Influence of two administration rates of propofol at induction of anaesthesia on its relative potency in cats: a pilot study

Abstract

Objectives

This was a randomised, blinded trial to investigate the influence of administration rate on the dose of propofol required for the orotracheal intubation of cats.

Methods

Twenty-four female domestic cats undergoing ovariohysterectomy were premedicated with oral tramadol (6 mg/kg) or intramuscular tramadol (4 mg/kg), and intramuscular dexmedetomidine (0.007 mg/kg). Oral or intramuscular (IM) tramadol was administered 60 or 30 mins prior to induction of anaesthesia, respectively. Dexmedetomidine was administered 30 mins prior to anaesthetic induction. Sedation scores were established prior to anaesthesia induction with propofol intravenously at 4 mg/kg/min (fast) or 1 mg/kg/min (slow) to effect until orotracheal intubation was achieved without coughing. If coughing occurred, the intubation process was paused for 15 s. Four groups were determined: IM tramadol/propofol fast (GIMF, n = 6); IM tramadol/propofol slow (GIMS, n = 6); oral tramadol/propofol fast (GOF, n = 6); oral tramadol/propofol slow (GOS, n = 6). The Shapiro–Wilk test was used to evaluate for normality of residuals. Sedation scores and propofol anaesthetic induction doses were compared between GIMF and GIMS groups, and between GOF and GOS groups using the Mann–Whitney test and the t-test, respectively (P = 0.05). The presence of hypotension (mean arterial blood pressure <60 mmHg) or apnoea (no breathing for 30 s or more) within the first 15 mins postintubation was recorded.

Results

The median sedation scores for GIMF and GOF were not significantly different compared with those for GIMS (P = 0.94) and GOS (P = 0.70). However, the mean ± SD propofol anaesthetic induction doses were higher in GIMF (9.1 ± 1.8 mg/kg) and GOF (7.9 ± 1.7 mg/kg) than in GIMS (5.1 ± 1.5 mg/kg; P <0.01) and GOS (5.4 ± 0.3 mg/kg; P <0.01). No hypotension or apnoea were detected.

Conclusions and relevance

Using the slower anaesthetic induction rate resulted in an increase in propofol relative potency.

Introduction

Propofol is an intravenous (IV) anaesthetic commonly used to induce anaesthesia in many species, which activates the inhibitory gamma-aminobutyric acid (GABA)_A receptors. In cats it can induce dose-dependant decreases in heart rate (HR), myocardial contractility and arterial blood pressure, and increase end-tidal partial pressure of carbon dioxide (EtCO₂), owing, partly, to a decrease in respiratory rate (RR).^1,2

In humans, slower propofol infusion rates have been associated with significantly lower doses of propofol to induce anaesthesia, and resulted in less cardiovascular and respiratory depression. ³ A recent study in cats demonstrated that a slower induction infusion rate of another commonly used IV anaesthetic (alfaxalone), which also activates the GABA_A receptors, resulted in a reduction in the alfaxalone dose needed to achieve orotracheal intubation. ⁴ The aims of the present study were to evaluate the influence of propofol administration rate at induction of anaesthesia on its relative potency in cats. The hypothesis was that a slower anaesthetic induction infusion rate would achieve anaesthesia using a lower dose of propofol.

Materials and methods

This randomised, controlled, masked clinical trial was approved by the animal ethics committee of the University of Melbourne Faculty of Veterinary and Agricultural Sciences. Between September 2015 and March 2016 the owners of all cats that were admitted to the University Veterinary Clinic and Hospital for elective ovariohysterectomy were asked if they wanted their cat to be included in the trial if the cats met the following inclusion criteria. The cats had to be determined healthy by means of a thorough physical examination and basic blood analysis (packed red blood cell volume, total protein, glucose, urea), and accommodating enough to allow arterial blood pressure measurements in triplicate using non-invasive oscillometric blood pressure while awake and non-sedated. Written informed consent was obtained from the cats’ owners. The study enrolment stopped after 24 domesticated female cats aged 17 weeks to 2 years were included in the trial.

Using the random function of a spreadsheet (Microsoft Excel 2010), cats were allocated by one of the authors (SHB) to one of the following four groups: intramuscular (IM) tramadol/propofol fast (GIMF, n = 6); IM tramadol/propofol slow (GIMS, n = 6); and oral tramadol/propofol fast (GOF, n = 6); oral tramadol/propofol slow (GOS, n = 6).

The cats were weighed and premedicated with oral tramadol (Tramal, 50 mg capsule; Grunenthal GmbH) 6 mg/kg, or IM tramadol (Tramal, 50 mg/ml; Grunenthal GmbH) 4 mg/kg, and IM dexmedetomidine (Dexdomitor; Zoetis) 0.007 mg/kg.

The content of each 50 mg tramadol capsule was weighed using a semi-microbalance (A&D GH-252; 101 g capacity, 0.01 mg readability) and the calculated appropriate dose for each cat was re-encapsulated.

Oral tramadol was administered 60 mins prior to induction of anaesthesia. IM tramadol was administered at the same time as dexmedetomidine, 30 mins prior to induction of anaesthesia. Ten minutes prior to induction of anaesthesia the sedation level was assessed using a published scoring system (Table 1) and a 22 G over-the-needle catheter was placed in a cephalic vein.^4,6 Anaesthesia was induced with propofol (Provine, propofol emulsion injection, 10 mg/ml; Claris Lifesciences) IV at 4 mg/kg/min (fast) or 1 mg/kg/min (slow) to effect until orotracheal intubation was achieved using a calibrated volumetric infusion pump (Baxter Colleague 3CX; Baxter Healthcare). Once the cat was not supporting its head and its jaw tone was relaxed, lidocaine (5 mg) was sprayed over the larynx (Co-Phenylcaine Forte spray, lidocaine 5%, phenylephrine 0.5%; ENT Technologies) and 15 s later orotracheal intubation attempted. If the jaw tone was sufficient to prevent intubation, the anaesthetist allowed 15 s to elapse before testing the jaw tone again. If the animal coughed or resistance to passing the endotracheal tube was met, the process was halted for 15 s before attempting intubation again. Immediately upon successful orotracheal intubation, the propofol infusion was stopped and the endotracheal tube was connected to a paediatric rebreathing system and isoflurane in oxygen was administered (1.5%, 1 l/min).

Table 1

Sedation scores were ascribed following a published scale^4,5

Sedation score	Score description
1	No discernible effect
2	Mild sedation (appears sleepy)
3	Moderate sedation (very sleepy, may be recumbent but could be roused)
4	Heavy sedation (recumbent, difficult rousing)
5	Profound sedation (lateral recumbency and not rousable)

The total dose of propofol given to achieve anaesthetic induction and orotracheal intubation was defined as propofol anaesthetic induction dose, and the anaesthetic induction time was calculated by dividing the propofol anaesthetic induction dose by the rate of administration.

A multi-parametric anaesthesia monitor (Vet Advisor V9203; Smiths Medical PM) was used to monitor electrocardiogram, HR, RR, EtCO₂ and haemoglobin oxygen saturation (by pulse oximetry [SpO₂]). Mean arterial blood pressures (MABP) were obtained via a non-invasive oscillometric blood pressure device (petMAP graphic; Ramsey Medical) placed above the metacarpal region.

Heart rate and RR were monitored continuously (using the ECG and by visual observation of the chest movement, respectively) starting at induction of anaesthesia. Heart rate, RR and MABP were recorded immediately postintubation and at 5, 10 and 15 mins postintubation.

The presence of excitement during induction of anaesthesia, bradycardia (HR <95 beats per min), hypotension (MABP <60 mmHg) or apnoea (no evidence of breathing for 30 s or more) within the first 15 mins postintubation were recorded. Positive pressure ventilation was implemented if the cat became hypoxaemic (SpO₂ <90%).

Postoperative analgesia consisted of meloxicam (Metacam; Boehringer Ingelheim) 0.2 mg/kg subcutaneously and methadone (Methone; Ceva Animal Health) 0.2 mg/kg IV, if required.

All cats were assessed for sedation, monitored and had their tracheas intubated by the same trained anaesthetist (WB), who was unaware of the treatment. Statistical analyses and graphic representations were performed using commercially available software (IBM SPSS Statistics 22, and Prism 6 for Windows [GraphPad Software]). The Shapiro–Wilk test was used to test for normality of data (age, weight) and residuals (propofol anaesthetic induction dose, duration of anaesthetic induction, MABP, HR and RR). Age, sedation scores and duration of anaesthetic induction were compared between the GIMF and GIMS groups, and between the GOF and GOS groups using Mann–Whitney tests. Mean weight and mean propofol anaesthetic induction doses were compared between GIMF and GIMS groups, and between GOF and GOS groups using t-tests. The effect of propofol infusion rates and the route of administration of tramadol on propofol anaesthetic induction dose were tested using two-way factorial ANOVA. The effect of propofol infusion rates during the first 15 mins post-tracheal intubation on HR, MABP and RR were tested using two-way ANOVA corrected for repeated measures (Sidak’s multiple comparisons test). Significance was set at P <0.05. Unless specified, results are reported as mean ± SD.

Results

For the following parameters no statistically significant difference was noted between the two groups: for GIMF and GIMS, respectively, weights were 2.8 kg ± 0.4 kg and 2.4 kg ± 0.7 kg (P = 0.38) and median age was 32 weeks (range 22–43 weeks) and 26 weeks (range 22–102 weeks) (P = 0.94); for GOF and GOS, respectively, weights were 2.9 kg ± 0.7 kg and 2.2 kg ± 0.4 kg (P = 0.13) and median age was 58 weeks (range 19–103 weeks) and 24 weeks (range 22–77 weeks) (P = 0.18). The median sedation scores for GIMF (2 [range 1–2]) and GOF (2 [range 1–3]) were not significantly different compared with those from GIMS (2 [range 1–3]; P = 0.94) and GOS (2 [range 1–3]; P = 0.70).

Sedation scores, anaesthetic induction times and propofol anaesthetic induction doses are shown in Figure 1. The median anaesthetic induction times were shorter in GIMF (140 s [range 104–172 s]) and GOF (126 s [range 75–145 s]) than in GIMS (312 s [range 163–428 s]; P <0.01) and GOS (328 s [range 288–344 s]; P <0.01). Propofol anaesthetic induction doses were higher in GIMF (9.1 mg/kg ± 1.8 mg/kg) and GOF (7.9 mg/kg ± 1.7 mg/kg) than in GIMS (5.1 mg/kg ± 1.5 mg/kg; P <0.01) and GOS (5.4 mg/kg ± 0.3 mg/kg; P <0.01). Overall, faster propofol infusion rates significantly increased propofol anaesthetic induction doses (P <0.001); however, the route of administration of tramadol appeared to have no influence (P = 0.45) (Figure 1d).

Figure 1

Box and whisker plots of the (a) preinduction sedation scores, (b) duration of induction of anaesthesia, (c) propofol induction doses, and (d) estimated marginal mean of propofol induction doses. Twenty-four cats undergoing ovariohysterectomy received dexmedetomidine (0.007 mg/kg IM) and either tramadol intramuscularly (IM; 4 mg/kg) and propofol fast induction rate intravenously (IV; 4 mg/kg/min) (GIMF, n = 6); tramadol IM (4 mg/kg) and propofol slow induction rate IV (1 mg/kg/min) (GIMS, n = 6); tramadol oral (6 mg/kg) and propofol fast induction rate (4 mg/kg/min) (GOF, n = 6); or tramadol oral (6 mg/kg) and propofol slow induction rate (1 mg/kg/min) (GOS, n = 6). Sedation scores were obtained by use of a published scale ranging from 1 (no sedation) to 5 (profound sedation).The box indicates the interquartile range (25th–75th percentile), the bold black line indicates the median and the whiskers indicate the range. *Statistical difference between two groups (P <0.01)

The cats that received the faster propofol infusion rate had, on average, significantly higher MABP (P = 0.03) and lower RR (P = 0.02) postinduction, but no significant effect of the infusion rate on HR (P = 0.26) was detected. HR, MABP, RR and statistical significances at the different time points are represented in Figure 2. None of the cats developed apnoea. The EtCO₂ remained ⩽50 mmHg in all cats. Neither bradycardia nor hypotension was seen in any of the groups.

Figure 2

Effects of two propofol anaesthetic induction infusion rates (1 and 4 mg/kg/min) on (a) heart rate (HR), (b) mean arterial blood pressure (MABP) and (c) respiratory rate (RR). Twenty-four cats undergoing ovariohysterectomy received dexmedetomidine (0.007 mg/kg IM) and either tramadol IM (4 mg/kg, n = 12) or tramadol oral (6 mg/kg, n = 12) as anaesthetic premedication. HR, RR and MABP were recorded immediately postintubation and at 5, 10 and 15 mins postintubation. *Statistically significant difference between the groups at a particular time point (P = 0.04)

Discussion

To our knowledge this study demonstrates, for the first time, that using propofol at a slower infusion rate increases its potency in cats. The cats that were enrolled in the study were representative of the domestic population and there were no outstanding differences in their temperament. The effects of the anaesthetic premedication were mild, and no cats exhibited signs of excitement or dysphoria during anaesthetic induction.

As reported previously with alfaxalone for induction of anaesthesia in cats, the slower infusion rate resulted in a decreased propofol anaesthetic induction dose requirement. ⁴ This phenomenon, also seen in humans and in a physiological model in sheep, was explained by a lower but more sustained propofol concentration gradient for even drug delivery throughout the central nervous system when using a slower infusion rate.^3,7 In sheep, the slower infusion rate was also associated with a decrease in propofol peak arterial concentration. ⁷ We also believe that the depth of anaesthesia keeps increasing after the propofol infusion is stopped as the concentration of propofol in the central nervous system continues to rise for some time. This phenomenon of overshooting may be exaggerated by a higher infusion rate.

As the two-way factorial ANOVA analysis failed to show that the route of administration of tramadol had any influence on propofol requirement, the MABP, HR and RR data were only segregated based on propofol infusion rate. As expected, RR was lower in GIMF and GOF combined when compared with GIMS and GOS combined; however, the higher infusion rate group had paradoxically greater postinduction MABP. Owing to the pilot nature of this study (ie, low number of subjects, weight of the animals and non-invasive nature of the data collected) it would be adventurous to draw firm conclusions based on these results, and we can only suggest some lines of thought that could explain those results. Tachycardia preceding a decrease in MABP was described by Child et al following anaesthetic induction with alfaxalone. ⁵ In the present study, an increase in HR could also be observed in the high propofol infusion rate group. However, unlike the cats used in the study by Child et al, ⁵ the cats in the present study received dexmedetomidine in their premedication, increasing their peripheral vascular resistance. The combination of an increase in HR and an increase in peripheral vascular resistance would result in an increase in MABP. The lower RR in the faster infusion rate group could be one other explanation for the higher MABP. Indeed, a lower RR would result in a lower isoflurane uptake and better cardiovascular stability. ⁸

Conclusions

This study demonstrated that using propofol at a slower infusion rate increases its potency in cats. However, further studies with higher numbers of cats and more invasive cardiovascular monitoring would need to be performed to investigate the paradoxical cardiovascular effects seen.