Blood glucose, acid–base and electrolyte changes during loading doses of alpha2-adrenergic agonists followed by constant rate infusions in horses

doi:10.1016/j.tvjl.2013.09.063

The Veterinary Journal

Volume 198, Issue 3, December 2013, Pages 684-689

https://doi.org/10.1016/j.tvjl.2013.09.063 Get rights and content

Abstract

The aim of the present study was to investigate changes in blood glucose concentration ([Glu]_B), acid–base status and electrolyte concentrations during constant rate infusions (CRI) of two alpha₂-adrenergic agonists in seven horses treated in a blinded, randomised, crossover design with xylazine or romifidine. An intravenous (IV) bolus of xylazine (1 mg/kg) or romifidine (80 μg/kg) was administered followed by an IV CRI of xylazine (0.69 mg/kg/h) or romifidine (30 μg/kg/h) for 2 h. Blood samples were collected from the pulmonary artery before and after loading doses, during the CRI, and for 1 h after discontinuing drugs.

Blood glucose, base excess (BE), pH, partial pressure of carbon dioxide (P $\bar{v}$ CO₂), strong ion difference (SID_est) and bicarbonate concentration ( ${[{HCO}_{3 std}^{-}]}_{B}$ ) increased significantly during the CRI with both alpha₂-adrenergic agonists. Chloride concentration ([Cl⁻]_B) and anion-gap (AG) decreased significantly compared to baseline. The decrease in sodium concentration ([Na⁺]_B) was only significant with xylazine. From 1 h after starting the CRI onwards, [Glu]_B was significantly higher with romifidine compared to xylazine. Except [Glu]_B, SID_est, and P $\bar{v}$ CO₂, all variables returned to normal values 1 h after discontinuing xylazine. After stopping romifidine, all variables except pH remained altered for at least 1 h.

It was concluded that loading doses of alpha₂-adrenergic agonists followed by CRIs produce [Glu]_B, acid–base and electrolyte changes. The clinical significance of the reported changes remains to be investigated and absolute values should be interpreted with caution, as fluid boli were used for cardiac output measurements, but may become important during prolonged infusion and in critically ill patients.

Introduction

Alpha₂-adrenergic agonists are routinely used for sedation and analgesia in veterinary medicine (Dart, 1999) and administration as an intravenous (IV) constant rate infusion (CRI) is becoming more frequent (Lamont et al., 2012, Ringer, 2012). The main advantages of alpha₂-adrenergic agonists in humans are the potent sedative and analgesic effects with minimal respiratory depression and less postoperative delirium compared to other drugs (Hoy and Keating, 2011). In human intensive care units (ICUs) interest in CRI of alpha₂-adrenergic agonists is increasing (Tan and Ho, 2010, Hoy and Keating, 2011). This tendency is also observed in veterinary critical care patients (Posner and Burns, 2009).

Concerns regarding alpha₂-adrenergic agonists mainly reflect their cardiovascular (CV) effects (England and Clarke, 1996, Murrell and Hellebrekers, 2005, Tan and Ho, 2010), and many studies have been designed to examine the CV effects of alpha₂-adrenergic agonist CRIs in horses (Bettschart-Wolfensberger et al., 1999, Ringer et al., 2013a). However, the use of alpha₂-adrenergic agonists is also associated with other side effects that might be less obvious, but may have important consequences, especially in critically ill patients. For example, hyperglycaemia is associated with worse outcomes in proportion to the elevations in blood glucose concentration ([Glu]_B) in human medicine (Klonoff, 2011). Hyperglycaemia is also associated with diuresis, which has been described following single doses of alpha₂-adrenergic agonists in horses (England and Clarke, 1996) and other species (Ambrisko and Hikasa, 2002, Kanda and Hikasa, 2008, Talukder and Hikasa, 2009, Murahata and Hikasa, 2011).

Despite the increasing use of alpha₂-adrenergic agonists, including in critically ill animals (Posner and Burns, 2009), changes in [Glu]_B, electrolyte concentrations and acid–base status during CRIs of alpha₂-adrenergic agonists remain insufficiently studied. Additionally, the different alpha₂-adrenergic agonists used as a CRI have not been compared regarding their effects on [Glu]_B, electrolytes and acid–base status. Xylazine and romifidine are both registered alpha₂-adrenergic agonists commonly used in equine clinical practice. Romifidine is more alpha₂ receptor-selective than xylazine or detomidine, but less than medetomidine (Muir, 2009). The aim of the present study was to investigate the effects of xylazine and romifidine CRIs on [Glu]_B, acid–base balance and electrolytes in horses, and to compare the two drugs.

Section snippets

Materials and methods

The study was approved by the Ethical Committee of the National Veterinary School of Lyon (0807, 13 May 2008) and was performed using blood samples obtained during a cardiovascular study reported elsewhere (Ringer et al., 2013a).

For the concurrent cardiovascular study, seven research horses (six French Standardbreds and one French Saddlebred; 8.7 ± 1.75 years; 515.2 ± 52.96 kg) were catheterised with Swan-Ganz thermodilution catheters placed in the pulmonary arteries. The catheters were advanced

Results

A significant increase in [Glu]_B was observed during both alpha₂-adrenergic agonist infusions (Treatment, P = 0.001; Time, P < 0.001; Treatment × Time, P < 0.001) (Fig. 1). The increase was more pronounced with romifidine compared to xylazine. An increase in [Glu]_B was also observed in horses receiving 0.9% NaCl instead of 5% glucose for cardiac output measurements (Fig. 1).

Significant changes in pH were seen over time and between treatments (Treatment, P = 0.007; Time, P < 0.001; Treatment × Time, P = 0.330) (

Discussion

The results of this study indicate that both xylazine and romifidine significantly alter [Glu]_B, electrolyte concentrations and acid base balance when administered as a bolus followed by a CRI during 2 h in healthy horses.

An increase in [Glu]_B has been described in the horse after administration of single doses of different alpha₂-adrenergic agonists (England and Clarke, 1996) and during detomidine CRI combined with buprenorphine (van Dijk et al., 2003). However, to our knowledge this is the

Conclusions

Xylazine and romifidine administered as a CRI had significant effects on [Glu]_B, electrolyte concentrations, and acid–base status in horses. Changes become progressively more prominent during CRI, and should be considered in patients receiving prolonged alpha₂-adrenergic agonist infusions.

Conflict of interest statement

None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper.

Acknowledgements

The authors would like to thank the Forschungskredit of the University of Zurich and the Stiftung Forschung für das Pferd for financial support. We further acknowledge Siemens Healthcare Diagnostics France for providing the point-of-care blood gas system (Rapidpoint 400) including reagent kits and technical support, and the companies Dr. E. Graeub AG and Boehringer Ingelheim France for providing the xylazine and romifidine for this study.

Parts of the results have been published as a poster

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To assess the effects of an α₂-adrenoceptor agonist (detomidine) constant rate infusion (CRI) with and without an α₂-adrenoceptor antagonist (vatinoxan) CRI on blood insulin and glucose concentrations, heart rate, intestinal borborygmi, and sedation during and after infusion in horses.
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An increase in plasma glucose concentration is induced by all α2-adrenoceptor agonists commonly used for sedation in horses, i.e. xylazine (Ringer et al., 2013; Kullmann et al., 2014; Kritchevsky et al., 2020), detomidine (Kullmann et al., 2014; Tapio et al., 2018; Kritchevsky et al., 2020), romifidine (Ringer et al., 2013; Kullmann et al., 2014; Pakkanen et al., 2018) and medetomidine (Grimsrud et al., 2012; Tapio et al., 2019).
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A single bolus of α2-agonists has been shown to increase glucose concentration in many species through inhibition of insulin release from the pancreas (Thurmon et al. 1982; Knych et al. 2012). Furthermore, Ringer et al. (2013) showed that when a CRI of xylazine or romifidine was administered to healthy standing horses, hyperglycaemia persisted throughout the infusion and then decreased to almost baseline 1 hour after the end of the infusion; romifidine CRI (0.03 mg kg−1 hour−1) increased glucose levels more than xylazine CRI. Our study also found an increase in blood glucose in all groups, including the control group (Fig. 2), but no significant difference was detected between the groups.
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Blood glucose, acid–base and electrolyte changes during loading doses of alpha2-adrenergic agonists followed by constant rate infusions in horses

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Conclusions

Conflict of interest statement

Acknowledgements

Journal of Veterinary Anaesthesia

Journal of Veterinary Anaesthesia

British Veterinary Journal

Research in Veterinary Science

Veterinary Anaesthesia and Analgesia

European Journal of Pharmacology

The Veterinary Journal

Veterinary Anaesthesia and Analgesia

Neurohormonal and metabolic effects of medetomidine compared with xylazine in beagle dogs

Canadian Journal of Veterinary Research

Strong ion approach to acid–base disorders

Mixed acid–base disorders

Cardiopulmonary effects and pharmacokinetics of i.v. dexmedetomidine in ponies

Equine Veterinary Journal

Cardiopulmonary and sedative effects of intravenous administration of low doses of medetomidine and xylazine to adult horses

American Journal of Veterinary Research

Effects of medetomidine on serum insulin and plasma glucose concentrations in clinically normal dogs

American Journal of Veterinary Research

Advantages and disadvantages of using alpha-2 agonists in veterinary practice

Australian Veterinary Journal

Cardiopulmonary and behavioral responses to computer-driven infusion of detomidine in standing horses

American Journal of Veterinary Research

Blood glucose, acid–base and electrolyte changes during loading doses of alpha₂-adrenergic agonists followed by constant rate infusions in horses