Cardiovascular effects of N-butylscopolammonium bromide and xylazine in horses

Authors

  • A. J. MORTON,

    Corresponding author
      email: mortona@ufl.edu
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  • C. R. VARNEY,

    1. Island Whirl Equine Colic Research Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida College, Gainesville, USA.
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  • A. B. EKIRI,

    1. Island Whirl Equine Colic Research Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida College, Gainesville, USA.
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  • A. GROSCHE

    1. Island Whirl Equine Colic Research Laboratory, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida College, Gainesville, USA.
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email: mortona@ufl.edu

Summary

Reasons for performing study: N-butylscopolammonium bromide (NBB) and xylazine are commonly used medications for the treatment of spasmodic colic and other forms of abdominal pain in horses. Both NBB and xylazine exert significant effects on the cardiovascular system and other vital systems of horses.

Objective: To evaluate the effects of i.v. administration of NBB, xylazine, and the combination of NBB and xylazine on heart rate, other commonly measured physiological parameters, cardiac rhythm and blood pressure.

Methods: Six mature horses of mixed breed were used. In a random cross-over design, each horse was given 0.3 mg/kg bwt of NBB i.v., 0.25 mg/kg bwt xylazine i.v., and a combination of 0.3 mg/kg bwt NBB and 0.25 mg/kg bwt xylazine. Heart rate, physiological parameters, cardiac rhythm and indirect blood pressure were recorded at timed intervals before and 60 min following administration.

Results: Heart rate and blood pressure were significantly elevated immediately following administration of NBB or NBB with xylazine. Administration of NBB with xylazine resulted in significantly greater initial and peak blood pressure values than with NBB alone. Administration of xylazine resulted in a decrease in heart rate, with an initial increase in blood pressure followed by a decrease in blood pressure. Sinus tachycardia was seen with NBB, and NBB and xylazine administration. First and second degree atrioventricular block was identified with xylazine administration. Ventricular tachycardia was identified in one horse following NBB and xylazine administration.

Conclusions: Results of this study suggest that the effects of administration of NBB alone or in combination with xylazine to horses with colic, especially to those with systemic cardiovascular compromise, should be considered carefully to assess condition and predict prognosis accurately, and to avoid potential adverse effects.

Introduction

Colic is one of the most common reasons horse owners seek veterinary attention and represents one of the largest causes of morbidity and mortality in horses worldwide (Traub-Dargatz et al. 1991). N-butylscopolammonium bromide (NBB) is a commonly used drug used for the treatment of spasmodic colic and other forms of abdominal pain in horses (Bertone 2002). It has been commercially available in Europe in combination with hyoscine (NBB-hyoscine) for these purposes and has recently been approved (without hyoscine) for similar use in the USA (Bertone 2002; Sanchez et al. 2008). NBB-hyoscine is also available in Europe for human use and is commonly used to treat gastrointestinal pain and to facilitate diagnostic procedures such as angiography, colonoscopy and barium enema (Dyde et al. 2008). NBB and NBB-hyoscine are anticholinergic agents, similar to atropine and scopolamine, which compete with acetylcholine and produce an antagonistic effect on muscarinic receptors of the parasympathetic nervous system (Cittadini et al. 1998; Margues et al. 1998; Roach et al. 2001; Dyde et al. 2008). As with the majority of muscarinic antagonists, they are nonselective and thus produce a number of autonomic responses (Dyde et al. 2008). These effects have been shown to be dose related (Dyde et al. 2008). At lower doses, muscarinic antagonists depress salivary and bronchial secretions and sweating; with further increase in dose, there is tachycardia and pupillary dilation, and at high doses there is inhibition of micturition and decrease gastrointestinal tone and motility (Dyde et al. 2008). It is for the gastrointestinal effects that NBB is used to treat spasmodic colic in horses, reducing pain caused by intestinal hypermotility (Roelvink et al. 1991; Margues et al. 1998). Transient tachycardia and cardiac arrhythmias have been reported with NBB and NBB-hyoscine administration due to its antiparasympathetic activity (Roelvink et al. 1991; Luo et al. 2006; Dyde et al. 2008; Sanchez et al. 2008).

Xylazine is an α2 adrenergic receptor agonist that is commonly used for sedation and analgesia for treatment of equine colic, and often is administered in combination with NBB (Roelvink et al. 1991; Sanchez et al. 2008). Alpha2 agonists are reported to produce decreases in heart rate and cardiac output with an increased incidence of second-degree atrioventricular block and transient hypertension followed by hypotension (Yamashita et al. 2000). These haemodynamic effects are usually well tolerated by otherwise healthy horses, but may lead to deterioration of cardiovascular function in clinically unstable horses or those administered additional agents that effect cardiovascular function (Yamashita et al. 2000).

The purpose of this study was to evaluate the effects of i.v. administration of NBB, xylazine and the combination of NBB and xylazine on the degree and duration of alterations of physiological parameters including heart rate (HR), respiratory rate (RR), rectal temperature (T), capillary refill time (CRT), mucous membrane (MM) colour, intestinal borborygmi, blood pressure (systolic [SBP], diastolic [DBP] and mean [MBP]), cardiac rhythm, packed cell volume (PCV), total protein (TP) and oxygen saturation of haemoglobin in horses. These parameters may be important indicators of pain, physiological status and prognosis of horses suffering from various forms of colic. Administration of medications that alter these parameters may result in inaccurate assessment of and potential adverse effects in horses with colic. The hypotheses of this study were that administration of NBB would result in transient tachycardia and hypertension, xylazine would result in transient bradycardia and first- and second-degree atrioventricular blockade, and the combination of NBB and xylazine would result in attenuation of NBB induced tachycardia and transient exacerbation followed by attenuation of NBB induced hypertension.

Materials and methods

Animals

Six mature Thoroughbred or Thoroughbred-crossbred mares with a mean bodyweight of 580 kg (range 539–613 kg) and a mean age of 14 years (range 8–19 years) were used in the study. The horses were brought into stalls from their pasture in pairs for the study. They were allowed 24 h to acclimate to the new environment before each experiment was conducted. Their stalls were cleaned and bedded, they were given ad libitum water and grass hay and they received grain twice daily. While the horses were stalled, they were monitored overnight by hospital technicians to ensure their comfort. At the end of the trial, the horses were returned to their resident pastures. All of the horses used in this project were clinically normal with no evidence of gastrointestinal or cardiac disease. All procedures were approved by the University of Florida Institutional Animal Care and Use Committee.

Treatments

For the experimental procedures, each horse was housed in a 3.7 × 3.7 m stall and restrained with a halter and attached lead rope. Using aseptic technique, a 14 gauge, 13.3 cm i.v. catheter was placed in the left jugular vein of each horse before each treatment. Using a random cross-over design, each horse received each of 3 treatments - NBB (0.3 mg/kg bwt i.v.), xylazine (0.25 mg/kg bwt i.v.), and the combination of NBB (0.3 mg/kg bwt i.v.) and xylazine (0.25 mg/kg bwt i.v.). The dosages of NBB and xylazine were chosen based on recommended label dosages and what is commonly used at our hospital to treat suspected spasmodic colic. A minimum of one week was allowed between trials.

Physiological parameters

Heart rate (beats/min); MM colour; RR (breaths/min); DP character (absent, normal or increased); T (°C); CRT (s); intestinal borborygmi (left dorsal and ventral abdominal quadrants, right dorsal and ventral quadrants); SBP, DBP and MBP (mmHg); cardiac rhythm; PCV (%); oxygen saturation of haemoglobin (%); and TP (g/l) were measured. The blood pressure was measured indirectly using a Cardell Veterinary Monitor 94021 with small (17–25 cm) adult cuff fitted to the proximal aspect of the tail of each horse. The cardiac rhythm was observed continuously by base-apex electrocardiogram (ECG) and oxygen saturation of haemoglobin was measured using pulse oximetry using a Surgivet Veterinary Anaesthesia monitoring device2. Oxygen saturation of haemoglobin was measured with the pulse oximeter probe placed on a nonpigmented area of the oral mucous membranes.

Experimental protocol

Baseline HR, RR, T, CRT, MM, intestinal borborygmi, DP, SBP, DBP, MBP, ECG, PCV, TP and oxygen saturation of haemoglobin were measured in all horses prior to drug administration. The HR, RR, CRT, MM, SBP, DBP, MBP, ECG and oxygen saturation of haemoglobin were measured at 0, 1, 2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 and 60 min immediately following drug administration. Intestinal borborygmi and DP were measured at 0, 1, 5, 10, 20, 30, 40, 50 and 60 min following drug administration. The T, PCV and TP were measured at 0, 30 and 60 min following drug administration. All measurements were taken with the horses restrained using a halter and lead rope and head position was maintained constant throughout the entire period. Indirect blood pressure readings were not corrected to heart level.

Statistical analyses

Continuous data were expressed as mean values ± s.d., and analysed using repeated measures ANOVA with SAS GLM procedure (SAS 9.2)3. Where group differences were found, Bonferroni test was used for post hoc comparisons.

Results

Animals

All treatments were well tolerated by the horses in this study. Following administration of xylazine and xylazine/NBB all horses experienced mild sedation. No adverse reactions were observed in any horses following administration of any treatments.

Heart rate

As expected, NBB significantly elevated HR immediately following administration (Fig 1). The peak effect was seen 5 min following administration with a mean HR of 86 ± 2.2 beats/min. HR gradually returned to baseline over time, but remained significantly elevated for 50 min following administration. Xylazine alone significantly decreased HR, although the effect was modest with the maximal effect seen 2 min following administration with a HR of 32 ± 2.7 beats/min returning to baseline 10 min following administration. When xylazine was administered in combination with NBB, a significant elevation was seen, although the initial peak was significantly lower than NBB alone, with a peak mean HR of 75.3 ± 2.4 beats/min.

Figure 1.

Mean heart rate ± s.d., *Significant difference from baseline, P<0.05.

Blood pressure

Mean arterial blood pressure, SBP and DBP were all affected similarly (Figs 2–4). NBB significantly elevated all blood pressure values for 25 min following administration. Peak effects were seen 1–2 min following administration with peak mean values of 115 ± 7.4, 144 ± 14 and 100 ± 11.9 mmHg for MBP, SBP and DBP, respectively (Fig 2). Administration of xylazine alone resulted in significantly greater blood pressure values compared to baseline, but this increase was modest and transient with values returning to baseline within 2 min of administration, and then significantly decreasing below baseline values at 20 min following administration and for the duration of the trial. Peak values reached 98.7 ± 9.2, 129 ± 14.4 and 94 ± 7.8; whereas trough values dropped to 58 ± 5.3, 82 ± 5.1 and 45 ± 12.3 mmHg for MBP, SBP and DBP, respectively. Administration of NBB and xylazine in combination resulted in similar findings to NBB alone, but with significantly greater initial and peak values. Peak effects were seen 1–2 min following administration with peak mean values of 142 ± 6.3, 177 ± 11.9 and 126 ± 14.4 mmHg for MBP, SBP and DBP, respectively.

Figure 2.

Mean arterial pressure ± s.d., (a) significantly greater than baseline, (b) significantly greater than baseline and NBB at 1 min, (c) significantly lower than baseline, P<0.05.

Figure 3.

Mean systolic blood pressure ± s.d., (a) significantly greater than baseline, (b) significantly greater than baseline and NBB at 1 min, (c) significantly lower than baseline, P<0.05.

Figure 4.

Mean diastolic blood pressure ± s.d., (a) significantly greater than baseline, (b) significantly greater than baseline and NBB at 1 min, (c) significantly lower than baseline, P<0.05.

Intestinal borborygmi

Intestinal borborygmi were reduced or absent in all abdominal quadrants in all 3 groups immediately following administration of treatments. Borborygmi gradually returned over time, with normal borborygmi returning at 50 min in the NBB and the xylazine groups, and 60 min in the NBB/xylazine group (Table 1).

Table 1.  : Physiological parameters
Time (min)013510152025
RR
(breaths/min)
NBB15.0 ± 3.315.3 ± 3.715.0 ± 3.315.0 ± 3.314.0 ± 3.114.0 ± 3.114.0 ± 3.113.0 ± 2.4
X16.0 ± 3.114.0 ± 3.112.0 ± 3.011.8 ± 2.412.0 ± 3.011.8 ± 2.412.0 ± 3.012.0 ± 3.0
NBB + X15.0 ± 5.013.0 ± 2.412.7 ± 2.712.7 ± 2.711.7 ± 1.811.3 ± 2.013.7 ± 3.412.3 ± 2.9
O2 sat
(%)
NBB99.2 ± 0.399.4 ± 0.998.7 ± 0.799.9 ± 0.199.0 ± 0.299.0 ± 0.299.0 ± 0.298.7 ± 0.7
X99.5 ± 0.199.5 ± 0.199.5 ± 0.199.0 ± 0.298.9 ± 0.498.7 ± 0.799.0 ± 0.299.5 ± 0.1
NBB + X98.7 (0.798.0 ± 1.198.8 ± 0.599.9 ± 0.299.9 ± 0.298.8 ± 0.599.4 ± 0.299.5 ± 0.1
CRT
(s)
NBB≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0
X≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0
NBB + X≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0
MM
(colour)
NBBPinkPinkPinkPinkPinkPinkPinkPink
XPinkPinkPinkPinkPinkPinkPinkPink
NBB + XPinkPinkPinkPinkPinkPinkPinkPink
DP
(character)
NBBNN NN N 
XNNNNN
NBB + XNNNNN
Borborygmi
(character)
NBB2.0 ± 00.8* ± 0.50.2* ± 0.40.3* ± 0.50.5* ± 0.7
X2 ± 01.5* ± 0.11.0* ± 0.60.4* ± 0.50.2* ± 0.4
NBB + X2 ± 00.6* ± 0.50* ± 00.2* ± 0.40.5* ± 0.6
T
(°C)
NBB99.8 ± 0.4 
X99.6 ± 0.3
NBB + X99.5 ± 0.3
PCV
(%)
NBB38.6 ± 3.1
X36.7 ± 5.2
NBB + X37.7 ± 4.9
TP
(g/l)
NBB68.0 ± 9.1
X67.5 ± 3.6
NBB + X63.9 ± 9.4
Time (min)30354045505560
  1. Continuous variables are expressed as mean ± s.d. *Significant difference from baseline, P<0.05. Borborygmi was assessed using a numerical score (0 = absent, 1 = reduced, 2 = normal, 3 = increased). For DP, N = normal.

RR
(breaths/min)
NBB14.0 ± 3.114.3 ± 3.714.3 ± 3.714.3 ± 3.714.3 ± 3.714.3 ± 3.713.2 ± 2.7
X12.0 ± 3.012.0 ± 3.012.0 ± 3.013.0 ± 2.413.0 ± 2.413.0 ± 2.414.0 ± 3.1
NBB + X12.3 ± 2.912.3 ± 2.912.3 ± 2.914.0 ± 3.113.0 ± 2.413.0 ± 2.413.0 ± 2.4
O2 sat
(%)
NBB98.7 ± 0.799.4 ± 0.999.5 ± 0.199.0 ± 0.298.7 ± 0.799.9 ± 0.199.0 ± 0.2
X98.7 ± 0.799.5 ± 0.199.2 ± 0.399.2 ± 0.398.7 ± 0.798.7 ± 0.799.5 ± 0.1
NBB + X98.2 ± 1.399.0 ± 0.298.8 ± 0.598.2 ± 1.398.8 ± 0.598.8 ± 0.598.4 ± 0.6
CRT
(s)
NBB≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0
X≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0
NBB + X≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0≤2 ± 0
MM
(colour)
NBBPinkPinkPinkPinkPinkPinkPink
XPinkPinkPinkPinkPinkPinkPink
NBB + XPinkPinkPinkPinkPinkPinkPink
DP
(character)
NBBN N N N
XNNNN
NBB + XNNNN
Borborygmi
(character)
NBB0.7* ± 0.80.8* ± 0.42.0 ± 02.0 ± 0
X0.5* ± 0.71.6 ± 0.51.8 ± 0.42.0 ± 0
NBB + X0.8* ± 0.41.0* ± 01.0* ± 0.81.7 ± 0.5
T
(°C)
NBB99.8 ± 0.4 99.5 ± 0.1
X99.4 ± 0.299.4 ± 0.2
NBB + X99.6 ± 0.499.4 ± 0.1
PCV
(%)
NBB38.5 ± 2.737.9 ± 4.8
X39.0 ± 4.638.4 ± 3.7
NBB + X38.6 ± 3.037.9 ± 4.2
TP
(g/l)
NBB65.0 ± 5.466.6 ± 3.3
X68.2 ± 5.567.1 ± 6.2
NBB + X65.1 ± 4.064.4 ± 6.5

Cardiac rhythm

Cardiac arrhythmias were identified in all 3 groups immediately following treatment administration. Sinus tachycardia was the most common arrhythmia and was identified in both the NBB and NBB/xylazine groups in all 6 horses. First- and second-degree atrioventricular block was seen in the xylazine group and was observed in all 6 horses. Ventricular tachycardia was seen transiently in one horse immediately following administration of NBB and xylazine.

Other parameters

No effects on RR, DP, T, CRT, MM, PCV, TP or oxygen saturation of haemoglobin were observed with any of the treatments given (Table 1).

Discussion

The administration of NBB, xylazine and NBB/xylazine resulted in alterations of cardiovascular parameters. As hypothesised, the administration of NBB resulted in tachycardia and hypertension. Administration of xylazine alone resulted in an initial increase in blood pressure values compared to baseline, but was followed by a return to baseline, and subsequently a decrease below baseline. The combination of NBB and xylazine resulted in partial attenuation of NBB induced tachycardia and exacerbation of NBB induced hypertension. The increases in SBP, DBP and MBP seen with the administration of NBB were expected, as was the tachycardia observed in all horses immediately following the administration of NBB. These findings are similar to results of other reports evaluating NBB and NBB-hyoscine in horses and ponies (Geimer et al. 1995; Boatwright et al. 1996; Cole et al. 2005; Sanchez et al. 2008). In one study evaluating the haemodynamic effects of NBB-hyoscine in ponies, values for HR were 63, 48 and 13% greater than control values at 1, 16 and 46 min, respectively (Geimer et al. 1995). In the same study, cardiac output was increased 16% at 16 min; stroke volume was decreased by 32% at 1 min; mean right atrial pressure was decreased by 79, 63, 45 and 52% at 1, 16, 46 and 61 min; and there was a trend of increased MBP after NBB-hyoscine administration (Geimer et al. 1995). In man, the main cardiovascular side effect is tachycardia (Dyde et al. 2008). Catecholamine levels are not increased after administration of NBB-hyoscine, making it unlikely that it has any sympathetic activity, with the tachycardia a result of muscarinic M2 receptor antagonism (Katoh et al. 2003). M2 receptors modulate pacemaker activity, atrioventricular conduction and the force of cardiac contraction (Dhein et al. 2001). Increases in HR and DBP have been reported in patients administered NBB-hyoscine for radiological procedures (Taylor et al. 2003; Mui et al. 2004; Dyde et al. 2008). In a study evaluating the administration of NBB-hyoscine to patients with a high risk of cardiac disease undergoing peripheral angiography, NBB-hyoscine induced tachycardia was associated with ischaemic episodes (Maher et al. 1999). It has also been demonstrated that variation in HR is reduced in healthy volunteers receiving NBB-hyoscine from loss of parasympathetic tone, and suggested that this could lead to arrhythmias and that caution should be taken in patients who are unstable (Kleiger et al. 1987; Dyde et al. 2008).

The immediate increases in SBP, DBP and MBP seen with the administration of xylazine were expected, as was the subsequent hypotension and bradycardia observed in all horses following the administration of xylazine. Xylazine is an α2 adrenoceptor agonist, although it does have affinity and efficacy at α1 adrenoceptors. The α2 agonists produce a spectrum of pharmacological effects, some of which are attributable to central effects and others to their action on peripheral receptors in target tissues. The α2 adrenoceptors are present in the brain, spinal cord and several other important tissues. They may be located presynaptically at nerve terminals, where they play a role in negative feedback of norepinephrine release, which is their primary role in the central nervous system (CNS). The α2 adrenoceptors can be located postsynaptically, where they respond to norepinephrine or circulating catecholamines (Mason 2004). The pharmacological effects of the α2 agonists in horses are well described. They are very good sedatives and analgesics, and are associated with an initial period of hypertension as a result of direct agonistic effect on postsynaptic α2 and α1 adrenoceptors that mediate vasoconstriction in vascular smooth muscle; at the same time, α2 agonists produce a rapid and significant decrease in HR, often second-degree atrioventricular block, decreased cardiac output, and negative inotropic effects as a result of a vagal reflex response to hypertension and decreased sympathetic output from the CNS (Chambers et al. 1993; Yamashita et al. 2000).

Several studies have identified HR and other variables that assess cardiovascular function as good prognostic guides for survival for horses with colic, finding that horses with an elevated HR are less likely to survive than those with a normal HR (Parry et al. 1983; Pascoe et al. 1990; Reeves et al. 1990; Furr et al. 1995; Sandholm et al. 1995; Thoefner et al. 2000; Morton and Blikslager 2002; Ihler et al. 2004). Heart rate is also an important variable used for predicting whether horses with colic need surgical intervention, especially if analgesics or nonsteroidal anti-inflammatory medications have been given before clinical evaluation (Blikslager and Roberts 1995; Ihler et al. 2004). Assessment of HR of a horse with colic treated with NBB or NBB with xylazine shortly prior to clinical examination may falsely influence surgical decision making and prognostication.

The findings of significant hypertension and cardiac tachyarrhythmias in healthy horses administered NBB, which are transiently exacerbated by administration of NBB in combination with xylazine immediately following administration, are concerning. Hypertension may result in poor tissue perfusion, syncopal episodes and other untoward effects in horses. Variations in blood pressure have been reported in horses for conditions such as colic, laminitis, and epistaxis (Parry et al. 1980). The effects of administration of NBB alone or in combination with xylazine to horses with colic, especially to those with systemic cardiovascular compromise, should be considered carefully to assess condition and predict prognosis accurately, as well as to avoid potential adverse effects. Future studies should be performed to address the effects of these treatments in horses with colic, and to examine the effects of these treatments in combination with other commonly used α2 agonists and other medications used to treat horses with colic.

Authors' declaration of interests

No conflicts of interest have been declared.

Source of funding

Supported in part by a student scholarship from Morris Animal Foundation.

Acknowledgements

The authors thank Brittany Martabano for technical assistance.

Manufacturers' addresses

1 Paragon Medical, Coral Springs, Florida, USA.

2 Smith Medical, Waukesha, Wisconsin, USA.

3 SAS Institute Inc., Cary, North Carolina, USA.

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