Sedative effects of propofol in horses

Veterinary Anaesthesia and Analgesia, 2009, 36, 421–425

doi:10.1111/j.1467-2995.2009.00474.x

RESEARCH PAPER

Sedative effects of propofol in horses Robert J. Brosnan

DVM, PhD, Diplomate ACVA

& Eugene P. Steffey

VMD, PhD, Diplomate ACVA

Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA

Correspondence: Robert Brosnan, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA. E-mail: [email protected]

Abstract Objective We hypothesized that propofol can produce rapidly-reversible, dose-dependent standing sedation in horses. Study design Prospective randomized, blinded, experimental trial. Animals Twelve healthy horses aged 12 ± 6 years (mean ± SD), weighing 565 ± 20 kg, and with an equal distribution of mares and geldings. Methods Propofol was administered as an intravenous bolus at one of three randomized doses (0.20, 0.35 and 0.50 mg kg)1). Cardiovascular and behavioral measurements were made by a single investigator, who was blinded to treatment dose, at 3 minute intervals until subjective behavior scores returned to pre-sedation baseline values. Continuous data were analyzed over time using repeatedmeasures ANOVA and noncontinuous data were analyzed using Friedman tests. Results There were no significant propofol dose or temporal effects on heart rate, respiratory rate, vertical head height, or jugular venous blood gases (pHv, PvO2, PvCO2). The 0.35 mg kg)1 dose caused mild sedation lasting up to 6 minutes. The 0.50 mg kg)1 dose increased sedation depth and duration, but with increased ataxia and apparent muscle weakness. Conclusions and clinical relevance Intravenous 0.35 mg kg)1 propofol provided brief, mild sedation

in horses. Caution is warranted at higher doses due to increased risk of ataxia. Keywords horse, propofol, sedation.

Introduction Propofol has been used as a general anesthetic in horses (Mama et al. 1995), but to our knowledge its use as a sedative in horses has not been reported. Propofol is commonly used in small animals (Glowaski & Wetmore 1999) and humans (Mackenzie & Grant 1987) to produce effects ranging from light sedation to deep hypnosis to general anesthesia. Rapid elimination kinetics afford increased control over sedation level as well as rapid recoveries that are free of excitement or residual delirium. In addition, cardiovascular and respiratory depression, which can be profound at anesthetic doses, is far less at doses that produce light levels of sedation (Pratila et al. 1993). We hypothesized that subanesthetic propofol concentrations would produce dose-dependent sedation of short duration in horses, and that this sedation would be without evidence of significant cardiovascular or respiratory compromise. Methods We studied 12 healthy adult horses aged 12 ± 6 years (mean ± SD) weighing 565 ± 68 kg, and with an equal distribution of mares and geldings. Horse breeds included five thoroughbreds, three quarter horses, and one each of Arabian, Holsteiner, Saddlebred, and Standardbred. The 421

Equine propofol sedation RJ Brosnan and EP Steffey

University Animal Use and Care Committee approved this protocol. Using an aseptic technique, we placed a 16 gauge polytetrafluoroethylene catheter in the jugular vein of each horse. Separately, horses were walked into the middle of an arena with minimal restraint by a halter and lead rope. After a 15-minute acclimatization period, heart rate, respiratory rate, and vertical head height position from the ground to the nose were measured, and a venous blood sample was collected and stored on ice until gas analysis. Tactile stimulus responsiveness was assessed by touching a ball point pen to the ventral nare, and ataxia was assessed while the horse was walked in a tight circle. Auditory responsiveness was assessed following a 1 second 115 dB air horn discharge (Seasense; Unified Marine, Newport, TN, USA) approximately 6 m in front of the horse. Tactile and auditory obtundation and ataxia were subjectively scored as none, mild, moderate, or severe (Table 1). Baseline behavior and temperament were also noted for subsequent sedation comparisons. All scoring and measurements were performed by a single investigator (R.J.B.) who was blinded to drug treatment doses. Propofol (Diprivan; AstraZeneca, Wilmington, DE, USA) was administered intravenously over 20 seconds at one of three doses: 0.20, 0.35, or 0.50 mg kg)1 by a single investigator (E.P.S.). Horses received only one propofol dose (four horses per dose), and the order in which the doses were administered was randomized over all 12 study horses. These doses are approximately 10–25% of an anesthetic induction dose of propofol (Mama et al. 1995). Every 3 minutes after drug administration, heart rate, respiratory rate, and vertical head height were measured; venous blood gas

samples were collected; and ataxia and tactile and noise responses were assessed. Using baseline temperament for comparison, a horse was assigned one of the following subjective sedation scores at 3 minute intervals: no sedation, mild sedation, moderate sedation, severe sedation, or excitement (Table 1). Sedation assessments were based on general activity and alertness of horses in the absence of specific tactile or auditory stimulation. Common baseline demeanor for most horses included pulling on the lead rope; frequent attempts to move away from or around the handler; and interest in exploring the new arena environment. Evaluations continued for at least 9 minutes after propofol administration or until all subjective evaluations returned to baseline levels. Venous blood samples were analyzed using an automated gas analyzer (ABL 5; Radiometer America, Westlake, OH, USA), and alpha-stat (37 °C) values for pHv, PvO2, and PvCO2 were recorded. Measurements were made at approximately 16 m above sea level. Continuous data were described by mean ± SD and compared with baseline measures over time using repeated-measures ANOVA with Dunn-Sidak tests. Ordinal behavioral responses for each propofol dose were analyzed over time using Friedman tests. Comparisons were statistically significant if p < 0.05. Results Baseline physiologic measurements across all doses were as follows: respiratory rate 29 ± 8 breaths minute)1, heart rate 45 ± 11 beats minute)1, head height 124 ± 28 cm, pHv 7.44 ± 0.02, PvO2 32 ± 6 mmHg (4.3 ± 0.8 kPa), PvCO2 42 ± 4 mmHg (5.6 ± 0.6 kPa). There were no

Table 1 Descriptions of subjective criteria used for behavioral scoring in horses. A score of ‘none’ signifies no discernable drug effect

Score

Tactile

Noise

Ataxia

Sedation

None

Vigorously moves head away from stimulus Sluggishly moves head away from stimulus

Jumping and running away from noise Jumping, but not running away from noise

No deficits detected

Baseline demeanor

Dragging toe on ground

Moderate

Moves nose/lip but not head

Looking around

Stumbling or weaving

Severe Excitement

No response to stimulus

No response to stimulus

Falling

Not pulling on lead rope, but looking around and alert Not looking around, but moving ears Unresponsive to environment Increased activity from baseline

Mild

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Ó 2009 The Authors. Journal compilation Ó 2009 Association of Veterinary Anaesthetists, 36, 421–425

Equine propofol sedation RJ Brosnan and EP Steffey

significant dose or temporal differences found for any of these physiologic responses. However, the largest effect observed was a 7 mmHg (0.9 kPa) decrease in PvO2 with the 0.35 mg kg)1 dose compared with the 0.20 mg kg)1 dose (p = 0.25). A post-hoc power analysis predicted a minimum of 18 horses would have been necessary to reach statistical significance as defined by this study. Behavioral responses in 10 horses returned to baseline scores within 9 minutes of propofol administration; scores for the remaining two horses, both of whom received 0.5 mg kg)1 propofol, returned to baseline at the 12 minute assessment time. Subjective behavioral evaluations are shown in Fig. 1. Sedation scores significantly increased over time

with both the 0.35 and 0.5 mg kg)1 propofol doses. Although trending in the same direction with the 0.35 mg kg)1 dose, ataxia increased significantly with 0.5 mg kg)1 propofol. Horses in the two highest dose groups also showed some decrease in tactile responsiveness, but this never reached statistical significance. When present, propofol behavioral effects manifested within 3 minutes of administration. Sedation lasted up to 6 minutes with the 0.35 mg kg)1 dose and up to 12 minutes with 0.5 mg kg)1 propofol. However, one horse initially appeared excited at the highest dose coincident with increased ataxia and muscle weakness. Other behaviors occurring in horses at the 0.5 mg kg)1 dose included head

Figure 1 Response frequency for tactile, auditory, ataxia, and sedation subjective scores over a 9-minute study period for 12 horses receiving one of the following propofol doses: 0.20, 0.35, or 0.50 mg kg)1. Each bar represents behavioral responses for four individual study horses at a single time period after administration of a single propofol dose. Propofol doses showing a significant (p < 0.05) temporal effect are designated by an asterisk (*). No behavioral responses were different from baseline 12 minutes following propofol administration in any horse. Ó 2009 The Authors. Journal compilation Ó 2009 Association of Veterinary Anaesthetists, 36, 421–425

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shaking, twitching, pelvic limb trembling, and drooping of the lower lip; these may have also been related to muscle weakness and were resolved by the 6 minute evaluation time. Two geldings, one at each of the two highest doses, had an extruded penis that retracted by the end of the study period. Discussion Propofol can produce brief dose-dependent sedation in horses. However, increased ataxia and muscle weakness at higher doses place an upper limit on the maximum hypnotic effect that can be safely achieved in standing horses. The quality of propofol sedation differs from that of other equine drugs in contemporary use (Kerr et al. 1972). For example, propofol causes greater muscle weakness and ataxia than acepromazine, although a moderate tranquilizing dose similarly decreases spontaneous activity and can cause penile extrusion. Far greater sedation, in addition to analgesia, is possible with a2-agonists such as xylazine with less risk of recumbency. Horses administered a2-agonists also appear more overtly sedate; head position is lowered and responses to tactile and auditory stimuli are markedly decreased. Although not significant in this study, it is still possible that propofol may mildly diminish responses to auditory and tactile stimuli. The Friedman test lacks sufficient power to detect small effects with small sample sizes (Friedman 1937), and the Type II error rate may be increased for some behavioral responses. Yet, the sedation produced by either phenothiazines or a2-agonists at doses causing mild-to-moderate ataxia in horses, such as seen with 0.5 mg kg)1 propofol, is not at all subtle. In fact, four horses allocated to each dose group would probably be more than sufficient to demonstrate significant behavioral changes for conventional phenothiazine or a2-agonist sedatives. It follows that the responses of propofol to tactile and auditory stimuli that are not significantly different from baseline, even at the highest doses used in this study, likely have overall effect sizes that are much smaller than those of conventional equine sedatives; hence propofol may not as reliably obtund these responses in either research or clinical settings. The putative advantages of propofol as an equine sedative lie not in its hypnotic effects compared with other commonly used drugs, but rather in its pharmacokinetic profile. In horses, 424

acepromazine (Marroum et al. 1994) and xylazine (Garcia-Villar et al. 1981), respectively, have terminal half-lives of 70 and 50 minutes and mean residence times of 85.8 and 47.6 minutes. In contrast, propofol has a 27.6 minute elimination half-life and a 12.9 minute mean residence time (Rezende et al. 2007), which explain the short duration of sedative effects observed in this study. Even with a comparatively small tranquilization response, propofol could perhaps offer greater control over sedation depth because of its rapid elimination kinetics, particularly if used in combination with a second more efficacious sedativehypnotic drug. Conscious sedation with propofol in people has minimal depressant effects on mean arterial blood pressure, heart rate, SpO2, respiratory rate and ventilation (Pratila et al. 1993). Similarly, no cardiorespiratory measurements differed from baseline in horses at any time with any propofol dose. Mild propofol sedation in the equine might therefore be associated with more mild adverse effects on heart rate, blood pressure, and ventilation than either phenothiazines or a2-agonists (Kerr et al. 1972). Yet, a decrease in cardiac output could underlie the trend toward lower PvO2 (Wetmore et al. 1987) observed with the 0.35 mg kg)1 propofol dose. Consequently, the effects of subanesthetic doses of propofol on cardiac output in horses may still warrant further investigation. The highest propofol dose suggested a biphasic behavioral response: excitement during the first 3 minutes followed by mild-to-moderate sedation by 6 minutes (Fig. 1). We postulate that increased muscle weakness and ataxia at the 0.50 mg kg)1 dose also increased anxiety, and this stress response overrode the hypnotic properties of propofol. However, dysphoria related to GABAA activity – analogous to paradoxical benzodiazepine reactions reported in humans (Mancuso et al. 2004) – cannot be ruled out. Is there a role for propofol sedation in horses? Equine research studies requiring the use of general anesthesia may be confounded by long-lasting physiologic effects of pre-anesthetic drugs. Because of its short half-life, propofol sedation prior to anesthetic induction may help avoid problems with prolonged time-dependent drifts in cardiorespiratory measurements. In clinical settings, sedation of horses with propofol infusions could improve recovery quality following general inhalation anesthesia (Steffey et al. 2004). Low-dose propofol infusions

Ó 2009 The Authors. Journal compilation Ó 2009 Association of Veterinary Anaesthetists, 36, 421–425

Equine propofol sedation RJ Brosnan and EP Steffey

might also provide mild background tranquilization to facilitate standing chemical restraint with a second agent, such as a phenothiazine, a2-agonist, and/or opioid, but the doses for such combinations would need to be worked out carefully before being applied in a clinical setting. Future research may show propofol to be very useful in overcoming some limitations of common equine hypnotic sedatives for select patients and procedures. Acknowledgements The authors thank Don Hermes for technical assistance. This project was supported by the Center for Equine Health with funds provided by the State of California pari-mutuel fund and contributions by private donors. References Friedman M (1937) The use of ranks to avoid the assumption of normality implicit in the analysis of variance. J Am Stat Assoc 32, 675–701. Garcia-Villar R, Toutain PL, Alvinerie M et al. (1981) The pharmacokinetics of xylazine hydrochloride: an interspecific study. J Vet Pharmacol Ther 4, 87–92. Glowaski MM, Wetmore LA (1999) Propofol: application in veterinary sedation and anesthesia. Clin Tech Small Anim Pract 14, 1–9.

Kerr DD, Jones EW, Holbert D et al. (1972) Comparison of the effects of xylazine and acetylpromazine maleate in the horse. Am J Vet Res 33, 777–784. Mackenzie N, Grant IS (1987) Propofol for intravenous sedation. Anaesthesia 42, 3–6. Mama KR, Steffey EP, Pascoe PJ (1995) Evaluation of propofol as a general anesthetic for horses. Vet Surg 24, 188–194. Mancuso CE, Tanzi MG, Gabay M (2004) Paradoxical reactions to benzodiazepines: literature review and treatment options. Pharmacotherapy 24, 1177–1185. Marroum PJ, Webb AI, Aeschbacher G et al. (1994) Pharmacokinetics and pharmacodynamics of acepromazine in horses. Am J Vet Res 55, 1428–1433. Pratila MG, Fischer ME, Alagesan R et al. (1993) Propofol versus midazolam for monitored sedation: a comparison of intraoperative and recovery parameters. J Clin Anesth 5, 268–274. Rezende ML, Stanley SD, Boscan P et al. (2007) Pharmacokinetics of a novel microemulsion formulation of propofol in horses. Vet Anaesth Analg 34, 293 (abstract). Steffey EP, Mama KR, Brosnan RJ et al. (2004) Use of propofol to modify equine recovery characteristics after 4 hours of isoflurane or desflurane anesthesia. Vet Anaesth Analg 31, 45 (abstract). Wetmore LA, Derksen FJ, Blaze CA et al. (1987) Mixed venous oxygen tension as an estimate of cardiac output in anesthetized horses. Am J Vet Res 48, 971–976. Received 7 January 2008; accepted 23 July 2008.

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