Behavioral and cardiorespiratory effects of a medetomidine and tramadol combination in horses

Abstract

Importance

The use of combinations of sedative and analgesic drugs during standing procedures in horses is necessary to provide reliable sedation with minimal ataxia and reduced responses to surgical or other stimuli in horses.

Objective

This study assessed the behavioral and cardiorespiratory effects of medetomidine (M) administered with and without tramadol (T) in horses.

Methods

Eight horses were sedated intravenously with M (5 µg/kg) alone or with T (2 mg/kg) in a arandomized, blind, two-way crossover trial. Behavioral responses, including head height above the ground (HHAG), postural instability (PI), and response to pressure stimulus (RPS), and cardiorespiratory responses, including vital variables and blood analyses, were assessed following administration.

Results

There were no clinically meaningful differences in cardiorespiratory values, HHAG, or PI between the groups. The RPS score over the scapula was significantly higher in the medetomidine and tramadol (MT) group (p < 0.05) and a trend towards a higher RPS score over the femur was observed (p = 0.08) in the MT group. Heart rate decreased significantly below baseline from 10 to 40 min in both treatments.

Conclusions and Relevance

These results suggest that the MT combination may provide sufficient sedation and analgesia with minimal cardiorespiratory changes in horses.

INTRODUCTION

Sedatives and analgesics are commonly used for clinical diagnosis and surgery on horses [1,2,3]. Several drug combinations, including alpha-2 agonists and opioids, have been used to minimize side effects and provide adequate analgesia and sedation [2,4,5,6]. Agonists of the alpha-2 adrenoreceptor with opioids are commonly used for standing surgery in horses, such as laparoscopy, wound repair, and castration [5,7,8,9].

Medetomidine (M) is a potent alpha-2 adrenergic receptor agonist with an exceptional alpha-2:alpha-1 selectivity ratio of 1,620:1 [10]. Numerous studies have investigated the use of M in horses [11,12,13,14] and reported an analgesic effect with a very short duration [13]. M has been reported to produce levels of ataxia and sedation comparable to those of xylazine [15], although another study found that while the level of sedation was similar, the duration of ataxia was longer [16].

Tramadol (T) is a synthetic analgesic opioid applied for pain control [17] that acts on the μ–opioid receptor with a low risk of substance dependence [18]. However, recent research shows its mechanism is more complex. T not only prevents the reuptake of serotonin and norepinephrine, but also interacts with various other receptors, including adrenoceptors, neurokinin-1, muscarinic, N-methyl-D-aspartate, and transient receptor potential vanilloid receptors [19,20,21].

T has potential opioid analgesic effects in horses and is not a controlled substance in South Korea [22,23]. Opioid analgesics are useful in pain management in horses, but the potential adverse effects, including excitatory signs, are a concern [24,25]. Previous studies investigated a physiologically based model for the pharmacokinetics of T [17] and the physiological responses to T combined with xylazine [23] and detomidine [22] in horses. However, no study has compared the behavioral and cardiorespiratory effects of M combined with or without T in horses. We hypothesized that the combined administration of medetomidine and tramadol (MT group) would exhibit superior sedation and a more sustained elevation of the nociceptive threshold compared to the medetomidine alone (M group). Therefore, this study compared the behavioral and cardiorespiratory effects of a M and T combination in horses.

METHODS

Animals

Eight healthy, adult horses (one stallion, four mares, and three geldings) of all Thoroughbreds, aged 10 ± 4 years, weighing 515 ± 38 kg, were included in the study. All horses were weighed, and physical examinations were performed before the experiment. The samples for the complete blood cell count (CBC) and serum chemistry were measured using an automated hematology analyzer (VetScan HM5; Abaxis, USA) and an automated chemistry analyzer (VetScan VS2; Abaxis), respectively, on the day before the first experiment. All values were confirmed to be within the normal reference range for horses.

Sample size was determined based on logistical constraints and by reference to the literature [26]. In that study, the number of horses needed was estimated using head height above the ground (HHAG) changes (mean ± standard deviation [SD]) under α = 0.05 and power = 0.80. Based on these considerations, the selected sample size was judged sufficient to detect clinically meaningful differences in sedation score and nociceptive threshold between the MT and M groups.

The animal experiments were approved by the Animal Ethics Committee of Jeju National University (approval No. 2020–0048). Food was withheld for at least 4 h prior to treatment and was reintroduced after the experiment. Water was provided ad libitum before and after the procedure.

Study design

The study was designed as a randomized, blinded, two-way crossover trial. Each horse sequentially received all treatments in randomized order, thereby serving as its own control. A washout period of 14 days was adopted, similar to other equine crossover studies [27,28].

Initially, horses were assigned to three treatment groups: medetomidine (M group, Dormitor; Pfizer Animal Health, Belgium), tramadol (T group: Trodone; Dongbang Medical, Korea), and medetomidine and tramadol (MT group). However, in the pilot phase, the first two horses exhibited marked excitement and muscle tremors following administration of T alone (2 mg/kg, intravenously). As a result, the T-only group was excluded from the main study. The final experiment was conducted using only the M and MT groups. Horses were randomly assigned to receive both treatments in a crossover manner, with a minimum washout period of 14 days between treatments.

Animal preparation

All horses were weighed, and physical examinations were performed before the experiment. A 14 G, 3.5-inch extended-use catheter (Milacath; Mila International, USA) was placed in the jugular vein the day before the experiment to allow drug administration without disturbing the horses. Before the experiments, the horses were individually selected for their tractable temperament and placed in the stocks, undergoing a habituation process to the monitoring equipment to minimize stress and ensure stable baseline readings. For the experiment, the horses were placed in stocks. The horses were instrumented with an inflatable cuff at the base of the tail for noninvasive blood pressure measurement and electrocardiogram (ECG) electrodes (Skintact FS50; Skintact, Austria) were attached to the chest. ECG electrodes were placed on the horse’s left thoracic apex, left neck, and right shoulder region following general base-apex lead configuration. The rectal temperature (RT) probe was positioned to measure the body temperature (BT) and was connected to a patient monitor Carescape Mornitor B850 (GE Healthcare, USA).

Experiments

After the baseline physiological and behavioral variables were recorded, M (5 μg/kg) or M followed by T (2 mg/kg) after 5 min was administered intravenously. The treatments were prepared and administered by an assistant blinded to the treatments.

Monitoring behavioral effects

The behavioral variables, including the HHAG, postural instability (PI), and response to pressure stimulus (RPS), were assessed at baseline, 5, 10, 20, 30, 40, 50, 60, 90, and 120 min after administration. Time 0 was defined as administration of M. The variables were always evaluated in the same order to prevent interference with the assessment of sedation and analgesic conditions.

The primary investigator measured HHAG using a tape measure. HHAG is a classical method to assess the depth of sedation in horses [29]. The height was measured from the lower point of the mandible to the ground [12,16,30]. While the height of the head for each horse was measured at the baseline and considered as 100% [30,31], in the present study, the height of the head was calculated in centimeters from the mandible to the floor, which is a modified method. To prevent disturbance to the horse, measurements were obtained from a distance of at least 2 meters, using a pre-calibrated measuring tape that had been fixed on the stall wall.

The PI was evaluated by the degree of ataxia or instability, assessed by observing the spontaneous posture of the extremities and describing the degree of leaning on the stocks on a numerical rating scale (score 0–6; Table 1), which is a modified scoring method [32,33,34]. The RPS was tested using the pressure algometry method (Wagner FPX Algometer, Model 10, Max. Capacity: 50 kg, Mfr; Wagner Instruments, USA). The algometer was used to measure the response to the pressure pain threshold. Algometry with a 1 cm diameter circular pole at the end was gently pressed over the spine of the scapula, and the mid part of the femur was evaluated by recording the force (kg/cm²).(Fig. 1). For consistency in the study, the same person applied slow and steady pressure until a response was observed for the measurement.

Table 1. Scoring system for postural instability.

Score	Description
0	No signs of instability
1	Stable but mild swaying
2	Swaying clearly, occasionally leaning against the stocks
3	Swaying clearly, constantly leaning against the stocks,
4	Leaning against the stocks for support, buckling of the limbs once
5	Heavily leaning on the stocks for support, buckling of the limbs more than twice
6	Recumbency

Fig. 1. Points of the RPS in the horse. (A) RPS over the scapula was measured just cranial to the spine of the scapula, (B) RPS over femur was measured in the mid part of the body of the femur.

RPS, response to pressure stimulus.

Three consecutive measurements were averaged for the baseline value. Reactions, such as moving the limb, shifting away from the pressure, or turning the head toward the stimulus, were considered positive.

Monitoring cardiorespiratory effects

Monitoring of heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR), and BT was performed concurrently with the behavioral effects assessment time points. The MAP, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and HR were assessed using a patient monitor Carescape Mornitor B850 (GE Healthcare, USA).

The blood samples were collected using the jugular catheter. We included CBC and biochemistry panels to ensure systemic safety by monitoring hematologic and biochemical parameters. The samples for the CBC were analyzed with a hematology analyzer at baseline, 15, 30, 60, 90, and 120 min after M or MT administration. The samples for the serum chemistry were measured with a clinical chemistry analyzer at the baseline, 30, 60, and 120 min after M or MT administration.

Statistical analysis

Data were recorded as the mean ± SD. All statistical analyses were performed with a statistical program (R studio Version 1.1.447; R Studio Inc, USA). Normality was assessed using the Shapiro-Wilk test for each variable. Cardiorespiratory variables were analyzed using a linear mixed—effect model, including one fixed effect (treatment) and random effects (individual horse). The covariance error structure with a first—order auto—regressive matrix was used to capture the similarity with the previous measurements in the repeated measures of the individual horse. The behavioral effects were compared using the linear mixed model analyses to determine the differences in HHAG between the treatment groups. Non-parametric analysis of variance with repeated measures was used to analyze the differences in PI and RPS between the treatment groups. A paired t-test or paired Wilcoxon sign rank test was used to assess the effects of the group at each time point. Each variable was provided in all time sets (overall time) and the data from 5 to 40 min (clinical time). Differences with p < 0.05 were considered significant.

RESULTS

Behavioral effects

The two groups showed similar HHAG values during the experiment. There were no significant differences between groups. The HHAG decreased significantly below baseline from 5 to 40 min in both groups (Fig. 2A). The mean ± SD of HHAG was the lowest at 20 min (126 ± 30 cm) in the M group, and at 10 min (121 ± 28 cm) in the MT group from the baseline. The HHAG approached to baseline at 60 min after the initial administration in both groups.

Fig. 2. Behavioral responses between group M and group MT (A) Head height above ground evaluation between the M and MT group. (B) Postural instability score. (Higher scores mean higher degrees of PI). (C) RPS over scapula evaluation (D) RPS over femur evaluation.

HHAG, head height above the ground; M, medetomidine; MT, medetomidine and tramadol; PI, postural instability; RPS, Response to a pressure stimulus.

^*Significant difference between treatments at a specific time point (p < 0.05). ^†Significantly different compared to the baseline of the same treatment (p < 0.05).

Although no significant differences in PI were observed between the two groups in overall time, point-specific comparisons revealed significant differences at 30 and 40 min post-administration (p < 0.05). The PI score increased significantly below baseline-from 5 to 50 min in both groups (Fig. 2B). The mean ± SD of PI score was the highest at 5 min (4.12 ± 0.76) in the M group, and at 5 min (4.57 ± 0.79) in the MT group from the baseline. The PI approached to baseline at 120 min after the initial administration in both groups.

There were significant differences in the RPS over the scapula between treatments during the overall time (p = 0.0103). The MT group showed a significantly higher RPS than the M group. Moreover, the two groups showed a significant difference in the RPS over scapula during the clinical time (p = 0.0078). Significant differences in RPS over the scapula were observed at 10 min after administration. There were significant differences from 10 to 30 min from the baseline (Fig. 2C). The mean ± SD of RPS over the scapula was the highest at 20 min (36 ± 18 kg/cm²) in the M group, and at 10 min (40 ± 19 kg/cm²) in the MT group from the baseline. The RPS returned to baseline at 120 min after the initial administration in both groups.

There were no significant differences in the RPS over the femur between treatments, but a trend towards significance was observed during the overall time (p = 0.0798) and clinical time (p = 0.081). The MT group showed a higher tendency of RPS than the M group. There were significant differences from 10 to 40 min from the baseline (Fig. 2D). The mean ± SD of RPS over the femur was the highest at 20 min (52 ± 20 kg/cm²) in the M group, and at 40 min (56 ± 9 kg/cm²) in the MT group from the baseline.

Cardiorespiratory effects

Throughout the full monitoring interval, treatments showed no significant differences. However, the two groups showed a significant difference in the HR from during the clinical time (p = 0.0103). The MT group showed significantly higher HR value than the M group. A significant difference in HR was observed between groups at 15 min after administration. HR decreased significantly below baseline from 10 to 40 min in both treatments (Fig. 3A). The mean ± SD of HR was the lowest at 20 min (30 ± 7 beats/min) in the M group, and at 30 min (33.5 ± 3 beats/min) in the MT group from the baseline.

Fig. 3. Cardiorespiratory variables between the M and MT group (A) Heart rate. (B) Mean arterial pressure. (C) Body Temperature. (D) Respiratory rate.

BT, body temperature; HR, heart rate; M, medetomidine; MAP, mean arterial pressure; MT, medetomidine plus tramadol; RR, respiratory rate.

^*Significant difference between treatments at a specific time point (p < 0.05). ^†Significantly different compared to the baseline of the same treatment (p < 0.05).

SAP, MAP, and DAP remained statistically similar between groups in both the overall and clinical timeframes. A significant difference in MAP was observed between the groups at 30 min after administration (Fig. 3B). There were no significant differences from the baseline. The mean ± SD of MAP was 129 ± 14 mmHg in the M group and 125 ± 16 mmHg in the MT group at 30 min after the administration.

The two groups showed similar BT during the overall time and clinical time. A significant difference in BT was observed between the groups at 50 and 60 min after administration (Fig. 3C). There were no significant differences from the baseline. The mean ± SD of BT was 37.8°C ± 0.4°C in the M group and 37.8°C ± 0.4°C in the MT group.

The two groups showed a similar RR throughout the experiment. A significant difference in RR was not observed between the groups at any time points after administration. RR decreased significantly below baseline from 25 to 40 min in both treatments (Fig. 3D).

The two groups showed a similar capillary refill time (CRT) throughout the experiment. A significant difference in CRT was not observed between the groups at any time points after administration. There were no significant differences from the baseline.

Blood analysis

The two groups showed similar values on CBC, including white blood cell (WBC), red blood cell (RBC), hemoglobin, packed cell volume, platelet, and total protein for the overall time. A significant difference in WBC was observed between the groups at 30 min and RBC at 90 min after administration (Table 2).

Table 2. Complete blood cell count evaluation between the M and MT groups.

Variables		Time (min)
		Baseline	15	30	60	90	120
WBC (×103/µL)
	M	7.4 ± 3.6	6.7 ± 2.7	6.4 ± 2.8*	7 ± 3.5	8.3 ± 5	7.4 ± 3.9
	MT	6.7 ± 3.9	6.5 ± 3.3	6.1 ± 2.5*	7.4 ± 2.8	6.2 ± 2.1	7.7 ± 3.9
RBC (×106/µL)
	M	9.5 ± 1.5	8 ± 1.5	7.7 ± 1.3	7.5 ± 1.4	7.2 ± 1.5*	8.8 ± 1.3
	MT	8.2 ± 2.4	7.4 ± 2.1	7.2 ± 1.9	7.9 ± 1	8.2 ± 1.4*	8.4 ± 1.3
HGB (g/dL)
	M	15.9 ± 3.1	12.4 ± 3.3	10.9 ± 2.9	11.6 ± 3.1	11.9 ± 3.6	13.6 ± 4.2
	MT	15.6 ± 2	12.6 ± 2.1	12.4 ± 1.5	12.6 ± 2	11.7 ± 1.9	13.2 ± 2.4
PCV (%)
	M	47 ± 7.1	40.4 ± 5.5	37.2 ± 4.1	36.9 ± 5	37.2 ± 6.5	43.2 ± 6.5
	MT	44.1 ± 6.4	38.8 ± 3.8	38.7 ± 3.7	39 ± 4.5	36.9 ± 4.8	40.5 ± 4.9
PLT (×103/µL)
	M	108.5 ± 51.6	90.4 ± 35	58.9 ± 31.5	62.3 ± 23.5	71 ± 35.6	100 ± 40.8
	MT	114.5 ± 86.5	80.7 ± 26.6	71.7 ± 39	73.2 ± 30.1	86.4 ± 46	86.6 ± 9.8
TP (g/dL)
	M	6.9 ± 0.5	7 ± 0.2	6.6 ± 0.6	6.7 ± 0.1	6.5 ± 0.6	6.5 ± 1
	MT	6.9 ± 0.6	7.1 ± 0.4	6.8 ± 0.7	7 ± 0.3	6.5 ± 0.6	6.6 ± 0.7

M, medetomidine; MT, medetomidine and tramadol; WBC, white blood cell; RBC, red blood cell; HGB, hemoglobin; PCV, packed cell volume; PLT, platelet; TP, total protein.

^*Statistically significant difference between treatments at the same time point (p < 0.05).

The two groups showed a similar serum biochemistry profile including potassium, glucose, Ca²⁺, blood urea nitrogen, creatinine, aspartate aminotransferase, and gamma glutamyl transferase. The MT group showed significantly lower sodium and total bilirubin (TBil) values than the M group. A significant difference was not observed at any time point between groups and from the baseline (Table 3).

Table 3. Serum biochemistry evaluation between the M and MT groups.

Variables		Time (min)
		Baseline	30	60	120
Na+(mmol/L)
	M	137.1 ± 3.1	136.6 ± 2.1	139.4 ± 6.3*	137.8 ± 1.9
	MT	136 ± 3.4	135 ± 4.2	135.7 ± 3.8*	136 ± 1.5
K+(mmol/L)
	M	4.1 ± 0.4	4.2 ± 0.4	4.2 ± 0.5	4.2 ± 0.3
	MT	4.1 ± 0.4	4.1 ± 0.3	4.2 ± 0.2	4 ± 0.3
Glucose (mg/dL)
	M	104 ± 16	112 ± 5	111 ± 10	111 ± 14
	MT	98 ± 9	111 ± 12	112 ± 10	102 ± 22
Ca2+ (mg/dL)
	M	12 ± 1	12 ± 1	12 ± 0	12 ± 1
	MT	12 ± 0	12 ± 1	12 ± 1	12 ± 0
BUN (mg/dL)
	M	18 ± 3	18 ± 3	18 ± 2	18 ± 2
	MT	17 ± 3	18 ± 3	18 ± 3	18 ± 3
Creatinine (mg/dL)
	M	1 ± 0	1 ± 0	2 ± 0	2 ± 0
	MT	1 ± 0	1 ± 0	1 ± 0	1 ± 0
AST (U/L)
	M	244 ± 55	238 ± 53	240 ± 47	238 ± 52
	MT	246 ± 59	240 ± 52	236 ± 50	244 ± 55
Tbil (mg/dL)
	M	2 ± 1	2 ± 1	2 ± 1*	2 ± 1*
	MT	2 ± 1	2 ± 1	2 ± 1*	2 ± 1*
GGT (U/L)
	M	13 ± 3	13 ± 2	12 ± 2	13 ± 2
	MT	12 ± 3	12 ± 3	11 ± 3	13 ± 2

M, medetomidine; MT, medetomidine and tramadol; Na⁺, sodium; K⁺, potassium; BUN, blood urea nitrogen; AST, aspartate aminotransferase; Tbil, total bilirubin; GGT, gamma glutamyl transferase.

^*Statistically significant difference between treatments (p < 0.05). For Tbil, the MT group showed significantly lower values than the M group at 60 and 120 min.

DISCUSSION

In the present study, sedation (measured by HHAG) and ataxia (measured by PI) reached their maximal levels at 10 and 5 min post-administration, respectively, and gradually returned to baseline by 120 min. This profile is characteristic of the sedative and ataxic effects of M as a potent alpha-2 agonist [1,12]. A previous study using a higher dose of M (10 µg/kg) reported more profound and prolonged ataxia [12]. In comparison, the 5 µg/kg dose used in our study appears to induce a clinically acceptable level of sedation and ataxia suitable for standing procedures, with a predictable recovery.

The primary finding of this study is that the addition of T to M significantly enhances analgesia in standing horses without compromising cardiorespiratory stability.

T is a centrally acting opioid analgesic with potential analgesic effects in horses [17,35,36,37]. This was evident from the significantly higher RPS over the scapula in the MT group (p < 0.05). The analgesic enhancement was particularly pronounced during the clinical time frame of 5 to 40 min post-administration (p = 0.0078), suggesting that this combination provides effective analgesia during the critical period for many standing diagnostic or surgical procedures. While the RPS over the femur also showed a tendency towards an increased analgesic effect in the MT group, it did not reach statistical significance (p = 0.081). This difference in regional sensitivity may be attributed to the thicker muscle layer over the femur compared to the spine of the scapula, potentially requiring a greater stimulus to elicit a response. The method used in this study evaluates the increase in tolerance to pressure applied to a specific and restricted dermatome area near the scapula and femur. While a high tolerance to nociceptive stimuli was observed, caution is warranted when claiming the induction of true clinical analgesia applicable to widespread or visceral pain (e.g., post-surgical pain) in a clinical phase.

Minor behavioral adverse effects possibly related to T administration were observed in this study. Behavioral adverse effects of opioids have been previously documented, including butorphanol-associated signs such as ataxia, reduced gastrointestinal sounds, and decreased defecation [38]. In addition, central nervous system (CNS) stimulant effects following a single administration of T, such as muscle tremors, frequent blinking, yawning, chewing, and tongue protrusion, have been described [23]. In this study, one horse in the present study exhibited transient muscle twitches at 5 min, and two horses showed slight head jerks at 10 min after MT administration. These behaviors might derive from T’s central actions on monoaminergic systems, particularly its inhibition of serotonin reuptake, thereby subtly raising neuronal excitability and eliciting mild CNS stimulation [39].

The cardiorespiratory effects observed were generally consistent with the known pharmacology of alpha-2 agonists. In both treatment groups, HR and RR decreased significantly from baseline values, a well-documented effect of M and other alpha-2 agonists like xylazine [13,16]. However, during the clinical time frame, the HR in the MT group was significantly higher than in the M group, despite similar arterial blood pressure and other vital variables.

This attenuation of bradycardia in the MT group is primarily attributable to the dual pharmacodynamic profile of T—specifically, its function as a norepinephrine (NE) and serotonin reuptake inhibitor [40,41]. Consequently, the resulting increase in synaptic NE concentrations provides mild, centrally mediated sympathetic stimulation. This stimulation partially counteracts the profound vagal and central sympatholytic effects induced by M, thereby leading to a statistically significant elevation in HR. This central action aligns with clinical evidence supporting T’s role in multimodal analgesia for complex equine pain [42].

Furthermore, T’s function as a serotonin reuptake inhibitor can increase central excitability, potentially leading to clinical signs such as anxiety or insomnia [43]. Specifically, this CNS-stimulating potential was the reason for excluding the T-only group, which exhibited unacceptable levels of excitement during the pilot phase. Therefore, combining T with M may partially mitigate the bradycardic effects of alpha-2 agonists, providing a clinically acceptable cardiovascular profile during standing sedation.

Hematological and serum biochemistry profiles remained largely within clinically normal ranges. While a previous study reported increased glucose concentrations following T administration [12], no such significant difference was observed in this study. Although statistically significant differences in Na⁺, TBil, WBC, and RBC values were detected at certain time points, all values remained within normal reference ranges without clinical relevance.

Although no substantial changes in CBC or chemistry were found, the known metabolic effects of alpha-2 agonists on glucose and potassium merit attention homeostasis. In horses, alpha-2 agonists can suppress insulin secretion and provoke transient hyperglycemia [44]. The absence of these changes in our study might reflect the relatively low dose, the timing of sampling, or the healthy status of the subjects.

This study has several limitations. First, a dose-response study was not performed to determine the optimal concentrations of MT. Second, although a crossover design was used to minimize individual variation, the relatively small sample size (n = 8) should be considered when interpreting the results. Further studies with a larger population and varied dose regimens are warranted to fully characterize the benefits of this combination. In addition to these design-related limitations, there are challenges in extrapolating from healthy standing horses to surgical patients. Furthermore, the absence of direct correlation between analgesic effects and pain biomarkers, and the lack of non-invasive autonomic indices such as heart rate variability to distinguish therapeutic effects from stress responses, remain areas for future work. Finally, a more objective and quantifiable assessment of recovery quality is also indicated.

In conclusion, the combination of MT in horses provides comparable somatic antinociception and enhanced sedation compared to M alone, while maintaining minimal adverse effects on cardiorespiratory function in healthy, standing horses. Further clinical studies are required to confirm its safety and efficacy in surgical patients.