Effect of administration rate on propofol requirement in cats

Abstract

Objectives

The objective of this study was to determine the effect of administration rate on propofol dose for induction of anesthesia and the effect of methadone on this dose.

Methods

This was a prospective, randomized, blinded clinical study. Forty male cats (mean ± SD age 1.5 ± 0.8 years) were admitted for orchiectomy. Cats were randomly allocated to receive acepromazine (0.05 mg/kg) with either methadone (MET; 0.3 mg/kg) or saline (SAL; 0.03 ml/kg). Each premedication group then received anesthetic induction with propofol at 5 (F) or 1.5 mg/kg/min (S), resulting in the following four groups: MET-F, SAL-F, MET-S and SAL-S. Sedation scores were assigned at 15 and 30 mins after premedication using a simple descriptive scale (SDS) and a visual analog scale (VAS). After assignment of sedation scores, respiratory frequency (f_R) was recorded, and anesthetic induction began and was continued until cats lost their palpebral reflexes and jaw tone, and the eye globe rotated ventromedially. The time for induction and the total amount of propofol needed was recorded, and intubation was then performed. After intubation, f_R was also recorded.

Results

SDS and VAS sedation scores were low at 15 and 30 mins after premedication. There was no significant difference in sedation scores by time or between the groups at any time on any scale. The amount of propofol needed to achieve anesthetic induction was 5.3 ± 1.1 mg/kg in group MET-F, which was statistically lower when compared with the other three groups, which demonstrated no difference among them.

Conclusions and relevance

Premedication with acepromazine and methadone was not able to produce adequate sedation in healthy cats. The slow induction rate is not adequate for use in cats considering that all of the animals demonstrated excitement during anesthetic induction. The fast administration rate was able to produce adequate induction of anesthesia and reduce the amount of propofol needed to achieve intubation only when using methadone.

Introduction

Propofol (2,6-diisopropyl-phenol) is an alkylphenol hypnotic agent that is insoluble in water and formulated as a lipid emulsion. In cats, propofol has a slow clearance rate and a prolonged elimination half-life compared with in humans and dogs. ¹ These properties are likely because cats do not express the UGT1A6 and UGT1A9 enzymes that are responsible for the metabolism of simple planar phenolic structure compounds. ¹ Cats must use alternative pathways to metabolize propofol, such as oxidation to 4-hydroxypropofol, in which the lungs play an important role, as described by Matot et al, ² followed by sulfation. Despite the differences among species, propofol remains widely used as an anesthetic induction agent in cats.^1,3 Injecting propofol slowly avoids overdose and minimizes cardiorespiratory depression, and the induction dose of propofol is reduced at slow infusion rates in humans and rats.^4,5

Premedication in veterinary patients allows for restraint, sedation, pre-emptive analgesia and a reduced need for other anesthetic agents. Previous studies have attempted to quantify this propofol-sparing effect in many protocols. Within these protocols, the use of acepromazine was successful in reducing propofol requirements. Acepromazine is often combined with opioids because of the use of opioids in treating acute pain, as well as their ability to enhance the sedation of acepromazine. Opioids constitute the main drug class used for the treatment of pain in most species, including cats, because of its efficacy, safety and versatility.

Methadone is a synthetic mu agonist opioid that acts on various non-traditional pain pathways. In cats, methadone used in association with acepromazine was found to produce low sedation scores yet provided adequate restraint for catheter placement. ⁶

The aim of this study was to evaluate the effect of different induction rates of propofol administration on the total amount of propofol needed to induce anesthesia. We also attempted to quantify the propofol-sparing effect of premedication with methadone.

Materials and methods

Forty healthy cats admitted to our institution for orchiectomy were included in this study. The study was approved by the ethics committee (CEUA/IV/UFRRJ; protocol 027/2015). Written informed consent was obtained from clients. Inclusion criteria determined that each cat should be at least 8 months old, weigh between 2.0 and 6.0 kg, and should meet the criteria of the American Society of Anesthesiologists class I.

Cats were fasted for 12 h prior to anesthesia. The animals were kept in individual cages in a calm and quiet environment for 30 mins before premedication to reduce stress interference in the sedation evaluation. Cats were then randomly assigned to one of four groups: (1) MET-F (n = 10), which received acepromazine (0.05 mg/kg Acepran; Vetnil) with methadone (0.3 mg/kg Mytedom; Cristália) intramuscularly (IM) and then 30 mins later received anesthetic induction with propofol (Propovan; Cistália) at 5 mg/kg/min intravenously (IV); (2) MET-S (n = 10), which received acepromazine (0.05 mg/kg) with methadone (0.3 mg/kg) IM and then 30 mins later received anesthetic induction with propofol at 1.5 mg/kg/min IV; (3) SAL-F (n = 10), which received acepromazine (0.05 mg/kg) with saline (0.03 ml/kg), in order to maintain the same injected volume in all groups, IM, and then 30 mins later received anesthetic induction with propofol at 5 mg/kg/min IV; and (4) SAL-S (n = 10), which received acepromazine (0.05 mg/kg) with saline (0.03 ml/kg) IM and then 30 mins later received anesthetic induction with propofol at 1.5 mg/kg/min IV. The anesthetist responsible for all of the evaluations was blinded to the premedication protocol administered to each cat. After premedication, the cats were returned to their cages in a silent environment for sedation evaluation before anesthetic induction.

Sedation scores were assigned at 15 and 30 mins after premedication, using a simple descriptive scale (SDS; score range 0–3), where 0 indicates no sedation and 3 indicates profound sedation; ⁶ and a visual analog scale (VAS; score range 0–100 mm), where 0 indicates no sedation and 100 indicates the most profound sedation possible. After the sedation scores were assigned, a 24 G catheter (Angiocath; BD) was placed in a cephalic vein, and lactated Ringer’s solution (Solução de Ringer lactato; B Braun) was administered at 5 ml/kg/h IV. Anesthetic induction was performed IV at one of the two rates previously determined: 5 mg/kg/min or 1.5 mg/kg/min. Propofol was administered with the aid of a syringe pump (DigiPump SR7x; Digicare Biomedical). The infusion was stopped as cats lost their jaw tone and palpebral reflexes and demonstrated ventromedial rotation of the eye globe. At this time, the total amount of propofol needed was recorded. Endotracheal intubation was performed with an uncuffed tube of adequate size immediately after the completion of the propofol infusion. Incidences of side effects, such as apnea or excitement, were also recorded. The respiratory frequency (f_R) was recorded immediately before propofol infusion and after the intubation. All cats underwent orchiectomy under local anesthesia and also received meloxicam and dipyrone.

Statistics

The data were analyzed using StatPlus:mac, version 5, a statistical analysis program for Mac OS (AnalystSoft). The Shapiro–Wilk test was used to test for normality. One-way repeated measures ANOVA with Tukey’s multiple comparison test was used to analyze the propofol dose. For sedation, groups SAL-F and SAL-S were evaluated as a single group (SAL), and MET-F and MET-S were evaluated together (MET). Sedation scores between groups were compared using the Mann–Whitney U-test and over time within groups using the Wilcoxon test. The incidence of adverse effects in different induction rates was analyzed with the Friedman test. Parametric data are reported as the mean ± SD, and non-parametric as median (range). Significance was set at P <0.05.

Results

Forty mixed breed cats entered and completed the study. Age (1.5 ± 0.8 years) and weight (3.8 ± 0.7 kg) did not differ among the groups.

All sedation scores were 0 prior to premedication. Using a SDS, the cats in groups MET-F and MET-S were grouped for sedation analysis and had scores of 0 (10/20) or 1 (10/20) 15 mins after premedication and scores of 0 (9/20) or 1 (11/20) 30 mins after premedication. There was no significant difference within time (P = 0.317). Cats in groups SAL-F and SAL-S were also grouped and presented SDS scores of 0 (12/20) or 1 (8/20) 15 mins after premedication and scores of 0 (10/20) or 1 (10/20) 30 mins after premedication. There was no significant difference by time (P = 0.180). When comparing groups, there was no difference between MET and SAL groups at 15 mins after premedication (P = 0.463) or at 30 mins after premedication (P = 0.767). On the VAS, groups MET (F and S) were evaluated together, as well as groups SAL (F and S). The median (range) for group MET was 23 (15–30) at 15 mins and 26 (15–30) at 30 mins, without differences by time (P = 0.091). The SAL group had a median (range) score of 18 (10–27) and 24 (10–27) at 15 and 30 mins after premedication, respectively, also without differences by time (P = 0.110). When comparing groups, there were no statistically significant differences at 15 mins (P = 0.112) or at 30 mins (P = 0.151).

Anesthetic induction was performed in 64 ± 14 s in group MET-F. This value did not differ significantly from that of group SAL-F, which required 95 ± 12 s (P = 0.460) for induction of anesthesia. However, fast-induction groups had significantly different results (P <0.001) from those of the MET-S (342 ± 61 s) and SAL-S (342 ± 67 s) groups, which did not differ among groups (P = 0.999). The total dose of propofol for anesthetic induction in group MET-F was 5.3 ± 1.1 mg/kg, significantly different (P <0.001) when compared with all groups: SAL-F (7.9 ± 0.9 mg/kg), MET-S (8.5 ± 1.4 mg/kg) and SAL-S (8.6 ± 1.6 mg/kg). Other groups did not differ among each other (P >0.05). The excitement incidence in group MET-S was significantly higher (P <0.001) than that in group MET-F. The same observation (P <0.001) was apparent between groups SAL-S and SAL-F.

None of the animals enrolled in this study experienced apnea. The f_R was significantly different (P <0.001) before and after induction among all groups. In group MET-F, after induction, we observed a f_R of 13 ± 3, which was significantly different from group MET-S (20 ± 2). Similarly, group SAL-F had a f_R of 14 ± 3, which was significantly different (P <0.001) from that of group SAL-S (19 ± 2).

Discussion

This study compared two different rates of propofol induction. The total amount of propofol needed to induce anesthesia was reduced only when methadone was combined with the fastest rate of propofol administration. Despite the incidence of excitement in all animals receiving a slow propofol induction (MET-S and SAL-S), we believe that excitement might have a minor role in the increasing of the total amount needed for induction, owing to the lack of difference in propofol dose among the SAL-F and SAL-S groups.

Propofol can produce a significant reduction in stroke volume and left cardiac work indices, even when using a single dose. ⁷ It has been suggested that slower induction rates can reduce anesthetic requirement and could therefore reduce these cardiac effects. ⁴ However, the increasing time for induction increases the chance of a low-quality induction, as demonstrated by signs of excitement. ⁸ Our research noted excitement in all cats under a slow induction rate, reaffirming this hypothesis.

In humans, the relation between rate and requirement is not linear. Stokes and Hutton noted that the increase in propofol rate follows the increase in anesthetic dose requirement, to some extent. ⁴ However, when increasing the rate of induction even more, the dose requirement was reduced. Larsson and Wahlström, ⁵ in rats, observed an ideal rate of induction related to minimal dose requirement. From this ideal rate, the reduction or increase in this rate is related to an increase in the dose requirement, and also demonstrates a non-linear relation between rate and requirement. Similarly, we have shown that the total amount needed for induction rises when using slower rates.

Similar to the results of this study, Warne et al used a slow induction rate and reported that high doses were needed to achieve induction, despite the premedication protocol. ⁹ Comparing groups SAL-S and SAL-F, the reduction of induction time depressed excitement, but no statistically significant differences in propofol dose requirement were observed. In one study, Pascoe et al concluded that acepromazine alone exerts minimal influence on propofol. ¹⁰ However, as described by Taboada and Murison, ¹¹ the effects of opioids used as premedication were potentiated by acepromazine. Taboada and Murison found dosage requirements of propofol very similar to those of the SAL-F group, at the same infusion rate. ¹¹ These data show the leverage of methadone with propofol, which can be demonstrated only at higher infusion rates, as in the MET-F group. When performing anesthetic induction with propofol at 5 mg/kg/min (MET-F), methadone reduced the total dose requirement of propofol by approximately a third. Using only two different induction rates we could not determine an ideal induction rate of propofol in cats. More studies are needed to determine this ideal rate.

Although apnea is a well-known side effect of propofol, none of the animals enrolled in this study experienced this complication. These data concur with those of Taboada and Murison, when using a similar infusion rate. ¹¹ A significant reduction on f_R after induction may also be due to stress at the time of catheter placement, because the animals presented a high f_R before induction. Apnea is related to, among other factors, the rate of anesthetic induction. ⁷ The lack of apnea in this study may be due to the rates used in this study. Even when using the fastest rate, induction was achieved within a minute, still a slow rate. Slower induction rates are associated with increased time necessary to induce unconsciousness. Additionally, slow induction rates result in a greater time requirement to achieve plasma concentrations of propofol able to depress the respiratory center. This can be explained by the uptake of propofol by other tissues, particularly the lungs, and its subsequent redistribution. ²

It was apparent that methadone is capable of promoting weak sedation, manifested as low sedation scores in both scales. This observation is in agreement with Mair et al, ¹² who demonstrated the same association of similar doses and low sedation scores. Bortolami et al reported low scores in association with ease of restraint. ⁶ Most cats demonstrated behavior consistent with euphoria, such as kneading the forepaws, purring and rubbing after premedication. These behaviors may have lessened the restraint requirements, although they were not able to be measured by the sedation scales. However, proper restraint was still required at catheter placement.

Conclusions

This study has demonstrated that methadone in conjunction with acepromazine, as well as acepromazine alone, promotes inadequate sedation for restraint at the doses used in this study. The use of methadone helped to reduce the amount of propofol needed to induce anesthesia in cats when a fast induction rate was used. The interaction between premedication and induction rate can alter the total dose of propofol needed to achieve anesthetic induction in cats. More research is needed to establish the relationship between the infusion rate of propofol and the total dose for induction, as well as safe rates, to induce anesthesia with minimum side effects.