with mixed and generalized linear mixed-effect models. Significance was set at P <0.05.
Results
There were no differences in demographic characteristics between treatment groups (all P ⩾0.2). Intraoperative esophageal temperature was lower in cats scheduled to receive morphine (mean ± SD 36.6 ± 0.2) than in those receiving buprenorphine (36.9 ± 1.0) (P <0.0001). Postoperative temperature was higher for cats receiving buprenorphine than for those receiving morphine (P <0.0001). The incidence of hyperthermia 16–20 h after opioid administration was 56% for morphine and 73% for buprenorphine (P = 0.03).
Conclusions and relevance
Buprenorphine 0.24 mg/kg SC for postoperative analgesia in cats was associated with hyperthermia that persisted for 16–20 h after administration, and the incidence of hyperthermia for this group was higher than in the cats that received morphine 0.1 mg/kg SC.
Introduction
Buprenorphine is a partial mu (µ)-agonist opioid that is widely used for perioperative analgesia in cats.1,2 A high concentration, US Food and Drug Administration-approved buprenorphine formulation (Simbadol; Zoetis) specifically labeled for use in cats is available as a single-dose subcutaneous (SC) injection and is reported to provide 24 h analgesia. The prolonged analgesic effect of this formulation is attributed to the concentration and dose of the compound, in addition to its high affinity for the µ receptor. 3 These characteristics make it an attractive agent for use in cats, particularly considering the subjective nature of pain recognition in this species. 4
An association between opioids and hyperthermia in cats has long been established.5–8 Opioids alter thermoregulation by resetting the hypothalamic temperature set point. 9 This adverse effect, in conjunction with concerns for increased excitability, may be responsible, at least in part, for inadequate pain management in cats. 6 Different opioids, including full µ agonists and buprenorphine, have been implicated in the development of self-limiting hyperthermia. 8 To our knowledge, an association between hyperthermia and buprenorphine at a dose recommended for long-acting analgesia has not yet been established in the cat. The purpose of this retrospective study was to evaluate a potential association between administration of high-dose buprenorphine and perpetuation of hyperthermia in cats following ovariohysterectomy (OVH). We hypothesized that buprenorphine administered SC at the labeled dose of 0.24 mg/kg would result in longer-lasting postoperative hyperthermia in cats vs a group receiving morphine 0.1 mg/kg SC.
Materials and methods
Anesthetic records from cats admitted for OVH as part of surgical exercises for second year veterinary medicine students in 2018 and 2019 were collected. All surgeries took place during May of each year. All cats were classified as American Society of Anesthesiologists physical status 1–2, based on physical examination and analysis of packed cell volume, plasma protein concentration, blood glucose concentration and semi-qualitative blood urea analysis. Cats were housed individually before and after surgery, and were fasted from solid food but not water for approximately 12 h prior to general anesthesia. In all cases, dexmedetomidine (Dexdomitor; Zoetis) 20 µg/kg and morphine (Morphine; West-Ward) 0.1 mg/kg combined in the same syringe were administered intramuscularly (IM) prior to anesthesia. Cats were left undisturbed in their cage for at least 10 mins. If sedation was insufficient for intravenous (IV) catheterization, ketamine (Ketathesia; Henry Schein Animal Health) 5 mg/kg was administered IM. General anesthesia was induced with propofol (Propofol; Sagent Pharmaceuticals) administered IV to effect after approximately 3 mins of oxygen supplementation via a face mask. The trachea was intubated with a cuffed tube and anesthesia was maintained with isoflurane in oxygen (2 l/min) using a pediatric circle respiratory circuit. All animals breathed spontaneously throughout. Cats were placed in dorsal recumbency and the abdomen was clipped and prepared for surgery. No methods for active warming were used during this stage.
Cats were transported to an adjacent surgical room and placed on a surgical table over a circulating warm water blanket (T/PUMP Heat Therapy Pump; Gaymar Industries) and a disposable impermeable underpad. The temperature of the circulating water blanket was set at 42°C. A midline laparotomy and OVH were performed. Monitoring included continuous electrocardiogram, pulse oximetry, capnography and esophageal temperature. Oscillometric blood pressure was measured every 2 mins. All cats received a balanced crystalloid solution (5 ml/kg/h). Warm water-filled gloves were placed around the cats’ neck and forelimbs if the esophageal temperature decreased below 36°C.
Upon completion of surgery, isoflurane was discontinued and the cats were allowed to awaken from anesthesia. Immediately after extubation, dexmedetomidine 1 µg/kg IV was administered at the discretion of the attending anesthesiologist to cats that were aggressive and/or difficult to restrain.
Postoperative opioids and temperature
During 2018, cats were operated on between 12:00 and 16:00 h and received morphine 0.1 mg/kg SC at extubation. During 2019, cats were operated on between 08:00 and 12:00 h and received buprenorphine 1.8 mg/ml (Simbadol; Zoetis), 0.24 mg/kg SC at extubation. In addition, all cats received robenacoxib (Onsior; Elanco) 6 mg PO administered 4 h after extubation.
Upon extubation, rectal temperature was measured (Digital Thermometer; AmerisourceBergen) and cats were returned to their cage, covered with a blanket and placed over a microwaveable warming pad. Cats that appeared excessively sedated received atipamezole (Antisedan; Zoetis) 0.1 mg/kg IM at the discretion of the attending anesthesiologist. Food and water were provided approximately 5 h after extubation.
Rectal temperature was obtained 1, 4 and 16–20 h after extubation. Cats were discharged from our program after 24 h.
Statistical analysis
Cats were divided into two treatment groups according to the postoperative opioid administered (morphine vs buprenorphine). The significance of differences in age, weight and administration of ketamine, supplemental dexmedetomidine or atipamezole were evaluated with t-tests for continuous variables and Fisher’s exact tests for binary ones. Because buprenorphine and morphine were administered at extubation, temperature values obtained prior to and during surgery were compared between groups with t-tests and interpreted as baseline information (prior to the treatments of interest); the average intraoperative temperature and the lowest registered value are presented and compared between treatment groups. Postoperatively, the effect of opioid treatment (morphine or buprenorphine), time and their interaction on temperature was assessed with a linear mixed-effect model; cat was used as the random effect, and treatment and time were used as fixed effects. The incidence of hyperthermia, defined as rectal temperature >39.2°C (102.5°F), was measured at baseline and at 1, 4 and 16–20 h post-extubation for each treatment group.
Given that long-lasting hyperthermia was our main outcome, the effects of treatment, time and their interaction on the incidence of hyperthermia at baseline and at 16–20 h were evaluated with a generalized linear mixed-effect model, using the family ‘binomial’ with a link function ‘cloglog’. Cats were assigned as a random effect and treatment, time and their interaction were assigned as fixed effects. Both the generalized and linear models were selected based on Akaike information criteria, Bayesian information criteria and –2 log likelihood criteria values.
Statistical analysis was carried out using the ‘lme4’ package of RStudio. Significance was set at P <0.05. Results are summarized as mean ± SD. Owing to the retrospective nature of this work, incomplete data sets were found. The number of animals analyzed for each variable is therefore indicated.
Results
One hundred cats were operated on in 2018 and received postoperative morphine, and 108 cats were operated on in 2019 and received postoperative buprenorphine.
The age and weight of cats in both treatment groups, as well as the number of animals that received ketamine, supplemental dexmedetomidine at recovery or atipamezole, are summarized in Table 1. There were no significant differences between treatment groups.
Age, weight and number of cats receiving ketamine (5 mg/kg IM), supplemental dexmedetomidine (1 μg/kg IV) or atipamezole (0.1–0.2 mg/kg IM) that had either buprenorphine 0.24 mg/kg or morphine 0.1 mg/kg SC for postoperative analgesia following ovariohysterectomy
Data are mean ± SD (n) or n (%)
Rectal temperature obtained prior to general anesthesia was not different between treatment groups (Table 2). The average intraoperative esophageal temperature and the lowest value registered during surgery were lower in those cats scheduled to receive postoperative morphine than in those scheduled to receive postoperative buprenorphine (both P ⩽0.0001) (Table 2). There were no cases of intraoperative hyperthermia.
Rectal (preoperative) and esophageal (intraoperative) temperatures in cats receiving buprenorphine 0.24 mg/kg or morphine 0.1 mg/kg SC for postoperative analgesia following ovariohysterectomy
Data are mean ± SD (n)
Postoperative rectal temperatures are shown in Figure 1. Significant effects of treatment and time (both P ⩽0.0001) were observed, where temperature increased over time, and cats receiving buprenorphine had higher temperatures than those receiving morphine. The maximum temperatures observed were 41.5°C in the buprenorphine group and 40.7°C in the morphine group.
Mean ± SD and individual values for rectal temperature measured in cats receiving buprenorphine 0.24 mg/kg (circles) or morphine 0.1 mg/kg (triangles) SC at recovery from ovariohysterectomy. A significant effect of time and treatment (both P ⩽0.0001) was observed, with temperature increasing over time and being higher for cats that received buprenorphine. Thresholds for hyperthermia and hypothermia are shown
The incidence of hyperthermia for those cats receiving buprenorphine or morphine at baseline and each postoperative time are shown in Table 3. When evaluating the effects of treatment and time on the incidence of hyperthermia at baseline and 16–20 h postoperatively, significant effects of time (P <0.0001) and treatment (P = 0.03) were observed; the incidence of hyperthermia was higher at 16–20 h than at baseline and was higher for cats receiving buprenorphine than for those receiving morphine.
Incidence of hyperthermia (rectal temperature >39.2°C) prior to sedation and 16–20 h after recovery from general anesthesia and ovariohysterectomy
Cats received either morphine 0.1 mg/kg or buprenorphine 0.24 mg/kg SC at extubation. There were significant effects of time and treatment whereby the incidence of hyperthermia was higher at 16–20 h after extubation than at baseline, and higher for cats receiving buprenorphine than for those receiving morphine
Discussion
In this retrospective analysis of anesthetized cats undergoing OVH at a veterinary teaching hospital, postoperative rectal temperature was higher in cats receiving buprenorphine 0.24 mg/kg SC postoperatively than in those receiving morphine 0.1 mg/kg SC postoperatively. Moreover, the incidence of hyperthermia measured 16–20 h after administration was exacerbated by buprenorphine.
We documented hyperthermia in both groups prior to anesthesia, with similar incidences of approximately 25%. The cause of preoperative hyperthermia was not determined, but ambient temperature, environmental conditions and stimuli, and stress may all have contributed to this finding.10,11 The incidence of hyperthermia increased in both groups 4 h after administration of either opioid. Almost a day after extubation and administration of postoperative opioids, the incidence of hyperthermia reached 73% in cats given buprenorphine; this value was higher than for those that received morphine and this difference was statistically significant. Presumably, any causes of preoperative hyperthermia may persist, at least in part, in the postoperative period. In addition, tissue trauma sustained during the operations may contribute to an increase in temperature in at least some of the cats.11,12 However, a higher incidence of hyperthermia occurred in cats receiving buprenorphine, despite otherwise equal management, suggesting that this agent administered at a large dose may prolong the duration of hyperthermia in addition to analgesia.
Hyperthermia of shorter duration secondary to opioid administration has been established previously using hydromorphone and buprenorphine in cats, with and without surgical procedures being performed.6,8 The effects of opioid administration on temperature is species-specific and typically manifests as hyperthermia in cats. 10 It has been shown that the influence of opioids on body temperature is due to alteration of the hypothalamic temperature set point, rather than impediment of thermoregulation.9,10 Given this previously established relationship, we chose to compare morphine, an opioid commonly used in our practice, with buprenorphine. In cats, morphine 0.2 mg/kg IM has been shown to have an elimination half-life of approximately 90 mins. This half-life was considerably shorter than that observed with 0.3 mg/ml buprenorphine administered at a dose of 0.01 mg/kg IM, which exceeded 6 h. 13 The elimination half-life of the dose and formulation of buprenorphine used in the present study ranged between 13 and 31 h. 3 Considering this information, we focused on the incidence of hyperthermia at 16–20 h post-extubation. Based on our results, the high dose of buprenorphine, intended to impart 24 h of analgesia, may perpetuate the short duration of hyperthermia already established for shorter-acting opioids. Our observations raise the question of whether or not smaller doses of buprenorphine, for example, 0.12 mg/kg, may provide sufficient analgesia while limiting the duration of hyperthermia.
Hyperthermia associated with opioid administration is typically self-limiting and benign. 8 As in Niedfeldt and Robertson’s study, 6 postoperative administration of a non-steroidal anti-inflammatory drug (in this case robenacoxib) to both groups did not avert continued temperature elevation. Sustained hyperthermia has the potential to confound recognition of postoperative fever and delay necessary interventions, or, alternatively, trigger unnecessary ones if hyperthermia is interpreted as fever. Despite the allure of long-lasting, single-injection analgesia in feline patients, this risk should be considered when including this agent in a surgical practice.
In this study, we examined temperature both as a continuous variable and as a binary one (presence or absence of hyperthermia). Hyperthermia in cats is poorly described in the literature. We defined hyperthermia as a rectal temperature >39.2°C. This definition was determined based on systematic review of previous studies on feline temperature.7,14,15 In a clinical setting, treatment for hyperthermia may not be necessary at these values of rectal temperature; however, careful monitoring for continued increases would be warranted to assure timely interventions or to diagnose if true fever is present.
The present study had several limitations. In 2018, surgeries occurred at 12:00 pm, while surgeries were performed at 8:00 am for the 2019 population. We cannot exclude any potential effects of the circadian cycle on rectal temperature. Nevertheless, surgical start times differed only by 4 h, and both groups were operated during daylight hours, making any effects of the circadian cycle likely smaller than if surgeries had been performed at opposite times of the light–dark cycle.16,17 Cats receiving postoperative morphine had lower intraoperative temperature than those receiving postoperative buprenorphine. This difference may reflect an improvement in prevention of hypothermia from one year to the next in our program. These values were monitored prior to administration of either agent and we cannot discount that these small differences may have influenced subsequent values. However, the difference between means was small (0.3°C). As with any retrospective study, the treatments were not assigned randomly; the anesthetic and monitoring protocols, however, were the same for both groups. In some cases, incomplete data sets were found. Despite this, the overall sample size was large enough that statistical power is not greatly affected by these omissions. Unfortunately, our anesthetic transcripts do not allow us to comment on the efficacy of postoperative analgesia in both groups, nor on the ultimate duration of hyperthermia. As seen from our results, a large number of cats in the buprenorphine group were discharged while hyperthermic.
Conclusions
The use of buprenorphine 0.24 mg/kg SC for postoperative analgesia in cats was associated with hyperthermia that persisted for 16–20 h after administration and the incidence of hyperthermia for this group was higher than in the cats that received morphine 0.1 mg/kg SC.
Footnotes
Author note
This paper was presented in part at the 2020 IVECCS conference.
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical approval
This work did not involve the use of animals and therefore ethical approval was not necessarily required.
Informed consent
This work did not involve the use of animals and therefore informed consent was not required. No animals or humans are identifiable within this publication, and therefore additional informed consent for publication was not required.
