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Frontiers in veterinary science2025; 12; 1691137; doi: 10.3389/fvets.2025.1691137

Impact of sequential administration of detomidine, butorphanol, and midazolam on sedation, ataxia, stimulus response, and bispectral index in horses.

Abstract: Standing sedation is a safe and cost-effective alternative to general anesthesia in horses, but challenges include achieving adequate drug effect to block the stimulus response without inducing ataxia or recumbency. A benefit of midazolam has been reported in equine dental procedures. Seeking synergy, a combination of lower doses of several pharmacologic agents, including midazolam, may improve the quality of sedation while minimizing adverse effects. Bispectral index (BIS) correlates with sedation scores in human ICU patients, but the correlation between sedation scores and BIS has not been evaluated in horses. Unassigned: This study aimed to evaluate observational sedation scores and BIS in horses sequentially administered low-dose detomidine, butorphanol, and midazolam bolus and constant rate infusions (CRIs). Unassigned: Fifteen healthy horses received a standardized sedation protocol with sequential bolus doses and CRIs of detomidine, butorphanol, and midazolam. Sedation was assessed using a numerical rating scale that evaluated depth/stimulus response and postural instability/ataxia, and BIS was recorded at the same time points. Linear mixed-effect models assessed treatment effects; correlations between BIS and sedation scores were calculated within and between horses. Unassigned: Sedation scores increased significantly with each drug added. The addition of midazolam increased sedation depth/reduced stimulus response ( = 0.01) and increased ataxia ( = 0.05). No horses became recumbent or displayed signs of excitement. Baseline BIS was 92 ± 4 (mean ± SD), decreased significantly after butorphanol administration ( < 0.001), and did not change significantly at any other evaluation point. Between-horse sedation scores were weakly correlated with BIS ( = -0.206; 95%CI: -0.664, 0.364;  = 0.478). Within-horse sedation scores were moderately correlated with BIS ( = -0.617; 95%CI: -0.756, -0.425;  < 0.001). Unassigned: In conclusion, the sequential addition of low-dose CRIs of butorphanol and midazolam to detomidine CRIs is associated with a stepwise increase in sedation and ataxia. Sedation score was not predicted by BIS. When sedating horses, low-dose midazolam may be added to improve sedation and reduce stimulus response, but the risk of pronounced ataxia should be considered.
Copyright © 2025 Thorn, Wilson, Wang and Horne.
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Publication Date: 2025-10-23 PubMed ID: 41200548PubMed Central: PMC12588816DOI: 10.3389/fvets.2025.1691137Google Scholar: Lookup
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  • Journal Article

Summary

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Overview

  • This study investigated how sequential administration of detomidine, butorphanol, and midazolam affects sedation depth, motor coordination (ataxia), response to stimuli, and brain activity (via bispectral index) in horses.
  • The goal was to determine if combining low doses of these drugs improves sedation quality while minimizing side effects like loss of balance or over sedation.

Background and Rationale

  • Standing sedation is preferred over general anesthesia in horses because it is safer and less costly.
  • A challenge in sedation is to achieve sufficient drug effect to block stimulus response (pain or procedural stimuli) without causing excessive sedation or ataxia (loss of coordination) that could lead to the horse falling over.
  • Midazolam, a sedative, has shown benefits in equine dental procedures, suggesting it might improve sedation quality.
  • Utilizing a combination of several drugs—each at lower doses—may create a synergistic effect, increasing sedation quality and reducing side effects compared to higher doses of a single agent.
  • Bispectral index (BIS) is a monitoring tool that measures brain electrical activity and correlates with sedation levels in humans, but its correlation with clinical sedation scores in horses has not been well studied.

Study Design and Methods

  • Subjects: Fifteen healthy horses.
  • Protocol:
  • Bolus and constant rate infusions (CRIs) of detomidine (a sedative and analgesic).
  • Followed by butorphanol (an opioid analgesic).
  • Then midazolam (a benzodiazepine sedative).
  • Assessments:
    • Numerical sedation scores evaluating:
      • Depth of sedation and response to stimuli
      • Postural instability or ataxia
    • Bispectral index (BIS) was recorded simultaneously at the same time points.
  • Statistical analysis: Linear mixed-effect models to test drug effects on sedation, correlations between BIS and sedation scores calculated both within individual horses and between horses.

    • Findings

    • Sedation scores significantly increased with each added drug, indicating progressively deeper sedation and reduced stimulus responsiveness.
    • The addition of midazolam notably:
      • Further increased sedation depth and reduced stimulus response (p = 0.01).
      • Increased ataxia (p = 0.05), meaning horses showed more unsteadiness.
    • No horses became recumbent or exhibited excitement, indicating a controlled sedation level without adverse excitation.
    • Baseline BIS was approximately 92 (with some variability), dropped significantly after butorphanol administration (p < 0.001), but did not change significantly after other drug administrations.
    • Correlations between sedation scores and BIS:
      • Between different horses: weak, non-significant correlation (r = -0.206, p = 0.478), suggesting BIS may not predict sedation differences across subjects.
      • Within individual horses over time: moderate, significant negative correlation (r = -0.617, p < 0.001), indicating BIS somewhat tracked sedation changes within the same horse.

    Conclusions and Clinical Implications

    • Sequential low-dose CRIs of butorphanol and midazolam added to detomidine produce stepwise increases in sedation depth and ataxia in horses.
    • BIS monitoring did not reliably predict sedation scores across different horses but was moderately correlated within individual horses over time.
    • Clinically, adding low-dose midazolam can improve sedation quality and reduce stimulus responsiveness, beneficial for procedures requiring standing sedation.
    • However, the risk of increased ataxia should be considered as this could affect horse safety and stability during standing procedures.
    • This suggests a careful balance is required when combining these agents, optimizing sedation while minimizing motor side effects.
    • The study helps guide dosing strategies and monitoring approaches in equine sedation protocols.

    Cite This Article

    APA
    Thorn CA, Wilson DV, Wang S, Horne WA. (2025). Impact of sequential administration of detomidine, butorphanol, and midazolam on sedation, ataxia, stimulus response, and bispectral index in horses. Front Vet Sci, 12, 1691137. https://doi.org/10.3389/fvets.2025.1691137

    Publication

    Frontiers in veterinary science
    ISSN: 2297-1769
    NlmUniqueID: 101666658
    Country: Switzerland
    Language: English
    Volume: 12
    Pages: 1691137
    PII: 1691137

    Researcher Affiliations

    Thorn, Caitlin A
    • Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, United States.
    Wilson, Deborah V
    • Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, United States.
    Wang, Sichao
    • Center for Statistical Training and Consulting, Michigan State University, East Lansing, MI, United States.
    Horne, William A
    • Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, United States.

    Conflict of Interest Statement

    SW was employed by Center for Statistical Training and Consulting, Michigan State University. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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